U.S. patent application number 14/705967 was filed with the patent office on 2015-10-29 for adenosine a1 agonists for the treatment of glaucoma and ocular hypertension.
The applicant listed for this patent is BAYER INTELLECTUAL PROPERTY GMBH. Invention is credited to Barbara ALBRECHT-KUPPER, Andreas KNORR, Hans-Georg LERCHEN, Daniel MEIBOM, Peter SANDNER, Carsten SCHMECK, Hubert TRUBEL.
Application Number | 20150306084 14/705967 |
Document ID | / |
Family ID | 44582992 |
Filed Date | 2015-10-29 |
United States Patent
Application |
20150306084 |
Kind Code |
A1 |
LERCHEN; Hans-Georg ; et
al. |
October 29, 2015 |
ADENOSINE A1 AGONISTS FOR THE TREATMENT OF GLAUCOMA AND OCULAR
HYPERTENSION
Abstract
The present invention relates to the use of selective adenosine
A1 agonists, in particular the dicyanopyridines of formula (I), for
the treatment and/or prophylaxis of glaucoma and ocular
hypertension as well as the their use for the production of a
medicament for the treatment and/or prophylaxis of glaucoma and
ocular hypertension.
Inventors: |
LERCHEN; Hans-Georg;
(Leverkusen, DE) ; ALBRECHT-KUPPER; Barbara;
(Wulfrath, DE) ; KNORR; Andreas; (Erkrath, DE)
; SANDNER; Peter; (Wuppertal, DE) ; MEIBOM;
Daniel; (Wuppertal, DE) ; SCHMECK; Carsten;
(Mulheim, DE) ; TRUBEL; Hubert; (Wuppertal,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BAYER INTELLECTUAL PROPERTY GMBH |
Monheim |
|
DE |
|
|
Family ID: |
44582992 |
Appl. No.: |
14/705967 |
Filed: |
May 7, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13819790 |
Apr 11, 2013 |
9040566 |
|
|
PCT/EP11/64829 |
Aug 29, 2011 |
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14705967 |
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Current U.S.
Class: |
514/20.8 ;
514/210.2; 514/342 |
Current CPC
Class: |
C07D 417/14 20130101;
A61P 43/00 20180101; A61K 38/05 20130101; A61K 31/4439 20130101;
C07D 413/12 20130101; A61K 45/06 20130101; A61K 9/0048 20130101;
A61P 27/00 20180101; A61P 27/02 20180101; A61K 9/08 20130101; A61P
27/06 20180101; C07D 417/12 20130101; A61P 25/02 20180101 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 38/05 20060101 A61K038/05; A61K 45/06 20060101
A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 2, 2010 |
EP |
10175151.9 |
Claims
1-9. (canceled)
10. An ophthalmic composition, comprising a compound of the formula
(I) and at least one active ingredients selected from the group
consisting of alpha adrenergic agonist, beta blocker and carbonic
anhydrase inhibitor, wherein the compound of formula (I) is:
##STR00030## in which A is oxygen or sulfur, R.sup.1 is hydrogen or
a group of the formula ##STR00031## in which # is the attachment to
the oxygen-atom, L.sup.1 is linear (C.sub.2-C.sub.4)-alkanediyl,
L.sup.2 is linear (C.sub.1-C.sub.3)-alkanediyl, R.sup.5 and R.sup.8
are identical or different and independently selected from the
group consisting of hydrogen or a side group of a natural
.alpha.-amino acid or its homologues or isomers, R.sup.6 and
R.sup.9 are independently selected from hydrogen or methyl, R.sup.7
is hydrogen or (C.sub.1-C.sub.4)-alkyl, or R.sup.7 and R.sup.5 form
together with the atoms which they are attached to a pyrrolidine-
or piperidine-ring, R.sup.10 and R.sup.11 are identical or
different and are independently selected from hydrogen or
(C.sub.1-C.sub.4)-alkyl, wherein (C.sub.1-C.sub.4)-alkyl may be
substituted with one group selected from hydroxy,
(C.sub.1-C.sub.4)-alkoxy, amino, mono-(C.sub.1-C.sub.4)-alkylamino
or di-(C.sub.1-C.sub.4)-alkylamino, or R.sup.10 and R.sup.8 form
together with the atoms which they are attached to a pyrrolidine-
or piperidine-ring, and R.sup.12 is hydrogen or hydroxycarbonyl,
R.sup.2 is hydrogen or a group of the formula --CH.sub.2OR.sup.1,
wherein R.sup.1 is defined as above, R.sup.3 is hydrogen, methyl or
ethyl, R.sup.4 is hydrogen, methyl or ethyl, or R.sup.3 and R.sup.4
form together with the nitrogen-atom, which they are bound to, a
azetidine-, pyrrolidine- or piperidine-ring, wherein the
azetidine-, pyrrolidine- or piperidine-ring may be substituted with
one or 2 substituents independently selected from the group fluoro,
trifluoromethyl, methyl, ethyl, methoxy and ethoxy, or a salt
thereof.
11. The ophthalmic composition of claim 10, wherein in the compound
of formula (I), A is sulfur, R.sup.1 is a group of the formula
##STR00032## in which # is the attachment to the oxygen-atom,
L.sup.1 is ethane-1,2-diyl, R.sup.5 is hydrogen, methyl,
propane-2-yl, 1-methylpropane-1-yl, 2-methyl-propane-1-yl,
hydroxymethyl or 1-hydroxymethyl, R.sup.6 is hydrogen, R.sup.7 is
hydrogen, R.sup.8 is hydrogen, methyl, propan-2-yl,
1-methylpropan-1-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl,
hydroxymethyl, hydroxyethyl, 2-carboxyethyl, 4-aminobutan-1-yl or
2-aminoethyl, R.sup.9 is hydrogen, R.sup.10 is hydrogen, R.sup.11
is hydrogen, or R.sup.10 and R.sup.8 form together with the atoms
which they are attached to a pyrrolidine-ring, R.sup.2 is hydrogen
R.sup.3 is hydrogen, R.sup.4 is hydrogen, or R.sup.3 and R.sup.4
form together with the nitrogen-atom, which they are bound to, a
azetidine-pyrrolidine- or piperidine-ring.
12. The ophthalmic composition of claim 10, wherein in the compound
of formula (I) A is sulfur, R.sup.1 is a group of the formula
##STR00033## in which # is the attachment to the oxygen-atom,
R.sup.5 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl,
benzyl, hydroxy-methyl or 1-hydroxyethyl, R.sup.6 is hydrogen,
R.sup.7 is hydrogen, R.sup.8 is hydrogen, methyl, propan-2-yl,
1-methylpropan-1-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl,
4-aminobutan-1-yl, 2-aminoethyl, 3-aminopropan-1-yl, aminomethyl or
3-guanidinopropan-1-yl, R.sup.9 is hydrogen, R.sup.10 is hydrogen,
R.sup.11 is hydrogen, R.sup.2 is hydrogen, R.sup.3 is hydrogen, and
R.sup.4 is hydrogen.
13. The ophthalmic composition of claim 10, wherein the compound of
formula (I) is selected from:
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3-
,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-alaninate-Dihydrochloride,
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3-
,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-alaninate-Dihydrochloride-
,
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)--
3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-valinate-Dihydrochloride,
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3-
,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-valinate-Trihydrochloride-
,
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)--
3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-phenylalaninate-Dihydrochl-
oride,
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]me-
thyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-beta-alaninate-Triflu-
oroacetate,
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}s-
ulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-ornithinate-Bis(trifluoro-
acetate),
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl-
]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-L-alaninat-
e-Bis(trifluoroacetate),
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicya-
no-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-alanyl-L-alaninate-Hydr-
ochloride,
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-
-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-isoleucyl-L-a-
laninate-Hydrochloride,
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicya-
no-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-glycyl-L-leucinate-Hydroc-
hloride,
(2S)-3-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl-
}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}propan-1,2-diyl-(2S,2'S)-bis(2--
{[(2S)-2-aminopropanoyl]amino}propanoate)-Dihydrochloride.
