AU2000283A - Esters and ethers of 16-methyl-9-halo-prednisolones - Google Patents

Description

11-1111

Ii II liii liii I.'

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4

002/83 II1) AINA-20002/83 C' 15 i tC~tt ~i u 21 p I t Itt:; a 42

2000 2183 FORM IAA T INSTRUCTION (ill InSert "C'Onivntl if applicable Sub-regulation 9 (1A) COMMONWEALTH OF AUSTRALI A

Patents Act 1952 if applicnble dfln,crt TTIF I o inve.ntion

APPLICATION FOR A STANDARD PATENT IN RESPECT OF EXCLUDED INVENT ION j lir c rt I V1.1 lo A.ND iadelrcssh dclarant(si Wet PLURICHFMIE ANSTALT, a body corporate organized and Ser hc,,dnc,

existing under the laws of Liechtenstein, of Vaduz, Liechtenstein, apply, by virtue of sub-section 191(3) of the Statute Law, 'for the grant of a standard patent for an invention entitled "New esters and ethers of l6-methyl-9 -halo-prednisolopas" wIic~ is~ described in the accompanying complete specification.

The application is not for the grant of a patent of addlition.

!ah, ImmIi Ir l rhe application is made in respect of an invention disclosed in the complete specification lodged in respect of Applica- tion No. 500,060 in the name of Plurichemie Anstalt but eclcuded before. I July, 1979, by an amendment under Section 49 of the Patents Act 1952, from that complete specification.

'A

OUr address for servico is: ILODGED AT SUB-OFfICE 983 )OC fill I Adatu.mid( J) ountr V

PHILLIPS ORMONDE AND FITPZPATRICK Patent and Trade Mark Attorneys 367 Collins Street, Melbourne, VIctoria 3000

DATED th-is fourth dlay of Octobe'r 1983 ilming

WI Irscor DAIFo

ii Snt"Iu

TO: Tphe Commissioner of PAtents Note: No' lega~lzatt r A itm:li reqfuire

PWJ: ST SYUART VAYIOA AUSTRAT IA

2 0 002 /B3 AUSTJALIA PatentsaAcl

DECLARATION FOR A PATENT APPLICATION

7' iNSTRUM~ONS Insert "Conventio'n" In Support of tile applicaltion made by A applicable 9 (lA) Ib! tnsurt Fl II t arne(%, o.f pphicatis) PIAJRICIEMLEE ANSTALT

Inwert "of addtirt if applicnble diereinafter calied "applicant(,,,( tor a pt for an lnmert TITt F of imtnCitioii entitled a inyrl~eiofl 1 Now e-sters and thr c' 6 ehl.9 -halc oreiniooro tinsrt I .I arnek ANDr~adre~sfu,,of J, Ererico Villax dclar an ts) Sre Iliidnow- of& and care of Plurichemie Anstaitol Liechtenstein, Vaduz, Liechtensteiri

do soiciifll\ and sinicerely declare follows;,

*Or* if? the t0C (1)1anlJpplicttpionbV fa bo dv c.rpr' ytc) II iam, kmxaulthorized. to make this, declaiat ion on behulf the applicant s). Iha n MtM the actual inventor(s) of the invention. for, il,'rc ti(,applican,'\) iytire fnot a, Ol !/ive'ltof(

iton. ANi a, ual addrc., pev .rvtri. of Joao Emerico Villax 3 Traessa O'o Ferreiro Lisbon 3, Portugal

t vie a'itt of iarc:tile ac:tual iniventorts) of tht, in vention and tlt. Net, upon xs ich the applicant(s,) losed !Iu fs liw ta sarc ntiled to make the application atre ;,,,tollovW. tt *dt'i4,'0 i ca- t The :applicant company is the assignee of the tion inventi'on from the actual inventor ation.

oe: fVararaphs 3 (and 4 npjpv only to (on vention applications) I Tiouuntry lilnw dale. unid I File basic application(s) for patent or similar protection on which the application is based is are identified counftrv, fiing date. an~d basic applicani(s) as follows:

OFFICF. "Tie Ihe aic appic ion arcwrr,.d In paragraph lerew wasw4enc the first application(s) dL IV in 1 ~t()cwon iiltrv in respect of ffhe mv. ution the subleet of tile application.

