Title of Invention

NEW BIOREVERSIBLE ESTER PRODRUG AND PHARMACEUTICAL COMPOSITON CONTAINING THE SAME

Abstract There is disclosed a novel bioreversible ester prodrug of general formula I, or pharmaceutically acceptable salts or hydrates thereof, wherein R represents unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted lower alkylamino or a saturated five or six membered heterocyclic group containing one or two nitrogen atoms.
Full Text NEW BIOREVERSIBLE ESTER PRODRUG AND PHARMACEUTICAL
COMPOSITION CONTAINING THE SAME
FIELD OF THE INVENTION
The present invention relates to novel bioreversible prodrugs of MPV-2426, which is
an alpha2 adrenergic agonist, and specifically to ester derivatives, to methods for
preparing said prodrug forms, to pharmaceutical compositions containing such
prodrug forms, and to methods for using the prodrug forms.
BACKGROUND OF THE INVENTION
MPV-2426 [4-(6-hydroxyindmvl-ylmethyl)-l#-iniidazol-l-ium chloride] is
disclosed in US 6,313,311 B1 as an alphas agonist useful in the treatment of
hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical
substances, anxiety, e.g. preoperative anxiety, and different neurological,
musculoskeletal, psychiatric and cognition disorders as well as a sedative and an
analgesic agent, nasal decongestant, and as an adjunct to anaesthesia. MPV-2426
provides a spatially restricted and effective antinociception with minor side effects.
Intraspinal, intrathecal or epidural administration of MPV-2426 is disclosed in
WO 00/18400 A1. The treatment of hypotension, shock, and cardiopulmonary
resuscitation by administering MPV-2426 is disclosed in WO 01/30347 Al.
Alpha2 agonists are known to decrease intraocular pressure (IOP). The first report of
the IOP lowering effects of these therapeutic agents was published in 1966 [Makabe,
K.Dtsch. Med. Wochenschr., 91 (1966) 1686].
Prodrugs are pharmacologically inactive derivatives of drug molecules that after
chemical or enzymatic transformation release the active drug exerting the therapeutic
action. Prodrugs are designed to overcome various pharmaceutical or
biopharmaceutical problems associated with the parent drug. A prodrug with good
permeation across biological membranes should exhibit optimum lipophilicity. In
addition, a prodrug should be stable enough against chemical degradation and revert
to the active parent drug via enzymatic hydrolysis in the body during or after
absorption.
The present invention provides novel bioreversible ester prodrugs of MPV-2426 that
are chemically stable in non-enzyme medium, have suitable lipophilicity (able to
permeate through biological membranes) and readily hydrolyze to the parent drug in
vivo.
The invention may also provide compounds for the manufacture of a medicament to
be used in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia,
addiction to chemical substances, hypotension, shock, cardiopulmonary resuscitation,
micturition disorders, withdrawal syndromes, congestive heart failure, anxiety, e.g.
preoperative anxiety, or different neurological, musculoskeletal, psychiatric or
cognition disorders or as a sedative or an analgesic agent, nasal decongestant or as an
adjunct to anaesthesia. In addition, the invention provides pharmaceutical
compositions comprising as an active agent a compound of the invention.
Furthermore, the invention provides methods for the treatment of diseases or
conditions, wherein alpha2 agonists are indicated to be useful, said method
comprising to a mammal in need of such treatment an effective amount of a
compound of the invention.
Additional embodiments of the invention will be set forth in part in the description,
which follows, and in part will be obvious from the description, or may be learned by
practice of the invention. The embodiments of the invention will be realized and
attained by means of the elements and combinations particularly pointed out in the
appended claims.
It is to be understood that the foregoing general description and the following
detailed description are exemplary and explanatory only and are not restrictive of the
invention as claimed.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING
Figure 1 shows the formation of MPV-2426 (D) upon hydrolysis of its pivaloyl ester
(A) in 80 % human serum at 37 °C.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel bioreversible ester prodrugs of general
formula I,
or pharmaceutically acceptable salts or hydrates thereof, wherein R represents
unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl,
unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl,
unsubstituted or substituted lower alkylamino or a saturated five or six membered
heterocyclic group containing one or two nitrogen atoms. For example, R represents
unsubstituted or substituted lower alkyl or unsubstituted or substituted aryl, e.g.
unsubstituted or substituted lower alkyl. Possibly, the compound is
4-[6-(2,2-4metoylpropanoyloxy)mdan-l-ylmetty
4-(6-acetoxymdan-l-ylmemyl)-1H-imidazol-l-ium chloride or
4-(6-butyryloxymdan-l-ylmemyl)-1H-imidazol-l-ium chloride, hi the definitions of
R, the term "lower" denotes residues with a maximum of 10 carbon atoms, e.g. a
maximum of 6 carbon atoms. The term "alkyl" taken alone or in combination with
terms such as "cycloalkyl" or "alkylamino" denotes straight or branched chain
hydrocarbon residues. The term "aryl" denotes a carbocyclic aromatic group, possibly
a mono- or bicyclic group. The term "heteroaryl" denotes a mono- or bicyclic
aromatic group containing 1 to 3 heteroatoms being nitrogen and/or oxygen and/or
sulfur, e.g. 1 or 2 heteroatoms being nitrogen and/or oxygen and/or sulfur. The term
"substituted" in connection with various residues refers to hydroxy, cyano, nitro,
halogen, amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, aryl or
trifluoromethyl substituents. The substituted residues may contain 1 to 3 of said
substituents, e.g. 1 or 2 of said substituents. The term "halogen" denotes fluorine,
chlorine, bromine or iodine, e.g. chlorine or bromine.
Compounds of formula I may provide adequate lipophilicity and stability against
chemical hydrolysis and revert to the active parent drug via enzymatic hydrolysis.
The invention may provide compounds for the manufacture of a medicament to be
used in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia,
addiction to chemical substances, hypotension, shock, cardiopulmonary resuscitation,
micturition disorders, withdrawal syndromes, congestive heart failure, anxiety, e.g.
preoperative anxiety, or different neurological, musculoskeletal, psychiatric or
cognition disorders or as a sedative or an analgesic agent, nasal decongestant or as an
adjunct to anaesthesia. In addition, the invention provides pharmaceutical
compositions comprising as an active agent a compound of the invention.
Furthermore, the invention provides methods for the treatment of diseases or
conditions, wherein alpha2 agonists are indicated to be useful, said method
comprising to a mammal in need of such treatment an effective amount of a
compound of the invention.
The compounds of the invention can be prepared by a variety of synthetic routes
analogously to or according to the methods known in the literature using suitable
starting materials.
In general, compounds of formula I, or pharmaceutically acceptable salts or hydrates
thereof, can be prepared e.g. analogously to or according to scheme 1, wherein R is
as defined above.