14. The ophthalmic composition of claim 10, wherein the compound of
formula (I) is ##STR00034## in which R.sup.1 is R.sup.3 is
hydrogen, R.sup.4 is hydrogen and HA is 2 HCl.
Description
[0001] The present invention relates to selective adenosine A1
agonists, in particular the dicyanopyridines of formula (I), for
the use in a method for the treatment and/or prophylaxis of
glaucoma, normotensive glaucoma, ocular hypertension and/or
combinations thereof as well as the their use for the production of
a medicament for the treatment and/or prophylaxis of glaucoma,
normotensive glaucoma, ocular hypertension and/or combinations
thereof.
BACKGROUND OF THE INTERVENTION
[0002] Glaucoma is a degenerative disease comprising a group of
debilitating eye diseases that are a leading cause of permanent
loss of visual function due to irreversible damage to the optical
nerve. Glaucoma refers further to a disease of the eye,
characterized and caused by damage of the optic nerve head,
degeneration of ocular tissues, and/or elevated intraocular
pressure. There are several functionally or morphologically
distinct types of glaucoma which in general are accompanied by
elevated intraocular pressure (IOP).
[0003] The increased IOP is considered to be causally related to
the pathological progress of the disease. In patients with ocular
hypertension intraocular pressure is elevated but no apparent loss
of visual function has occurred. These patients are considered to
be at high risk for a potential development of visual loss
associated with glaucoma. Some patients which show a glaucomatous
vision field loss have a normal to low intraocular pressure. These
so called normotension or low tension glaucoma patients can also
benefit form agents that decrease intraocular pressure. The loss of
visual function and the progressive deterioration associated with
glaucoma and ocular hypertension can generally be ameliorated with
medications that reduce elevated intraocular hypertension when
glaucoma or ocular hypertension is detected early.
[0004] Glaucoma--on the basis of its etiology--refers also to
primary or secondary glaucoma. Primary glaucoma in adults
(congenital glaucoma) may be either open-angle or acute or chronic
angle-closure.
[0005] Primary glaucoma is characterized by increased intraocular
tension which is due to the obstruction of aqueous humor outflow.
In chronic open-angle glaucoma (POAG), the anterior chamber and its
anatomic structures appear normal, but drainage of the aqueous
humor is hampered. In acute or chronic angle-closure, the
filtration angle is narrowed, the anterior chamber is shallow and
the iris may obstruct the trabecular meshwork at the entrance of
the canal of Schlemm. Dilation of the pupil may push the root of
the iris forward against the angle, and may produce pupilary block
and thus precipitate an acute attack. A predisposion to acute
angle-closure glaucoma attacks with various degrees of severity is
know in patients eyes with narrow anterior chamber angles
[0006] Secondary glaucoma is characterized and caused by any
interference which effects the flow of aqueous humor from the
posterior chamber into the anterior chamber and subsequently, into
the canal of Schlemm. Also inflammatory disease of the anterior
segment may inhibit aqueous outflow by causing complete posterior
synechia in iris bombe and may plug the drainage channel with
exudates. Other common causes are intraocular tumors, enlarged
cataracts, central retinal vein occlusion, trauma to the eye,
operative procedures and intraocular hemorrhage.
[0007] Several therapies for treating glaucoma or ocular
hypertension have been proven to be effective in clinical practice
via reduction of IOP by lowering aqueous humor production or by
increasing outflow facility. Many of the used drugs are
administrated topically direct to the eye or orally. However a
relevant number of patients do not respond to the current existing
glaucoma treatment options. In addition a significant number of
patients face side effects like local intolerance and allergic
reactions, subconjunctival hyperemia, miosis or uveitis which lead
to cessation of the glaucoma therapy. Therefore the need of new and
innovative therapeutic agents which control IOP is given. Since
glaucoma is caused by progressive damage to the optic nerve head in
particular additional neuroprotective effects in the eye would be
beneficial.
[0008] Thus intense research efforts are currently ongoing for new
glaucoma therapies with improved efficacy and reduced side effect
profile (Lee A. J., Goldberg I., Exp. Opin. Emer. Drugs 2011,
16(1), 137-161; Traverso C. E. et al., Exp. Opin. Emer. Drugs 2011,
16(2), 293-307; Fogagnolo P., Rossetti L., Exp. Opin. Investig.
Drugs 2011, 20(7), 947-959).
[0009] Adenosine, a purine nucleoside, is an ubiquitous modulator
of numerous physiological activities which is mediated by specific
cell surface receptors. Adenosine is formed intracellularly as an
intermediate during the degradation of adenosine 5'-monophosphate
(AMP) and S-adenosylhomocysteine, but it can be released from the
cell, in which case it acts as a hormone-like substance or
neurotransmitter by binding to specific receptors.
[0010] The first identified biological action of adenosine was the
effect on heart rate, atrioventricular conduction and blood
pressure (Drugy A. et al., J. Physiol. 1929, 68, 213-237). Since
then it has been reported that adenosine is involved in many
physiological processes and that these effects are mainly mediated
by four known subtypes of adenosine receptors--referred to as A1,
A2a, A2b and A3--each of which has a unique pharmacological
profile, tissue distribution and effector coupling (Jacobsen K. A.
et al., Exp. Opin. Emer. Drugs 2007, 12, 479-492). According to the
invention, "adenosine-receptor-selective ligands" are substances
which bind selectively to one or more subtypes of the adenosine
receptors, thus either mimicking the action of adenosine (adenosine
agonists) or blocking its action (adenosine antagonists).
[0011] The actions of these adenosine receptors are mediated
intracellularly by the messenger cAMP. In the case of the binding
of adenosine to the A2a or A2b receptors, the intracellular cAMP is
increased via activation of the membrane-bound adenylate cyclase,
whereas binding of adenosine to the A1 or A3 receptors results in a
decrease of the intracellular cAMP concentration via inhibition of
adenylate cyclase.
[0012] In the cardiovascular system, the main consequences of the
activation of adenosine receptors are: bradycardia, negative
inotropism and protection of the heart against ischemia
("preconditioning") via A1 receptors, dilation of the blood vessels
via A2a and A2b receptors and inhibition of the fibroblasts and
smooth-muscle-cell proliferation via A2b receptors. In the case of
A1 agonists (coupling preferably via G.sub.i proteins), a decrease
of the intracellular cAMP concentration is observed (preferably
after direct prestimulation of adenylate cyclase by forskolin).
Correspondingly, A2a and A2b agonists (coupling preferably via
G.sub.s proteins) leads to an increase and A2a and A2b antagonists
to a decrease of the cAMP concentration in the cells. In the case
of A2 receptors, a direct prestimulation of adenylate cyclase by
forskolin is of no benefit.
[0013] The development of many subtype specific adenosine receptor
agonists or antagonists have been described and tested in clinical
trials for many different diseases e.g. cardiac arrhythmias,
neuropathic pain, myocardial perfusion imaging, inflammatory
diseases and colon cancer (Jacobsen K. A. et al., Nature Rev. Drug
Disc. 2006, 5, 247-264; Muller C. E. et al., Exp. Opin. Emer. Drugs
2003, 8, 537-57).
[0014] In humans, activation of A1 receptors by specific A1
agonists leads to a frequency-dependent lowering of the heart rate,
without any effect on blood pressure. Selective A1 agonists may
thus be suitable inter alia for treating angina pectoris and atrial
fibrillation.