L; lt,rriPt A( Frf Declared at 'Irscr! DAt U of Daled f L :i 11

,fici lo: ['he Commissioner of Platents

PHILLIPS ORMONDE FITZPATRICK !Jil ST Patent and Frade Mark Attorneys 367 Collins Street Melbourne, Australia

STURt*T IAT'IOfl

This invention relates to new esters and ethers of 16a- or 16 V- Iethyl.-9ca-cioro- or finoroprednisolones r ari 0211lei Usk SI

I il k% )plicant(s)

Op I,' :11kololl, ation is hased

applicationl(s) I 0mi

Lpplication.

r1~~& I il OS

01'l

iers -2- 'ie S

(12) AUSTRALUi, L_,_ATENT AB3STRACT (19) AU (11) AU-A-20002/83

(54) E STE RS ANO) E FIER S 0 F 16 -ME TH-YL 9HALO -PRED N ISOLO NE S (71) PLUR ICHEM 1E ANSTAL11' (21) 20002/83 (21) 5 10.83 (24) 27.3.74 (31 6 1636 (32) 21.3.74 (31) PT 61637 2?.3.74 PT 61636 10. 3.75 P

(51 COI 510 AWK 31 /0~ (72) dWAi LLR I C0 V t.LAX (74) P (57 lnp com'poundi have antinf lammratory activity, I a Iin A pi n f or- th pcepratiu of ester o nnd e thers Af 16 awt

VP ty or fluorop'rv&Aolone: the forw~i~ta

R L:K K ich.' w. is an acyl nCtup. lrin Froin a V k car

ed kvriu a pharn.awpot ira1 wev~c~ptahl raI~rxl i- avid V 1 to 9 carbonr atonq

rivedo f rom a phnarmi~ccuti oa iI ac cuptat rurbonyl vi ac id of 1t o A ~-Car0n 4 atomso, of hiyh top icoiI itvi ty ic-i-IA- i-(Turate activ';. A&A a i1't-

in tip c st roup in u! V C fron Onmac~wr i call z :i1l to r Y:I

Ni1) 2 1/

5 X 9/2 9

(11) At>A-20002/813 I 4rcup, is oted at the 21-pos it inan, 1w 1 tso brainmno-->i O

K rca-1 U vwith a n I ix' a ocup OCT

OWN c a cid haixng f rom .Ito 16&carbon atoms1-,to ti 012-

a) I ,2l Lster Fid-1.1- VP or t ri-(chloro- or thnoro-acetyl 6privaivy of a pred-n~ isolnc which cpu be1 thur hydrolysod by aqu~''.is soliu-o

Warhiatv r Fovoly,& i actvat&silia ngi to forq Mnh17,21-von-

r IVed cl:i vat i 'v ofa pIIod:1iiso I Ior can be sI-i ct IX clvolylicIby

nd na 1iichloi c 0v c to x c-d t 1' iuK 1-vcrAWllytAur d ~it -h cro-

w, Quoro-Wtyldvt X i hvo of a pro.W11 on \uhiuh upon Ht 1 C't7Illnl wi th

-t110 11 cdiWNW IColwn ct n'Oora ,tvaut 4silica ye1, to Weld th; W

V 1; ,2 I di -nt( WON 1W (I r! hliro pyrou?-WA) derivative of a

Y nOw NW'.of7 1I W h CO"1 Owt' nuinn' a PIP'Cut ic'~1v

an1\ a cidi to0 Vi I don .11' \InL A~

prionivo0on

105SX 191/30C

AUSTRALIA

Patents~ACf

COMPLETE SPECIFICATION (ORrIGINAL)

mi. (lass icatior~ Nt il%' IOdv.'l

i'm I!IeI NcIi1.iIo

Acceptedk ii he

ANIt1ANJ S Rid PRP/GN-289/83

m QqjiilMrit N

Liechtensteinu, Vaduz, Li echtenrstein

o~iao- Hre,.moi-i V! I. I;I

'kd loervikst 'o i>- PHI ORMONiM' FITZPATRI( K Patenit and Trade Mai k Al rornevs 367 MRlin Strme Meihoune, Ait lud. 3000 (';iplvi~ SpedCiua iolot til Iiveittioi oitied,

NEW ESTBRS AND OTH1ERS OF 1.6 -METFIYIb-9 -HIAIO- PREDN ISOTONES

The followin stactnmenm is a Iull dem rpon uf thils invnion including thi! best method of pert ornunig it kiiown to applicantj):

P 19/11/7

I This invention relates to new esters and ethers of 16a- or 160- methyl-9a-chloro- or fluoroprednisolones of useful pharmacological activity and to a process for preparing them. The present application is a divisional application of Australian patent 500,060, the entire disclosure of which is incorporated herein by reference.