Hydroxyindan compound II, or a pharmaceutically acceptable salt or hydrate thereof,
is dissolved in a solvent, e.g. trifiuoroacetic acid (TFA), and a carboxylic acid
chloride is added. The mixture is stirred, for example, at room temperature, for
example, for 24 h. The solvent is evaporated and product compound I is isolated
from the reaction mixture in a conventional manner. The compounds of the invention
may be converted, if desired, into their pharmaceutically acceptable salts or hydrates
using methods well known in the art.
The synthetic route described above is meant to illustrate the preparation of the
compounds of the invention and the preparation is by no means limited thereto, i.e.
there are also other possible synthetic methods which are within the general
knowledge of a person skilled in the art.
Example 1
4-cetoxyindan-l-ylmethyiy-1H-imidazoH-inm chloride
4-(6-hydroxy-mdan-l-ylmemy1)lif-imidazol-l-ium chloride (100 mg, 0.399 mmol)
was dissolved in 1 ml of trifluoroacetic acid (TFA) and acetic acid chloride
(0.510 mmol) was added. The mixture was stirred at room temperature for 24 h. TFA
was evaporated and the residue was dissolved in water and made basic with 2 M NH3
(aq.). The aqueous phase was extracted with dichloromethane (DCM). The combined
extracts were dried (Na2SO4) and evaporated. The residue was dissolved in diethyl
ether and the solution was saturated with dry HC1 gas. The precipitate was filtered
and dried under vacuum. Yield 105 mg (82%) of a white hygroscopic solid. !H NMR
(CDCI3, TMS): 8 1.72 (m, 1H), 2.18-2.26 (m, 4H), 2.72-2.87 (m, 3H), 3.17 (dd,
1H), 3.56 (qui, 1H), 6.85 (m, 2H), 6.92 (s, 1H), 7.16 (d, 1H), 8.61 (s, 1H), 14.44 (s,
2H). 13C NMR (CDCI3, TMS): 8 21.11,29.60,30.46,31.68,43.93,115.72,117.00,
120.29,125.33,132.32,132.40,141.37,146.32,149.39,170.11. HPLC-MS (EI):
m/z = 257.2 ((M+H)+- CI"). Anal. -Calc. for C15H16O2HC1.02CH2CL2: C 58.94,
H 5.66, N 9.04. Found C 58.66, H 5.78, N 8.83.
Example 2
4-(6-ButyryIoxyindan-l-ylmethyl)-lJyr-imidazoH-ium chloride
4-(6-hydroxy-indan-1 -ylmethyl)- liZ-imidazol-1 -ium chloride (100 mg, 0.399 mmol)
and butyric acid chloride (510 mmol) were reacted in TFA (1 ml) and purified as
described in example 1. Yield 90 mg (77%) of a white hygroscopic solid. JH NMR
(CDCI3, TMS): 8 1.02 (t, 3H), 1.70-1.79 (m, 3H), 2.18-2.24 (m, 1H), 2.52 (t, 2H),
2.73-2.86 (m, 3H), 3.18 (dd, 1H), 3.53 (qui, 1H), 6.84 (dd, 1H), 6.87 (s, 1H), 6.92 (s,
1H), 8.66 (s, 1H), 11.28 (s (broad), 2H). ,3C NMR (CDC13, TMS): 8 13.66,18.45,
29.68,30.52, 31.68, 36.24,43.98,115.79,117.05,120.36,125.36,132.32,132.59,
141.32, 146.36,149.51,172.85. - HPLC-MS (EI): m/z = 285.2 ((M+H)+ - CT). Anal.
-Calc. for C17H20N2H2.-HCl-0.2CH2CL2: C 61.16, H 6.39, N 8.29. Found C 61.30,
H 6.46, N 8.22.
Example 3
4-l6-(2^-Dimethylpropanoyloxy)indan-l-ylmethyl]-lfr-imidazoH-iaiii chloride
4-(6-hydroxy-indan-l-ylmethyl)-lJyr-imidazol-l-iiim chloride (100 mg, 0.399 mmol)
and 2,2-dimethylpropionic acid chloride (510 mmol) were reacted in TFA (1 ml) and
purified as described in example 1. Yield 74 mg (56%) of a white solid. M.p. 176-
177 °C. lH NMR (CDC13, TMS): 5 1.33 (s, 9H), 1.69-1.78 (m, 1H), 2.16-2.25 (m,
1H), 2.74-2.88 (m, 3H), 3.23 (dd, 1H), 3.57 (qui, 1H), 6.83 (dd, 1H), 6.89 (s, 1H),
6.93 (s, 1H), 7.16 (d, 1H), 8.85 (s, 1H), 14.38 (s, 1H), 14.47 (s, 1H).
13CNMR(CDCl3, TMS): 8 27.17,29.64,30.55,31.57,39.07,43.95,115.69,116.96,
120.24,125.33,132.12,132.66,141.20,146.30,149.30,177.87. HPLC-MS (EI):
m/z = 297.7 (M+ - 2H+ - CI-). Anal. -Calc. for C18H22N2O2.HCl: C 64.57, H 6.92,
N 8.37. Found C 64.05, H 7.00, N 8.24.
EXPERIMENTS
A prodrug with good permeation across biological membranes should exhibit
optimum lipophilicity (generally described as octanol-water partition coefficient, log
Papp). In addition a prodrug should be stable enough against chemical degradation and
revert to the active parent drug via enzymatic hydrolysis in the body during or after
absorption.
Experiment 1. Lipophilicity
The lipophilicity was evaluated by determining apparent partition coefficients
(log Papp) between 1-octanol and phosphate buffer pH 5.0 or 7.4 at room temperature.
Generally log Papp value in the range of 2-3 is considered optimal for absorption and
membrane penetration in general.
Method
The apparent partition coefficients (Papp) were evaluated from the distribution of the
test compounds between 1-octanol and phosphate buffer (0.16 M, pH 5.0 or pH 7.4,
µ = 0.5). The buffer and 1-octanol phases were saturated before use by stirring
vigorously for 24 h at room temperature. A known concentration of die compound in
phosphate buffer was shaken with a suitable volume of 1-octanol to achieve
equilibrium. After 1 h shaking, the phases were separated by centrifugation and the