[0015] The cardioprotective action of the A1 receptors in the heart
may be utilized inter alia by activating these A1 receptors with
specific A1 agonists for treatment and organ protection in cases of
acute myocardial infarction, acute coronary syndrome, heart
failure, bypass operations, heart catheter examinations and organ
transplantations.
[0016] For the adenosine A1 receptor several subtype specific
agonists have been reported like NNC-21-0126, GR79236, selodenoson
and capadenoson which have been reported to be in clinical
development (Jacobsen K. A., Handbook Exp. Pharmacol., 2009, 193,
1-24). Also the effect of adenosine A1 receptor agonists on
intraocular pressure has been intensively studied and
characterized. It was shown that two relatively selective adenosine
A1 agonists N6-cyclohexyl-adenosine (CHA) and
R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA) lower intraocular
pressure in rabbits (Crosson C. E., Curr. Eye Res. 1995, 11,
453-458; Crosson C. E. et al. J. Ocul. Pharmacol. 1994, 10,
379-383; Crosson C. E., J. Pharmacol. Exp. Ther. 1995, 273,
320-326) and cynomolgus monkeys (Kaufman P. L. et al., Exp. Eye
Res. 1997, 64, 979-989). However the use of adenosine A1 agonists
as therapeutic drugs for glaucoma or ocular hypertension is
significantly limited by the effects on hemodynamic parameters as
it is known that adenosine A1 agonists are crucially involved in
heart rate and blood pressure regulation (Zablocki J. et al.,
Handbook Exp. Pharmacol., 2009, 193, 25-58).
[0017] Prodrugs are derivatives of an active ingredient which
undergo in vivo an enzymatic and/or chemical biotransformation in
one or more stages before the actual active ingredient is
liberated. A prodrug residue is ordinarily used in order to improve
the profile of properties of the underlying active ingredient [P.
Ettmayer et al., J. Med. Chem. 47, 2393 (2004)]. In order to
achieve an optimal profile of effects it is necessary in this
connection for the design of the prodrug residue as well as the
desired mechanism of liberation to be coordinated very accurately
with the individual active ingredient, the indication, the site of
action and the administration route. A large number of medicaments
is administered as prodrugs which exhibit an improved
bioavailability by comparison with the underlying active
ingredient, for example achieved by improving the physicochemical
profile, specifically the solubility, the active or passive
absorption properties or the tissue-specific distribution. An
example which may be mentioned from the wide-ranging literature on
prodrugs is: H. Bundgaard (Ed.), Design of Prodrugs: Bioreversible
derivatives for various functional groups and chemical entities,
Elsevier Science Publishers B.V., 1985. A review of prodrug
derivatives based on carboxylic acid esters and possible properties
of such compounds can be found, for example, in K. Beaumont et al.,
Curr. Drug Metab. 4, 461-485 (2003). Also known are dipeptide
prodrugs of acyclovir for treating ocular herpes infections (B. S.
Anand et al., Curr. Eye Res. 26, No. 3-4, 151-163 (2003)) which
interact with the oligopeptide transporter on the cornea, thus
increasing the bioavailability of acylovir in the eye.
[0018] WO 2008/130520 claims alkinyl-substituted purine derivatives
as therapeutic agent for glaucoma or ocular hypertension. WO
2010/127210 describes Adenosine derivatives like INO-8875 for
reducing intraocular pressure in humans.
[0019] Substituted 3,5-dicyano-4-phenylpyridines and their prodrugs
as potent and selective adenosine A1 agonists are disclosed in WO
03/53441, WO 2009/015776, WO 2009/015811, WO 2009/015812, WO
2010/072314, WO 2010/072315 and WO 2010/086101.
[0020] The object of the present invention is to provide an
effective therapeutic agent for the use in the treatment and/or
prophylaxis of glaucoma and/or ocular hypertension without showing
the above mentioned side effects.
[0021] Surprisingly, it has now been found that the
dicyanopyridines of formula (I) lower intraocular pressure after
topical application to the eye without effecting hemodynamics and
are thus suitable for the production of medicaments for the use in
the treatment and/or prophylaxis of glaucoma and ocular
hypertension.
[0022] The present invention relates to compounds of formula
(I)
##STR00001## [0023] in which [0024] A is oxygen or sulfur, [0025]
R.sup.1 is hydrogen or a group of the formula
[0025] ##STR00002## [0026] in which [0027] # is the attachment to
the oxygen-atom, [0028] L.sup.1 is linear
(C.sub.2-C.sub.4)-alkanediyl, [0029] L.sup.2 is linear
(C.sub.1-C.sub.3)-alkanediyl, [0030] R.sup.5 and R.sup.8 are
identical or different and independently selected from the group
consisting of hydrogen or a side group of a natural .alpha.-amino
acid or its homologues or isomers, [0031] R.sup.6 and R.sup.9 are
independently selected from hydrogen or methyl, [0032] R.sup.7 is
hydrogen or (C.sub.1-C.sub.4)-alkyl, [0033] or [0034] R.sup.7 and
R.sup.5 form together with the atoms which they are attached to a
pyrrolidine- or piperidine-ring, [0035] R.sup.10 and R.sup.11 are
identical or different and are independently selected from hydrogen
or (C.sub.1-C.sub.4)-alkyl, [0036] wherein (C.sub.1-C.sub.4)-alkyl
may be substituted with one group selected from hydroxy,
(C.sub.1-C.sub.4)-alkoxy, amino, mono-(C.sub.1-C.sub.4)-alkylamino
or di-(C.sub.1-C.sub.4)-alkylamino, [0037] or [0038] R.sup.10 and
R.sup.8 form together with the atoms which they are attached to a
pyrrolidine- or piperidine-ring, [0039] and [0040] R.sup.12 is
hydrogen or hydroxycarbonyl, [0041] R.sup.2 is hydrogen or a group
of the formula --CH.sub.2OR.sup.1, [0042] wherein R.sup.1 is
defined as above, [0043] R.sup.3 is hydrogen, methyl or ethyl,
[0044] R.sup.4 is hydrogen, methyl or ethyl, [0045] or [0046]
R.sup.3 and R.sup.4 form together with the nitrogen-atom, which
they are bound to, a azetidine-, pyrrolidine- or piperidine-ring,
[0047] wherein the azetidine-, pyrrolidine- or piperidine-ring may
be substituted with one or 2 substituents independently selected
from the group fluoro, trifluoromethyl, methyl, ethyl, methoxy and
ethoxy, and its salts, solvates and solvates of the salts, for the
use in a method for the treatment and/or prophylaxis of glaucoma,
normotensive glaucoma, ocular hypertension and/or combinations
thereof.
[0048] In a preferred embodiment the present invention relates to
compounds of formula (I), in which [0049] A is sulfur, [0050]
R.sup.1 is a group of the formula
[0050] ##STR00003## [0051] in which [0052] # is the attachment to
the oxygen-atom, [0053] L.sup.1 is ethane-1,2-diyl, [0054] R.sup.5
is hydrogen, methyl, propane-2-yl, 1-methylpropane-1-yl,
2-methylpropane-1-yl, hydroxymethyl or 1-hydroxymethyl, [0055]
R.sup.6 is hydrogen, [0056] R.sup.7 is hydrogen, [0057] R.sup.8 is
hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl,
2-methylpropan-1-yl, imidazol-4-ylmethyl, hydroxymethyl,
hydroxyethyl, 2-carboxyethyl, 4-aminobutan-1-yl or 2-aminoethyl,
[0058] R.sup.9 is hydrogen, [0059] R.sup.10 is hydrogen, [0060]
R.sup.11 is hydrogen, [0061] or [0062] R.sup.10 and R.sup.8 form
together with the atoms which they are attached to a
pyrrolidine-ring, [0063] R.sup.2 is hydrogen, [0064] R.sup.3 is
hydrogen, [0065] R.sup.4 is hydrogen, [0066] or [0067] R.sup.3 and
R.sup.4 form together with the nitrogen-atom, which they are bound
to, a azetidine-, pyrrolidine- or piperidine-ring, and its salts,
solvates and solvates of the salts, for the use in a method for the
treatment and/or prophylaxis of glaucoma, normotensive glaucoma,
ocular hypertension and/or combinations thereof.
