THE SYNTHESIS AND BIOLOGICAL ACTIVITY OF ALKYLOXY PROSTAGLANDIN ANALOGUES
Jean Bowler, N.S. Crossley* and R.I. Dowell
ICI Pharmaceuticals Division Alderley Park, Macclesfield, Cheshire, England.
ABSTRACT Prostaglandin analogues in which the alkyl chain attached to C-15 in the natural compounds is replaced by an alkyloxyalkyl group have been synthesised. Compounds of the 17-oxa series are particularly potent luteolytic as~nts and are selective in the sense that they are less effective than PGF2~ in causing isotonic contractions of isolated uterus muscle. ACKNOWLEDGMENTS We thank Dr A.L. Walpole and his colleagues for the biological results.
PROSTAGLANDINS MARCH 1975
VOL. 9 NO. 3
391
PROSTAGLANDINS
Despite the large number of prostaglandin analogues which have been made and patented in recent years few details of their biological activity are available and structure-activlty relationships in any series of compounds have rarely been revealed. We have recently described the synthesis and biological activity of some 16-aryloxy prostaglandins, for example ICI 819008 ("Equimate"*), which are extremely potent luteolytic agents in many animal species. Since these aryloxy compounds are more potent than the analogous compounds lacking the oxygen atom, for example the 17-phenyl compound (I) (2), the activity of other types of oxa prostaglandins is obviously of interest. This paper is concerned with prostaglandins containing alkyloxy groups. Where the group attached to C-15 in the F series of compounds is alkyl a marked increase in luteolytic potency in the hamster is observed if the chain is lengthened from n-pentyl (PGF2u) to n-heptyl (ICI 74,205) (3). Therefore the first part of our work was concerned with the effect on luteolytic activity of replacing a methylene group in the heptyl chain of ICI 74,205 with an ether oxygen. The Corey synthesis (4), which was used to make these compounds, is a particularly convenient procedure for varying the side chains of the prostaglandin molecule since the phosphonate reagents (general formula III) which are condensed with the aldehyde (II) are easily made from esters (IV) or acid chlorides (V), by reaction with the anion (Vl). The enones (VII) obtained can then be converted into the prostaglandins (VIII> by similar methods to those used for the synthesis of PGF2=. The required esters or acid chloride were made as shown in Scheme i. Reaction of each of these esters and the acid chloride with the anion (VI) from dimethyl methylphosphonate (BuLi/THF) gave five isomeric phosphonates which on condensation (BuLi/DME) with the racemic aldehyde (II) gave five isomeric enones (i0). Physical data for four of these is given in Table I. Reduction of each enone with zinc borohydride followed by a) hydrolysis (K2CO3/MeOH) of the p-phenylbenzoate group, b) protection of the hydroxyl groups as tetrahydropyranyl ethers, c) reduction of the lactone to the lactol with diisobutylaluminium hydride, d) reaction with the Wittig reagent from 5-triphenylphosphoniopentanoic acid and e) acid catalysed removal of the tetrahydropyranyl protecting groups gave the corresponding prostaglandins as mixtures of equal parts of 15~ and 15~ alcohol epimers. These could be separated by chromatography and, by analogy with the natural compounds, the more polar epimer was assigned the 15~ configuration. In no case was a crystalline prostaglandin obtained and the products were characterised by n.m.r, and mass spectroscopy.t The luteolytic activity of these compounds compared to racemic PGF2a and ICI 74,205 when dosed to pregnant hamsters is shown in Table II. As with the aryl prostaglandins the presence of an oxygen atom attached Trade mark
t Mass measurement of the tetra (trimethylsilyl) derivatives
392
MARCH 1975
VOL. 9 NO. 3
PROSTAGLANDINS to C-16 results in an increase in luteolytic potency and 20-ethyl-17oxaPGF2a (IX) is twice as potent as the carbon isostere ICI 74,205, and ten times more potent than racemic PGF2~ itself. When the ether oxygen is in the middle of the alkyl chain (X and XI) a considerable drop in potency is observed but the 20-oxa compound (XII) is as potent as ICI 74,205 and 20-methoxyPGF2~ is more than twice as potent as PGF2~. In view of these results we have looked at the effect of varying the chain length in the 17-oxa series. The compounds (XIV, XV and XVI) wemnede b y L r e ~ s identical to those described above and their luteolytic activity is shown at the bottom of Table II. None of the three was any more potent than the pentyloxy compound (IX). The smooth muscle effects of prostaglandins can be conveniently measured using an isolated guinea-pig uterus preparatiQn and the results from this test correlate approximately with the observed side effects in vivo (ii). The pentyloxy compound (IX) is a tenth as effective as PGF2a in causing isotonic contractions of isolated uterus muscle and therefore in this compound a considerable separation of luteolytic and smooth muscle effects has been achieved. REFERENCES I.