1A

According to the invention, there is provideid 16aL- and l.66-methyl- 9a-chloro- or fluoro-prednisolone esters and ethers of the general formula-

100

wherein Ri and R3 are each hydrogen or a-i acyl group of a pharmaceutical ly acceptable carboxylic acid, having from 1 to 16 carbon zatoms, Rj is a tetrahydropyran-2'-yl group, X is chlorine or fluorine, and the 16-methyl Lroup i~s in the a- or g- position. The invention also provides a process for preparing compounds of fornuii: 1, wherein Ri is an esterified hydroxy group of 1 to 16 carbon atoms, R2 is h dr'Oy, or an esterified hydro-xy group of 1 "o 8 carbon atoms, or a tetrahydropyran-2'-yl group, R3 is a hydroxy group or an esterified hydroxy group of I to 16 carbon atoi., X is chlorine or fluorine and the 16-methyl gioup is in the Ci- or position, whiich comprises iodinating a 16 or 16~iichy-9i-c~oo-or fluoro- 23-deoxyprednisolone or 17at-monoester there ofh~rir~tlhe cster group contaii.s from 1 to 16 carbon atoms, and Wherein ;1I- ydroxr 'rou;p is protecteJ l.'c a di-~ or tri-(chloro- or fiuoro-) acety.1 i.*cr 1ly L tE Lalydropyra'nyl groun, to forms a 21-mono- or 21-di-icodo deni ccti; the si dcriv ot >e with a saIL of a carboxylic aciac con to 16, carI!%-;i atc::i cz oo, phosphori c or sulphuric acid to obtain, a 2 nc~(3) uimt ionra.iy LF in thu 2i-est(-r jgroup and/or th, 2 7,:c

hc: j~1 t~.ct~i' :~neus~vc(-echIanging .the 16ter c- 9 cVrTk(' t an ct cr groLI T f roM 1 to 8 Carbon a: VT7.

4,r -a iac'Iknown it jods tohat described in rr

t oo i: a(c:pound f or-,il a z- dnc,cribec acvL. Cr ~j~:au iVCritiv( V::a of the prfrsent invenz arm

Sj 3-

is the hydrolysis of an llP-di-, or tri-(chloro- or fluoro-)acetate group

with aqueous sodium bicarbonate. The most surprising and unexpected aspect of this transformation is the fact that negligible hydrolysis of 17 and 21-

ester groups occurs and that in the preparation of 17-mono-esters there is

either no or minimal isomerisation to the 21-isomer. This trans-esterification reaction is well known to occur in aci

dic or basic conditions, especially the latter.

The selective removal of 11l-trihaloacetates was described in Bri

tish Patent 1,097,164, wherein the group was solvolysed by a salt or an alka

li or alkaline earth metal with an acid having a pKa between 2.3 and 7.3. Unfortunately, no yields are given, whilst trials have shown that there is a

strong tendency for the Froducts to be contaminated with starting material. This necessitates the ddeelopment of purification techniques in order to ob tain the required product in a pure form. In the case of hydrolysis by sodium bicarbonate, the reaction is carried out in methanol, and yields essentially pure products in yields ap-

proaching stoichiometric. In some instances, it might be found judicious to add, on solubility grounds, a reaction-inert solvent to the methanolic reac tion mixture. Such a solvent is preferably tetrahydrofuran. The selective removal of 1-di-, or tri-(chloro- or fluoro-)aceta tes can also be effected by the use of activated silica gel under carefully controlled conditions. The products obtained in good yield are usually ex tremely pure since the elution from the silica gel can be carried out in such a fashion, if so desired, as to leave impurities absorbed on the silica gel. The invention further provides a pharmaceutical composition which comprises a compound of formula I as defined above and an inert pharmaceuti cally acceptable carrier therefor. In the process of this invention, the 11l-protected 16-methyl-9a- fluoro- or 9a-chloro-21-deoxyprednisolones and the 17a-monoesters thereof, used as starting materials may be prepared as described and claimed, in our Australian Patent N9 500,060, to which reference should be made for further details. It has been found that the new 11,17ct,21-triesters, having a total of 6 to 11 carbon atoms in the three ester functions, exert a high anti-inflam matory potency and are of a very slow systemic activity when administered to pically, especially those containing a chlorine atom, and when the total num ber of carbon atoms in the ester groupings is above 11, the new triesters exert a protracted activity when administered parenterally, especially tho se containing a fluorine atom. According to the invention, the preferred new compoun are among others:- A. For topical use:

160-methyl-9a-chloro and 9a-fluoroprednisolone l18,17a-dipropionata 21-acetate 16B-methyl-9a-chloro and 9a-fluoroprednisolone ll-propionate 17a- valerate 21-acetate All these preferred compounds have a high anti-inflammatory poten cy and very low systemic activity when applied locally and their ratio is mo re favourable than any of the hitherto described anti-inflammatory topical steroids.