[0068] In a preferred embodiment the present invention also relates
to compounds of formula (I), in which [0069] A is sulfur, [0070]
R.sup.1 is hydrogen [0071] R.sup.2 is hydrogen, [0072] R.sup.3 is
hydrogen, [0073] R.sup.4 is hydrogen, [0074] or [0075] R.sup.3 and
R.sup.4 form together with the nitrogen-atom, which they are bound
to, a azetidine-, pyrrolidine- or piperidine-ring, and its salts,
solvates and solvates of the salts, for the use in a method
treatment and/or prophylaxis of glaucoma, normotensive glaucoma,
ocular hypertension and/or combinations thereof.
[0076] In a preferred embodiment the present invention also relates
to compounds of formula (I), in which
A is oxygen, R.sup.1 is hydrogen R.sup.2 is hydrogen or
--CH.sub.2OH, R.sup.3 is hydrogen, R.sup.4 is hydrogen, and its
salts, solvates and solvates of the salts, for the use in a method
for the treatment and/or prophylaxis of glaucoma, normotensive
glaucoma, ocular hypertension and/or combinations thereof.
[0077] In a preferred embodiment the present invention also relates
to compounds of formula (I), in which
A is sulfur, R.sup.1 is a group of the formula
##STR00004## [0078] in which [0079] # is the attachment to the
oxygen-atom, [0080] R.sup.5 is hydrogen, methyl, propan-2-yl,
2-methylpropan-1-yl, benzyl, hydroxymethyl or 1-hydroxyethyl,
[0081] R.sup.6 is hydrogen, [0082] R.sup.7 is hydrogen, [0083]
R.sup.8 is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl,
2-methylpropan-1-yl, imidazol-4-ylmethyl, 4-aminobutan-1-yl,
2-aminoethyl, 3-aminopropan-1-yl, aminomethyl or
3-guanidinopropan-1-yl, [0084] R.sup.9 is hydrogen, [0085] R.sup.10
is hydrogen, [0086] R.sup.11 is hydrogen, R.sup.2 is hydrogen,
R.sup.3 is hydrogen, R.sup.4 is hydrogen, and its salts, solvates
and solvates of the salts, for the use in a method for the
treatment and/or prophylaxis of glaucoma, normotensive glaucoma,
ocular hypertension and/or combinations thereof.
[0087] In a preferred embodiment the present invention relates to a
compound of the formula (1) selected from: [0088]
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3-
,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-alaninate-Dihydrochloride,
[0089]
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulf-
anyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-alaninate-Dihydroc-
hloride, [0090]
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3-
,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-valinate-Dihydrochloride,
[0091]
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulf-
anyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-valinate-Trihydroc-
hloride, [0092]
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3-
,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-phenylalaninate-Dihydrochlo-
ride, [0093]
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}s-
ulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-beta-alaninate-Trifluoroace-
tate, [0094]
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}s-
ulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-ornithinate-Bis(trifluoro-
acetate), [0095]
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}s-
ulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-L-alaninate-Bis(tri-
fluoroacetate), [0096]
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicya-
no-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-alanyl-L-alaninate-Hydr-
ochloride, [0097]
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicya-
no-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-isoleucyl-L-alaninate-H-
ydrochloride, [0098]
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicya-
no-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-glycyl-L-leucinate-Hydroc-
hloride, [0099]
(2S)-3-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfany-
l)-3,5-dicyanopyridin-4-yl]phenoxy}propan-1,2-diyl-(2S,2'S)-bis(2-{[(2S)-2-
-aminopropanoyl]amino}propanoate)-Dihydrochloride and their salts,
solvates and solvates of the salts for the use in a method for the
treatment and/or prophylaxis of glaucoma, normotensive glaucoma,
ocular hypertension and/or combinations thereof.
[0100] In a preferred embodiment the present invention relates to a
compound of the formula (I) selected from: [0101]
2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-
-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile [0102]
2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxy-
ethoxyl)phenyl]-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile
[0103]
2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxy-
ethoxyl)phenyl]-6-(azetidin-1-yl)pyridine-3,5-dicarbonitrile [0104]
2-Amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-(4-{[(-
2R)-2,3-dihydroxy-propyl]oxy}phenyl)pyridin-3,5-dicarbonitrile and
its salts, solvates and solvates of the salts, and their salts,
solvates and solvates of the salts for the use in a method for the
treatment and/or prophylaxis of glaucoma, normotensive glaucoma,
ocular hypertension and/or combinations thereof.
[0105] In a preferred embodiment the present invention relates to a
compound of the formula (I) selected from: [0106]
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3-
,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-alaninate-Dihydrochloride,
[0107]
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulf-
anyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-valinate-Dihydrochlo-
ride, [0108]
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3-
,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-valinate-Trihydrochloride-
, and their salts, solvates and solvates of the salts for the use
in a method for the treatment and/or prophylaxis of glaucoma,
normotensive glaucoma, ocular hypertension and/or combinations
thereof.
[0109] In a preferred embodiment the present invention also relates
to compounds of formula (I), in which
R.sup.3 is hydrogen, R.sup.4 is hydrogen, and its salts, solvates
and solvates of the salts, for the use in a method for the
treatment and/or prophylaxis of glaucoma, normotensive glaucoma,
ocular hypertension and/or combinations thereof.
[0110] In a preferred embodiment the present invention also relates
to compounds of formula (I), in which [0111] R.sup.3 and R.sup.4
form together with the nitrogen-atom, which they are bound to, a
azetidine-pyrrolidine- or piperidine-ring, and its salts, solvates
and solvates of the salts, for the use in a method for the
treatment and/or prophylaxis of glaucoma, normotensive glaucoma,
ocular hypertension and/or combinations thereof.
[0112] The compounds of formula (I), their production and their
action as potent and selective adenosine A1 agonists are disclosed
in WO 03/53441, WO 2009/015776, WO 2009/015811, WO 2009/015812, WO
2010/072314, WO 2010/072315 and WO 2010/086101 respectively. The
compounds mentioned in WO 03/53441, WO 2009/015776, WO 2009/015811,
WO 2009/015812, WO 2010/072314, WO 2010/072315 and WO 2010/086101
in general and especially the compounds specifically are an
explicit part of the description of the present invention and are
hereby incorporated by reference.
[0113] Depending on the substitution pattern, the compounds of the
formula (I) can exist in stereoisomeric forms, which behave either
as image and mirror image (enantiomers) or which do not behave as
image and mirror image (diastereomers). The invention relates both
to the use of the enantiomers or diastereomers and to their
respective mixtures. Just like the diastereomers, the racemic forms
can be separated into the stereoisomerically uniform constituents
in a known manner. Equally, the present invention also relates to
the use of the other tautomers of the compounds of the formula (I)
and their salts.
[0114] Salts of the compounds of the formula (I) can be
physiologically acceptable salts of the substances according to the
invention with mineral acids, carboxylic acids or sulfonic acids.
Particularly preferred salts are, for example, those with
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic
acid, benzenesulfonic acid, naphthalenedisulfonic acid,
trifluoroacetic acid, acetic acid, propionic acid, lactic acid,
tartaric acid, citric acid, fumaric acid, maleic acid or benzoic
acid.
[0115] The compounds of the present invention appear preferably as
hydrochlorides or trifluoroacetates.