Binder, D., J. Bowler, E.D. Brown, N.S. Crossley, J. Hutton, M. Senior, L. Slater, P. Wilkinson and N.C.A. Wright, 16-Aryloxyprostaglandins: A new class of potent luteolytic agent, Prosteglandins, 6:87, 1974.
2.
German Patent 2154309.
3.
Labhsetwar, A.P., New antifertility agent - an orally active prostaglandin - ICI 74,205, Nature 238:400, 1972.
4.
Corey, E.J., N.M. Weinshenker, T.F. Schaaf and W. Huber, Stereocontrolled synthesis of Prostaglandins F2~ and E2, J.Amer.Chem. Soc., 91:5675, 1969.
5.
Nerdel, F., G. Heck and G. Potzscher, J. prakt.chem., 8:171, 1959.
6.
Croxall, W.J., J.O. Van Hook and R. Luckenbaugh, J.Amer.Chem.Soc., 71:2736, 1949.
7,
Palomaa, M.H. and A. Kenetti, Bet. 64B:797, 1931.
8.
Nesmeyanov, A.N. and L.I. Zakharkin, Izvest.Akad.Nauk S.S.S.R., 1955, 224, C.A. 50:4849.
9.
Vartanyan, S.A., G.A. Musakhyan and D.V. Organova, Izvest.Akad.Nauk S.S.S.R., 1961, 337, C.A. 57:9655.
i0. All the compounds in this paper are racemic but for convenience only the enantiomer having the same absolute configuration as the natural compounds is shown. ii. Dukes, M., W. Russell and A.L. Walpole, Nature 250:330, 1974.
MARCH 1975
VOL. 9 NO. 3
393
PROSTAGLANDINS
Schemel
nCsHIIONa + CICH2CO2H
L
Reference
nC5HIIOCH2CO2H nC4HgONa + CH2=CHCO2Et
nC3HTONa
nC5HIIOCH2CO2CH3
5
)
nC4H90(CH2)2CO2C4H 9
6
)
~C3H?O(CH2)3CO2CH3
7
C2H50(CH2)4CO2C2H5
8
CH30(CH2)5COC1
9
+ Br(CH2)3CO2H
nCaH70(CHz)3COzH
C2HsOCH2CH2CHO
1
C2H5OCH2CH2CH=CHCO2C2H 5
CH3ONa
+ Br(CH2)5CO2H
[
CH30(CH2)5C02H
394
)
MARCH 1975
VOL. 9 NO. 3
PROSTAGLANDINS
HO
HO ~
C02H 0 -'~
HO
'
~
~
COzH
CF3
HO
HO
HO (I)
ICI 81~008
0
~CHO
+
(MeO)2" PO"CH2" CO"CH2" R"
O" CO
I~~)~'~+C
H2. (~
Ph
(Vl)
(11)
0
RO"CO"CH2" R (IV)
o_r
(III)
Cl" CO"CH2" R (V)
J
~CH2R O.CO
0
J
HO
COH CH2R HO
H()
Ph
( VII )
( VIII )
MARCH 1975
VOL. 9 NO. 3
395
PROSTAGLANDINS
Table I
Group R in (VII)
m.pt. oC
Analysis (Theory C,73.I; H,6.7%)
85
C,73.3; H,6.8
nC3H70(CH2)2
I06-I07
C,73.0; H,6.7
C2HsO(CH2)3
93- 95
C,73.2; H,6.8
CX~O(CH2)~
89- 92
C,73.3; H,6.6
84-
nC5HIIO
w
nC4HgOCH 2
*
Unstable enone - reduced without purification Table II
R in (Vlll)
Minimum effective dose to termiru~te pregnancy given s.c. on each of days 4-6 ~g/hamster
nC4H 9 (racemic PGF2~)
50
nC6HI3
(ICI 74,205)
IO
(IX)
5
(X)
i00
nC3H70(CH2) 2
(XI)
>too
C2HsO(CH2)3
(XII)
i0
CH30(CH2) 4
(Xlll)
20
nC3H70
(XIV)
20
nC4HTO
(XV)
5
nC6Hl30
(XVI)
i0
nCsHIIO nC4H9OCH 2
* Consistent results are obtained only if hamsters from the same supplier are used.