concentration of the compound in the buffer phase was determined by HPLC.
Results
The log Papp values of the compounds are given in Table 1. The lipophilicity of the
compounds was substantially higher than that of the parent drug. Increased
lipophilicity may result in enhanced membrane permeation as well as in longer
duration of action as a consequence of altered pharmacokinetic properties (longer
retention in the body).
Experiment 2. Chemical stability
Method
An appropriate amount of the test compound (initial concentrations were
0.1-0.4 mM) was dissolved in pre-heated phosphate buffer (0.16 M, ji=0.5, pH 7.4 or
pH 5.0). The solution was placed in a thermostated water bath at 37°C and aliquots
were taken at suitable intervals and analyzed by HPLC to determine the degradation
rate of the compound. The pseudo-first-order half-life (tm) was calculated from the
linear slopes of semi-logarithmic plots of remaining compound over time.
Results
The degradation of the compounds in aqueous solution at pH 5.0 and 7.4 followed
pseudo-first-order kinetics. The half-life (Un) for the degradation is shown in
Table 2. The stability of the compounds was substantially higher at pH 5.0 than at
7.4.
Experiment 3. Enzymatic hydrolysis
To exert the pharmacological effect in the body, a prodrug should be enzymatically
degraded to the parent drug. Therefore, the susceptibility of the compounds to serum
esterases was evaluated.
Method
An appropriate amount of the test compound was dissolved in one volume (e.g. 1 ml)
of phosphate buffer (0.16 M, u=0.5, pH 7.4) at 37°C. Four volumes (e.g. 4 ml) of
pre-heated human serum were added and the solutions were mixed in a water bath at
37°C (initial concentrations were 0.2-0.5 mM). At suitable intervals, 300 ul aliquots
were withdrawn and deproteinated with 600 ul of acetonitrile. After mixing and
centrifugation, 600 ul of the supernatant was evaporated to dryness under a stream of
air at 40°C. The residue was re-dissolved in 300 ul of the mobile phase and analyzed
by HPLC. The pseudo-first-order half-life (t1/2) was calculated from the linear slopes
of semi-logarithmic plots of remaining compound over time. Also the formation of
the parent drug was determined.
Results
The hydrolysis of the prodrugs in 80% human serum followed pseudo-first-order
kinetics. The half-life (t1/2) for the degradation is shown in Table 2. All the prodrugs
of MPV-2426 released the parent drug, MPV-2426, quantitatively via enzymatic
hydrolysis in 80% human serum (pH 7.4). The formation of MPV-2426 upon
hydrolysis of its pivaloyl ester in 80 % human serum at 37 °C is illustrated in
Figure 1.
Experiment 4. IOP study in rabbits
The IOP study was performed to prove that the present prodrugs are able to release
the parent drug and are thereby pharmacologically active in vivo. The IOP lowering
effect of the prodrug was also compared to the effect of MPV-2426.
Method
To perform the IOP test, a rabbit was placed in a plastic restraining box located in a
quiet room. A single drop (25 µl) of the test solution was instilled unilaterally into its
left eye on the upper corneoscleral limbus. During installation, the upper eyelid was
pulled slightly away from the globe. IOP was measured using a BioRad (Cambridge,
MA) Digilab Modular One Pneumatonometer. Before each measurement one or two
drops of oxybuprocaine (0.06%) were applied to the cornea before tonometry to
eliminate discomfort. The upper and lower eyelids were then gently retracted, and the
applanation sensor was brought into contact with the center of the cornea. For each
determination at least two readings were taken from each treated (ipsilateral) and
untreated (contralateral) eye, and the mean of these readings was used. IOP of the
rabbits was measured at 2,1, and 0 h before and at 0.5,1,2,3,4 and 5 h after
eyedrop administration. IOP at the time of eyedrop administration (0 h) was used as a
baseline value. All studies were set up using a masked and randomized crossover
design. At least 72 h washout time was allowed for each rabbit between each dosing.
Results
The change in intraocular pressure (IOP) after topical unilateral administration of
three different doses (0.1 ug, 1.0 µg, and 2.5 ug) of the pivaloyl ester of MPV-2426
is shown in Table 3. The IOP lowering effect lasted from 1 h through the duration of
the 5 h experiment. Less significant changes were observed in the untreated eyes.
The pivaloyl ester of MPV-2426 showed increased IOP lowering potency as
compared to an equimolar dose of MPV-2426 (Table 3). Also a prolonged duration
of action was observed with the pivaloyl ester of MPV-2426.
WE CLAIM:
1. A novel bioreversible ester prodrug of general formula I,

