Process for stereoselective synthesis of prostacyclin...

Details Process for stereoselective synthesis of prostacyclin... Process for stereoselective synthesis of prostacyclin...

2002-07-01

2004-07-20

Wilson, James O. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S807000

Reexamination Certificate

active

06765117

ABSTRACT:

FIELD OF THE INVENTION
The present application relates to a process for producing prostacyclin derivatives and novel intermediate compounds useful in the process.
BACKGROUND OF THE INVENTION
Prostacyclin derivatives are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, and bronchodilation.
For convenience, the novel prostacyclin derivatives will be referred to by the trivial, art-recognized system of nomenclature described by N. A. Nelson, J. Med. Chem. 17:911 (1974) for prostaglandins. Accordingly, all of the novel prostacyclin derivatives herein will be named as 9-deoxy-PGF
1
-type compounds.
The prostacyclin derivatives prepared by the method disclosed in the '075 patent are as follows:
wherein L
1
is &agr;-R
3
:&bgr;-R
4
, &agr;-R
4
: &bgr;-R
3
, or a mixture of &agr;-R
3
:&bgr;-R
4
and &agr;-R
4
: &bgr;-R
3
, wherein R
3
and R
4
are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R
3
and R
4
is fluoro only when the other is hydrogen or fluoro;
wherein M
1
is &agr;-OH: &bgr;-R
5
or &agr;-R
5
: &bgr;-OH, wherein R
5
is hydrogen or methyl;
wherein R
7
is
(1) -C
m
H
2m
-CH
3
, wherein m is an integer from one to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C
1
-C
3
)alkyl, or (C
1
-C
3
)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R
7
is phenoxy or substituted phenoxy, only when R
3
and R
4
are hydrogen or methyl, being the same or different,
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C
1
-C
3
)alkyl, or (C
1
-C
3
)alkoxy, with the proviso that not more than two substituents are other than alkyl,
(4) cis—CH=CH-CH
2
-CH
3
,
(5) (CH
2
)
2
-CH(OH)-CH
3
, or
(6) -(CH
2
)
3
—CH=C(CH
3
)
2
;
wherein -C(L
2
)-R
7
taken together is
(1) (C
4
-C
7
)cycloalkyl optionally substituted by one to 3 (C
1
-C
5
) alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
wherein R
8
is hydroxy, hydroxymethyl, or hydrogen;
wherein
(1) R
20
, R
21
, R
22
, R
23
, and R
24
are all hydrogen with R
22
being either &agr;-hydrogen or &bgr;-hydrogen,
(2) R
20
is hydrogen, R
21
and R
22
taken together form a second valence bond between C-9 and C-6
a
, and R
23
taken together form a second valence bond between C-8 and C-9 or are both kydrogen, or
(3) R
22
, R
23
, and R
24
are all kydrogen, with R
22
being either &agr;-hydrogen or &bgr;-hydrogen, and
(a) R
20
and R
21
taken together are oxo, or
(b) R
20
is kydrogen and R
21
is hydroxy, being &agr;-hydroxy or &bgr;-hydroxy;
wherein X
1
is
(1) -COOR
1
, wherein R
1
is
(a) hydrogen,
(b) (C
1
-C
12
)alkyl,
(c) (C
3
-C
10
)cycloalkyl,
(d) (C
6
-C
12
)aralkyl,
(e) phenyl, optionally substituted with one, 2 or 3 chloro or (C
1
-C
1
)alkyl,
(f) phenyl substituted in the para position by
(i) -NH-CO-R
25
,
(ii) -CO-R
26
,
(iii) -O-CO-R
54
, or
(iv) -CH=N-NH-CO-NH
2
wherein R
25
is methyl, phenyl, acetamidophenyl, benzamidophenyl, or -NH
2
: R
26
is methyl, phenyl, -NH
2
, or methoxy; and R
54
is phenyl or acetamidophenyl; inclusive, or
(g) a pharmacologically acceptiable cation;
(2) -CH
2
OH,
(3) -COL
4
, wherein L
4
is
(a) amino of the formula - - NR
51
R
52
, wherein R
51
and R
52
are
(i) hydrogen,