B. For protracted activity when administered intramuscularly: 16B-methyl-9x-fluoroprednisolone llB-propionate 17c-heptanoate 16g-methyl-9a-fluoroprednisolone 11, 21-dipropionate 17a-valerate These preferred compounds are characterised by a depot effect when administered intramuscularly and provide clinically useful maintenance le- vels during a long period of time, 2 to 12 days according to the dosage and the vehicle of administration, in patients where a long cortisone therapy is indicated. Thus, the frequency of administration is diminished and the secon dary effects, such as gastric haemorrhages which may occur on prolonged oral therapy, are avoided.

Naturally, the equivalent 16c-methyl analogues are also preferred. In the process of the present invention, a 21-esterified hydroxy group can be introduced in the lil-esters or ll,17a-diesters of the 21-deoxy prednisolones. It has been found that the per se known 21-hydroxylation vi.a the 21-mono or 21,21-di-iodo derivatives may successfully be carried out with

out hydrolysing the ester group at the 17a-.or 11- position. The 21-mono or di-iodo derivatives are prepared, as is known in the art, by reacting the llB- esters or 110,17(x-diesters of the 21-deoxy steroids with iodine in methanol optionally mixed with tetrahydrofuran, in the presence of an alkali, such as calcium oxide, and in the absence of water, yielding the 2 1-monoiodinated de rivative. When the reaction mixture contains calcium chloride, the corres- ponding 21-di-iodo derivative is formed. The mono or di-iodo derivatives are subsequently reacted with, for example, an alkali metal salt or amine salt of a carboxylic acid or of phosphoric or sulphuric acid, yielding the corresponding 21-hydroxylated derivative in esterified form. When the compound to be iodinated has an ll-di, or tri-(chloro- or fluoro--)acetoxy group, the conditions of iodination and subsequent acyl oxylation can be chosen in such a way that this protective group remains in the molecule, or alternatively is eliminated: if the precipitation is carried out by adding the reaction mixture very slowly to iced water having a volume of about 10 times the volume of the reaction mixture, no appreciable hydrolysis will occur at.18-; however, when water is added slowly to the r'action mixture, over,a period of 1 to 4 hours, the 11P-protecting group will be completely hydrolysed without hydrolysing the 17a- and 21- ester groups. Thus, the 21-acyloxylation provides, in high and uniform yield, the 17a,21-diesters and llB,17a,21-triesters of 16a- or 16-methyl-9a-fluoro or 9a-chloro-prednisolone, where all ester groupings can be different from each other. The 11-di, or tri-(chloro- or fluoro-)acetyl-17a,21-diesters can be selectively hydrolysed at the 21- position using perchloric acid in methanol to yield the 1-di-, or tri-(chloro- or fluoro-)acetoxy- 17-l-mono-esters. The reaction temperature is between 00 C and room temperatu re and the time of reaction is 12 to 24 hours. However, when using weak alkaline hydrolysis, the llB-di-, or tri- (chloro- or fluoro-)acetyl group can be selectively removed without affect ing the 17a- and 21-ester functions. This highly useful hydrolysis is unex pected, based upon the prior knowledge that ester functions can be removed or isomerised in basic conditions. The selective hydrolysis may be carried out by adding 0.35 to 1.0 mol of a diluted aqueous sodium bicarbonate solu tion to each mol of the triester in methanol, with stirring for 30 minutes to lh 30m, at room temperature. After acidification with 0.5N acetic acid and precipitation in water, the 17a,21-diesters are obtained in a nearly quan titative yield. In contrast to the above, the treatment of llP-tetrahydropyran-2'- yl-17a,21-diester with perchloric acid in methanol as above, followed by the slow addition of water, will-precipitate the respective 17a-monoester as

T sensitive to acid conditions mine the ll -tetrahydropyran-2 -yl group is mnch.'more than the ll-trifluoroacetate. However, th6' l6-tetrahydropyranyloxy group ig the will not undergo cleavage in lower carboxylic acids such as acetic acid and Iloro- propionic acid at room temperature. acyl 5 Furthermore, it has been found that the l1 or tri-(chloro--