or pharmaceutically acceptable salts or hydrates thereof, wherein R represents
unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl,
unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl,
unsubstituted or substituted lower alkylamino or a saturated five or six membered
heterocyclic group containing one or two nitrogen atoms.
2. A novel bioreversible ester prodrug as claimed in claim 1, wherein R represents
unsubstituted or substituted lower alkyl or unsubstituted or substituted aryl.
3. A novel bioreversible ester prodrug as claimed in claim 2, wherein R represents
unsubstituted or substituted lower alkyl.
4. A novel bioreversible ester prodrug as claimed in claim 3, which is
4-[6-(2,2-dimethylpropanoyloxy)indan-l-ylmethyl]-1H-imidazol-l-ium chloride
5. A novel bioreversible ester prodrug as claimed in claim 3, which is
4-(6-acetoxyindan- 1-ylmethyl)-\H- imidazol- 1-ium chloride
6. A novel bioreversible ester prodjug as claimed in claim 3, which is
4-(6-butyryloxyindan-1 -ylmethyl)- \H- imidazol-1 -ium chloride
7. A pharmaceutical composition which comprises as an active agent, a novel
bioreversible ester prodrug of formula I,

or pharmaceutically acceptable salts or hydrates thereof, wherein R is as defined in
claim 1, and optionally a pharmaceutically acceptable excipient, such as herein
described.
8. A pharmaceutical composition as claimed in claim 7, wherein the novel bioreversible
ester prodrug is 4-[6-(2,2-dimethylpropanoyloxy)indan-l-ylmethyl]-
1H-imidazol-l-ium chloride.
9. A pharmaceutical composition as claimed in claim 7 or 8, which is capable of being
used in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia,
addiction to chemical substances, hypotension, shock, cardiopulmonary resuscitation,
micturition disorders, withdrawal syndromes, congestive heart failure, anxiety or
different neurological, musculoskeletal, psychiatric or cognition disorders or as a
sedative or an analgesic agent, nasal decongestant or as an adjunct to anaesthesia.

