CA2558908C - 10-deacetylbaccatine iii and 10-deacetyl 14.beta.-hydroxybaccatine iii derivatives and intermediates useful in the preparation thereof - Google Patents

Abstract

The present invention is directed to intermediates useful in the preparation of novel derivatives of 10-deacetylbaccatine III and of 10-deacetyl-14.beta.-hydroxybaccatine III. These novel derivatives have cytoxic and anti-tumoral activity. They are prepared starting from the so-called syntons or from other taxanes of natural origin, by selective oxidation of the hydroxyl in position 10 to keto function and subsequent esterfication in position 13, if necessary, with isoserine chains variously substituted. The products of the invention can be administered by injection or orally, when suitably formulated.

Description

10-DEACETYLBACCATINE III AND 10-DEACETYL 14~-HYDROXYBACCATINE III
DERIVATIVES AND INTERMEDIATES USEFUL IN THE PREPARATION THEREOF
The present application has been divided out of Canadian Patent Application Serial No. 2,215,682 filed March 4, 1996 as PCT
International Application Serial No. PCT/EP1996/00904 published September 26, 1996 as WO 96/29321.
Paclitaxel (taxol), as it is already well-known, is a diterpenoid extracted from plants of the Taxus genus having anticancerogenic activity on different forms of human tumours. Its clinical use still involves some drawbacks due to the poor water solubility, which makes its administration complex, as well as to the onset of serious side-effects. Moreover, paclitaxel induces resistance quickly. Due to these reasons, researches have been in progress for some years aiming at synthesizing novel paclitaxel ,analogues which cause less adverse effects compared with the parent molecule.
WO-A-9501969 describes taxoids oxidized in position 10 and variously substituted in 7 and 13. EP-A-577 083 describes cyclopr.opantaxanes variously substituted in position 10 and 13. w "Gazzetta Chimica Italiana", 124, 2994, describes methods for oxidizing the hydroxyl of 10-deacetylbaccatine III. "Heterocycles", Vol. 38 No. 5, 1994, describes new taxol related diterpenes isolated from the roots of Taxus Yunnanensis (Taxiyunnanine A).
The present invention relates to novel derivatives with taxane skeleton endowed with a marked anti-tumoural activity. The novel derivatives have the general structure 1:

s wherein R1 and RZ are hydrogen atoms, or R1 is an hydrogen atom and R2 is an hydroxyl or an acetyloxy group, or OR1 and R2 together form a cyclic carbonate group of formula:' I I

R3, which can be a- o p-oriented, is an hydrogen atom or an alkylsilyl group, preferably triethylsilyl (TES); R4 is hydrogen, or the residue CH3 ~CH3 C = C
CH3 C=0 I
or an isoserine residue of formula R2~ NH ~ (e~ .
C\
Zo R~, OH
wherein R1' is a straight or branched alkyl or alkenyl group, containing one to five carbon atoms, or an ary:.
2~ residue; R2' us a straight or branched alkyl or alkenyi group, containing one to five carbon atoms, or an ary'_ residue, or a tert-butoxy group.
The novel derivatives of general formula (1) are prepared by semisynthesis, starting from the natural 30 syntons 10-deacetylbaccatine III (~) and 10-deacetyl 14p-hydroxybaccatine LII (~). For this purpose, they are selectively oxidized in position l0 and then esterified in position 13 with a suitable acylating agent which allows the introduction of the group R4.
H 0. ~ OH
~o Wi/
2 R2=H
f t~ ~3' 1 2 ~~ O ~ R2 =OH

R2 0~ 0 When taxanes of natural or synthetic origin already containing the desired isoserine chain in position 13.
the molecules of structure 1 can be obtained from said taxanes by selective oxidation in position 10. As i_ will be described hereinafter, the selective oxidation in position 10 of 2, ~ and of the taxanes already containing the isoserine chain in position 13, can be obtained by treatment with copper (II) salts.
IO-Deacetylbaccatine III (~) and its 14p-hydroxl (~) analogues can be recovered from suitably selected vegetable material (see. Indena Patent US-x,269,591).
however, and it is one of the objects of the present invention, it is possible to synthesize taxane syntons containing an oxygenated function in position 4~
14, which are therefore useful for the preparation of compounds of structure 1, containing an oxygenated function in position 14, starting from 10-deacetylbaccatine III (~). In fact, it has surprisingly S been found that, after protecting the hydroxyl in position 7 of compound 2 as a silyl ether, the oxidation to ketone of the carbon in 13 and the introduction of a p-oriented alcohol function on the carbon in 14 take place by treatment with manganese dioxide. After protection of the hydroxyls in 10 and 14, for example as acetates, by treatment with hydrides, the 13-keto function is reduced to 23a-hydroxy.
The process, which is schematized below, leads to the formation of synton 4, useful for the preparation of compounds with structure 1.
TES-CI 13~~ 2 '~ Ac20 1 ~, _____ _, Mn0 . ~ ~ ~ ~ . Red-A1~
2 ~ « n ~,--' HO_ ~ 0-TES