[0116] Salts which can be mentioned are also salts with customary
bases, such as, for example, alkali metal salts (e.g. sodium or
potassium salts), alkaline earth metal salts (e.g. calcium or
magnesium salts) or ammonium salts, derived from ammonia or organic
amines such as, for example, diethyl-amine, triethylamine,
ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,
dihydroabietylamine, 1-ephenamine or methylpiperidine.
[0117] Hydrates or solvates are designated according to the
invention as those forms of the compounds of the formula (I) which
in the solid or liquid state form a molecular compound or a complex
by hydration with water or coordination with solvent molecules.
Examples of hydrates are sesqui-hydrates, monohydrates, dihydrates
or trihydrates. Equally, the hydrates or solvates of salts of the
compounds according to the invention are also suitable.
[0118] In the context of the present invention, the substituents,
unless stated otherwise, have the following meaning:
[0119] "Alkyl" is in the context of the invention a straight-chain
or branched alkyl radical having 1 to 4 carbon atoms. The following
radicals may be mentioned by way of example and by way of
preference: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl and tert-butyl.
[0120] "Alkanediyl" is in the context of the invention a
straight-chain or branched divalent alkyl radical having 1 to 4
carbon atoms. Examples which may be preferably mentioned are:
ethane-1,2-diyl(1,2-ethylene), ethane-1,1-diyl,
propane-1,3-diyl(1,3-propylene), propane-1,1-diyl,
propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl(1,4-butylene),
butane-1,2-diyl, butane-1,3-diyl, butane-2,3-diyl.
[0121] "Alkoxy" is in the context of the invention a straight-chain
or branched alkoxy radical having 1 to 4 carbon atoms. The
following radicals may be mentioned by way of example and by way of
preference: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and
tert-butoxy.
[0122] "Mono- or di-(C.sub.1-C.sub.4)-alkylamino" is in the context
of the invention an amino group having one or having two identical
or different straight-chain or branched alkyl substituents, which
in each case contain 1 to 4 carbon atoms. For example, the
following may be mentioned: methylamino, ethyl-amino,
n-propylamino, isopropylamino, t-butylamino, N,N-dimethylamino,
N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,
N-isopropyl-N-n-propylamino and N-t-butyl-N-methylamino.
[0123] The "side group of an .alpha.-amino acid" in the meaning of
R.sup.3 encompasses both the side groups of naturally occurring
.alpha.-amino acids and the side groups of homologs and isomers of
these .alpha.-amino acids. The .alpha.-amino acid may in this
connection have both the L and the D configuration or else be a
mixture of the L form and D form. Examples of side groups which may
be mentioned are: methyl (alanine), propan-2-yl (valine),
propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine),
1-methylpropan-1-yl (isoleucine), butan-1-yl (norleucine),
tert-butyl (2-tert-butylglycine), phenyl (2-phenylglycine), benzyl
(phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl
(tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl
(serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine),
mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine),
2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine),
carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine),
carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid),
4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl
(hydroxylysine), 3-aminopropan-1-yl (ornithine), 2-aminoethyl
(2,4-diaminobutyric acid), aminomethyl (2,3-diaminopropionic acid),
3-guanidinopropan-1-yl (arginine), 3-ureidopropan-1-yl
(citrulline). Preferred .alpha.-amino acid side groups in the
meaning of R.sup.3 are methyl (alanine), propan-2-yl (valine),
2-methylpropan-1-yl (leucine), benzyl (phenylalanine),
imidazol-4-ylmethyl (histidine), hydroxymethyl (serine),
1-hydroxyethyl (threonine), 4-aminobutan-1-yl (lysine),
3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric
acid), aminomethyl (2,3-diaminopropionic acid),
3-guanidinopropan-1-yl (arginine). The L configuration is preferred
in each case.
[0124] The term "effective amount" as used herein refers to an
amount of a compound of formula (I) that is effective for treatment
and/or prophylaxis glaucoma, normotensive glaucoma, ocular
hypertension and/or combinations thereof.
[0125] The present invention relates to selective adenosine A1
agonists, in particular the dicyanopyridines of formula (I), for
the use in a method for the treatment and/or prophylaxis of
glaucoma, normotensive glaucoma, ocular hypertension and/or
combinations thereof.
[0126] The compounds of formula (I) act as selective adenosine A1
agonists and show a beneficial profile when administered topically
to the eye, and are thus useful as an effective therapeutic agent
for the treatment and/or prophylaxis of glaucoma and/or ocular
hypertension.
[0127] The compounds of the present invention lower intraocular
pressure when administered topically to the eye without effecting
hemodynamic parameters as demonstrated in section B. Experimental
methods.
[0128] The present invention relates to compounds of formula (I)
for the use in a method for the treatment and/or prophylaxis of
glaucoma and/or ocular hypertension.
[0129] Furthermore the present invention relates to compounds of
formula (I) for the use in a method for the treatment and/or
prophylaxis of high IOP resulting from traumatic hyphema, orbital
edema, postoperative visco-elastic retention, intraocular
inflammation, corticosteroid use, pupillary block, or idiopathic
causes.
[0130] In addition the compounds of formula (I) are useful for the
treatment and/or prophylaxis of various ocular hypertensive
conditions, such as post-surgical and post-laser trabeculectomy
ocular hypertensive episodes and as presurgical adjuncts.
[0131] The present invention further relates to a method of
treating glaucoma, or other disease or disorder of the eye related
to elevated intraocular pressure.
[0132] The present invention further relates to the use of
compounds of formula (I) for the manufacture of medicaments for the
treatment and/or prophylaxis of glaucoma and/or ocular
hypertension.
[0133] A further subject of the present invention is a
pharmaceutical composition comprising a compound of the formula
(I).
[0134] A further subject of the present invention is a medicament,
comprising a compound of the formula (I) as defined in any of
claims 1 to 4 in combination with one or more further active
ingredients selected from the group consisting of alpha adrenergic
agonist, beta blocker and carbonic anhydrase inhibitor.
[0135] A further subject of the present invention is the use of a
combination of one or more compounds of the formula (I) with one or
more other active compounds in a method for the treatment and/or
prophylaxis of glaucoma, high IOP resulting from traumatic hyphema,
orbital edema, postoperative visco-elastic retention, intraocular
inflammation, corticosteroid use, pupillary block, or idiopathic
causes. Examples of suitable combination active ingredients may for
example and preferably be mentioned: [0136] alpha adrenergic
agonist such as for example alphagan; iopidin, isoglaucon,
catapres, aruclonin [0137] beta blocker such as for example
timolol, timoptol, optimal, carteolol, ocupress, betoptic, betagan
[0138] carbonic anhydrase inhibitor such as for example
dorzolamide, trusopt, diamox, Acetazolamid, brinzolamid,
dorzolamid, dichlorphenamid, methazolamid.
[0139] Further disclosed herein is a method for the treatment
and/or prophylaxis of high IOP, including glaucoma, ocular
hypertension, normotensive glaucoma or a combination thereof
comprising administering an effective amount of at least one
compound of formula (I) or of a medicament comprising at least one
compound of formula (I) in combination with an inert, non-toxic,
pharmaceutically suitable excipent to the eye.
[0140] Further disclosed herein is a method for the treatment
and/or prophylaxis of high IOP, including glaucoma, ocular
hypertension, normotensive glaucoma or a combination thereof
comprising administering an effective amount of at least one
compound of formula (I) or of a medicament comprising at least one
compound of formula (I) in combination with an inert, non-toxic,
pharmaceutically suitable excipent to the eye and at least one
further active compound selected from the group consisting of alpha
adrenergic agonists, beta blockers and carbonic anhydrase
inhibitors.
[0141] Preferred administration route is topical administration to
the eye.
