U.S. patent application number 13/934665 was filed with the patent office on 2014-01-09 for pro-drug compounds.
The applicant listed for this patent is Proximagen Limited. Invention is credited to Mike Ashwood, Martyn Pritchard, Edward Savory.
Application Number | 20140011773 13/934665 |
Document ID | / |
Family ID | 48782540 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140011773 |
Kind Code |
A1 |
Savory; Edward ; et
al. |
January 9, 2014 |
Pro-drug Compounds
Abstract
A compound of formula (I), or a pharmaceutically acceptable salt
thereof: ##STR00001## The compound is used in pharmaceutical
compositions and in a method of treatment of a disease or medical
condition which benefits from inhibition of gap junction activity
by administering to a subject suffering from such disease or
condition.
Inventors: |
Savory; Edward; (London,
GB) ; Pritchard; Martyn; (London, GB) ;
Ashwood; Mike; (London, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Proximagen Limited |
London |
|
GB |
|
|
Family ID: |
48782540 |
Appl. No.: |
13/934665 |
Filed: |
July 3, 2013 |
Current U.S.
Class: |
514/100 ;
514/456; 549/220; 549/399 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 311/68 20130101; C07D 311/70 20130101; C07F 9/65522
20130101 |
Class at
Publication: |
514/100 ;
549/220; 549/399; 514/456 |
International
Class: |
C07D 311/68 20060101
C07D311/68; C07F 9/655 20060101 C07F009/655 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 3, 2012 |
GB |
1211788.3 |
Mar 15, 2013 |
GB |
1304812.9 |
Claims
1. A compound of formula (I), or a pharmaceutically acceptable salt
thereof: ##STR00033## wherein Z.sub.1, Z.sub.2, and Z.sub.3 are
each independently selected from H, F, or Cl; Q is O; R.sup.2 is H;
A is a direct bond, --C(O)O*--, --C(R.sup.3)(R.sup.4)O*--,
--C(O)O--C(R.sup.3)(R.sup.4)O*--, or
--C(R.sup.3)(R.sup.4)O--C(O)O*-- wherein the atom marked * is
directly connected to R.sup.1, R.sup.3 and R.sup.4 are selected
independently from H, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl, or R.sup.3 and R.sup.4 together with the atom to which
they are attached form a cyclopropyl group; R.sup.1 is selected
from groups [1], [2], [2A], [2B], [3], [4], [5] or [6] wherein the
atom marked ** is directly connected to A: ##STR00034## R.sup.5 and
R.sup.6 are independently selected from H, C.sub.1-4 alkyl,
C.sub.1-4 fluoroalkyl or benzyl; R.sup.7 is independently selected
from H, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl; R.sup.8 is
selected from: (i) H, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl, or
(ii) the side chain of a natural or unnatural alpha-amino acid or
R.sup.7 and R.sup.8 together with the atom to which they are
attached form a C.sub.3-7 carbocyclic ring; R.sup.9 is selected
from H, --N(R.sup.11)(R.sup.12), or
N.sup.+(R.sup.11)(R.sup.12)(R.sup.13)X.sup.-, or
--N(R.sup.11)C(O)R.sup.14 wherein R.sup.11, R.sup.12, and R.sup.13
are independently selected from H, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl, or R.sup.11 and R.sup.12 together with the nitrogen
atom to which they are attached form a 3-8 membered heterocyclic
ring; R.sup.14 is H, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl;
R.sup.10 and R.sup.15 are independently selected from C.sub.1-4
alkyl or C.sub.1-4 fluoroalkyl; X.sup.- is a pharmaceutically
acceptable anion.
2. A compound according to claim 1 wherein A is a direct bond, or
--C(R.sup.3)(R.sup.4)O*--.
3. A compound according to claim 1 wherein R.sup.3 and R.sup.4 are
both H, or R.sup.3 and R.sup.4 are both C.sub.1-4 alkyl, or R.sup.3
is H and R.sup.4 is C.sub.1-4 alkyl.
4. A compound according to claim 1 wherein R.sup.3 is H and R.sup.4
is methyl, ethyl or isopropyl.
5. A compound according to claim 1 wherein -A-R.sup.1 has the
formula wherein the atom marked ** is directly connected to the
oxygen atom: ##STR00035##
6. A compound according claim 1 wherein Z.sub.1 is Cl, Z.sub.2 is
F, and Z.sub.3 is H; or Z.sub.1 is Cl, Z.sub.2 and Z.sub.3 are H;
or Z.sub.1 is H, Z.sub.2 is F, and Z.sub.3 is H; or Z.sub.1 is F,
Z.sub.2 is H, and Z.sub.3 is F.
7. A compound according to claim 1 wherein the compound of formula
(I) is selected from:
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-d-
ihydro-2H-1-benzopyran-3-yl]oxy}phosphonic acid,
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl 2-(dimethylamino)acetate hydrochloride,
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl acetate,
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-d-
ihydro-2H-1-benzopyran-3-yl]oxy}methyl acetate,
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-d-
ihydro-2H-1-benzopyran-3-yl]oxy}methyl 2-(dimethylamino)acetate,
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl 2-aminoacetate hydrochloride,
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl 2-(methylamino)acetate hydrochloride, or
({[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4--
dihydro-2H-1-benzopyran-3-yl]oxy}methoxy)phosphonic acid diamine
and a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound as claimed in
claim 1, together with one or more pharmaceutically acceptable
carriers and/or excipients.
9. (canceled)
10. (canceled)
11. A method of treatment of a disease or medical condition which
benefits from inhibition of gap junction activity, comprising
administering to a subject suffering from such disease or condition
and effective amount of a compound as claimed in claim 1.