~13~' ~ , Z
From synton 4, after remold ng the protective groups with known methods described in literature, for example using hydrochloric acid to remove the si'_yl group anu a base to remove the acetate groups, 10-deacetyl-14p-hydroxybaccatine III (~j is obtained. Therefore, as mentioned, i.n order to prepare compounds o. formula .;, 10-deacetylbaccatine III (Z), 10-deacetyl-14r-hydrox,ybaccatine III (~), natura? or semisynthetic, er othe: taxanes having an hydroXy? function at 10 a::o' already containing in position 13 the zsoserine c::a=.~.
represented by the group R4, must be available.
.t has surprisingly been found that aii these 2~ syr.tons, by treatment with coppe: (IIj salts, preferably copper acetate, undergo a selective oxidation :.:' posy t ~ oa 10 , wi thout need for the protection. o. t'.~..
other hydroxyl funct'_ons. For example, 10 deacetylbaccatine IiI (2), 10-cieacetyl-14~
hydroxybaccatine IIT_ (~) and the natural taxane 1G-.
deacetyl-cephalomannine give the respective 10-keto Ac0_ 0 0-TES

derivatives ~=7 in yields from 75 to 85%. The oxidation generally requires protracted times (100-140 hours) and an oxidizer excess, and it is carried out at room temperature and in alcoholic solvent.
S
o . o oR3 1 ~ R1=R2=R3=R4=H
6 R1=R3=R4=H;R2=OH
B R1,R2=-CO-O;R3=R4=H
R 0'' ~3 ~ ' Z 0~;>~0 C H3 C .~
o Ry o Z o 0 7 R1=R2=R3=H; R4=

When, in the compound of formula l.to prepare, the 20 presence of a cyclic carbonate group between the positions 1 and 14 is required, .synton Y is previousll treated with phosgene in pyridine and the resultinc carbonate is then oxidized in position 10 with copper (.:) acetate, to give carbonate synton u.
2~ Hv treatment with bases, d~ketones 5-B undergo a.~.
inversion in position 7, i.e: she hydroxyl .gin pos~tior. .
becomes a-oriented. Syntons ,~, ~ anc $ o-~ optiona:.iy their epimers in position 7, are therefore used for the preparation of taxanes o~f structure ~, after protection 30 of the alcoholic functions present. The alcohol function in 13, contrary to the other hydroxyalcohol functions, is poorly reactive to silylation and therefore does not undergo derivatization.
For the esterification in position 13, the suitably activated isoserine chains are used, according to what reported in literature for the semisynthesis of paclitaxel and of its analogues (see. for example Eur.
Pat. Appl. 400971, 1992; Fr. Dem. 86, 10400; E. Didier ., Tetrahedron letters ~, 2349, 1994; E. Didier 3063, 1994). Preferably, isoserin chains are used in the activated forms of oxazolidinecarboxylic acids Q~ and R~, I I ~C02H C
i N~~ Rryi N D
°~"s ~3 9b 35 I.~. formulae ~,; and 9~, R1' and R-,' have the meaninc descr;bed above. The ester~W catio.n of the oaazclidinecarboxylic acids with the ta:~:ane syntons any' the subsequent elim=natio:~ of the protective groups are carried out as desc=ibed is litera;.ure for the synthesis 30 of paclitaxel and the analogues thereof.
Among the compounds of formula ? , compounds ZQ, ,~_.~., and 1,,~ turned out to be particularly active . Compound IQ
' is 13-[(2R,3S)-3-ter-butoxycarbonylamino-2-hydroxy-3 isobutyl-propanoyl]-10-deacetyl-10-dehydro-baccatine III. Therefore, referring to general formula 1, compound 1Q has: R1 - R2 - H, OR3 - j3-OH, R1' - iso-But, R2' - t-BuO. Compound ~ is 13-[(2R,3S)-3-ter-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl]-10-dehydro-10-deacetyl-14(3-hydro~y-baccatine III' 1,14-carbonate. Therefore ~?, referring to general formula 1, has R1, R2 - -CO-0, OR3 - (3-OH, R1' - iso-But, R2' - t-BuO.
Compound ~ is 13-[(2R,3S)-3-caproylamino-2-hydrox,y-3-isobutyl-propanoyl]-10-dehydro-10-deacetyl-14j3-hydroxy-baccatine III 1,14-carbonate. Therefore 12, referring to general formula ~, has R1, RZ - -CO-0, OR3 - B-OH, R1' - iso-But, R2' - C5H11.
H
io R /
H .0 ,. ~0 Os, ~ ~ Z 0,~>~
iBu ~ ~
0 Ri 0 OH Q _ .. l ~Q R1 = - H, R~, t-butoxy RL -30 "1 R1, R2 CO-0, R2. - t-butoxy -~ R1, R2 CO-0, R2. - C5H11 -The cytotoxicity data of the compounds 10 and 11 ;.
compared with those of paclitaxel are reported in the following Table.