Lins in, or fluoro-)acetyl group can be selectively solvolysed starting from the ll ,17c-diesters oi the 21-deoxy and 21-hydroxy compounds, as well as from tion the respective ll ,17a,2-triesters, without solvolysing the other ester about functio.is present. The solvolysis is carried out in a suitable organic sol

ciable 10 vent, such as di-, tri- or tetrachloromethane, tetrahydrofuran, dioxan, ben

zene, ethylacetate or mixtures thereof, by catalytic action of activatd Si

ixture, licic acid, i.e. silica gel. However, to ensire good yields,,tthe silica gel 0 A preferred way of carrying out up will should preferably be'activated at 110 C. and 21- this activation is as follows: a water-saturated silica gel is dried out by t heating to a t mperature of 11000 for 1 to 2 hours. The solvolysis yield

jeld, may vary as much as from 3 to 100%, depending on the origin and grade of the

a-f luoro silica gel as well as on its activation. Good yields may be obtained using

Lt from "Silica Gel for of "Camag", Muttern, (Switzerland) quality which

es ters contans 20Z water after activation for 1 hour at 1100C. The silica gel

cid (60- 20 is -,resent in a considerable excess ind it is contacted with the solutio of t etoxy- the compound to be solvolysed between lto12 hours. The solvolysis can be

:emperatu carried out either by passing the organic solution slowly through a chroma tographic column or by simply stirring the organic solution with the silica, a or tri- followed by filtration. The optimum time of solvolysis should be determined

affect 25 by thin-layer chromatography in the course of the reaction, as the optimum

is unex time may vary considerably according to the quality, degree of activation of

removed the silica gel and the compound to be solvolysed. It should be noted that

carried prolongation of the time of contact over the optimum is detrimental and te solu yields will decrease. The silica gel, which absorbs the steroid completely,

minutes 30 is then dried at low temperature between 250 and 4500 and eluted with a sui ic acid table solvent mixture, such as 1 1 chloroform and methanol. However, other

Learly quan solvent mixtures may be useful, depending of the substituents present in the molecale. The eluate is subsequenly evaporatetd under reduced pressure and

pyran-2 recrystallized. The silica gel catalysed solvolysis is also applicable to

ed by 35 the soivolysis of the 1lltetrahydropyran--2'-yl group under the same conditions ioester as as for the 11B-di', or tri-(chloro- or fiuoro--)acetates, the yield being abo ye 90%. Solvolysis catalysed by activated silica gel has been described by

J. Lehrfeld, Org. Chem., vol. 32, p. 2344-6 (1967). All the mono-, di- and triesters herein described are only slight ly soluble in water, therefore can'be isolated through precipitation by add ing water to the reaction mixture. Th. crude esters are subsequently puri fied by methods known in the art. The Examples appearing hereinafter illus 5 c trate the various ways of isolation and purification. It is evident that the process herein described, besides yielding the new pharmaceutically useful steroid compound, permits the known 17a-mono esters and 17C,21-diesters of 16a- and 16B-methyl-9a-fluoro or chloro-predni t solone to be obtained with high yields and in a simple manner. The prepara 10 t tion of these esters is described in British Patents Nos. 996,080, 1,047,518, 1,047,519 and in U.S. Patent N9 3,529,060. All these inventions make use of an esterification via 17a,21-(l'-alkoxy-l'-substituted methylenedioxy) steroids (17c,21-cyclic orthoesters) which are subsequently hydrolysed in acid condi 1 tions to yield the corresponding 17a-acylates. British Patent N9 1,047,519 describes the preparation of the 17a,21-diesters by acylating the 21-hydroxy 172-monoesters under alkaline conditions by processes known per se. It is to be noted that this British Patent also claims the direct esterification of the 17l-hydroxy group of the 21-esters of 1,17Q,21-trihydroxy steroid com pounds. The sole Example 25 demonstrates that this process is devoid of prac 20 t tical interest due to the formation of mixtures of 113,17a,21-triacetate, 11, c 21-diacetate and l7a,21-diacetate. The desired 17a,21-diacetate was not ob t tained in pure form even after preparative chromatographic column separation and its presence could only be demonstrated by thin-layer chromatography. Consequently, all the known practically useful processes prepare 25 1 first the cyclic orthoesters using as reagent the respective orthoesters which are not commercially available and the preparation of which is compli cated and limited to the lower alkyl chains up to 9 carbon atoms. The pharmaceutically useful new compounds of the present invention may be mixed with a suitable carrier for the preparation of lotions, oint- 30 3 ments, creams, other topical formulations, including sprays for inhalation, and injections for intraarticular intramuscular administration. t The following Examples illustrate steps in the process of the in- vention: U