12. The method as claimed in claim 11 wherein the disease or
condition is selected from among migraine, aura with or without
migraine, epilepsy, non-epileptic seizures, cerebrovascular
accidents including stroke, intracranial haemorrhage (including or
traumatic brain injury, epidural hematoma, subdural hematoma and
subarachnoid haemorrhage), and intra-cerebral haemorrhage
(including CADASIL), spinal cord vascular accidents arising from
trauma, epidural hematoma, subdural hematoma or subarachnoid
haemorrhage, pain including pain arising from hyperalgesia caused
by damage to sensory neurons (i.e. neuropathic pain including but
not limited to diabetic neuropathy, polyneuropathy, cancer pain,
fibromyalgia, myofascial pain, post herpetic neuralgia, spinal
stenosis, HIV pain, post-operative pain, post-trauma pain) or
inflammation (including pain associated with osteoarthritis,
rheumatoid arthritis, sciatica/radiculopathy, pancreatitis,
tendonitis), neurodegenerative disease (including but not limited
to Alzheimer's Disease, Parkinson's Disease, Huntington's Disease
and Amyotrophic Lateral Sclerosis) and cardiovascular disease
including myocardial infarction, coronary revascularization or
angina.
13. A pharmaceutical composition according to claim 8 formulated as
a liquid for intravenous dosage.
14. A pharmaceutical composition according to claim 8 formulated as
a solid for oral dosage.
15. The method as claimed in claim 11 wherein in formula (I) A is a
direct bond, or --C(R.sup.3)(R.sup.4)O*--.
16. The method as claimed in claim 11 wherein in formula (I)
R.sup.3 and R.sup.4 are both H, or R.sup.3 and R.sup.4 are both
C.sub.1-4 alkyl, or R.sup.3 is H and R.sup.4 is C.sub.1-4
alkyl.
17. The method as claimed in claim 11 wherein in formula (I)
R.sup.3 is H and R.sup.4 is methyl, ethyl or isopropyl.
18. The method as claimed in claim 11 wherein in formula (I)
-A-R.sup.1 has the formula wherein the atom marked ** is directly
connected to the oxygen atom: ##STR00036##
19. The method as claimed in claim 11 wherein in formula (I)
Z.sub.1 is Cl, Z.sub.2 is F, and Z.sub.3 is H; or Z.sub.1 is Cl,
Z.sub.2 and Z.sub.3 are H; or Z.sub.1 is H, Z.sub.2 is F, and
Z.sub.3 is H; or Z.sub.1 is F, Z.sub.2 is H, and Z.sub.3 is F.
20. The method as claimed in claim 11 wherein the compound of
formula (I) is selected from:
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-d-
ihydro-2H-1-benzopyran-3-yl]oxy}phosphonic acid,
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl 2-(dimethylamino)acetate hydrochloride,
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl acetate,
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-d-
ihydro-2H-1-benzopyran-3-yl]oxy}methyl acetate,
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-d-
ihydro-2H-1-benzopyran-3-yl]oxy}methyl 2-(dimethylamino)acetate,
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl 2-aminoacetate hydrochloride,
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl 2-(methylamino)acetate hydrochloride, or
({[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4--
dihydro-2H-1-benzopyran-3-yl]oxy}methoxy)phosphonic acid diamine
and a pharmaceutically acceptable salt thereof.
Description
[0001] The present invention relates to neuronal gap junction
blocking compounds having improved pharmacokinetic properties, the
compounds being useful for the treatment or prevention of a range
of conditions including migraine, epilepsy, non-epileptic seizures,
brain injury (including stroke, intracranial haemorrhage and trauma
induced) or cardiovascular disease including myocardial infarction,
coronary revascularization or angina.
BACKGROUND TO THE INVENTION
[0002] Cortical spreading depolarization (CSD) is a wave of
depolarisation with consequent depressed electrical activity which
spreads across the surface of the cerebral cortex (at a rate of 2-6
mm/min) usually followed by hyperaemia and neuronal
hyperpolarisation. The reduction in electrical activity is a
consequence of neuron depolarisation and swelling, with K+ efflux,
Na and Ca influx and electrical silence. This abnormal neuronal
activity is associated with delayed neuronal damage in a number of
pathological states including cerebral ischaemia (arising from e.g.
stroke, haemorrhage and traumatic brain injury Strong et al., 2002
Fabricius et al., 2006; Dreier et al., 2006 Dohmen et al., 2008),
epilepsy and the aura associated with migraine (Lauritzen 1994;
Goadsby 2007). As the CSD wave moves across the cortex it is
associated with a reactive increase in local blood flow which may
serve to help restore the more normal ionic balance of the neurons
affected. After the CSD induced hyperaemia the local increase in
blood flow attenuates (oligaemia) potentially resulting in
imbalances in energy supply and demand. Under certain conditions,
the reactive hyperaemia is not observed, but instead the local
vasculature constricts resulting in ischaemia which in turn can
lead to neuronal death. The conditions triggering this abnormal
response in experimental models are high extracellular levels of K+
and low NO availability. These conditions are typically seen in
ischaemic areas of the brain, and clusters of CSD waves in these
circumstances result in spreading ischaemia (see Dreier 2011). Of
particular importance is the spreading ischaemia seen after
sub-arachnoid haemorrhage (SAH), in the penumbra of an infarct and
after traumatic brain injury where delayed neuronal damage can have
a significant effect on clinical outcomes (Dreier et al., 2006,
2012; Hartings et al., 2011a, 2011b; Fabricius et al., 2006).
[0003] Given the detrimental effect of clusters of CSDs in humans
and experimental animals, and the poor prognosis associated with
CSDs, there is an unmet medical need for new compounds useful for
inhibiting CSDs for patients with and without brain injuries.