j I .-1 N ~'7<t'N N 1 1 I t . . . . . . i a I 1 0 0 0 0 0 ~ 1 I I I
I ~ I +l +i +I +i +I +1 I

1 I O vD .-1vD 00 b I N

I I . . . . . N 1 I N c-iN O O 1 +
I

E I I I v7 I 1 1 T7 T7 -1 I Pr , I

1 , . . . - N I W
I I o 0 0 0 0 - 1 x 1 ~ I N I
O 1 ~ ~ 1 +I +I +i +1 +1 1 I ~ I +I I

, 1 vD N ~ ~' N 1 X I O I . . . . . r-7I O
I I O O c-1O '-i~ 1 N

-rl1 H I I

I r-1 I I O
U l a~ I O M m ~D ri t~ I
.x 1 I cn I c~o 0 0 0 o m I --1 y~ I 1 I

,O1 .-I I +I +I +1 +I +I +I I H
J~f ~ I I
I U I O I~ ~' O M ~ I 04' I c13 l .

L~ 1 t~- th uw D d~ c~ 1 I

I I E
I I

I I
I r-1 1 ~ I

. I a~
I O ~ I
J t~ I "~ I 1 E
O I +~ ~ I N N N N 1 O I .,~~- I J V 1 .--i ,~ I u1 1 I cd C1.--1 I O ~ I Wit't~ ~ ~ ~ ~ I V7 E I GL , 1 o ,-, I x E I I ~
U ~ 1 W -~I I
+~

U j I ~ +~ I N
O ~ ~ ~ ' ~ I I td ~ t~ C >~
<n1 U I
I w O t~ ~C O
o o I . s~ a r-I~a ~ I .~I

U E I 1 rt U O a~ v1 ~ I 1 > V7 U N -.-1I ..1 H ~ I I O .."'-. .A 111I 't3 I I )~ ~ tiS!; lr I O
'r-I

, 1 tryt~ E ~ ~- 1 U
l-~

I I a~ I ~ E E ~ E I m ~

I !~ I rt1 ~ ~ .~ ~ W 1 T3 E

I ..~ 1 .-1 .C ~ -- .~ D 1 1-a -- ~-1 I .-I I E -- ..-- .....~ , r~
_ E

1 , a~ a. 1 1 2r r--II H o '~' .-IO~ N t~ f~ I ro ,>,~( ri 1 ~ N V' 1 C G4 I G
.-1 r (if I
N

