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Patent 2269616 Summary

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(12) Patent Application: (11) CA 2269616
(54) English Title: 2R,4S,S,R- AND 2S,4R,S,R-HYDROXYITRACONAZOLE
(54) French Title: 2R,4S,S,R- ET 2S,4R,S,R-HYDROXY-ITRACONAZOLE
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07D 405/14 (2006.01)
  • A61K 31/495 (2006.01)
  • C07D 249/12 (2006.01)
  • C07D 405/06 (2006.01)
  • C07D 521/00 (2006.01)
(72) Inventors :
  • TANOURY, GERALD J. (United States of America)
  • HONG, YAPING (United States of America)
  • MCCULLOUGH, JOHN R. (United States of America)
  • SENANAYAKE, CHRIS H. (United States of America)
  • KOCH, PATRICK (United States of America)
(73) Owners :
  • SEPRACOR INC. (United States of America)
(71) Applicants :
  • SEPRACOR INC. (United States of America)
(74) Agent: BORDEN LADNER GERVAIS LLP
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 1997-11-12
(87) Open to Public Inspection: 1998-05-22
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US1997/020460
(87) International Publication Number: WO1998/021203
(85) National Entry: 1999-04-22

(30) Application Priority Data:
Application No. Country/Territory Date
60/029,998 United States of America 1996-11-12

Abstracts

English Abstract




A method of preparation of optically pure isomers of hydroxyitraconazole, in
particular the two cis dioxolane diastereomers of the sec-butyl (S,R)-isomer,
and to phosphate and sulfate derivatives thereof is disclosed. Pharmaceutical
compositions containing these compounds and to their use for the treatment of
fungal infection are also disclosed.


French Abstract

L'invention concerne un procédé de préparation d'isomères optiquement purs d'hydroxy-itraconazole, en particulier les deux diastéréomères cis dioxolane du (S,R)-isomère du sec-butyl, et pour réaliser la phosphatation et la sulfatation des dérivés de ces isomères. L'invention concerne également des compositions pharmaceutiques renfermant ces composés, et leur utilisation dans le traitement de mycoses.

Claims

Note: Claims are shown in the official language in which they were submitted.



Claims

W claim:

1. A substantially pure single enantiomer of a compound of formula:

Image

wherein X1 and Xz are independently chlorine or fluorine and R is hydrogen, -
P(O)(OH)2
or -SO3H, or a salt thereof.

2. A compound according to claim 1 of formula:

Image

3. A compound according to claim 1 of formula:

Image

-23-




4. A compound according to any of claims 1-3 wherein R is hydrogen.

5. A compound according to any of claims 1-3 wherein R is phosphate.

6. A compound according to any of claims 1-3 wherein R is sulfate.

7. A pharmaceutical composition comprising a compound of formula:

Image

containing less than 10% by weight of other enantiomers or diastereomers of
said
compound, wherein X1 and X2 are independently chlorine or fluorine and R is
hydrogen,
-P(O)(OH)2 or -SO3H, or a salt thereof and a pharmaceutically acceptable
carrier.

8. A pharmaceutical composition according to claim 7 comprising a single
enantiomer of said compound and less than 10% by weight of other enantiomers
of said
compound.

-24-




9. A method for treating fungal infection comprising administering to a
mammal suffering from said fungal infection a therapeutically effective amount
of a
compound of formula:

Image

containing less than 10% by weight of other enantiomers of said compound,
wherein X1
and X2 are independently chlorine or fluorine and R is hydrogen, -P(O)(OH)2 or
-SO3H, or
a salt thereof.

10. A method for preventing fungal infection comprising administering to a
mammal at risk from said fungal infection a therapeutically effective amount
of a
compound of formula:

Image

containing less than 10% by weight of other enantiomers of said compound,
wherein X1
and X2 are independently chlorine or fluorine and R is hydrogen, -P(O)(OH)2 or
-SO3H, or
a salt thereof.

-25-



11. A method according to claim 9 or 10 comprising administering a
therapeutically effective amount of a substantially pure single enantiomer of
said
compound containing less than 10% by weight of other enantiomers of said
compound.

12. A method according to claim 9 or 10 comprising administering a
compound of formula:

Image

13. A method according to claim 9 or 10 comprising administering a
compound of formula:

Image

14. A method according to claim 9 or 10 wherein said fungal infection is
central candidiasis.

-26-




15. A process for preparing a 2,4-disubstituted 3H-1,2,4-triazol-3-one of
formula

Image

wherein R1 is aryl or substituted aryl, comprising reacting a 2-aryl-3H-1,2,4-
triazol-3-one
of formula

Image

with a trans 4,5-dimethyl-1,2,3-dioxathiolane 2,2-dioxide of formula

Image

by forming the potassium salt of said 2-aryl-3H-1,2,4-triazol-3-one with an
excess of
potassium hydride in an inert solvent in the presence of at least one
equivalent of
1,4,7,10,13,16-hexaoxocyclooctadecane (18-crown-6) and adding said
dioxathiolane at
-5°C to 25°C.


-27-




16. A process according to claim 15 wherein R1 is

Image

wherein R2 is methyl or benzyl and said dioxothiolane is (4R,5R)- 4,5-dimethyl-
1,2,3-
dioxathiolane 2,2-dioxide.

17. A process for preparing a dioxolane tosylate of formula

Image

wherein Ph is phenyl or substituted phenyl, Tos is toluenesulfonyl and R3 is
heterocyclylmethyl comprising

a. dissolving a ketone of formula R3C(O)Ph and about one equivalent of an
optically active 1,2-dihydroxypropyl toluenesulfonate in an inert solvent;
b. cooling to a temperature below 15°C;
c. adding an excess of trifluoromethanesulfonic acid at <15°C;
d. allowing the foregoing materials to react to form a ketal; and
e. introducing said ketal in solution into an excess of alkali metal carbonate
or bicarbonate in water at 0 to 10°C.

18. A process according to claim 17 wherein R3 is (1,2,4-triazol-2-yl)methyl,
Ph is 2,4-dichlorophenyl and said optically active 1,2-dihydroxypropyl
toluenesulfonate is
of the S configuration.