(ii) (C
1
- C
12
)alkyl,
(iii) (C
3
-C
10
)cycloalkyl,
(iv) (C
7
- C
12
)aralkyl,
(v) phenyl, optionally substituted with one, 2 or 3 chloro, (C
1
-C
3
)alkyl, hydroxy, carboxy, (C
2
-C
5
)alkoxycarbonyl, or nitro,
(vi) (C
2
-C
5
)carboxyalkyl,
(vii) (C
2
-C
5
)carbamoylalkyl,
(viii) (C
2
-C
5
)cyanoalkyl,
(ix) (C
3
-C
6
)acetylalkyl,
(x) (C
7
-C
11
)benzoalkyl, optionally substituted by oe, 2 or 3 chloro, (C
1
-C
3
)alkyl, hydroxy, (C
1
-C
3
)alkoxy, carboxy, (C
2
-C
5
)alkoxycarbonyl, or nitro,
(xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C
1
-C
3
)alkyl, or (C
1
-C
3
)alkoxy,
(xii) (C
6
-C
9
)pyridylalkyl optionally substituted by one, 2 or 3 chloro, (C
1
-C
3
)alkyl, hydroxy, or (C
1
-C
3
)alkyl,
(xiii) (C
1
-C
4
)kydroxyalkyl,
(xiv) (C
1
-C
4
)dihydroxyalkyl,
(xv) (C
1
-C
4
)trihydroxyalkyl,
with the further proviso that not more than one of R
51
and R
52
is other than hydrogen or alkyl,
(b) cycloamino selected from the group consisting of lyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (C
1
-C
12
)alkyl of one to 12 carbon atoms, inclusive,
(c) carbonylamino of the formula -NR
53
COR
51
, wherein R
53
is hydrogen or (C
1
-C
4
)alkyl and R
51
is other than hydrogen, but otherwise as defined above,
(d) sulfonylamino of the formula -NR
53
SO
2
R
51
, wherein R
51
and R
53
are as defined in (c),
(4) -CH
2
NL
2
L
3
, wherein L
2
and L
3
are kydrogen or (C
1
-C
4
)alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when X
1
is -CH
2
NL
2
L
3
,
wherein Y
1
is trans-CH=CH-, cis-CH=CH-, CH
2
CH
2
-, or -C≡C-; and
wherein Z
4
is -CH
2
- or -(CH
2
)-CF
2
, wherein ƒ is zero, one, 2 or 3.
When X
1
is -COOR
1
of the Formulac in the '075 patent, the novel compounds so described are used for the purposes described and are in free acid form, in ester form, or in pharmacologically acceptable salt form. When the ester form is used, the ester is any of those within the above definition of R
1
. However, it is preferred that the ester be alkyl of one to 12 carbon atoms, inclusive. Of the alkyl esters, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system; and straight-chain oxtyl, nonyl, decyl, undecyl, and dodecyl are especially preferred for prolonged activity.
Pharmacologically acceptable salts of the novel prostagladin analogs of this invention for the purposes described are those with pharmacologically acceptiable metal cations, ammonia, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are within the scope of this invention.
Pharmacologically acceptable amine cations are those derived from primary, secondary, and tertiary amines. Example of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, &agr;-phenylethylamine, &bgr;-phenylethylamine, ethylenediamine, diethylenetriamine, adamantylamine, and the like aliphatic, cycloaliphatic, araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazie, and lower-alkyl derivatives thereto, e.g., 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl,-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxymethyl) aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, galactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrie, procaine, and the like. Further useful amine salts of the basic amino acid salt, e.g., lysie and arginine.
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.
U.S. Pat. No. 4,306,075 discloses methods for making prostacyclin derivatives. Ho

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