I ~ I .-1 m .-I~7 H U U I ~
E-~I U 1 a ~1 ~ ~ x ~ ~ I v1 ~1 Compounds of formula ,~ show surprising advantages compared with paclitaxel on cell lines resistant to other anti-tumoural substances, such as adriamycin or cis-platinum. The differences between paclitax,el and these products are even more evident in iD vivo models, such as athymic nude mouse with human tumour implant.
Moreover, it has been found that the compounds of the l nvention in which R' 2 is an alkyl or alkenyl group are surprisingly devoid of cardioto:~ic activity, contrary to ta:col and the known derivatives thereof, and therefore they can advantageously be used in the treatment of tumours in cardiopathic patients who cannot be treated with taxol and its known derivatives..
The products of the invention can be j I5 incorporated in suitable pharmaceutical formulations for the administration of the products both parenterally and orally. For the intravenous administration, mixtures of Chremoform~ L and ethanol, poiysorbates or liposomial preparations prepared mth natural or synthetic phosp::atidylcholine or mixtures of natural phosphoiipids in the presence of. cholesterol are mair.'_t used.
The iollow!ng examples furt;~er illustrate the lwen:.ion .
Example 1 Preparation c. IJ-deacety?-iG-dehydrobaccatine ii= (~).
10 g of _0-deacetylbaccamne I~I (~),_ (isolates, as described by G. Chauviere at a.., C.R. Acad. Sc~. Ser.
Ii 293. 591. 1931) are suspended in 350 ml of methanol and added with 65 g of Cu(OAc)2. The suspension is stirred at room temperature for 120 h. The salts are filtered off and the solution is chromatographed or. 100 g of silica gel eluting with a hexane/ethyl acetate 6:4 mixture. Upon crystallization from ligroin, 9.5 g of (~) are obtained, M+a m/z 542.
Example 2 - Preparation of 10-deacetyl-10-dehydro-14p-S hydroxybaccatine III 1,14-carbonate ($).
g of 10-deacetyl-143-hydroxybaccatine II_T ($), isolated as described by G. Appendino et al., J. Chem.
Soc. Perkin Trans I, 2925. 1992, are dissolved ..:~ SO ml of anhydrous pyridine and treated for one hour w_th l.5 10 eq. of 5~ phosgene in toluene at -10°C. The reaction mixture is poured onto ice and the aqueous suspension is extracted with ethyl acetate, washing thoroughly the organic phase with diluted HCl. A~~er drying over Na2S04, the organic phase is concentrated to dryness.
9 g of 1, I4-carbonate are obtained, whic5 are suspended in 350 ml of methanol and treated with 50 g ef Cu(OAc)2 under stirring at room temperature for 120 h. The suspension is filtered and the solution is evaporated to dryness. The residue is chromatographed oa 100 g c_ silica gel eluting with a hexane/ethyl acetate .:.
mixture. 2 g of ($) are obtained, M+a m/~ 584.
Example 3 - Preparation o~ 13-[~(2R,3S)-3-te:-buto:<ycarbonylamino-2-hydroxy-3-isobutyl-propanoyl;i0-deacetyl-10-dehydrobaccatine III (~j A solution o~ 300 mg (1.8s mmol) c. 7-~-triethylsilyl-10-deacetyl-10-dehydrobaceam ne II_.
obtaineC from compound ("~) (Example l) by silylation in position 7 with the method described by. J. Denis e~ al., J. am. Chem. Soc. 10C. 5917. 1988. in o0 ml o~ toluene is added With 500 mg of (4S, 5R)-N-(ter-buto::v carbonyl)-2.2-dimethyl-4-isobutyl-5-oxazolidinecar boxylic acid, 240 mg of dicyclohexylcarbodiimide (1.2 eq.) and 24 mg of N,N-dimethylaminopyridine (0.2 eq).
The reaction mixture is kept at 80'C for 2 hours, then is filtered and washed with water; the organic phase is concentrated to dryness. The residue is treated with methano3 containing 0.1$ of H~SO;~, at 10°C. The methanol solution is diluted with water and the product is e:~tracted with ethyl acetate; the oraani~ phase is concentrated to dryness and the residue is chromatographed on silica gel eluting with acetone/hexane 4:6. 350 mg of (1Q) are obtained. M~'a m/z 785.