Without wishing to be bound by theory, the spread of CSD is
believed to be mediated by gap junctions rather than by neuronal
synaptic communication (Nedergard et al., 1995; Rawanduzy et al.,
1997, Saito et al., 1997), the gap junctions providing a means of
spreading the depolarisation in the absence of normal synaptic
communication. Gap junctions are comprised of connexin proteins of
which there are 21 in the human genome. Each Gap junction is made
of two hemichannels, each comprising six connexin monomers.
[0004] Gap junctions are also implicated in a number of other
disease states including hereditary diseases of the skin and ear
(e.g. keratitis-ichthyosis deafness syndrome, erythrokeratoderma
variabilis, Vohwinkel's syndrome, and hypotrichosis-deafness
syndrome). Blockade of gap junction proteins has been shown to
beneficial in some preclinical models of pain (e.g. Spataro et al.,
2004 J Pain 5, 392-405, Wu et al., 2012 J Neurosci Res. 90,
337-45). This is believed to be a consequence of gap junction
blockade in the spinal cord resulting in a reduction in the
hypersensitivity of the dorsal horn to sensory nerve input. In
addition gap junctions and their associated hemichannels have been
implicated in neurodegenerative diseases including Alzheimer's
disease, Parkinson's Disease, Huntington's Disease and amyotrophic
lateral sclerosis (Takeuchi et al 2011 PLoS One.; 6, e21108).
[0005] Tonabersat (SB-220453/PRX201145) is a gap junction blocker
(Silberstein, 2009; Durham and Garrett, 2009) which binds
selectively and with high affinity to a unique stereo-selective
site in rat and human brains. Consistent with its action on gap
junctions Tonabersat also inhibits high K+ evoked CSD in cats
(Smith et al., 2000; Read et al., 2000; Bradley et al., 2001) and
rats (Read et al., 2001).
[0006] However, known gap junction blockers, including Tonabersat
and Carabersat, suffer from undesirable physiochemical properties.
Tonabersat is a crystalline solid with a high melting point
(152-153 C) and with a relatively high lipophilicity (log P 3.32).
The compound has no readily ionisable groups and consequently has a
low aqueous solubility of 0.025 mg/ml over a range of pH values
including pH of 7.4. The low aqueous solubility of Tonabersat makes
both intravenous (IV) and oral (PO) modes of administration
problematic. The poor aqueous solubility prevents rapid injection
of the required dose of Tonabersat which is required for the
treatment of head injuries and stroke or for emergency treatment of
epileptic seizures where the patient may be unconscious and unable
to swallow an oral drug. At present the effective plasma
concentrations needed to reduce the cortical spreading depression
caused by head injury or stroke can only be reached by slow IV
infusion given over a period of hours. With respect to the PO
administration of Tonabersat for the treatment of other
indications, solubility limited dissolution of the tablet form of
Tonabersat given PO leads to a significant "food effect" with
differences in the maximum blood concentration of Tonabersat (Cmax)
seen depending on whether the drug is given with or without food.
These differences make it difficult to accurately predict the
plasma exposure of Tonabersat when given orally, thus increasing
the risk of under or over dosing the patient.
[0007] Therefore it is an object of the present invention to
provide gap junction blocker compounds having improved
physiochemical properties thus improving the utility of these
agents in treating a range of disease states.
BRIEF DESCRIPTION OF THE INVENTION
[0008] The present invention makes available three classes of
compounds, each class having one or more solubilising pro-drug
groups.
DETAILED DESCRIPTION OF THE INVENTION
[0009] In a first aspect, the present invention makes available a
class of compounds of formula (I) or a hydrate, solvate, or
pharmaceutically acceptable salt thereof:
##STR00002##
[0010] wherein
[0011] Z.sub.1, Z.sub.2, and Z.sub.3 are each independently
selected from H, F, or Cl,
[0012] Q is O,
[0013] R.sup.2 is H,
[0014] A is a direct bond, --C(O)O*--, --C(R.sup.3)(R.sup.4)O*--,
--C(O)O--C(R.sup.3)(R.sup.4)O*--, or
--C(R.sup.3)(R.sup.4)O--C(O)O*-- wherein the atom marked * is
directly connected to R.sup.1,
[0015] R.sup.3 and R.sup.4 are selected independently from H,
fluoro, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl, or
[0016] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a cyclopropyl group,
[0017] R.sup.1 is selected from groups [1], [2], [2A], [2B][3],
[4], [5] or [6] wherein the atom marked ** is directly connected to
A:
##STR00003##
[0018] R.sup.5 and R.sup.6 are each independently selected from H,
C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or benzyl;
[0019] R.sup.7 is independently selected from H, C.sub.1-4 alkyl,
or C.sub.1-4 fluoroalkyl;
[0020] R.sup.8 is selected from:
[0021] (i) H, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl, or
[0022] (ii) the side chain of a natural or unnatural alpha-amino
acid;
[0023] or R.sup.7 and R.sup.8 together with the atom to which they
are attached form a C.sub.3-7 carbocyclic ring;
[0024] R.sup.9 is selected from H, --N(R.sup.11)(R.sup.12), or
--N.sup.+(R.sup.11)(R.sup.12)(R.sup.13)X.sup.---, or
--N(R.sup.11)C(O)R.sup.14 wherein R.sup.11, R.sup.12, and R.sup.13
are independently selected from H, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl, or R.sup.11 and R.sup.12 together with the nitrogen
atom to which they are attached form a 3-8 membered heterocyclic
ring,
[0025] R.sup.14 is H, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl,
[0026] R.sup.10 and R.sup.15 are independently selected from
C.sub.1-4 alkyl or C.sub.1-4 fluoroalkyl,
[0027] X.sup.- is a pharmaceutically acceptable anion.