396
M A R C H 1975
VOL. 9 NO. 3
Jean Bowler, N.S. Crossley* and R.I. Dowell
ICI Pharmaceuticals Division Alderley Park, Macclesfield, Cheshire, England.
ABSTRACT Prostaglandin analogues in which the alkyl chain attached to C-15 in the natural compounds is replaced by an alkyloxyalkyl group have been synthesised. Compounds of the 17-oxa series are particularly potent luteolytic as~nts and are selective in the sense that they are less effective than PGF2~ in causing isotonic contractions of isolated uterus muscle. ACKNOWLEDGMENTS We thank Dr A.L. Walpole and his colleagues for the biological results.
PROSTAGLANDINS MARCH 1975
VOL. 9 NO. 3
391
PROSTAGLANDINS
Despite the large number of prostaglandin analogues which have been made and patented in recent years few details of their biological activity are available and structure-activlty relationships in any series of compounds have rarely been revealed. We have recently described the synthesis and biological activity of some 16-aryloxy prostaglandins, for example ICI 819008 ("Equimate"*), which are extremely potent luteolytic agents in many animal species. Since these aryloxy compounds are more potent than the analogous compounds lacking the oxygen atom, for example the 17-phenyl compound (I) (2), the activity of other types of oxa prostaglandins is obviously of interest. This paper is concerned with prostaglandins containing alkyloxy groups. Where the group attached to C-15 in the F series of compounds is alkyl a marked increase in luteolytic potency in the hamster is observed if the chain is lengthened from n-pentyl (PGF2u) to n-heptyl (ICI 74,205) (3). Therefore the first part of our work was concerned with the effect on luteolytic activity of replacing a methylene group in the heptyl chain of ICI 74,205 with an ether oxygen. The Corey synthesis (4), which was used to make these compounds, is a particularly convenient procedure for varying the side chains of the prostaglandin molecule since the phosphonate reagents (general formula III) which are condensed with the aldehyde (II) are easily made from esters (IV) or acid chlorides (V), by reaction with the anion (Vl). The enones (VII) obtained can then be converted into the prostaglandins (VIII> by similar methods to those used for the synthesis of PGF2=. The required esters or acid chloride were made as shown in Scheme i. Reaction of each of these esters and the acid chloride with the anion (VI) from dimethyl methylphosphonate (BuLi/THF) gave five isomeric phosphonates which on condensation (BuLi/DME) with the racemic aldehyde (II) gave five isomeric enones (i0). Physical data for four of these is given in Table I. Reduction of each enone with zinc borohydride followed by a) hydrolysis (K2CO3/MeOH) of the p-phenylbenzoate group, b) protection of the hydroxyl groups as tetrahydropyranyl ethers, c) reduction of the lactone to the lactol with diisobutylaluminium hydride, d) reaction with the Wittig reagent from 5-triphenylphosphoniopentanoic acid and e) acid catalysed removal of the tetrahydropyranyl protecting groups gave the corresponding prostaglandins as mixtures of equal parts of 15~ and 15~ alcohol epimers. These could be separated by chromatography and, by analogy with the natural compounds, the more polar epimer was assigned the 15~ configuration. In no case was a crystalline prostaglandin obtained and the products were characterised by n.m.r, and mass spectroscopy.t The luteolytic activity of these compounds compared to racemic PGF2a and ICI 74,205 when dosed to pregnant hamsters is shown in Table II. As with the aryl prostaglandins the presence of an oxygen atom attached Trade mark
t Mass measurement of the tetra (trimethylsilyl) derivatives
392
MARCH 1975
VOL. 9 NO. 3
PROSTAGLANDINS to C-16 results in an increase in luteolytic potency and 20-ethyl-17oxaPGF2a (IX) is twice as potent as the carbon isostere ICI 74,205, and ten times more potent than racemic PGF2~ itself. When the ether oxygen is in the middle of the alkyl chain (X and XI) a considerable drop in potency is observed but the 20-oxa compound (XII) is as potent as ICI 74,205 and 20-methoxyPGF2~ is more than twice as potent as PGF2~. In view of these results we have looked at the effect of varying the chain length in the 17-oxa series. The compounds (XIV, XV and XVI) wemnede b y L r e ~ s identical to those described above and their luteolytic activity is shown at the bottom of Table II. None of the three was any more potent than the pentyloxy compound (IX). The smooth muscle effects of prostaglandins can be conveniently measured using an isolated guinea-pig uterus preparatiQn and the results from this test correlate approximately with the observed side effects in vivo (ii). The pentyloxy compound (IX) is a tenth as effective as PGF2a in causing isotonic contractions of isolated uterus muscle and therefore in this compound a considerable separation of luteolytic and smooth muscle effects has been achieved. REFERENCES I.