There is disclosed a novel bioreversible ester prodrug of general formula I,

or pharmaceutically acceptable salts or hydrates thereof, wherein R represents
unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl,
unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl,
unsubstituted or substituted lower alkylamino or a saturated five or six membered
heterocyclic group containing one or two nitrogen atoms.

Documents:

01045-kolnp-2005-abstract.pdf

01045-kolnp-2005-claims.pdf

01045-kolnp-2005-description complete.pdf

01045-kolnp-2005-drawings.pdf

01045-kolnp-2005-form 1.pdf

01045-kolnp-2005-form 3.pdf

01045-kolnp-2005-form 5.pdf

01045-kolnp-2005-international publication.pdf

1045-kolnp-2005-assignment.pdf

1045-kolnp-2005-correspondence 1.1.pdf

1045-KOLNP-2005-CORRESPONDENCE.pdf

1045-kolnp-2005-examination report.pdf

1045-kolnp-2005-form 18.pdf

1045-KOLNP-2005-FORM 27.pdf

1045-kolnp-2005-form 3 1.1.pdf

1045-kolnp-2005-form 3.pdf

1045-kolnp-2005-form 5 1.1.pdf

1045-kolnp-2005-form 5.pdf

1045-kolnp-2005-gpa.pdf

1045-kolnp-2005-granted-abstract.pdf

1045-kolnp-2005-granted-claims.pdf

1045-kolnp-2005-granted-description (complete).pdf

1045-kolnp-2005-granted-drawings.pdf

1045-kolnp-2005-granted-form 1.pdf

1045-kolnp-2005-granted-specification.pdf

1045-kolnp-2005-reply to examination report.pdf

abstract-01045-kolnp-2005.jpg


Patent Number 243339
Indian Patent Application Number 1045/KOLNP/2005
PG Journal Number 41/2010
Publication Date 08-Oct-2010
Grant Date 06-Oct-2010
Date of Filing 01-Jun-2005
Name of Patentee ORION CORPORATION
Applicant Address ORIONINTIE 1, FIN-02200 ESPOO
Inventors:
# Inventor's Name Inventor's Address
1 NIEMI RIKU KEVATKUJA 12 C 5, FI-87100 KAJAANI
2 JARVINEN TOMI SOMPATIE 3 1 6, FIN-70200 KUOPIO
3 HUUSKONEN JUHANI HILLAKUJA 7, FIN-40340, JYVASKYLA
PCT International Classification Number A61K 31/415
PCT International Application Number PCT/FI2003/000933
PCT International Filing date 2003-12-05
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 20022159 2002-12-05 Finland