-28-

Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02269616 1999-04-22
WO 98/21203 PCTJUS9'I/20460
2R,4S,S,R- AND 2S,4R,S,R-HYDROXYITRACONAZOLE
Field of the Invention
The present invention relates to a method of preparation of optically pure
isomers
of hydroxyitraconazole, in particular the two cis dioxolane diastereomers of
the sec-butyl
(S,R)-isomer, and to phosphate and sulfate derivatives thereof. The invention
also relates
to pharmaceutical compositions containing these compounds and to their use for
the
treatment of fungal infection.
acj~ground of the Invention
Itraconazole, a well-known antifungal agent, is defined in the USAN and USP
Dictionary of Drus Names as 4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(lII-l,2,4-
triazol-1-
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-
2-(1-
methylpropyl)-3H-l,2,4-triazol-3-one or alternatively as (~)-I-sec-butyl-4-[p-
[4-[p-
[[{2R*,4S*)-2-(2,4-dichlorophenyl)-2-( 1 H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-
yl]methoxy]phenyl]-1-piperazinyl]phenyl]-OZ-l,2,4-triazolin-5-one. The
commercially
available material is the cis isomer in the dioxolane ring and is represented
by the
structural formula I:
c~
O CH3
C
O
N
O CH2 O ~ N N ~ N
Ni N
N
It will be noted that there are three asymmetric carbons in formula I {denoted
by
asterisks}: two in the dioxolane ring and one in the sec-butyl side chain on
the triazolone.
There are eight possible isomers of a structure having three asymmetric
carbons: (R,R,R),
(R,R,S), (R,S,S), (S,S,S), (R,S,R), (S,R,S), (S,R,R) and (S,S,R). Because the
commercially
available itraconazole is a cis isomer, it comprises a mixture of only those
isomers that
describe a cis relationship in the dioxolane ring. Adopting the convention
that the first
denoted chirai center is at C-2 of the dioxolane ring, the second is at C-4 of
the dioxolane


CA 02269616 1999-04-22
WO 98I21203 PCT/US9'1/20460
and the third is in the sec-butyl group, commercial itraconazole is a mixture
of (R,S,S),
(R,S,R), (S,R,S) and (S,R,R) isomers. Compounds of this invention have the
(2R,4S) and
(2S,4R) configurations in the dioxolane ring.
The hydroxylation of the methylene carbon of the sec-butyl side chain creates
an
additional chiral center and gives rise to eight additional possible
enantiomers. The
compounds of the present invention are those in which the two asymmetric
centers in the
butyl chain are S {at the a carbon) and R (at the (3 carbon).
cl
0 0
~,C 1 N '
O
O~CH O ~ N N ~ N
N~ N\
/> H O H
N
The graphic representations of racemic, ambiscalemic and scalemic or
enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed.
62,
114-120 (198S): solid and broken wedges are used to denote the absolute
configuration of
a chiral element; wavy lines indicate disavowal of any stereochemicai
implication which
the bond it represents could generate; solid and broken bold lines are
geometric
descriptors indicating the relative configuration shown but denoting racemic
character;
and wedge outlines and dotted or broken lines denote enantiomerically pure
compounds of
indeterminate absolute configuration. Thus, among the structures below, those
having
open wedges are intended to encompass both of the pure enantiomers of that
pair, those
having solid wedges are intended to encompass the single, pure enantiomer
having the
absolute stereochemistry shown.
Itraconazole is an orally active, broad-spectrum anti-fungal agent and is
structurally related to miconazole and clotrimazole. It impairs the synthesis
of ergosterol,
which is the principal sterol of fungal cell membranes. This presumably
results in an
increased permeability and leakage of intracellular content. At high
concentration,
cellular internal organelles involute, peroxisomes increase, and necrotic
changes occur.
Following oral administration, itraconazole is slowly absorbed. Peak plasma
2


CA 02269616 1999-04-22
WO 98/21203 PCT/US97/20460
levels are attained after 15 days of daily administration, and the
pharmacokinetic behavior
of itraconazole is nonlinear. The compound is eventually metabolized through
the
biologically active hydroxyitraconazole to several inactive metabolites.
Metabolism is
apparently through hepatic mechanisms, and in most subjects no metabolites are
excreted
in the urine [see, Hardin et al., AntimicrcZ Agents and Chemother~v 32, 13I0-
1313
{1988)].
The racemic mixture of itraconazole has been approved for use as an antifungal
agent for blastomycosis and histoplasmosis. The compound is also being
investigated for
use in aspergillosis, coccidioidomycosis, cryptococcosis, onychomycosis,
dermatophyte
and candidiasis infections.
Systemic fungal diseases (systemic mycoses) are usually chronic, very slowly
developing conditions induced by opportunistic causative fungi which may not
normally
be pathogenic. However when they enter a host compromised by HIV, ionizing
irradiation, corticosteroids, immunosuppressives, etc. or by such conditions
as
emphysema, bronchiectasis, diabetes mellitus, leukemia, burns and the like,
they may
become pathogenic. Symptoms in such fungal diseases are generally not intense,
and may
include fever, chills, anorexia and weight loss, malaise, and depression.
Fungal diseases
are often confined to typical anatomic distributions, and many involve a
primary focus in
the lung, with more characteristic manifestations of specific fungal
infections when the
fungus disseminates from a primary focus. For example, coccidioidomycosis
occurs in a
primary form as an acute, benign, self limiting respiratory disease, with
progressive
disease developing from the primary form as a chronic, often fatal infection
of the skin,
lymph glands, spleen and liver. Similarly, blastomycosis primarily involves
the lungs,
and occasionally spreads to the skin. Other infectious diseases such as
candidiasis and
paracoccidioidomycosis offer a different course, and depending on the etiology
may
exhibit several forms involving the skin, mucous membranes, lymph nodes, and
internal
organs.
Superficial fungal infections are caused by dermatophytes or fungi that
involve
the outer layers of the skin, hair or nails. The infections may result in a
mild
inflammation, and cause intermittent remissions and exacerbations of a
gradually
extending, scaling, raised lesion. Yeast infections including candidiasis, and
oral