[0028] In a second aspect, the present invention makes available a
class of compounds of formula (II) or a hydrate, solvate, or
pharmaceutically acceptable salt thereof:
##STR00004##
[0029] wherein
[0030] Z.sub.1, Z.sub.2, and Z.sub.3 are each independently
selected from H, F, or Cl,
[0031] Q is O,
[0032] A is a direct bond and R.sup.1 is H,
[0033] R.sup.2 is B--R.sup.21 wherein,
[0034] B is a direct bond, --C(O)O*--, --C(R.sup.23)(R.sup.24)O*--,
--C(O)O--C(R.sup.23)(R.sup.24)O*--, or
--C(R.sup.23)(R.sup.24)O--C(O)O*-- wherein the atom marked * is
directly connected to R.sup.21,
[0035] R.sup.23 and R.sup.24 are selected independently from H,
fluoro, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl, or
[0036] R.sup.23 and R.sup.24 together with the atom to which they
are attached form a cyclopropyl group,
[0037] R.sup.21 is selected from groups [21], [22], [22A], [22B],
[23], [24], [25] and [26] wherein the atom marked ** is directly
connected to B:
##STR00005##
[0038] R.sup.25 and R.sup.26 are each independently selected from
H, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl or benzyl;
[0039] R.sup.27 is independently selected from H, C.sub.1-4 alkyl,
C.sub.1-4 fluoroalkyl;
[0040] R.sup.28 is selected from:
[0041] (i) H, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl, or
[0042] (ii) the side chain of a natural or unnatural alpha-amino
acid;
[0043] or R.sup.27 and R.sup.28 together with the atom to which
they are attached form a C.sub.3-7 carbocyclic ring;
[0044] R.sup.29 is selected from H, --N(R.sup.31)(R.sup.32), or
--N.sup.+(R.sup.31)(R.sup.32)(R.sup.33)X.sup.-, or
--N(R.sup.31)C(O)R.sup.34 wherein R.sup.31, R.sup.32, and R.sup.33
are independently selected from H, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl, or R.sup.31 and R.sup.32 together with the nitrogen
atom to which they are attached form a 3-8 membered heterocyclic
ring,
[0045] R.sup.34 is H, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl,
[0046] X.sup.- is a pharmaceutically acceptable anion,
[0047] R.sup.30 and R.sup.35 are independently C.sub.1-4 alkyl or
C.sub.1-4 fluoroalkyl.
[0048] In a third aspect, the present invention makes available a
class of compounds of formula (IIIa) or (IIIb), or a hydrate,
solvate, or pharmaceutically acceptable salt thereof:
##STR00006##
[0049] wherein Z.sub.1, Z.sub.2, and Z.sub.3 are each independently
selected from H, F, or Cl; and
[0050] R.sup.2 and -A-R.sup.1 are both H; and
[0051] In the case of formula (IIIa):
[0052] R.sup.41 and R.sup.42 are independently H, C.sub.1-4
fluoroalkyl or optionally substituted C.sub.1-4 alkyl, or
[0053] R.sup.41 and R.sup.42 together with the carbon atom to which
they are attached form a 5-8 membered heterocycle, any carbon atom
of which is optionally substituted; or
[0054] In the case of formula (IIIb):
[0055] Q is an oxime of formula .dbd.NHOR.sup.43, wherein R.sup.43
is
[0056] (i) selected from H, C.sub.1-4 fluoroalkyl or optionally
substituted C.sub.1-4 alkyl, or
[0057] (ii) -A.sup.300-R.sup.300 wherein
[0058] A.sup.300 is a direct bond, --C(O)O*--,
--C(R.sup.3)(R.sup.4)O*--, --C(O)O--C(R.sup.3)(R.sup.4)O*--, or
--C(R.sup.3)(R.sup.4)O--C(O)O*-- wherein the atom marked * is
directly connected to R.sup.300,
[0059] R.sup.3 and R.sup.4 are selected independently from H,
fluoro, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl, or
[0060] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a cyclopropyl group,
[0061] R.sup.300 is selected from groups [1], [2], [2A], [2B], [3],
[4], [5] or [6] wherein the atom marked ** is directly connected to
A.sup.300:
##STR00007##
[0062] R.sup.5 and R.sup.6 are each independently selected from H,
C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or benzyl;
[0063] R.sup.7 is independently selected from H, C.sub.1-4 alkyl,
or C.sub.1-4 fluoroalkyl;
[0064] R.sup.8 is selected from:
[0065] (iii) H, C.sub.1-4 alkyl, or C.sub.1-4-fluoroalkyl, or
[0066] (iv) the side chain of a natural or unnatural alpha-amino
acid;
[0067] or R.sup.7 and R.sup.8 together with the atom to which they
are attached form a C.sub.3-7 carbocyclic ring;
[0068] R.sup.9 is selected from H, --N(R.sup.11)(R.sup.12), or
--N.sup.+(R.sup.11)(R.sup.12)(R.sup.13)X.sup.-, or
--N(R.sup.11)C(O)R.sup.14 wherein R.sup.11, R.sup.12, and R.sup.13
are independently selected from H, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl, or R.sup.11 and R.sup.12 together with the nitrogen
atom to which they are attached form a 3-8 membered heterocyclic
ring,
[0069] R.sup.14 is H, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl
[0070] R.sup.10 and R.sup.15 are independently selected from
C.sub.1-4 alkyl or C.sub.1-4 fluoroalkyl,
[0071] X.sup.- is a pharmaceutically acceptable anion.
[0072] In an embodiment R.sup.43 is C.sub.1-4 alkyl optionally
substituted with a phosphate group (--P(O)OR.sup.61R.sup.62). In an
example of such an embodiment OR.sup.43 is
--OCH.sub.2P(O)OR.sup.61OR.sup.62, wherein R.sup.61 and R.sup.62
are independently H or C.sub.1-4 alkyl.