[0142] Topical preparations of the invention include solutions,
sprays, lotions, gels, creams, powders, powder sprays, pastes,
emulsions, foams and sticks which comprise the active ingredient of
the formula (I), where appropriate also a plurality of active
ingredients.
[0143] Suitable pharmaceutically-acceptable carriers for topical
application include those suited for use in lotions, creams, gels,
solutions, ointments, viscous solutions, eye drops, emulsions,
gel-forming solutions and the like.
[0144] The topically applicable preparations of the invention
comprise 0.1 to 99%, preferably 0.5 to 20% by weight of active
ingredient of the formula (I).
[0145] Ointments comprise hydrocarbon gels, lipogels, absorption
bases, W/O ointment bases, mixed emulsions or polyethylene glycols
as base.
[0146] Gels comprise solvents such as water, ethanol, isopropanol
or propylene glycol and are produced using gel formers such as
cellulose ethers, alginates, polyacrylates, bentonite, gelatin,
tragacanth, polyvinylpyrrolidone or polyvinyl alcohol. Lipophilic
gel bases or microemulsions can also be used.
[0147] Advantageously, the composition is sterile and can be in
dosage unit form, e.g., suitable for topical ocular use. The
composition can be packaged in a form suitable for metered
application, such as in container equipped with a dropper.
[0148] In a preferred embodiment, the composition is a solution
prepared using a physiological saline solution as a carrier. The pH
of the solution is, preferably, maintained between 4.5 and 8.0
using an appropriate buffer system. A neutral pH is more preferred.
Compositions of the invention can also comprise pharmaceutically
acceptable preservatives, stabilizers and/or surfactants.
[0149] For this purpose, the active compounds can be converted into
the customary preparations in a manner known per se. This takes
place using inert, nontoxic, pharmaceutically suitable carriers,
excipients, solvents, vehicles, emulsifiers and/or dispersants.
[0150] Suitable excipients which may be mentioned are, for example:
water, nontoxic organic solvents such as, for example, paraffins,
vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol,
glycerol), glycols (e.g. polyethylene glycol), solid carriers such
as natural or synthetic ground minerals (e.g. talc or silicates),
sugars (e.g. lactose), emulsifiers, dispersants (e.g.
polyvinylpyrrolidone) and glidants (e.g. magnesium sulfate).
[0151] Further disclosed herein is an ophthalmic composition
comprising a compound of formula (I) and a pharmaceutically
acceptable vehicle or excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0152] FIG. 1A: A graph showing IOP as mmHg in unconscious rats
after topical administration of 10 mg/ml of the compound of Example
1, 10 mg/ml N.sup.6-cyclopentyladenosine, and control
[0153] FIG. 1B: A graph showing IOP as percent of zero value in
unconscious rats after topical administration of 10 mg/ml of the
compound of Example 1, 10 mg/ml N.sup.6-cyclopentyladenosine, and
control.
[0154] FIG. 2: A graph of IOP as percent of zero value in
unconscious rats, after topical administration of 10 mg/ml of the
compound of Example 9 and control.
[0155] FIG. 3: A graph of blood pressure in conscious rats after
topical administration of 10 mg/ml of the compound of Example 1 and
N.sup.6-cyclopentyladenosine.
[0156] FIG. 4: A graph of blood pressure in conscious rats after
topical administration of 10 mg/ml of the compound of Example 9 and
control.
[0157] FIG. 5: A graph of IOP in conscious rabbits after topical
administration of INO-8875 and control.
[0158] FIG. 6: A graph of IOP in conscious rabbits after topical
administration of the compound of Example 1 and control.
[0159] FIG. 7: A graph showing the effect on mean arterial pressure
of conscious rabbits after topical administration of INO-8875.
[0160] FIG. 8: A graph of blood pressure in conscious rabbits after
topical administration of the compound of Example 1.
EXAMPLES
##STR00005##
TABLE-US-00001 [0161] TABLE 1 Example R.sup.1 R.sup.3 R.sup.4 HA 1
##STR00006## H H 2 HCl 2 ##STR00007## H H 2 HCl 3 ##STR00008## H H
2 HCl 4 ##STR00009## H H 3 HCl 5 ##STR00010## H H 2 HCl
[0162] The synthesis of examples 1 to 5 and corresponding starting
materials is described in WO 2009/015811 in detail.
TABLE-US-00002 TABLE 2 Ex- ample R.sup.1 --NR.sup.3R.sup.4 HA 6
##STR00011## ##STR00012## CF.sub.3CO.sub.2H 7 ##STR00013##
##STR00014## CF.sub.3CO.sub.2H 8 ##STR00015## ##STR00016##
CF.sub.3CO.sub.2H 9 ##STR00017## ##STR00018## HCl 10 ##STR00019##
##STR00020## HCl 11 ##STR00021## ##STR00022## HCl * is the
attachment to the dicyanopyridine
[0163] The synthesis of examples 6 to 11 and corresponding starting
materials is described in WO 2010/086101 in detail.
Example 12
2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2--
hydroxyethoxyl)phenyl]pyridine-3,5-dicarbonitrile
##STR00023##
[0165] The synthesis of example 12 is described in WO 03/53441
(example 6) in detail.
Example 13
2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxye-
thoxyl)phenyl]-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile
##STR00024##
[0167] The synthesis of example 13 is described in WO 2010/086101
(example 1) in detail.
Example 14
2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxye-
thoxyl)phenyl]-6-(azetidin-1-yl)pyridine-3,5-dicarbonitrile
##STR00025##
[0169] The synthesis of example 14 is described in WO 2010/086101
(example 49) in detail.
Example 15
2-Amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-(4-{[(2-
R)-2,3-dihydroxy-propyl]oxy}phenyl)pyridin-3,5-dicarbonitrile
##STR00026##
[0171] The synthesis of example 15 is described in WO 2009/015776
(example 8A) in detail.
Example 16
(2S)-3-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl-
)-3,5-dicyanopyridin-4-yl]phenoxy}propan-1,2-diyl-(2S,2'S)-bis(2-{[(2S)-2--
aminopropanoyl]amino}propanoate)-Dihydrochloride
##STR00027##
[0173] The synthesis of example 16 is described in WO 2010/072314
(example 33) in detail.
B. Experimental Methods
[0174] Advantageous pharmacological properties of the compounds of
the present invention can be determined by the following
methods.
[0175] The abbreviations are used in the following experiments:
IOP intraocular pressure SEM (standard error of mean) PBS
(phosphate buffered saline)
[0176] In each experiment the control animals received the
corresponding solvent.
B-1. IOP Measurements in Rats
[0177] Wistar rats with a body weight of about 300 g were
anesthetized with isoflurane (2-3% in O.sub.2:N.sub.2O=1:2). The
compounds were dissolved/suspended in an aqueous solution of sodium
chloride (0.9%) and administered topically to the eye in 10 .mu.l
volume at a concentration of 10 mg/ml. IOP was measured with a
rebound tonometer (TonoLab) at different time points after
application of the compounds. Ocular pressure and effects of
hemodynamic parameters can be monitored in this model.
N.sup.6-Cyclopentyl-Adenosine (CPA) is a known adenosine A1 agonist
having the structure shown below:
##STR00028##
[0178] FIG. 1A shows IOP (as mm Hg) over time after topical
administration of control, N.sup.6-Cyclopentyl-Adenosine (CPA) and
Example 1 at a dose of 10 mg/ml.
[0179] FIG. 1B shows IOP (as percent of zero value) over time after
topical administration of control, N.sup.6-Cyclopentyl-Adenosine
(CPA) and Example 9 at a dose of 10 mg/ml.