CA 02269616 1999-04-22
WO 98/21203 PCT/US97/20460
candidiasis (thrush) are usually restricted to the skin, and mucous membranes,
and the
symptoms vary with the site of infection.
Adverse effects associated with the administration of itraconazole include
hepatotoxicity and inhibition of drug metabolism in the liver, leading to
numerous,
clinically significant, adverse drug interactions. [See, Gascon and Dayer Eur.
J. Clin.
Pharmacol. 41, 573-578 (1991) (interaction with midazolam); Honig et al. J.
Clin.
Pharmacol. 33, 120l-1206 (1993) (interaction with terfenadine); and Neuvonen
et al.
Clin. Pharmacol. Theran. 60, 54-61 ( 1996) (lovastatin).] Hypersensitivity
reactions
including urticaria and elevations in serum liver enzymes are also associated
with the
administration of the drug. Hepatoxicity is a less common but more serious
adverse
effect. Indeed, the use of oral conazoles as first line antifungals is usually
discouraged
because of the potentially serious consequences of the low incidence of
hepatotoxicity
[See, e.g., Lavrijsen et al., Lancet 340, 251-252 ( 1992)].
We have found evidence in our own studies in isolated guinea pig or rabbit
hearts
that the administration of racemic conazoles may be associated with an
increased risk of
cardiac arrhythmia. Arrhythmia has not been heretofore reported as a side
effect of
systemic itraconazole, although a particular subtype of arrhythmia, Torsades
de Pointes,
has been reported when racemic itraconazole was administered concurrently with
terfenadine [Pohjola et al. Eur. J. Clin. Phannacol. 45, 19I-193 ( 1993)]. The
lack of
clinical reports of arrhythmia or QT anomalies may simply be a reflection of
the fact that
there is to date a relatively small subject population.
The relative non-polarity and insolubility of itraconazole give rise to two
other
drawbacks: it cannot be readily formulated in parenteral solution and it does
not penetrate
the blood-brain barrier. As a result, numerous therapeutic indications which
require rapid
achievement of efficacious blood levels or access to the CNS are beyond
treatment with
itraconazole. In particular, central candidiasis, which may be responsible for
AIDS
related dementia, cannot be treated with itraconazole.
Thus it would be particularly desirable to find a compound with the advantages
of
itraconazole which would not have the aforementioned disadvantages.


CA 02269616 1999-04-22
WO 98/21203 PCT/US97/20460
Summary of the Invention
The compounds and compositions of the invention possess potent activity in
treating local and systemic fungal, yeast and dermatophyte infections while
avoiding
adverse effects associated with the administration of itraconazole. The
compounds and
compositions of the invention also enjoy the particular advantage of being
much more
soluble in physiologically compatible solutions than is itraconazole. The
preparation, for
the first time, of the individual enantiomers of hydroxyitraconazole permits
the
preparation of unusually soluble single enantiomers and derivatives thereof.
In one aspect the invention relates to substantially pure single enantiomers
of a
compound of formula:
x'
O CHa
Xz
O / 'N
CHz O N N N
N'~N ~N OR
o N~ H
wherein X' and XZ are independently chlorine or fluorine and R is hydrogen, -
P(O)(OH)z
or -S03H, or a salt thereof. There are two such possible single enantiomers,
represented
by the formulae A and B:
x'
0 0 ~H~
Xz
O o / IN
N~~CHZ O ~ N~N ~ N\ - N OR
~H
N
A


CA 02269616 1999-04-22
WO 98/21203 PCT/US97/20460
x'
O CNa
~xz
O / 'N
n ~,. C H O ~ N N ~ N
N~ N\ O
~N OR
I
N B
In another aspect the invention relates to pharmaceutical compositions
comprising
the compounds above and a pharmaceutically acceptable carrier. The
compositions
contain less than 10% by weight of other enantiomers or diastereomers having
the same
structural formula. Preferably, the compositions contain a single enantiomer A
or B.
In another aspect, the invention relates to a method for treating or
preventing
fungal infection comprising administering to a mammal suffering from (or at
risk from) a
fungal infection a therapeutically effective amount of the above compounds.
In another aspect, the invention relates to a process for preparing a 2,4-
disubstituted 3H-1,2,4-triazol-3-one of formula
O CH3
~N
R'
1 ~ _ K.
/ N Oa
wherein R' is aryl or substituted aryl. The process comprises reacting a 2-
aryl-3H-1,2,4-
triazol-3-one of formula
O
~N-H
R'
/N
with a traps 4,5-dimethyl-1,2,3-dioxathiolane 2,2-dioxide of formula
6


CA 02269616 1999-04-22
WO 98I21203 PCT/US97/20460
O\ %
o~\s~o
by forming the potassium salt of the 2-aryl-3H-1,2,4-triazol-3-one with an
excess of
potassium hydride in an inert solvent in the presence of at least one
equivalent of
1,4,7,10,13,16-hexaoxocyclooctadecane (18-crown-6) and adding the
dioxathiolane at
-5 ~C to 25 ~C. For the synthesis of enantiomers of itraconazole, R' is
preferably
/ \ /
wherein RZ is methyl or benzyl.
In another aspect, the invention relates to a process for preparing a
dioxolane
tosylate of formula
Ph
O ~--OTos
Rs..
O VH
wherein Ph is phenyl or substituted phenyl, Tos is toluenesulfonyl and R' is
heterocyclylmethyl. The process comprises the sequential steps of (a).
dissolving a
ketone of formula R3C(O) Ph and about one equivalent of an optically active
1,2-
dihydroxypropyl toluenesulfonate in an inert solvent; (b). cooling to a
temperature below
15~C; (c). adding an excess oftrifluoromethanesulfonic acid at <15~C; (d),
allowing the
foregoing materials to react to form a ketal; and (e). introducing the ketal
in solution into
an excess of alkali metal carbonate or bicarbonate in water at 0 to 10~C.
7


CA 02269616 1999-04-22
WO 98/2Z203 PCT/US97/20460
Detailed Descru~tion of the Invention
The compounds of the invention are synthesized by the general route shown in
Schemes 1, 2, 3 and 4:
Scheme I
x' x'
0 0
~x2 ~x2
0
~CHZ-OTs
HO ''
iN O CHZ-OTs NON O
H
NII ~> HO~H
N N
~TsOH DTTT
Scheme 2
,~o
HO OH
~~\ ---J/ S O C K ~ O O
CHa CHy CH/ CH3
4
Scheme 3
0
o. , o
oNH
CH30 ~ N~N ~ N~ I + O O
' N ~~.
6
5
O CHa
/ _N
CH30 N N N
~N OS03 ~ K+
7
O CHa
~N
HO ~ N N N\' N OH
8
g