[0073] In another embodiment R.sup.43 is an amino acid derivative
having the structure --C(O)CH(R.sup.100)NH.sub.2 wherein the group
R.sup.100 is the side chain of a natural or unnatural amino acid.
In an embodiment OR.sup.43 is
--OC(O)CH(CH(CH.sub.3).sub.2)NH.sub.2.
[0074] Preferably the invention is as set out in the claims.
TERMINOLOGY
[0075] As used herein, the term "(C.sub.a-C.sub.b)alkyl" wherein a
and b are integers refers to a straight or branched chain alkyl
radical having from a to b carbon atoms. Thus when a is 1 and b is
6, for example, the term includes methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and
n-hexyl.
[0076] As used herein, the term "(C.sub.a-C.sub.b)fluoroalkyl" has
the same meaning as "(C.sub.a-C.sub.b)alkyl" except that one or
more of the hydrogen atoms directly connected to the carbon atoms
forming the alkyl group is replaced by the corresponding number of
fluorine atoms.
[0077] As used herein the unqualified term "carbocyclic" refers to
a mono-, bi- or tricyclic radical having up to 16 ring atoms, all
of which are carbon, and includes aryl and cycloalkyl.
[0078] As used herein the unqualified term "cycloalkyl" refers to a
monocyclic saturated carbocyclic radical having from 3-8 carbon
atoms and includes, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0079] As used herein the unqualified term "aryl" refers to a
mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes
radicals having two monocyclic carbocyclic aromatic rings which are
directly linked by a covalent bond. Illustrative of such radicals
are phenyl, biphenyl and napthyl.
[0080] As used herein the unqualified term "heteroaryl" refers to a
mono-, bi- or tri-cyclic aromatic radical containing one or more
heteroatoms selected from S, N and O, and includes radicals having
two such monocyclic rings, or one such monocyclic ring and one
monocyclic aryl ring, which are directly linked by a covalent bond.
Illustrative of such radicals are thienyl, benzthienyl, furyl,
benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl,
benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl,
benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl,
benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, triazinyl, indolyl and indazolyl.
[0081] As used herein the unqualified term "heterocyclyl" or
"heterocyclic" includes "heteroaryl" as defined above, and in
addition means a mono-, bi- or tri-cyclic non-aromatic radical
containing one or more heteroatoms selected from S, N and O, and to
groups consisting of a monocyclic non-aromatic radical containing
one or more such heteroatoms which is covalently linked to another
such radical or to a monocyclic carbocyclic radical. Illustrative
of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,
pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl,
piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl,
isoxazolyl, benzimidazolyl, methylenedioxyphenyl,
ethylenedioxyphenyl, maleimido and succinimido groups.
[0082] Unless otherwise specified in the context in which it
occurs, the term "substituted" as applied to any moiety herein
means substituted with up to four compatible substituents, each of
which independently may be, for example, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, hydroxy, hydroxy(C.sub.1-C.sub.6)alkyl,
mercapto, mercapto(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylthio, halo (including fluoro, bromo and
chloro), fully or partially fluorinated (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy or (C.sub.1-C.sub.3)alkylthio such as
trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, nitro,
nitrile (--CN), oxo, phenyl, phenoxy, monocyclic heteroaryl or
heteroaryloxy with 5 or 6 ring atoms, tetrazolyl, --COOR.sup.A,
--COR.sup.A, --OCOR.sup.A, --SO.sub.2R.sup.A, --CONR.sup.AR.sup.B,
--SO.sub.2NR.sup.AR.sup.B, --NR.sup.AR.sup.B, OCONR.sup.AR.sup.B,
--NR.sup.BCOR.sup.A, --NR.sup.BCOOR.sup.A,
--NR.sup.BSO.sub.2OR.sup.A or --NR.sup.ACONR.sup.AR.sup.B wherein
R.sup.A and R.sup.B are independently hydrogen or a
(C.sub.1-C.sub.6)alkyl group or, in the case where R.sup.A and
R.sup.B are linked to the same N atom, R.sup.A and R.sup.B taken
together with that nitrogen may form a cyclic amino ring, such as a
morpholine, piperidinyl or piperazinyl ring. Where the substituent
is phenyl, phenoxy or monocyclic heteroaryl or heteroaryloxy with 5
or 6 ring atoms, the phenyl or heteroaryl ring thereof may itself
be substituted by any of the above substituents except phenyl,
phenoxy, heteroaryl or heteroaryloxy. An "optional substituent" may
be one of the foregoing substituent groups.
[0083] As used herein the term "salt" includes base addition, acid
addition and quaternary salts. Compounds of the invention which are
acidic can form salts, including pharmaceutically acceptable salts,
with bases such as alkali metal hydroxides, e.g. sodium and
potassium hydroxides; alkaline earth metal hydroxides e.g. calcium,
barium and magnesium hydroxides; with organic bases e.g.
N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane,
L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the
like. Those compounds of formula (I), (II), (IIIa) or (IIIb) which
are basic can form salts, including pharmaceutically acceptable
salts with inorganic acids, e.g. hydrohalic acids such as
hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or
phosphoric acid and the like, and with organic acids e.g. acetic,
tartaric, succinic, fumaric, maleic, malic, salicylic, citric,
methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic,
glutamic, lactic, and mandelic acids and the like.
[0084] The formation of specific salt forms can provide compounds
of the invention with improved physicochemical properties. For a
review on suitable salts, see Handbook of Pharmaceutical Salts:
Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,
Weinheim, Germany, 2002).
[0085] The term `solvate` is used herein to describe a molecular
complex comprising the compound of the invention and a
stoichiometric amount of one or more pharmaceutically acceptable
solvent molecules, for example, ethanol. The term `hydrate` is
employed when said solvent is water.