Binder, D., J. Bowler, E.D. Brown, N.S. Crossley, J. Hutton, M. Senior, L. Slater, P. Wilkinson and N.C.A. Wright, 16-Aryloxyprostaglandins: A new class of potent luteolytic agent, Prosteglandins, 6:87, 1974.
2.
German Patent 2154309.
3.
Labhsetwar, A.P., New antifertility agent - an orally active prostaglandin - ICI 74,205, Nature 238:400, 1972.
4.
Corey, E.J., N.M. Weinshenker, T.F. Schaaf and W. Huber, Stereocontrolled synthesis of Prostaglandins F2~ and E2, J.Amer.Chem. Soc., 91:5675, 1969.
5.
Nerdel, F., G. Heck and G. Potzscher, J. prakt.chem., 8:171, 1959.
6.
Croxall, W.J., J.O. Van Hook and R. Luckenbaugh, J.Amer.Chem.Soc., 71:2736, 1949.
7,
Palomaa, M.H. and A. Kenetti, Bet. 64B:797, 1931.
8.
Nesmeyanov, A.N. and L.I. Zakharkin, Izvest.Akad.Nauk S.S.S.R., 1955, 224, C.A. 50:4849.
9.
Vartanyan, S.A., G.A. Musakhyan and D.V. Organova, Izvest.Akad.Nauk S.S.S.R., 1961, 337, C.A. 57:9655.
i0. All the compounds in this paper are racemic but for convenience only the enantiomer having the same absolute configuration as the natural compounds is shown. ii. Dukes, M., W. Russell and A.L. Walpole, Nature 250:330, 1974.
MARCH 1975
VOL. 9 NO. 3
393
PROSTAGLANDINS
Schemel
nCsHIIONa + CICH2CO2H
L
Reference
nC5HIIOCH2CO2H nC4HgONa + CH2=CHCO2Et
nC3HTONa
nC5HIIOCH2CO2CH3
5
)
nC4H90(CH2)2CO2C4H 9
6
)
~C3H?O(CH2)3CO2CH3
7
C2H50(CH2)4CO2C2H5
8
CH30(CH2)5COC1
9
+ Br(CH2)3CO2H
nCaH70(CHz)3COzH
C2HsOCH2CH2CHO
1
C2H5OCH2CH2CH=CHCO2C2H 5
CH3ONa
+ Br(CH2)5CO2H
[
CH30(CH2)5C02H
394
)
MARCH 1975
VOL. 9 NO. 3
PROSTAGLANDINS
HO
HO ~
C02H 0 -'~
HO
'
~
~
COzH
CF3
HO
HO
HO (I)
ICI 81~008
0
~CHO
+
(MeO)2" PO"CH2" CO"CH2" R"
O" CO
I~~)~'~+C
H2. (~
Ph
(Vl)
(11)
0
RO"CO"CH2" R (IV)
o_r
(III)
Cl" CO"CH2" R (V)
J
~CH2R O.CO
0
J
HO
COH CH2R HO
H()
Ph
( VII )
( VIII )
MARCH 1975
VOL. 9 NO. 3
395
PROSTAGLANDINS
Table I
Group R in (VII)
m.pt. oC
Analysis (Theory C,73.I; H,6.7%)
85
C,73.3; H,6.8
nC3H70(CH2)2
I06-I07
C,73.0; H,6.7
C2HsO(CH2)3
93- 95
C,73.2; H,6.8
CX~O(CH2)~
89- 92
C,73.3; H,6.6
84-
nC5HIIO
w
nC4HgOCH 2
*
Unstable enone - reduced without purification Table II
R in (Vlll)
Minimum effective dose to termiru~te pregnancy given s.c. on each of days 4-6 ~g/hamster
nC4H 9 (racemic PGF2~)
50
nC6HI3
(ICI 74,205)
IO
(IX)
5
(X)
i00
nC3H70(CH2) 2
(XI)
>too
C2HsO(CH2)3
(XII)
i0
CH30(CH2) 4
(Xlll)
20
nC3H70
(XIV)
20
nC4HTO
(XV)
5
nC6Hl30
(XVI)
i0
nCsHIIO nC4H9OCH 2
* Consistent results are obtained only if hamsters from the same supplier are used.
396
M A R C H 1975
VOL. 9 NO. 3