CA 02269616 1999-04-22
WO 98/21203 PCT/US97/20460
Scheme 4
x'
O CHa
O X // \\ // \\ N
CHZ-OTa + HON N~N
N ~N OH
N ~ O
H
N DTTT
~TsOH
3
X'
O CHa
~XZ
O ~ / 'N
N/N~ O~ CH O N N~N~N OH
\~-~--~/ VH
N
9
As shown in Scheme 1, the chiral dioxolane DTTT (3) is prepared by a
stereospecific literature method from either R-3-tosyloxy-1,2-propanediol or S
3-
tosyloxy-1,2-propanediol by acid-catalyzed ketalization to provide
enantiomerically pure
RR or SS-DTTT respectively.
As shown in Scheme 2, the dioxothiolane 5 is prepared from a butanediol of
appropriate configuration by treatment with thionyl chloride, followed by in
situ oxidation
of the resulting cyclic sulfite with sodium periodate in the presence of
ruthenium
trichloride.
As shown in Scheme 3, 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-
piperazinyl]phenyl]-3H 1,2,4-triazol-3-one (6), prepared by the method of
example XVII
in US patent 4,267,179, is reacted with the dioxothiolane 5, prepared by the
procedure of
Gao and Sharpless [J. Am. Chem. Soc. 110, 7S38 (l988)], using potassium
hydride in
DMF in the presence of crown ether. The resulting methoxy-sulfate salt is
cleaved to the
phenol-alcohol 8 by heating with 48% HBr at 100-110~C.
9


CA 02269616 1999-04-22
WO 98l21203 PCT/US97I20460
As shown in Scheme 4, the tosyl ester 3 from Scheme 1 and the phenol-alcohol 8
from Scheme 3 are reacted in the presence of potassium hydroxide in DMF to
provide the
substantially enantiomerically pure product 9.
When it is desired that R in A or B be sulfate, the order of steps in Schemes
3 and
4 can be rearranged so that the methoxyl of 6 is cleaved before the addition
of the residue
of the sec-butyl side chain, and instead, 3 is added first, then 5.
When it is desired that R in A or B be phosphate, 8 is treated first with
t-butyldimethylsilyl chloride and diisopropylethylamine to protect the phenol,
then with
dibenzyl diisopropylphosphoramidite and t-butylhydroperooxide according to the
procedure of PCT application W095/17407, to phosphoryiate the alcohol. The
silyl
protecting group is removed with anhydrous tetrabutylammonium fluoride and the
benzyl-
protected phosphate is coupled with the doxolane tosylate as in Scheme 3. The
benzyl
protecting groups are cleaved by hydrogenoIysis in the presence of a palladium
catalyst to
provide the phosphate product.
Preparation of (-)-(2R,4S~-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-
ylmethyl)-4-
tosyloxymethyl-1,3-dioxolane tosylate DTTT (3a tosylate salt).
ci
ci
~o
\ -CHZ-OTs
~O
N H
DTTT
~TsOH
3a
A suspension of (R)-tosyloxy-1,2-propanediol (10.0 g, 40 mmol) and 1-(2,4-
dichlorophenyl)-2-(1H-l,2,4-triazol-i-yl) ethanone (10.0 g, 39 mmol) in
toluene (SOmL) is
cooled to 5 ~ C, Triflic acid ( 15 mL, 4 eq) is slowly added so that the
temperature stays
below 15 ~ C. After complete addition the reaction mixture (2 phases) is
stirred at 25 ~ C
for 60 h. The mixture is diluted with ethyl acetate (EtOAc) (200 mL) and
slowly dropped
into a solution of KzC03 (50 g) in water (400 mL) at 5 ~ C. The organic layer
is separated
and the aqueous layer washed with EtOAc ( 150 mL). The combined organic
extracts are
-10-


CA 02269616 1999-04-22
WO 98I21203 PCT/US97/20460
dried over Na,S04 ( 10 g) and filtered. A solution of toluenesulfonic acid
(TsOH) (7.6 g
monohydrate in EtOAc (50 mL) is slowly added at 25 ~ C. The white solid
product is
filtered after 30 min, washed and dried to give cis DTTT containing 5% traps.
Two
crystallyzations from CH,CN (400 mL) gives 13.5 g pure (2R,4S)-DTTT (50%
yield).
[a]D25 = +16.6 ~ (c=1, MeOH); ee = 99.6%.
Preparation of(-)-(2S,4R)-2-(2,4-dichlorophenyl)-2-(IH-1,2,4-triazol-1-
ylmethyI)-4-
tosyloxymethyl-1,3-dioxolane tosylate DTTT (3b tosylate salt).
ci
ci
0
\ 'CH2-OTs
N
H
DTTT
~TsOH
3b
A suspension of (S)-tosyloxy- I ,2-propanediol ( 14.8 g, 60 mmol) and 1-{2,4-
dichlorophenyl)-2-( 1 H-1,2,4-triazol-1-yl) ethanone ( 15.2 g, 58 mmol) in
toluene (80 mL)
is cooled to 5 ~ C. Triflic acid ( 18 mL) is slowly added so that the
temperature stays
below I 5 ~ C. After complete addition the reaction m fixture (2 phases) is
stirred at 25 ~ C
for 60 h. The mixture is diluted with CH~CIz (300 mL) and slowly dropped in a
solution
of K,CO, (30 g) in water (300 mL) at 5 ~ C. the organic layer is separated and
concentrated to about 100 mL. The residue is diluted with methyl
isobutylketone (MIBK)
(300 mL) and a solution of TsOH (11.0 g monohydrate) in MIBK (100 mL) is
slowly
added at 25 ~ C. The white solid product is filtered after 30 min., washed and
dried to give
cis DTTT containing 6% traps. Two crystallizations from CH3CN (600 mL) gives
16.6 g
pure (2S,4R)-DTTT (44% yield). [a]DZS = _ 16.6 ~ (c=1, MeOH) ee = 99.6%
Preparation of (4R,SR)-4,5-dimethyl-1,2,3-dioxathiolane 2,2-dioxide (5).
A three-necked 500 mL round-bottom flask fitted with a reflux condenser and a
calcium chloride drying tube was charged with (2R,3R)-(+)-2,3-butanediol (4) (
10.0 g,