[0086] Compounds with which the invention is concerned which may
exist in one or more stereoisomeric form, because of the presence
of asymmetric atoms or rotational restrictions, can exist as a
number of stereoisomers with R or S stereochemistry at each chiral
centre or as atropisomers with R or S stereochemistry at each
chiral axis. The invention includes all such enantiomers and
diastereoisomers and mixtures thereof. In particular, the carbon
atom to which the groups R.sup.7 and R.sup.7 are attached may be in
either the R or the S configuration.
[0087] The compounds of the invention include compounds of formula
(I), (II), (IIIa) or (IIIb) as hereinbefore defined, including all
polymorphs and crystal habits thereof, prodrugs and isomers thereof
(including optical, geometric and tautomeric isomers) as
hereinafter defined and isotopically-labeled compounds of formula
(I), (II), (IIIa) or (IIIb).
[0088] Also included within the scope of the invention are
metabolites of compounds of formula (I), (II), (IIIa) or (IIIb),
that is, compounds formed in vivo upon administration of the drug.
Some examples of metabolites include: [0089] (i) where the compound
of formula I contains a methyl group, an hydroxymethyl derivative
thereof (--CH.sub.3->--CH.sub.2OH): [0090] (ii) where the
compound of formula I contains an alkoxy group, an hydroxy
derivative thereof (--OR->--OH); [0091] (iii) where the compound
of formula I contains a tertiary amino group, a secondary amino
derivative thereof (e.g. --NR.sup.1AR.sub.2A->NHR.sup.1A or
--NHR.sup.2A); [0092] (iv) where the compound of formula I contains
a secondary amino group, a primary derivative thereof
(--NHR.sup.1A->--NH.sub.2); [0093] (v) where the compound of
formula I contains a phenyl moiety, a phenol derivative thereof
(-Ph->-PhOH); and [0094] (vi) where the compound of formula I
contains an amide group, a carboxylic acid derivative thereof
(--CONH.sub.2->COOH).
[0095] For use in accordance with the invention, the following
structural characteristics are currently contemplated, in any
compatible combination, in the compounds of formula (I):
[0096] The groups Z.sub.1, Z.sub.2, and Z.sub.3 are each
independently selected from H, F, or Cl. In an embodiment Z.sub.1
is Cl, Z.sub.2 is F, and Z.sub.3 is H. In another embodiment
Z.sub.1 is Cl, Z.sub.2 and Z.sub.3 are H. In another embodiment
Z.sub.1 is H, Z.sub.2 is F, and Z.sub.3 is H. In another embodiment
Z.sub.1 is F, Z.sub.2 is H, and Z.sub.3 is F. The above definitions
of Z.sub.1, Z.sub.2, and Z.sub.3 is H are applicable to compounds
of formula (I), (II), (IIIa), and (IIIb). As an illustration, the
preferred definition of Z.sub.1, Z.sub.2, and Z.sub.3 applied to
the compounds of formula (I) is as follows:
##STR00008##
[0097] In a preferred embodiment Z.sub.1 is Cl, Z.sub.2 is F or H,
and Z.sub.3 is H.
[0098] The group Q is an oxygen atom
[0099] The group R.sup.2 is a hydrogen atom
[0100] The group A is a direct bond, --C(O)O*--,
--C(R.sup.3)(R.sup.4)O*--, --C(O)O--C(R.sup.3)(R.sup.4)O*--, or
--C(R.sup.3)(R.sup.4)O--C(O)O*-- wherein the atom marked * is
directly connected to R.sup.1.
[0101] The groups R.sup.3 and R.sup.4 are selected independently
from H, fluoro, C.sub.1-4 alkyl such as methyl, ethyl, propyl or
isopropyl, or C.sub.1-4 fluoroalkyl such as trifluoromethyl, or
R.sup.3 and R.sup.4 together with the atom to which they are
attached form a cyclopropyl group,
[0102] In an embodiment A is a direct bond. In another embodiment A
is --CH.sub.2O*--, or --CH(CH.sub.3)O*--, or
C(CH.sub.3).sub.2O*--.
[0103] The group R.sup.1 is selected from groups [1], [2], [2A],
[2B], [3], [4], [5] or [6] wherein the atom marked ** is directly
connected to A:
##STR00009##
[0104] The groups R.sup.5 and R.sup.6 are each independently
selected from H, C.sub.1-4 alkyl such as methyl, ethyl, propyl or
isopropyl, C.sub.1-4 fluoroalkyl such as trifluoromethyl, or
benzyl. In an embodiment R.sup.5 and R.sup.6 are hydrogen.
[0105] The group R.sup.7 is independently selected from H,
C.sub.1-4 alkyl such as methyl, ethyl, propyl or isopropyl, or
C.sub.1-4 fluoroalkyl such as trifluoromethyl. In another
embodiment R.sup.7 and R.sup.8 are both hydrogen, or R.sup.7 is
hydrogen and R.sup.8 is methyl, or both R.sup.7 and R.sup.8 are
methyl. In an embodiment R.sup.7, R.sup.8 and R.sup.9 are hydrogen.
In an embodiment R.sup.7 is hydrogen.
[0106] The group R.sup.8 is selected from: [0107] (i) H, C.sub.1-4
alkyl such as methyl, ethyl, propyl, or isopropyl, or
C.sub.1-4-fluoroalkyl such as trifluoromethyl, or [0108] (ii) the
side chain of a natural or unnatural alpha-amino acid;
[0109] or R.sup.7 and R.sup.8 together with the atom to which they
are attached form a C.sub.3-7 carbocyclic ring such as cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl;
[0110] The term "side chain of a natural or non-natural alpha-amino
acid" refers to the group R.sup.100 in a natural or non-natural
amino acid of formula NH.sub.2--CH(R.sup.100)--CO.sub.2H.