[0180] Table 3 gives IOP (as percent of zero value) after topical
administration of N.sup.6-Cyclopentyl-Adenosine (CPA) and Example 1
at a dose of 10 mg/ml at time points from 0 min to 120 min
TABLE-US-00003 TABLE 3 compound Time [min] IOP [%] .+-.SEM Control
0 100.0 0.0 Control 15 89.6 3.7 Control 30 92.3 4.8 Control 45 88.6
2.9 Control 60 93.4 5.1 Control 90 95.7 4.4 Control 120 96.3 4.3
Example 1 0 100.0 0.0 Example 1 15 93.6 5.7 Example 1 30 80.6 2.6
Example 1 45 77.7 3.0 Example 1 60 70.0 1.7 Example 1 90 75.9 5.9
Example 1 120 76.6 3.5 CPA 0 100.0 0.0 CPA 15 65.0 3.3 CPA 30 58.5
3.5 CPA 45 46.3 4.9 CPA 60 42.5 3.6 CPA 90 44.8 2.3 CPA 120 59.0
2.0 Example 4 0 100.0 0.0 Example 4 30 73.8 6.1 Example 4 60 80.0
7.9 Example 4 90 76.0 7.7 Example 2 0 100.0 0.0 Example 2 30 95.3
9.9 Example 2 60 73.3 3.9 Example 2 90 73.8 6.6
[0181] FIG. 2 shows IOP (as percent of zero value) over time after
topical administration of control and Example 9 at a dose of 10
mg/ml.
[0182] Table 4 gives IOP (as percent of zero value) after topical
administration of Example 9 and control at a dose of 10 mg/ml at
time points from 0 min to 120 min.
TABLE-US-00004 TABLE 4 compound Time [min] IOP [%] .+-.SEM Control
0 100.0 0.0 Control 15 96.7 3.8 Control 30 106.9 6.4 Control 60
104.4 6.1 Control 90 97.7 5.5 Control 120 101.7 6.5 Example 9 0
100.0 0.0 Example 9 15 81.6 3.1 Example 9 30 84.4 2.4 Example 9 60
83.7 4.0 Example 9 90 85.3 2.4 Example 9 120 83.7 3.9
B-2. Blood Pressure Measurement in Telemetric Rats
[0183] Normotensive wistar rats with a body weight of 300 to 350 g
were used for this experimental study. Blood pressure was monitored
in freely moving conscious animals by radiotelemetry. Briefly, the
telemetric system (DSI Data Science International, MN, USA) is
composed on 3 basic elements: implantable transmitters
(TA11PA-C40), receivers (RA1010) and a computer-based acquisition
software (Dataquest A.R.T 2.1 for Windows). Rats were instrumented
with pressure implants for chronic use at least 14 days prior the
experiments. Rats were anesthetized with isoflurane (2-3% in
O.sub.2:N.sub.2O=1:2). During catheter implantation under
anesthesia, rats were kept on a heating mat. A fluid-filled sensor
catheter was inserted upstream into the exposed descending aorta
between the iliac bifurcation and the renal arteries. According to
the DSI guidelines the tip of the telemetric catheter was located
just caudal to the renal arteries and secured by tissue adhesive.
The transmitter body was affixed to the inner peritoneal wall
before closure of abdomen. In a hardware configuration equipped for
24 animals, each rat cage was positioned on top of an individual
receiver platform. After activation of the implanted transmitters,
A.R.T., an on-line data acqusition system, samples data and
converts telemetric pressure signals into mm Hg. The compounds were
dissolved/suspended in an aqueous solution of sodium chloride
(0.9%) and administered topically to the eye in 10 .mu.l volume at
a concentration of 10 mg/ml. Given are % deviations from the
control run-in period of 2 hours before substance
administration.
[0184] FIG. 3 shows effects on mean arterial blood pressure after
topical administration of control, N.sup.6-Cyclopentyl-Adenosine
and Example 1 at a dose of 10 mg/ml over time.
[0185] Table 5 gives mean arterial pressure (MAP) as percent change
of zero value after topical administration of control,
N.sup.6-Cyclopentyl-Adenosine and Example 1 at different time
points from -0.25 h to 6.25 h.
TABLE-US-00005 TABLE 5 Time control CPA Example 1 Example 4 Example
2 [hours] MAP .+-.SEM MAP .+-.SEM MAP .+-.SEM MAP .+-.SEM MAP
.+-.SEM -0.25 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.25 4.5 1.8
-25.4 2.8 1.2 1.3 7.3 1.5 10.7 3.3 0.75 0.1 1.1 -71.3 5.0 -6.1 0.8
1.0 2.3 1.6 2.6 1.25 -4.7 2.0 -58.9 7.7 -6.0 0.5 -2.0 1.5 0.3 2.0
1.75 -1.2 3.4 -42.6 7.1 -2.5 1.2 -0.8 2.0 -0.2 1.8 2.25 4.2 3.3
-30.3 5.5 -2.5 1.6 0.7 2.6 -1.1 1.6 2.75 -3.4 0.8 -17.6 6.1 -1.5
2.3 0.6 2.2 1.9 2.7 3.25 -2.3 1.8 -16.4 5.5 -1.4 3.2 0.1 2.5 2.0
2.3 3.75 -4.9 1.1 -9.0 3.1 -1.6 3.5 1.0 2.9 -2.2 1.5 4.25 -3.4 1.1
-8.4 2.9 -1.5 4.1 -1.5 1.6 -0.9 1.2 4.75 -2.0 1.2 -5.3 3.6 -1.7 3.7
-0.3 1.8 -0.8 1.7 5.25 -3.3 0.9 -0.7 4.4 -6.0 4.4 -1.7 2.3 -3.1 1.4
5.75 4.5 1.7 -2.9 2.2 -3.8 4.6 -3.8 2.2 -4.2 1.8 6.25 -4.6 1.1 -2.7
3.2 -6.0 3.7 -3.6 1.6 -4.0 1.6
[0186] FIG. 4 shows effects on mean arterial blood pressure after
topical administration of control and Example 9 at a dose of 10
mg/ml over time.
[0187] Table 6 gives mean arterial pressure (MAP) as percent change
of zero value after topical administration of control and Example 9
at different time points from -0.25 h to 6.25 h.
TABLE-US-00006 TABLE 6 Time Control Example 9 [hours] MAP .+-.SEM
MAP .+-.SEM -0.25 0.00 0.0 0.00 0.0 0.25 10.26 2.1 7.05 1.3 0.75
0.04 1.1 0.94 1.8 1.25 -1.16 1.6 -3.02 1.9 1.75 0.74 1.0 -2.50 1.0
2.25 -0.27 1.0 0.37 1.3 2.75 0.62 1.8 -0.95 1.6 3.25 3.67 2.3 -1.51
1.0 3.75 1.38 2.6 0.08 1.1 4.25 -1.52 1.0 -1.54 1.5 4.75 0.46 1.0
-1.99 1.9 5.25 -1.68 1.2 -0.43 1.6 5.75 -1.37 1.8 -0.04 1.9 6.25
-1.03 2.2 -2.42 1.9
B-3. Nerve Crush Model
[0188] Mice (all at least 7 weeks old) are deeply anesthetized, and
optic nerves are intraorbitally crushed. After treating the mice
for two weeks with compounds, i.e. the adenosine A1 agonists they
are sacrified and eyes are withdrawn. Flatmounts of the retinas are
prepared. The degenerated retinal ganglion cells are analyzed and
counted in the different treatment groups.
B-4. Retinal Ischemia Model
[0189] Male Lewis rats weighing 200 to 250 g and male C57BL/6J mice
weighing 25 to 30 g are anesthetized. The anterior chamber of one
eye is cannulated with a needle attached to a line infusing normal
saline to increase intraocular pressure. IOP is measured by a
handheld tonometer (TonoLab) in rat eyes for the next up to 120
minutes. The other eye of the same animal is set up as a control.