CA 02269616 1999-04-22
WO 98/21203 PCT/US97/20460
10.1 ml, 0.11 mol) and carbon tetrachloride { 120 mL). Thionyl chloride ( 16.0
g, 9.8 mL,
0.13 mol) was added dropwise at room temperature. Rapid gas evolution began.
The
reaction mixture was stirred at room temperature for 10 min, then warmed to
reflux for 30
min to insure complete removal of HCl gas. The reaction mixture was cooled to
0~ C in
an ice-water bath and acetonitrile (120 mL), RuCl3 H20 (14 mg, 0.07 mmol),
NaI04
(3 5.6 g, 0.17 mol) and water ( 180mL) were added, respectively. The reaction
mixture
was allowed to warm to room temperature and stirred for 1.5 hr. The mixture
was poured
into methyl t-butyl ether (900 mL), and water was added to dissolve the
remaining Na104
(ca. 600 mL). The phases were separated and the aqueous phase was extracted
with
l0 methyl t-butyl ether (2 x 100mL). The combined organic phases were washed
with water
( 1 x 50mL), saturated aqueous sodium bicarbonate (2 x 50mL) and saturated
aqueous
bicarbonate (2 x 50mL) and saturated aqueous sodium chloride ( I x SOmL). The
organic
solution was dried over anhydrous magnesium sulfate and filtered through a bed
of silica
gel to give a clear and colorless solution. The solvent was removed in vacuo
to give 16.0l
g (95% yield) of the title compound.
Preparation of Potassium (2R,3,S'~-3-[2,4-Dihydro-4-[4-[4-(4-methoxyphenyl]-1-
piperazinyl]phenyl]-3H-1,2,4-triazol-3-on-2-yl]but-2-yl Sulfate (7).
To a suspension of potassium hydride (S30 mg, 4.6 mmol, 35 wt% dispersion in
oil), prewashed with hexane (2 x l OmL), in dimethylformamide (37 mL) at room
temperature was added 18-crown-6 (980 mg, 3.7 mmol) and 2,4-dihydro-4-[4-[4-(4-

methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (6} (l.09 lg, 3.3
mmol).
The solution was warmed to 80-85 ~ C for 2 hr. then cooled in an ice-water
bath to 0 ~ C.
To this solution was added (4R,5R)-4,5-dimethyl-I,2,3-dioxathiolane 2,2-
dioxide (5) (500
mg, 3.3 mmol}. The reaction mixture warmed to 4~ C. After recooling to 0~ C,
the
reaction mixture was warmed to room temperature and stirred for 21 hours. To
the
reaction mixture was added 150 mL of toluene and 400 mL of methyl t-butyl
ether, and
the white precipitated product was filtered from the mixture. The solid was
dried irr vacuo
to give 1.70 g (quantitative yield) of a 87:13 mixture (by HPLC) of the title
compound
and triazolone starting material. A portion of this mixture was purified by
flash
chromatography (gradient from 95:5 chloroform:methanol to methanol) for
-12-


CA 02269616 1999-04-22
WO 98I21203 PCT/US97/20460
characterization.
Preparation of 2,4-Dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-
[(IS,2R)-
2-hydroxy-I-methylpropyl)]-3H-l,2,4-triazol-3-one (8).
To potassium (2R,3S)-3-[2,4-Dihydro-4-[4-[4-(4-methoxyphenyl-1-
piperazinyl]phenyl]-3H-1,2,4-triazol-3-on-2-yl]but-2-yi[sulfate(7) (I.50 g,
2.98 mmol)
and sodium sulfite (84 mg, 0.67 mmol) was added 48% HBr (6.0 mL). The solution
was
heated to I 10-1 l S~ C for 7 hr and cooled to room temperature. The reaction
mixture was
poured into a wide-mouthed beaker and the pH raised to 7 by slow addition of
solid
potassium carbonate. Water was added ( 100 mL), and the product was collected
by
filtration and dried in vacuo. Flash chromatography of the crude material
eluting with a
gradient of chloroform to 95:5 chloroform:methanol gave 1.03 g (70% yield) of
the title
compound as an adduct with SO,.
Preparation of (2S,4R)-4-[4-[4-[4-[[2,4-dichlorophenyl)-2-( I H-1,2,4-triazol-
1-ylmethyl)
l ,3-d ioxolan-4-yl)methoxy] phenyl]- I -piperazinyl]-2,4-dihydro-2-[( 1 S,2R)-
(2-hydroxy-1
methylpropyl)]-3H-I,2,4,-triazol-3-one (B).
To 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[(1S,2R)-(2-
hydroxy-I-methylpropyl)]-3H-I,2,4-triazol-3-one S03 adduct (8) (420 mg, 0.86
mmol)
and (1~-(2S,4S)-2-(2,4-dichlorophenyl)-2-(IH-1,2,4-triazol-1-ylmethyl-4-
tosyloxymethyl-
1,3-dioxolane tosylate (3b tosylate) (637 mg., 0.97 mmol) was added powdered
potassium
hydroxide (277 mg, 4.94 mmol) and N,N dimethylformamide (IS mL). The reaction
mixture was warmed to 50-55 ~ C for 8 hr and cooled to room temperature. Water
was
added ( 150 mL) and the crude product was collected by filtration and dried in
vacuo.
Purification by flash chromatography, eluting with ethyl acetate, followed by
chloroform,
98:2 chloroform:methanol, then 9S:5 chloroform:methanol, gave 320 mg (52%
yield) of
the title compound [a]DZS = _22.0~ (c=0.1, MeOH).
(2S,4R)-4-[4-[4-[4-[[2,4-Dichlorophenyl)-2-( 1 H-1,2,4-triazol-1-yimethyl)-1,3-

dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-2,4-dihydro-2-[( 1 S,2R)-(2-
hydroxy-I-
methylpropyl)]-3H-1,2,4; triazol-3-one (A) can be prepared in analogous
fashion from the
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CA 02269616 1999-04-22
WO 98/21203 PCTlUS97/20460
dioxolane tosylate 3b.
The compounds in which X' and Xz are fluorine may be made in analogous
fashion from the appropriate 3, which is available by condensation as shown in
Scheme 1
from the appropriate 2,4-dihalophenylethanone.
The term "substantially pure single enantiomer" as used herein means that less
than 10% by weight of other enantiomers is present. The compositions contain
hydroxyitraconazole or a derivative thereof, in which at least 90% by weight
of the
hydroxyitraconazole has a cis dioxolane and a sec-butyl side chain of the
stereochemistry
shown above.
Microbiological and pharmacologic studies can be used to determine the
relative
potency and the profile of specificity of the optically pure enantiomers, and
the racemic
mixture of itraconazole as antimycotic agents with a broad spectrum of
activity against
many fungi, yeast, and dermatophytes.
With respect to antimicrobial activity of the aforementioned compounds,
selected
experiments are illustrated to profile useful antimicrobial activity, and not
to limit this
invention in any way, including the scope of susceptible microorganisms.
Antifungal
conazoles may be evaluated in vitro at several concentrations (in pg/mL)
against a
number of fungi and bacteria. [See, Van Cutsem Chemotherany 38 Sup~l 1, 3-I 1
(I992)
and Van Cutsem et al. Rev. Infec. Dis. 9 Suppl 1, S 15-S32 ( 1987)]. The
fungistatic assay
is carried out in Sabouraud's liquid ( 1 g of neopeptone Difco and 2 g of
glucose Difco per
100 mL of distilled water) in 16 X I 60 mm test tubes, each containing 4.5 mL
of liquid
medium which has been autoclaved at l20~ for 5 min. The compounds to be tested
are
dissolved in 50% alcohol at initial concentration of 20 mg/mL. The solutions
are
subsequently diluted with sterile distilled water to give a concentration of
10 mg/mL.
Successive decimal dilutions are made in distilled water. To tubes containing
4.5 mL of
Sabouraud's liquid medium 0.5 mL of the solution of the drug is added, thereby
obtaining
concentrations of l000, 500, 100, 10, and 1 pg/mL of medium. Control tubes are
prepared by adding 0.5 mL of distilled water to 4.5 of mL medium, alcohol
being added to
give concentrations identical with the tubes containing 1000 and 500 p.g of
the drug. The
filamentous fungi are incubated in Sabouraud's agar at 25 ~ for 2-3 weeks. A
block of 2 X
2 X 2 mm is then inoculated into the medium. All cultures are made in
duplicate and are
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CA 02269616 1999-04-22
WO 98I21203 PCT/US97/20460
incubated at 25 ~ for 14 days. Itraconazole antifungal activity is enhanced in
vitro in
Sabouraud broth containing 10% inactivated bovine serum, and depends on the
test
medium used. Complete or marked inhibition of growth in Sabouraud broth after
14 days
of incubation may be observed with Microsporum canis, Trichophyton
mentagrophytes,
Candida albicans, Sporothrix schenckii, Paracoccidioides brasiliensis,
Blastomyces
dermatitides, Histoplasma spp., Aspergillus spp. and other fungi and bacteria.
A l OmL tube containing 4mL of Sabourauds dextrose broth was inoculated with 1
colony of Candida albicans picked from a plate of pure culture. The strain was
ordered
from the American Type Culture Collection (ATCC). The organism was grown for 4
hours at 30~ C while shaking at 150 RPM. While the organism was growing,
samples of
hydroxy-itraconazoles A and B were solubilized to a concentration of l Omg/mL
in
DMSO. Each sample was then diluted 1:10 to make 1 mg/mL samples or 1 OOOpg/mL.
These samples were then diluted by serial 2-fold dilutions to produce samples
now
containing 1000, 500, 250, 125, 62.5, 31.25, 15.6 ~.g/mL. A 96-well microtiter
dish was
set up with 981tL of liquid growth media in each test well, along with 1 pL of
hydroxy-
itraconazole solution. At 4 hours of growth time the Candida albicans was
diluted to a
0.5 McFarland standard representing about l Os-106 cells/mL and 1 uL of this
inoculum
placed into each test well of the microtiter dish. The dish was then covered
and incubated
at 30~ C for 16 hours. The MIC's for both A and B were below 0.I56 ~g/mL.
Kirby-Bauer Testing
Actively growing cultures of Candida albicans, Cryptococcus neoformens and
Saccharomyces cerevisiae were prepared as described above. The cultures were
diluted to
a 0.5 MeFarland standard and swabbed onto a 1 SOmm Sabouraud Dextrose agar
plates.
Paper disks (7mm) were placed onto the agar plates using a disk dispenser.
Next l Opl of
10 mglmL solutions of each sample hydroxy-itraconazole was pipetted onto
separate
paper disks. The plates were then incubated at 30~ C for 16 hours. Zones of
inhibition
were then measured in mm. The data are summarized below.
-15-


CA 02269616 1999-04-22
WO 98I21203 PCT/US97/20460
Candida Cryptococcus Saccharomyces
Compound albicans neoformens cerevisae