ii

Example I Preparation of 17a,21.-diester of 16 -methyl-9ci-chloro-prednisolonle Stage a) 21.3 g of l6 -methyl--9cx-chloro-lll ,7a-dih-yiro'y-l;4-pregnhadiene- 3,20-dione* l1-trifluoroacetate 17nx-valerate is added to a mixture of 56 ml of absolute methanol and 14 ml of a 10% methanolic solution of calcium chlo ride. After stirring for 5 minutes, 7 g of calcium oxide powder is added and stirring is continued for 15 minutes at room temperature. Subsequently, a solution of 18.8 g of resublimed iodine in 42 ml of a 10% methanolic solu tion of anhydrous calcium chloride and, 28 ml of absolute methanol is added to the reaction mixture of the steroid, under nitrogen atmosphere with the exclusion of direct light, at a temperature of 25 0 to 280 C, in such a way as to maintain a constant discoloration, the addition taking about 40 to Is minutes. After an additional stirring of 20 minutes, the reaction mixture is cooled to -15 Cand poured into 2000 ml of water containing 500 g of ice and 25 ml of acetic acid. It is stirred for 30 minutes, filtered, washed with water and dried at 300 to 35 0 C. The 21,21--di-iodo derivative thus oh tained is sufficiently pure to be used in the stibsequent reaction step. Stage b) 27.5 g of the 21,21-di-iodo derivative obtained in the previous btage is dissolved in dimethylformamide and this solution is added to a mix ture of 210 ml of acetone and 2.1 ml of acetic acid containing 21 g of anh~y drous potassium acetate. It is ref luxed for lb 30m in the darlk under a 'ni- 0 trogen atmosphere. It is then cooled to +10 C and ade.ed to 1200 ml of water coiutaining 300 g of ice and 20 ml of acetic acid. It is filtered and dried, yielding 20.1 g of the desired 16 -me thy 1-9c-chloro-llI 17C, 21- trihydroxy- 1,4-pregnadi ene-3, 20-di one l1 -trifluoroacetate 17ct-valerate 21-acetate. The main peaks of the irifrared absorption in mineral oil. mull are at 5.59 -P, 5.19-'5.2411(doublet), 5.99 vi, 6.1 1P, 6.18 ji, 8.1 11, 8.5 11, 8.7 p, 11.28 pi. There is no peak 'n the region of 2.5 to 3.0 Stage c) l1f; of the product obtained in the previous stage is dissolved in 10 ml of methanol and 1 ml of a 5%4 aqueous solution of sodium bicarbonate is added at room temperature. After stirring for 1 hour, it is acidified t o pH 5 with 0.5N acetic acid and -precipitated with 200 ml of water, yield ing 16$-methyl- 9o-chloro-1l ,l7ct,21-trilhydro~xy-1,4-preguaidiene-3,20-dione 17(1-valerate 21-acetate. By repeating the same process but using 1 g of 16 mnethyl-9ax-clhloro-prednisolone 11$-trilfuoroacetate 17aL,21-dipropionite and ml of a 5% sodium bicarbonate solution, one obtain:; 16g-methyl-9a-chlo ro-prednisolone l7cc,21-dipropio-nate with a yield of 96.2. In an angalogous manner, the following 17a,21-diesters are prepared through the respective 11f-trifluoroacetates.- 16cc- or l6a-methyl--9a-chloro-prednisolone: 17ct,21-d;iacetate 17t, 21-dipropi onate 17c,21-dibutyrate 1.7a, 21-divalerate 17a--propionate 21-acetate 17cx--valerate 21-acetate l7cx-heptanoate 21-propionate l7a-heptanoate 21-sulphate