Example 4 - Preparation of 13-[(2R;3S)-3-tert-butoxycarbonyl-amino-2-hydroxy-3-isobutyl-proganoyl]10-deacetyl-10-dehydro-14p-hydroxybaccatine III 1,I4-carbonate (~],,) .
0.5 g of 7-0-triethylsilyl-10-deacetyl-10-dehydro-24~i-hydroxybaccatine III 1,14-carbonate, obtained from compound ($) (Example 2) by silylation in position 7 according to what reported by J. Denis et al.,.J. Am.
Soc. i00. 5917. 1988. are dissolve3 ~n 60 ml of toluene.
The solution is added with 800 mg c. (4S,5R)-N-(tert-butoxycarbonyl)-~.2-dimethyl-4-isobLtyl-~-oxazolidine carbofylic acid, -X00 mg of c_;=lohe:~_vca_bod!imide and "-_J
mg Of N,N-G''lmpW':YlaTlPOpyi? ~l::e. Th°_ r°_3Ct3On m1.''.~'.lr° ~.S
° :.i kep t a t °0 C to= two hour s , then ~ s ~ _ _ ta= ed anc was:~ed w~ t. water and :.he orgar.uc phase is concentrates' tc ~'ryness. ~_'he residue is treated wi;.z methanol conta~mnc 0.1$ o' H'S04 at 20'C. The methano.,solut~on is diluted with water and the product is extracted with ethyl acetate; the organic phase is concentrated to dryness and the residue is chromatographed on silica gel, eluting with acetone/hexane 4:6. 580 mg of (1l) are obtained, M+a m/z 827.
Example 5 - Preparation of 10-deacetyl-10-dehydro-14(3-hydro~:ybaccatine III
g of 10-deacetyl-14p-hydroxybaccatine IIT
are suspended in 350 ml of methanol and added with 65 g of Cu(OAc)2. The suspension is kept under stirring at room temperature for 120 h. The salts are filtered off, 10 the solution is evaporated to dryness and the residue is chromatographed on 100 g of silica gel eluting with a hexane/ethyl acetate 6:4 mit:ture. Upon crystallization from ligroin, 9.3 g of (~) are obtained, M+a m/z 558.
Example 6 - Preparation of 10-deacetyl-10-dehydro-cephalomannine (Z).
0.4 g of 10-deacetylcephalomannine (J. L. Laughlin et al . ; J . Nat . Prod . 44 . 312 . 19E~ ) are dissolved in 5 ml of MeOH and added with 600 mg c. Cu(OAc)2. T_he reaction mixture is left unde_ stirring 'or 54 hours a:.
roo m temperature. After elimination o. the salts for f _lt=ati on, the sol ution the salts a: j '_=tered o_'_' , t!:e solution is evaporated to dryness and chromatographed on silica gel (10 g) using a hexane-ethyl acetate 1:'_ m.%tL=a as eluent. '20 mg c. '~1 an. cbta_nec, M+a m,'=
829.
Example 7 - Preparat!on o7-t==ethylsiitl-14p-:~ycro~;ybaccatine III (y) 500 mg o. 7-~~iethyisilyl-i0-deacetl'_baccatm~ I_T=, pr epared according to ;.he method by J . Denis et al. , ,; .
Am. Chem. Soc. 100. 5917. 19°8 are dissolved in 15 m' o.
an ethyl acetate-methylene trio=ide 9:? mixture. The solution is added with 10 g o f Mn02 leaving the suspension at room temperature under stirring for 24 hours. After filtration, the solution is evaporated to dryness and the residue is chromatographed on silica gel 5 (20 g) eluting with a hexane-ethyl acetate 8:2 mixture.
310 mg of 7-triethylsilyl-?0-deacetyl-13-dehydro-14p-hydroxybaccatine III are obtained (M'~a m/z 672).
300 mg of this product are dissolved in 2 ml of pyridinE. The solution is added with 910 mg o~ Ac20.
?0 After 16 hours the reaction mixture is poured onto ice and then e::tracted with ethyl acetate. The organic phasa is washed with diluted HC1 and then with water to neutrality. After evaporation of t'~e solvent, t'~e residue is crystallized from ether (220 mg, N~a m/z 15 756). The solid is dissolved in 10 ml o~ a::!:ycrous TuF;
the solution is added with 160 u1' of sodium bis(2-methoxy-ethoxy)aluminium hydride (65$ solution). After about 10 minutes, 10 ml of a NH4Cl saturated scluticn a. a added , ex ~racting then m th ethy' ace to to . ~_':~~
organic phase is evaporated to dryness. The residue 's pu: if iec on silica gel ( 15 g ) Elu:,ir:g wlth a hexane-ethyl acetate 7:3 mixture. 80 mg o(~; are obtained, M+a 716.
' -'~-:.ao: 0 1 Example 8 - Pr epa= anon o _ , 4 S , 5R ) , y -..- ( _ .
2= d_!tethc::.Jpheny; j-e-~sobu;.yi-.-c::azol:.;:_::e carbo~:yl:_ aC_'_' me~.~,r'_ estE.". .