A 22 28 22


B 25 25 20


+Itraconazole 17 22 15


Data represent zones of inhibition in mm.
In vivo activity of hydroxyitraconazole and derivatives may be compared
against
experimental cutaneous candidosis in guinea pigs, and vaginal candidosis in
rats. The in
vivo activity of the compounds in vaginal candidosis is evaluated by inducing
vaginal
infection with C. albicans in ovariectomized and hysterectomized Wistar rats
(100g)
which are treated weekly with 100 p.g of estradiol undecanoate in sesame oil,
subcutaneously. Animals in pseudooestrus are infected intravaginally with a
fixed
concentration of C. albicans in saline. Control of infection or cure is
estimated by taking
vaginal smears at fixed days after infection. Drugs to be evaluated, and
compared on a
mgikg basis, may be given prophylactically, or therapeutically and their
efficacy judged
by comparison the ratio of negative animals to the total number in each drug
group. In
similar studies, the activity against cutaneous candidosis in guinea pigs
[(Van Cutsem et
al. Chemothera~,v 17, 392, ( 1972)] provides the basis of comparison.
The compounds of the present invention allow the treatment of fungal
infections
while avoiding the adverse effects associated with itraconazole. The term
"adverse
effects" includes, but is not limited to, arrhythmogenicity, hepatotoxicity
and elevations in
serum liver enzymes, drug interactions, and hypersensitivity reactions
including urticaria,
nausea, vomiting, abdominal pain, headache, dizziness and the like.
The potential for promoting arrhythmia is evaluated by examining the effects
of
the isomers of hydroxyitraconazole on cardiac action potential and
contractility in human,
canine and rabbit hearts. Torsades de Pointes is a well known side effect of
antiarrhythmic drugs, such as quinidine, sotalol and acetyl-procainamide,
which cause a
prolongation of cardiac repolarization. All of these drugs have in common the
ability to
block a cellular potassium channel called the delayed rectifier (IK), and it
is generally
assumed that this is mechanistically linked to their ability to induce the
syndrome of
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CA 02269616 1999-04-22
WO 98l21203 PCT/LTS97/20460
Torsades de Pointes. [See, Zehender et al. Cardiovascular Drugs Ther.. 5 515-
530
( 1991 ).] Increases in QT duration and action potential duration in isolated
guinea pig or
rabbit hearts can therefore be used to indicate an arrhythmogenic effect.
Hearts are
perfused with an oxygenated Tyrode's solution, containing 0.0; 1.0; 5.0, 10.0
or 30.0 pM
of racemic itraconazoie. QT duration and action potential duration (APD) are
measured
from cardiac electrodes.
To observe the effects in vivo, mongrel dogs of either sex weighing 5-20 kg
are
anesthetized and instrumented by standard techniques for blood pressure and
EKG. A
solid state transducer for dP/dT is placed in the left cardiac ventricle, and
an epicardial
~ electrode is put into place. The test compound is infused at progressively
higher doses,
beginning at 1 pg/kg/min for 15 to 30 minutes and increased incrementally
until a
cardiovascular collapse ensues. Parameters measured are: blood pressure, heart
rate,
dP/dT, and the QT-interval. Measurements of hemodynamics and electrical
activity,
including QTR interval, are made in response to the test compound and
compared.
The potential for promoting hepatotoxicity is assessed in vitro in human
hepatic
microsomes, human lymphocytes and other cell culture systems. Hepatic
microsomes are
prepared from human liver. Tissue is thawed and then homogenized in 0.15 M KC1
in a
Polytron homogenizer. The homogenate is centrifuged and the pellet is
resuspended and
homogenized in 0.15 M KCI. Aliquots are frozen and stored at -70~ C. Human
lymphocytes are aseptically isolated from fresh, heparinized human blood.
Blood is
diluted with Eagle's minimal essential medium and layered on Ficoll-Paque. The
samples
are centrifuged, and lymphocytes are then removed from the aqueous-Ficoll
interface and
suspended in medium ( 1 SMm HEPES, pH, 7.4). The cells are then centrifuged,
washed
once in the HEPES medium, and resuspended.
Cytotoxicity is assessed by the conversion of 3-(4,5 dimethylthiazol-2-yl)-2,5-

diphenyltetrazolium bromide (MTT) to a purple formazan. The conversion of MTT
to
dye is done in multiwell plates. After preparation, hepatic microsomes or
lymphocytes
are incubated alone or with the test compound in a concentration range from 1
to 400 p,M
at 37~ C in a humidified incubator. After incubation, the microsomes/cells are
washed
with 5% albumin in HEPES-buffered medium and resuspended. The microsomes/cells
are then incubated at 37 ~ C in a humidified incubator. After the incubation,
l25 p,g of
_17_


CA 02269616 1999-04-22
WO 98/21203 PCT/US97/20460
MTT is added to each well. The plates are incubated at 37~ C and centrifuged.
After
centrifugation, I00 pL of isopropanol is added and, after incubation, the
optical density is
determined using an automated plate-reader.
The magnitude of a prophylactic or therapeutic dose of hydroxyitraconazole or
derivative in the acute or chronic management of disease will vary with the
severity of the
condition to be treated, and the route of administration. The dose, and
perhaps the dose
frequency, will also vary according to the age, body weight, and response of
the
individual patient. In general, the total daily dose range, for
hydroxyitraconazole or a
derivative, for the conditions described herein, is from about 50 mg to about
1200 mg, in
single or divided doses. Preferably, a daily dose range should be between
about l00 mg
to about 800 mg, in single or divided doses, while most preferably, a daily
dose range
should be between about 200 mg and 400 mg, in divided doses. In managing the
patient,
the therapy should be initiated at a lower dose, perhaps about 100 mg to about
200 mg,
and increased up to about 400 mg or higher depending on the patient's global
response. It
is further recommended that children, and patients over 65 years, and those
with impaired
renal, or hepatic function, initially receive iow doses, and that they be
titrated based on
individual responses) and blood level(s). It may be necessary to use dosages
outside
these ranges in some cases as will be apparent to those skilled in the art.
Further, it is
noted that the clinician or treating physician will know how and when to
interrupt, adjust,
or terminate therapy in conjunction with individual patient response. An
amount
sufficient to alleviate or prevent infections but insufficient to cause
adverse effects is
encompassed by the above-described dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing the patient
with an effective dosage of hydroxyitraconazole or derivative. For example,
oral, rectal,
parenteral (subcutaneous, intramuscular, intravenous), transdermal, topical
and like forms
of administration may be employed. Dosage forms include tablets, troches,
dispersions,
suspensions, solutions, capsules, patches, ointments, creams, shampoos and the
like.
The pharmaceutical compositions of the present invention comprise
hydroxyitraconazole or derivative as the active ingredient, or a
pharmaceutically
acceptable salt thereof, and may also contain a pharmaceutically acceptable
carrier, and
optionally, other therapeutic ingredients.
-18-