Example 2 Preparation of the l7c-valerate 21--acetate of 16 -methyl-9a-chloro- prednisolone Stage b) of Example 1.is repeated, but carrying out the precipita tior On, n inverse order, as follows: Once the reflux is finished, the reac ta~~n a~i~is cooled down to 500C and 80 ml of water is added to the reac tion mixture iz oraler to dissolve the inorganic salts. Subsequently, 1300 ml of water is added dropwise, tinder stirring, which takes about 4 hours. Vhe prezipitate is then filtered and dried, yielding 17.4 g of 16 -methyl- 9uchloro-11,7a,2-trihydroxy-,4-pregnadiene-3,2Q-dione 17a-valerate 21- acetate. The 21-acetate thus obtained is recrystallized from acetone. Nelt 0 1 22 ing point 200-205 C. E 288 at 234 ini in methanol. {a} +75' in .1cm Dl dioxan). It is soluble in methanol and chloroform, fairly soluble in acetone and insoluble in water. The main peaks of the infrared absorption in mineral oil mull are at 2.95 ji, 5.7 p, 5.8 I, 6.02 6.2 p, 6.24 p, 8.0 8.12 P, 11.9 pi, 11.32 p.

Example 3 Preparation of 17cx,21-diesters of l6cx- and 16 -methylt-9a-fluoro- predniso lone Stage a) -21/4, of the l1 -trifluoroacetate, 17a--valerate of 16 fluoro-21--decoxypre-disolonr-, is diiodinated as in stage a) and acetoxylated as in stagil b) of Example 1,1 yielding 20.8 g of 166-methyl-9X-fluoro-ll ,17cc,

21-aetat. Metingrang 13510C t27: nmtaoTemi 21-trihydroxy-l 4 -pre gaadi en e-3, 20-d ione ll -trifluoroacetate l7ct-valerate pontmc mehnl h of anpeaks the infrared absorption in mineral oil amull.90 are .9 at5.72 -p ,5 9 j (doublet) .11, 6.05 vi, 6. 1. 25 8.1 .4 it, 11.0-p

tae b-3 I-g of the-rodlutobtained incvatrhe 21-aces tatei otained wtg sia) ofe Example ,i250m of musthlanol Paded 14,00) yildfg70%7 per ebloric acid. -A-fturo stnIng I7,1ovrih a room-1 temperauren, t i prep

floaceelc-valerate of bearqehasoe. Melting point 135-2038 E1 C. 0 t29mji 27a23miinmethanol The main peaks of the infrared abs orption in miealuf~ul r

v~11.24 1j, at l2.92 r i 5.589-,5.78Y 6. ii, 5.98lt) 6.1-6.2 9.4 8.55 110 p

Example

S aga -To2 g of 16-metylWctethydro-.pyra21-txy.9x..fluorori7 hydroxypregnaione. diene--3luo-dicetais add-ved t mixruetof 0 m ofamnthano sag a0)m of Etaplref3 in0 lo mubethntl, 1isgaofeda14iumloxide7andp10-

for lh30 ad Aoter tmadigren t atpodtom a mture of is lires ofj w0 ater b adij 4 liotresin 3f waeyedg1. of ci.T pep thei crue is ashed and dried at 350 C, yielding 12 g of 16W-methyl-9c-fluoro-llg-(tetrahydro pyran-2 .oxy) -17ce-hydroxy-21-iod o-i, 4--pre gnad iene--3 20-d ione. The 21- mono-iodo derivative thur obtained is refluxed in 300 ml of acetone and ml of dimethylforicamide containing 4.5 g of potassiumi acetate, for 3 _s hours. It is then cooled down to 10 C and 60 g of ice is added, which dissolves the inorganic salts. The precipitation with 3 litfes of water and ice yields 7.8 g of the corresponding 21-acetate. Stage c) The product obtained in the previous stage Is then heated to 1000 C in 80 ml of propionic acid for 2h 30m. It is cooled to 1000C and pre cipitated with 1 litre of water and ice, yielding 7.4 g of l-pnethyl-9a- fluoro-ll 17r, 21--trihydroxy-l ,4-pregniadiene-3 ,20-dione llg-propionate 21- acetate. Stage d) The product obtained in the previous stage is added to 1400 ml, of benzene, 250 ml of propionic anhydride and 0.25 ml. of perchloric acid The mixture if. stirred overnight and then washed three times with 750 ml of 5% sodium bicarbonate and then with water. The organic phase is subsequently dried with anhydrous magnesium sulphate and filtered. The ben zene is then evaporated under reduced pressure and the oily product thus ob tamued i~s dissolvod in iv..thanol and precipitated with watnAr. Subsequently, 2(1 the crude- product is- recrystallised from acetone and water to, yield the nor responding I 17a-dipropionate 21-acetate,. The main peaks o f the infrared ab'(~T~tOCin minerarzl oAi L ijll are at 5.7 pi (shoulder) 57 bod i 6.12 p, 6.21 p (shoulder), 8.1 ii,8.5 1j, 9.4 1j, 11,1-11.5 1j. There is no pt-:ik iii the rregioni at 2.5-3.0 jp.

