Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-05-21
2004-02-24
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06696592
ABSTRACT:
FIELD OF THE INTENTION
The present invention relates to methods for making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives and also relates to intermediates useful in making such compounds.
BACKGROUND OF THE INVENTION
Corticosteroids are known to have anti-inflammatory and immunomodulatory properties useful in the treatment of numerous diseases, including autoimmune and inflammatory diseases. However, treatment with corticosteroids may cause undesirable side-effects.
Steroid nitrate ester (ONO
2
) derivatives have been used as nitric oxide donors to potentially increase the therapeutic actions of and counteract or lessen the side-effects of corticosteroids. For example, U.S. Pat. No. 5,985,862 discloses pharmaceutical compositions having steroid nitrate ester (ONO
2
) derivatives and their use in treating undesired smooth muscle contractions and inflammatory diseases. The '862 patent also discloses using nitric acid and acetic acid to form certain steroid nitrate ester derivatives.
WO 98/15568 entitled “Nitrate Esters of Corticoid Compounds and Pharmaceutical Applications Thereof” relates to steroid-structured compounds having anti-inflammatory, immunodepressive, and angiostatic activities. One of the disclosed synthetic routes includes the use of silver nitrate (AgNO
3
) in acetonitrile. However, silver nitrate is known to be hazardous and toxic if ingested.
It would be desirable to provide an efficient and low-cost method of making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives without using heavy metal compounds such as silver nitrate.
SUMMARY OF THE INVENTION
The present invention relates to methods for making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives and also relates to intermediates useful in the methods for making such compounds.
In one aspect, a method for making a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative is provided comprising:
reacting:
(a) a 21-hydroxyalkyl corticosteroid;
(b) a compound of formula (I):
wherein:
R
1
is selected from the group consisting of OH, Cl, Br, F, I, and —OC(O)R
10
;
m is an integer from 0 to 4;
n is an integer from 0 to 5;
R
2
is independently selected at each occurrence from the group consisting of amino, substituted amino, halogen, C
1-6
alkyl, C
1-6
haloalkyl, alkoxy, aryl, C
1-6
alkylamino, C
1-6
substituted alkylamino, and —OR
7
;
R
3
and R
4
are independently selected at each occurrence from the group consisting of hydrogen, amino, substituted amino, halogen, C
1-6
alkyl, C
1-6
haloalkyl, alkoxy, aryl, C
1-6
alkylamino, C
1-6
substituted alkylamino, and —OR
7
;
R
5
and R
6
are independently selected from the group consisting of hydrogen, amino, substituted amino, halogen, C
1-6
alkyl, C
1-6
haloalkyl, alkoxy, aryl, C
1-6
alkylamino, C
1-6
substituted alkylamino, and —OR
7
;
R
7
is independently selected at each occurrence from the group consisting of hydrogen, —C(O)R
8
, and —C(O)NR
8
R
9
;
R
8
and R
9
are independently selected at each occurrence from the group consisting of hydrogen and C
1-6
alkyl; and
R
10
is selected from the group consisting of C
1-6
alkyl, C
1-6
chloroalkyl, alkoxy-substituted C
1-6
alkyl, and aryl; and
(c) a coupling agent or a base; with the proviso that when R
1
is OH the coupling agent is used and when R
1
is Cl, Br, F, I, or —OC(O)R
10
the base is used.
In another aspect of the invention, a two-step method for producing a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative is provided comprising:
(a) reacting a compound of formula (II):
with acetic anhydride and nitric acid to form a compound of formula (IA):
and
(b) reacting the compound of formula (IA) with a 21-hydroxyalkyl corticosteroid and a coupling agent to produce a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative; wherein m, n, and R
2
-R
6
are as defined above.
In yet another aspect, a three-step method for producing a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative is provided comprising:
(a) reacting a compound of formula (II):
with acetic anhydride and nitric acid to form a compound of formula (IA):
(b) reacting the compound of formula (IA) with a halogenating agent to form a compound of formula (IB):
wherein X is selected from the group consisting of Cl, Br, F, and I; and
(c) reacting the compound of formula (IB) with a 21-hydroxyalkyl corticosteroid and a base to produce a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative; wherein m, n, and R
2
-R
6
are as defined above.
In a further aspect, another three-step method for producing a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative is provided comprising:
(a) reacting a compound of formula (II):
with acetic anhydride and nitric acid to form a compound of formula (IA):
(b) reacting the compound of formula (IA) with an acid anhydride or an acid chloride to form a compound of formula (IC):
and
(c) reacting the compound of formula (IC) with a 21-hydroxyalkyl corticosteroid and a base to produce a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative; wherein m, n, and R
2
-R
6
, and R
10
are as defined above.
In yet a further aspect, the present invention provides intermediates of formula (I) useful in the methods for making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives as well as processes for making such intermediates.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to methods for making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives and also relates to intermediates useful in the methods for making such compounds. Prior to describing this invention in further detail, however, the following terms will first be defined.
Definitions:
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
“Alkyl” means a branched or straight hydrocarbon group having the general formula C
n
H
2n+1
, where n is an integer equal to or greater than 1.
“C
1-6
alkyl” means an alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, t-butyl, and the like.
“Amino” refers to the group —NH
2
.
“Hydroxy” refers to the group —OH.
“Thioalkyl” refers to the group —S—(C
1-6
alkyl).
“Alkoxy” refers to the group —O—(C
1-6
alkyl), which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, and the like.
“Substituted amino” means an amino group in which one or both of the hydrogens are independently replaced with a C
1-6
alkyl group, hydroxy, an alkoxy group, or a thioalkyl group.
“Halogen” means chlorine (Cl), bromine (Br), iodine (1), or fluorine (F).
“C
1-6
haloalkyl” means a C
1-6
alkyl group in which one or more of the hydrogens are independently replaced with a halogen.
“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinione).
“C
1-6
alkylamino” means a C
1-6
alkyl group in which one or more of the hydrogens are independently replaced with an amino group.
“C
1-6
substituted alkylamino” means a C
1-6
alkyl group in which one or more of the hydrogens are independently replaced with a substituted amino group.
“21-hydroxy corticosteroid” means any synthetic or naturally-occurring corticosteroid having a hydroxy group attached to the carbon in position 21. Corticosteroids include glucocorticoids and mineralocorticoids. Examples of 21-hydroxy corticosteroids include, but are not limited to, alclometasone, aldosterone, beclomethasone, betamethasone, clocortolone, hydrocortisone, budesonide, cortisone, desoximetasone, desonide, dexamethosone, flucloronide, fludrocortisone, flumethasone, flunisolide, fluocinolone acetonide, fluocortolone, fluprednisolone, flurandrenolide, halometasone, methylprednisolone, paramethason
Burns Doane Swecker & Mathis L.L.P.
Killos Paul J.
NicOx-S.A.
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