CA 02269616 1999-04-22
WO 98l21203 PCTlUS97/20460
The terms "pharmaceutically acceptable salts" or "a pharmaceutically
acceptable
salt thereof ' refer to salts prepared from pharmaceutically acceptable non-
toxic acids or
bases including inorganic acids and bases and organic acids and bases. Since
the hydroxy
compound of the present invention is basic, salts may be prepared from
pharmaceutically
acceptable non-toxic acids including inorganic and organic acids. Suitable
pharmaceutically acceptable acid addition salts for the compound of the
present invention
include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,
ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,
isethionic, lactic,
malefic, malic, mandelic, methanesulfonic (mesylate), mucic, nitric, pamoic,
pantothenic,
phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. The
phosphate
and sulfate, being acidic, allow for the preparation of salts of bases as well
as internal
salts. Suitable pharmaceutically acceptable base addition salts for the
compounds of the
present invention include metallic salts made from aluminum, calcium, lithium,
magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-
dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
ethylenediamine,
meglumine (N-methylglucamine) and procaine.
The compositions of the present invention include compositions such as
suspensions, solutions, elixirs, aerosols, and solid dosage forms. Carriers
such as
starches, sugars, microcrystalline cellulose, diluents, granulating agents,
lubricants,
binders, disintegrating agents, and the like, are commonly used in the case of
oral solid
preparations (such as powders, capsules, and tablets), with the oral solid
preparations
being preferred over the oral liquid preparations. The most preferred oral
solid
preparation is tablets.
Because of their ease of administration, tablets and capsules represent the
most
advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are
employed. If desired, tablets may be coated by standard aqueous or nonaqueous
techniques.
A second preferred route of administration is topically, for which creams,
ointments, shampoos, and the like are well suited.
In addition to the common dosage forms set out above, the compounds of the
present invention may also be administered by controlled release means and/or
delivery
-19-


CA 02269616 1999-04-22
WO 98/21Z03 PCT/US97/20460
devices and, because of their solubility, may also be employed in parenteral
solutions,
such as for intravenous administration.
Pharmaceutical compositions of the present invention suitable for oral
administration may be presented as discrete units such as capsules, cachets,
or tablets, or
aerosol sprays, each containing a predetermined amount of the active
ingredient, as a
powder or granules, or as a solution or a suspension in an aqueous liquid, a
non-aqueous
liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such
compositions
may be prepared by any of the methods of pharmacy, but all methods include the
step of
bringing into association the active ingredient with the carrier which
constitutes one or
. more necessary ingredients. In general, the compositions are prepared by
uniformly and
intimately admixing the active ingredient with liquid carriers or finely
divided solid
carriers or both, and then, if necessary, shaping the product into the desired
presentation.
For example, a tablet may be prepared by compression or molding, optionally,
with one or more accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredient in a free-flowing form
such as
powder or granules, optionally mixed with a binder, lubricant, inert diluent,
surface active
or dispersing agent. Molded tablets may be made by molding in a suitable
machine, a
mixture of the powdered compound moistened with an inert liquid diluent.
Desirably,
each tablet contains from about l00 mg to about 300 mg of the active
ingredient. Most
preferably, the tablet, cachet or capsule contains either one of three
dosages, about 50 mg,
about 100 mg, or about 200 mg of the active ingredient.
For topical application, there are employed as non-sprayable forms, viscous to
semi-solid or solid forms comprising a carrier compatible with topical
application and
having a dynamic viscosity preferably greater than water. Suitable
formulations include
but are not limited to solutions, suspensions, emulsions, creams, ointments,
powders,
liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed
with auxiliary
agents, e.g., preservatives, stabilizers, wetting agents, buffers or salts for
influencing
osmotic pressure, etc. For topical application, also suitable are sprayable
aerosol
preparations wherein the active ingredient, preferably in combination with a
solid or
liquid inert carrier material, is packaged in a squeeze bottle or in admixture
with a
pressurized volatile, normally gaseous propellant, e.g., a freon.
-20-


CA 02269616 1999-04-22
WO 98I21203 PCT/ITS97/20460
The invention is further defined by reference to the following examples
describing in detail the preparation of the compositions of the present
invention as well as
their utility. It will be apparent to those skilled in the art that many
modifications, both to
materials and methods may be practiced without departing from the purpose and
interest
of this invention.
EXAMPLE 1 ORAL FORMULATION --- Capsules
Quantity
per capsule
in mg
'


Formula A B C


Hydroxyitraconazole50 100 200


Lactose 380 330 230


Cornstarch 65 65 65


Magnesium Stearate5 5 5


Compression 500 500 500
Weight


The active ingredient, hydroxyitraconazole or derivative, is sieved and
blended
with the excipients. The mixture is filled into suitably sized two-piece hard
gelatin
capsuies using suitable machinery. Other doses may be prepared by altering the
fill
weight and if necessary, changing the capsule size to suit.
EXAMPLE 2
ORAL FORMULATION Tablets:
Quantity
per tablet
in mg


Formula
A B C


Hydroxyitraconazole50 100 200


Lactose 109 309 209


Cornstarch 30 30 30


Water (per thousand300 mL 300 mL 300 mL
tabs)*


Cornstarch 60 60 60


Magnesium Stearate1 1 1


Compression Weight250 500 500


*The water evaporates during manufacture
-21-


CA 02269616 1999-04-22
WO 98/21203 PCT/US97/20460
The active ingredient is blended with the lactose until a uniform blend is
formed.
The smaller quantity of cornstarch is blended with the water to form the
resulting
cornstarch paste. This is then mixed with the uniform blend until a uniform
wet mass is
formed and the remaining cornstarch is added and mixed unti I uniform granules
are
obtained. The granules are screened through a suitable milling machine using a
1/4"
stainless steel screen. The milled granules are dried in a suitable drying
oven and milled
through a suitable milling machine again. The magnesium stearate is then
blended and
the resulting mixture is compressed into tablets of desired shape, thickness,
hardness and
disintegration.
-22-

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Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 1997-11-12
(87) PCT Publication Date 1998-05-22
(85) National Entry 1999-04-22
Dead Application 2001-11-13

Abandonment History

Abandonment Date Reason Reinstatement Date
2000-11-14 FAILURE TO PAY APPLICATION MAINTENANCE FEE

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Registration of a document - section 124 $100.00 1999-04-22
Application Fee $300.00 1999-04-22
Maintenance Fee - Application - New Act 2 1999-11-12 $100.00 1999-10-13
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
SEPRACOR INC.
Past Owners on Record
HONG, YAPING
KOCH, PATRICK
MCCULLOUGH, JOHN R.
SENANAYAKE, CHRIS H.
TANOURY, GERALD J.
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Description 1999-04-22 22 898
Claims 1999-04-22 6 115
Cover Page 1999-07-02 1 31
Abstract 1999-04-22 1 48
PCT 1999-04-22 13 440
Assignment 1999-04-22 7 257