Examiple 6 Stagt- d) of the previous Example is repeated but substitilfting the p-ropiozitc acid by an equal awourtt of n-valcric the reaction time being hours. It yields 6.78 fl- of 16fi-mtyl-9-fluoro-fl'i,17e.,2l-trihydroxy- l,/i-pregnadivee,,20-dione llB--proionate l7L-vaerate 21-acetate. A compound obtained in the present invention1 Was tested according to McKenzie'.,; vasoconstriction test MIcKonzie and R.N. Atkinson, Arch. of Derma., Vol,. 89,741-746, 3964). Thirty-fouir healthy subjects took part in the miain experiment. The doses applied wetre 0.01.25, 0.025, 0.05 and 0.1 Jig. Each dose was repeated at least six times, i.e. at least 18 applications pp., compound were made, whilst the application with betaimethasone 17-valerate,

NOD 17

5 X 9/2 9

-12-

used as standard, was repeated 68 times at four dosage levels. Witt. a view to facilitating comparison with Y4cKenzie's results, the values for betamethasone valerate were taken as 360, i.e. the potency expressed in relation to fluocinolone acetonide taken as 100. On this b.E sis, the compound of the invention (l 6 -methyl-9a-fluoro-prednisolone 12. 17a-di prop ionate 21-acetate) had a relative potency of 470:- Every clearly visible white aureola or patch was considered po sitive. A-Fter 15 hours, the occlusive polyethylene tubing was removed and the oh!- tions weemade after 15 minutes, 1, 2, 3, 4, and 5 hours. The Examples appearing hereinafter illustrate the preparation of pharmaceutical compositions (all percentages are expressed in weight! weight)

A) Tablets: Each !Lablet cout'ains; 16 -methyl-9n--filuoroprednisoloie 17Qc-heptanoate 1 nag Lacrose 70 mag starch 28 mag M4agnesixum stearate (100 mesh) 1 nag 100 m"0

B) Intramuscular Injecticex:. 16 fi-methy-9k-f luoropredni sol one 17ci-capryl ate (sterile) 10 nag Seasau oil (steri le) 1 nag per ampqoule. The intramuscular adi ~nis tration provokes effective maintenance levels off the steroid for about 8 days. Ointments anid water mis~cible creams, for example, can also be prepared.

C) Lot ioil:

dipropionate 21- actate: 0.025 -01

Liquid paraffin i0% Alcohol 2%

4./L

2 17

'Fie fouiooA 105a,.19 /30 applicaot(s

P 19/ 11/7 7

313

Glycerin e 's results, propyleneglycol .2.57. the potency Polyethylene 1000 inonoacietyl ether On this ba Non-ilonic emulsifier isolone iig, Water q.sM ad 100%

osidered po removed and hours. reparation in weight!

1 mig mag 28 mag 1 mag 100 ma

maintenance

in also be

NEW ESTERS AND ETHERS OF L6-METHlYi-9 -HALO-PREDN ISOLONES

Thec following statement is a full description of tis invention, including the best method of performing it known tO 4

rM, p

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1 7V2, 1 l l .3 inrrL:. 11LIL ester tuflctions, exert a' high anti-inf lam 35 iatory Potency and are of a very slow des systemic activity when administered to pically, especially those containing a chlorine atom, and when the total num Inve n o n)

I.

wheIrinthe, acVl ir~:op ae urve rom phai7 i. t .1ly a,2ceThtaIbl( Put rarlb. :v

t i~ F Ar accisf: wprrairi'on vi it '?or odxi c r

IcJ, vt *21'pro., L! rtp: u: .nLntL 22Cuti~cally a c'(2tnle Ic~arrier tbhert

DATED: 4 October, 1983

PH-ILLIPS ORMONDE AND FITZPATRICK Attorneys for: PL1JRICHEMIE ANSTALT

L~ >1 optionally mixed with tetrahydrofuran, in the presence of an alkali, such as i anti-inflam calcium oxide, and in the absence of water, yielding the 21-ionoiodinated de .nistered to rivative. When the reaction mixture contains calcium chloride, the corres- !total num poniding 2l-di--iodo derivative is formed. The mono or di-jodo derivatives rrb. o~ oro- o~r n' to lcYrU- r~r

3cr tbtrr