[0111] In an embodiment the group -AR.sup.1 is selected from the
following groups wherein the atom marked ** is directly connected
to the oxygen atom of the parent drug:
##STR00010##
[0112] Examples of side chains of natural alpha amino acids include
those of alanine, arginine, asparagine, aspartic acid, cysteine,
cystine, glutamic acid, histidine, 5-hydroxylysine,
4-hydroxyproline, isoleucine, leucine, lysine, methionine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine,
valine, .alpha.-aminoadipic acid, .alpha.-amino-n-butyric acid,
3,4-dihydroxyphenylalanine, homoserine, .alpha.-methylserine,
ornithine, pipecolic acid, and thyroxine.
[0113] Natural alpha-amino acids which contain functional
substituents, for example amino, carboxyl, hydroxy, mercapto,
guanidyl, imidazolyl, or indolyl groups in their characteristic
side chains include arginine, lysine, glutamic acid, aspartic acid,
tryptophan, histidine, serine, threonine, tyrosine, and cysteine.
When R.sup.8 in the compounds of the invention is one of those side
chains, the functional substituent may optionally be protected.
[0114] The term "protected" when used in relation to a functional
substituent in a side chain of a natural alpha-amino acid means a
derivative of such a substituent which is substantially
non-functional. For example, carboxyl groups may be esterified (for
example as a C.sub.1-C.sub.6 alkyl ester), amino groups may be
converted to amides (for example as a NHCOC.sub.1-C.sub.6 alkyl
amide) or carbamates (for example as an NHC(.dbd.O)OC.sub.1-C.sub.6
alkyl or NHC(.dbd.O)OCH.sub.2Ph carbamate), hydroxyl groups may be
converted to ethers (for example an OC.sub.1-C.sub.6 alkyl or a
O(C.sub.1-C.sub.6 alkyl)phenyl ether) or esters (for example a
OC(.dbd.O)C.sub.1-C.sub.6 alkyl ester) and thiol groups may be
converted to thioethers (for example a tert-butyl or benzyl
thioether) or thioesters (for example a SC(.dbd.O)C.sub.1-C.sub.6
alkyl thioester).
[0115] Examples of side chains of non-natural alpha amino acids
include: an optional substituent, C.sub.1-C.sub.6 alkyl, phenyl, 2,
-3-, or 4-hydroxyphenyl, 2, -3-, or 4-methoxyphenyl, 2, -3-, or
4-pyridylmethyl, benzyl, phenylethyl, 2-, 3-, or 4-hydroxybenzyl,
2, -3-, or 4-benzyloxybenzyl, 2, -3-, or 4-C.sub.1-C.sub.6
alkoxybenzyl, and benzyloxy(C.sub.1-C.sub.6alkyl)-groups, wherein
any of the foregoing non-natural amino acid side chains is
optionally substituted in the alkyl, phenyl or pyridyl group;
or
[0116] groups -[Alk].sub.nR.sub.50 where Alk is a
(C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.6)alkenyl group optionally
interrupted by one or more --O--, or --S-- atoms or --N(R.sub.51)--
groups [where R.sub.51 is a hydrogen atom or a
(C.sub.1-C.sub.6)alkyl group], n is 0 or 1, and R.sub.50 is an
optionally substituted cycloalkyl or cycloalkenyl group; or
[0117] a heterocyclic(C.sub.1-C.sub.6)alkyl group, either being
unsubstituted or mono- or di-substituted in the heterocyclic ring
with halo, nitro, carboxy, (C.sub.1-C.sub.6)alkoxy, cyano,
(C.sub.1-C.sub.6)alkanoyl, trifluoromethyl (C.sub.1-C.sub.6)alkyl,
hydroxy, formyl, amino, (C.sub.1-C.sub.6)alkylamino,
di-(C.sub.1-C.sub.6)alkylamino, mercapto,
(C.sub.1-C.sub.6)alkylthio, hydroxy(C.sub.1-C.sub.6)alkyl,
mercapto(C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkylphenylmethyl; and
[0118] The group R.sup.9 is selected from H,
--N(R.sup.11)(R.sup.12) such as --NH.sub.2, NH(CH.sub.3),
--NH(CH.sub.3).sub.2, or
--N.sup.+(R.sup.11)(R.sup.12)(R.sup.13)X.sup.- such as
--N.sup.+(CH.sub.3).sub.3X.sup.-, or --N(R.sup.11)C(O)R.sup.14
[0119] wherein R.sup.11, R.sup.12, and R.sup.13 are independently
selected from H, C.sub.1-4 alkyl such as methyl, ethyl, propyl or
isopropyl, or C.sub.1-4 fluoroalkyl such as trifluoromethyl, or
R.sup.11 and R.sup.12 together with the nitrogen atom to which they
are attached form a 3-8 membered heterocyclic ring such as
pyrrolidine, piperidine, piperazine, morpholine or homomorpholine.
In an embodiment R.sup.11 and R.sup.12 are both methyl.
[0120] R.sup.14 is H, C.sub.1-4 alkyl such as methyl, ethyl, propyl
or isopropyl, or C.sub.1-4 fluoroalkyl such as trifluoromethyl
[0121] R.sup.10 and R.sup.15 are independently selected from
C.sub.1-4 alkyl or C.sub.1-4 fluoroalkyl.
[0122] The counterion X.sup.- is a pharmaceutically acceptable
anion such as chloride, or any other anion fromed by removal of one
or more protons from an inorganic acid, e.g. hydrohalic acids such
as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid
or phosphoric acid and the like, or from an organic acids e.g.
acetic, tartaric, succinic, fumaric, maleic, malic, salicylic,
citric, methanesulphonic, p-toluenesulphonic, benzoic,
benzenesunfonic, glutamic, lactic, and mandelic acids and the
like.
[0123] Specific compounds of the invention include those of the
Examples herein.