:J C :r: ti-Cdp=~J1 _.'~_:.sv.bL:tl _-1S'vsEr-.._ mEt i'~ ~ estE~
are d_ss;,lved in ?00 m' of a mi::tu:e c= an'~yd:css T~:
and benzene and the sol::~~on is trea;.ed with 2 equivale:~ts of 2.:-dimethoYy benzaldehyde dimethyl acetal in the presence o_-' 120 mg e. pyridinium p-toluenesulfonate. The solution is refluxed for 1 hour.
The solvent is distilled and the residue is chromatographed on silica gel eluting the main compound with a ethyl acetate/hexane 3:2 mixture. After removing under vacuum the solvent from the fractions containing the desired isomer, the residue is crystallized from he~:ane/isopropyl ether. 2.5 g of a compound having m.p.
98°C are obtained.
Example 9 - Preparation of (4S,5R)-P;-caproyl-~-(2.~
dimethoxyphenyl)-4-isobutyl-5-oxazolidine carboxylic acid 2 g of the compound of Example 8 are suspended in 50 ml of a mixture of ~ methanol aqueous c ° : ~ ) conta~ :~:~ng 5 g of K2C03. The reaction mixture is left under stirring until complete dissolution o. the isoserine derivative. The reaction mixture is carefully acidified to pH 5. with stirring, in the presence of ethyl acetate. The aqueous phase ~s disca=dec, whereas t!~e organic one is dried over socuurr, sul:ate a::
concentrated to dryness at low temperature under vacuum.
The residue is dissolved in a toluene/methylene chlo=ode ml x ture and it is ready f or the react~o:. w_ t to selected taxanes.
Example 10 - Prepay ati~r. o: ' 3-[ ! 2?~, 3S )-3-capro~rl aml: c-2-~ydroxy-3-isobutyl-prcpaneyl;--C-dehycro-10-deacety_ ? 4p-hydroxy-baccatine II I _ , 1~-~=a=bonat= f?..'. ) 5 g of 1,14-carbonate-7-TES-10-dehydTo-baccamne I T . ay a dissolved in 100 ml ef a ml ~ture of toluer.~ any methylene chloride in a E.2 ratio, together with o g c.
(4S,SR)-N-caproyl-2-(2.4-dimethoxyphenyl)-4-isobutyl-5-oxazolidine carboxylic acid. The reaction mixture is added with 500 mg of 4-dimethylaminopyridine and 2.5 g of 1.3-dicyclohexylcarbodiimide, then heated for 2 hours under mild refluf: until the reagents disappear. The compounds insoluble in the medium are filtered off and the solution is concentrated to dryness. The residue is taken up with 50 ml of methanol/HCl (0.0I$) and the reaction mixture is left at room temperature for 1 hour.
The solution is alkalinized to pH 5 and concentrated to dryness in the vacuum. The residue is chromatographed on a silica gel column eluting with a methylene chloride/methanol 98:2 mixture. Upon crystallization from ethyl acetate, 1.2 g of compound (1~) are obtained.
Example 11 - Solution of compound (1.Q) for the parenteral administration ~15 Compound 10 2 mg CremophorTM EL 17 5 mg Absolute alcohol q.s: to 0.4 ml.
Example 12 - Solution of compound (;.,~,) for the parenteral administration Compound 11 2 mg Cremophor EL -175 mg Absolute alcohol q.s. to 0.4 ml.
Example 13 - Tablets containing compound (~,Q) Compound 10 10 mg Cross-linked sodium carboxymethyl cellulose 15 mg Lactose (spray dried) 41.5 mg Microcrystalline cellulose 40 mg Colloidal silicon dioxide 0.5 mg Magnesium stearate 1 mg.
Example 14 - Tablets containing compound (L) Compound 11 10 mg Cross-linked sodium carboxymethyl cellulose 15 mg Lactose (spray dried) 41.5 mg Microcrystalline cellulose 40 mg Colloidal silicon dioxide 0.5 mg Magnesium stearate 1 mg.

Example 15 - Capsules containing compound (~Q) Compound 10 10 mg Lactose (spray dried) 30 mg Microcystalline cellulose 48.5 mg Pre-gelatinized starch 10 mg Magnesium stearate 1 mg Colloidal silicon dioxide 0.5 mg.

Example 16 - Capsules containing compound (~

Compound 11 10 mg Lactose (spray dried) 30 mg Microcrystalline cellulose 48.5 mg Pre-gelatinized starch 10 mg Magnesium stearate 1 mg Colloidal silicon dioxide 0.5 mg.

Claims

CLAIMS:

1. Intermediates of formula 9b:

wherein R2' is straight or branched alkyl or alkenyl group, containing one to five carbon atoms, or an aryl residue, or a tert-butoxy group.