After ischemia, the needle is withdrawn, IOP is normalized, and
reflow of the retinal circulation is documented visually. Animals
are killed at different times after I/R injury.
B-5. IOP Measurements in Conscious Rabbits
[0190] Female New Zealand rabbits with a body weight of about 4-5
kg were used to measure inner eye pressure (IOP). The compounds
were dissolved/suspended in a solution of 10% transcutol, 10%
solutol and 80% PBS, and given by topical administration at the eye
in 30 .mu.l volume. IOP was measured with a rebound tonometer
(TonoVet) at different time points after application of the drugs.
INO-8875 is a known adenosine A1 agonist having the structure shown
below:
##STR00029##
[0191] FIG. 5 shows IOP as percent of zero value in rabbits of
INO-8875 at dosages of 1.0, 3.0 and 10.0 mg/mL after topical
administration.
[0192] Table 7 gives IOP as percent of zero value in rabbits of
INO-8875 at dosages of 1.0, 3.0 and 10.0 mg/mL after topical
administration.
TABLE-US-00007 TABLE 7 INO-8875 INO-8875 INO-8875 time (1.0 mg/mL)
(3.0 mg/mL) (10.0 mg/mL) control [min] IOP .+-.SEM IOP .+-.SEM IOP
.+-.SEM IOP .+-.SEM 0 100.0 0.0 100.0 0.0 100.0 0.0 100.0 0.0 30
85.3 5.0 89.3 3.7 74.0 3.6 105.0 4.7 60 86.7 5.5 81.3 1.3 60.0 2.6
99.0 4.0 90 93.3 5.8 79.0 1.5 61.3 3.0 99.3 5.8 120 100 8.9 87.3
7.4 65.0 4.6 99.0 1.0
[0193] FIG. 6 shows IOP as percent of zero value in rabbits of
Example 1 at dosages of 3.0 and 10.0 mg/mL after topical
administration.
[0194] Table 8 gives IOP as percent of zero value in rabbits of
Example 1 at dosages of 3.0 and 10.0 mg/mL after topical
administration.
TABLE-US-00008 TABLE 8 Example 1 Example 1 Time (3.0 mg/mL) (10.0
mg/mL) control [min] IOP .+-.SEM IOP .+-.SEM IOP .+-.SEM 0 100.0
0.0 100.0 0.0 100.0 0.0 30 82.7 4.3 79.8 7.0 104.6 3.4 60 76.7 3.1
66.2 4.8 90.6 3-9 90 82.1 3.6 71.3 5.1 98.0 5.2 120 81.9 3.0 68.5
4.8 92.2 4.0
B-6. Assessment of Blood Pressure and Heart Rate in Telemetric
Rabbits
Implantation of Telemetric Senders in Female New Zealand
Rabbits:
[0195] New Zealand rabbits were used for implantation of the
telemetric senders. Rabbits were pre-anaesthetized with Rompun.RTM.
and Ketavet.RTM. i.m. at a dose of 5 mg/kg (in 0.25 ml/kg)+40 mg/kg
(in 0.40 ml/kg) respectively. Anaesthesia was maintained with an
i.v. infusion of Rompun.RTM. and Ketavet.RTM. (5-15 ml/h) with a
solution of Rompun 2 ml (20 mg/1 ml)+Ketavet 4 ml (100 mg/ml) and
60 ml 0.9% aqueous solution of sodium chloride. Before surgery the
hairs at the inner side of the back leg were completely removed and
the skin were treated with local anaesthetic Xylocain.RTM. Spray
and disinfected with Braunol.RTM.. The rabbits were transferred to
a sterile surgery unit and covered with sterile swabs and
compressions. The skin was opened and the arteria femoralis was
carefully dissected free and the pressure catheter of the
telemetric implant C50 PXT.RTM. (DSI/Data Science International,
St. Paul, Minn., U.S.A.) was inserted in the vein and forwarded
abdominally under control of the pressure signal. The signal was
detected with the RMC1-DSI.RTM. receiver plates and visualized with
the PONEMAH.RTM. physiology platform software DSI/Data Science
International, St. Paul, Minn., U.S.A.). After detection of a
stable blood pressure signal the catheter was fixed with
tissue-glue "Gewebepad" (DSI) and the two ECG electrodes were cut
close to the transmitter. The transmitter was fixed under the skin
of the rabbit. The wound was closed and finally treated with
Nebacetin.RTM. Powder Spray. Post-operative analgesia was done with
Metamizol i.m. 50 mg/kg in 0.1 ml/kg for 5 days after surgery. In
addition a 5 day antibiotic therapy with Terramycin.RTM./LA 20
mg/kg with 0.1 ml/kg was applied i.m.. All rabbits recovered fully
within one week of the surgery and were after 2 weeks adjustment to
the measurement procedure used for the blood pressure
detection.
Registration of MAP and HR in Conscious Female New Zealand
Rabbits:
[0196] The rabbits with telemetric implants were housed for 5 hours
in a transportation box which was placed on the RMC1-DSI.RTM.
receiver plates. The signals were visualized, compiled and analyzed
with the PONEMAH.RTM. physiology platform software. The systolic
(SAP), diastolic (DAP) and mean arterial blood pressure (MAP)
levels were registered in mmHg and the heart rate (HR) in
beat/minutes was calculated from the interval between the systoles.
Baseline levels for SAP, DAP and MAP as for HR were registered over
a 2 hour equilibration period. The compounds were
dissolved/suspended in a solution of 10% transcutol, 10% solutol
and 80% PBS, and given by topical administration at the eye in 30
.mu.l volume. Controls received the corresponding solvents.
Baseline levels for SAP, DAP and MAP as for HR were registered over
a 3 hour period after application.
[0197] FIG. 7 shows effects of INO-8875 at dosages of 1.0, 3.0 and
10.0 mg/mL on mean arterial blood pressure after topical
administration.
[0198] Table 9 gives mean arterial pressure (MAP) as mm Hg of
INO-8875 at dosages of 1.0, 3.0 and 10.0 mg/mL after topical
administration.
TABLE-US-00009 TABLE 9 INO-8875 INO-8875 INO-8875 (1.0 mg/mL) (3.0
mg/mL) (10.0 mg/mL) control Time MAP MAP MAP MAP [min] [mmHg]
.+-.SEM [mmHg] .+-.SEM [mmHg] .+-.SEM [mmHg] .+-.SEM 0 123.9 12.1
118.5 13.2 114.5 7.3 113.6 9.4 30 111.3 13.3 101.8 17.7 89.5 11.4
114.2 13.2 60 110.9 13.6 104.9 17.8 86.9 10.5 113.8 13.4 90 112.6
13.3 105.7 17.1 90.3 8.9 114.8 10.3 120 106.0 14.5 109.0 20.4 90.0
40.0 108.3 18.2
[0199] FIG. 8 shows effects of Example 1 at dosages of 3.0 and 10.0
mg/ml on mean arterial blood pressure after topical
administration.
[0200] Table 10 gives mean arterial pressure (MAP) as mm Hg of
Example 1 at dosages of 3.0 and 10.0 mg/mL after topical
administration.
TABLE-US-00010 TABLE 10 Example 1 Example 1 Time (3.0 mg/mL) (10.0
mg/mL) control [min] MAP .+-.SEM MAP .+-.SEM MAP .+-.SEM 0 117.1
28.6 115.9 10.7 113.6 9.4 30 114.5 29.4 118.8 15.0 114.2 13.2 60
110.4 28.7 112.0 14.2 113.8 13.4 90 117.8 34.0 112.8 14.1 114.8
10.3 120 106-7 31.6 105.4 17.9 108.3 18.2
* * * * *