[0124] It will be understood that the compounds of formula (I),
(II), (IIIa) or (IIIb) may be further modified by adding one or
more of the prodrug groups Q, -AR.sup.1 or R.sup.2. For example the
compounds of formula (I) or (ii) may be modified by exchanging the
oxygen atom Q for a prodrug Q group as defined in (IIIa) or (IIIb).
Alternatively, the compounds of formula (I) could be modified by
replacing the hydrogen atom R2 by the prodrug group R2 as defined
in formula (II), and vice versa.
[0125] The present invention makes available a pharmaceutical
composition comprising a compound of formula (I), (II), (IIIa) or
(IIIb) together with one or more pharmaceutically acceptable
carriers and/or excipients.
[0126] The present invention makes available a compound of formula
(I), (II), (IIIa) or (IIIb) for use in medicine.
[0127] In an embodiment the inventions encompasses the use of a
compound of formula (I), (II), (IIIa) or (IIIb) treatment of a
disease or medical condition which benefits from inhibition of gap
junction activity. Inhibition of gap junction activity may be
achieved by blocking the gap junction as a whole or by blocking one
or more hemichannels.
[0128] In an embodiment the inventions encompasses a method of
treatment of a disease or medical condition which benefits from
inhibition of gap junction activity, comprising administering to a
subject suffering from such disease or condition and effective
amount of a compound of formula (I), (II), (IIIa) or (IIIb).
[0129] In an embodiment the disease or condition which benefits
from inhibition of gap junction activity is selected from among
migraine, aura with or without migraine, epilepsy, non-epileptic
seizures, cerebrovascular accidents including stroke, intracranial
haemorrhage (including traumatic brain injury, epidural hematoma,
subdural hematoma and subarachnoid haemorrhage), and intra-cerebral
haemorrhage, spinal cord vascular accidents arising from trauma,
epidural hematoma, subdural hematoma or subarachnoid haemorrhage,
pain including pain arising from hyperalgesia caused by damage to
sensory neurons (i.e. neuropathic pain including but not limited to
diabetic neuropathy, polyneuropathy, cancer pain, fibromyalgia,
myofascial pain, post herpetic neuralgia, spinal stenosis, HIV
pain, post-operative pain, post-trauma pain) or inflammation
(including pain associated with osteoarthritis, rheumatoid
arthritis, sciatica/radiculopathy, pancreatitis, tendonitis),
neurodegenerative disease (including but not limited to Alzheimer's
Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic
Lateral Sclerosis) and cardiovascular disease including myocardial
infarction, coronary revascularization or angina.
[0130] It will be understood that the specific dose level for any
particular patient will depend upon a variety of factors including
the activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of administration, route of
administration, rate of excretion, drug combination and the
severity of the particular disease undergoing treatment. Optimum
dose levels and frequency of dosing will be determined by clinical
trial, as is required in the pharmaceutical art. However, for
administration to human patients, the total daily dose of the
compounds of the invention may typically be in the range 1 mg to
1000 mg depending, of course, on the mode of administration. For
example, oral administration may require a total daily dose of from
10 mg to 1000 mg, while an intravenous dose may only require from 1
mg to 500 mg. The total daily dose may be administered in single or
divided doses and may, at the physician's discretion, fall outside
of the typical range given herein. These dosages are based on an
average human subject having a weight of about 60 kg to 100 kg. The
physician will readily be able to determine doses for subjects
whose weight falls outside this range, such as infants and the
elderly, and especially obese patients.
[0131] The compounds with which the invention is concerned may be
prepared for administration by any route consistent with their
pharmacokinetic properties. Suitable routes for administration
include oral, intravenous, buccal, intranasal, inhalation, rectal,
and intradermal. The orally administrable compositions may be in
the form of tablets, capsules, powders, granules, lozenges, liquid
or gel preparations, such as oral, topical, or sterile parenteral
solutions or suspensions. Tablets and capsules for oral
administration may be in unit dose presentation form, and may
contain conventional excipients such as binding agents, for example
syrup, acacia, gelatin, sorbitol, tragacanth, or
polyvinyl-pyrrolidone; fillers for example lactose, sugar,
maize-starch, calcium phosphate, sorbitol or glycine; tabletting
lubricant, for example magnesium stearate, talc, polyethylene
glycol or silica; disintegrants for example potato starch, or
acceptable wetting agents such as sodium lauryl sulphate. The
tablets may be coated according to methods well known in normal
pharmaceutical practice. Oral liquid preparations may be in the
form of, for example, aqueous or oily suspensions, solutions,
emulsions, syrups or elixirs, or may be presented as a dry product
for reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as
suspending agents, for example sorbitol, syrup, methyl cellulose,
glucose syrup, gelatin hydrogenated edible fats; emulsifying
agents, for example lecithin, sorbitan monooleate, or acacia;
non-aqueous vehicles (which may include edible oils), for example
almond oil, fractionated coconut oil, oily esters such as
glycerine, propylene glycol, or ethyl alcohol; preservatives, for
example methyl or propyl p-hydroxybenzoate or sorbic acid, and if
desired conventional flavouring or colouring agents.
[0132] The pro-drug may also be administered parenterally in a
sterile medium. Depending on the vehicle and concentration used,
the drug can either be suspended or dissolved in the vehicle.
Advantageously, adjuvants such as local anaesthetic, preservative
and buffering agents can be dissolved in the vehicle. The person
skilled in the art is aware of many excipients useful for IV
formulation.
[0133] Preparation of Compounds of the Invention
[0134] The compounds of formula (I) above may be prepared by, or in
analogy with, conventional methods. The preparation of
intermediates and compounds according to the Examples of the
present invention may in particular be illuminated by the following
Schemes. Definitions of variables in the structures in Schemes
herein are commensurate with those of corresponding positions in
the formulas delineated herein.
##STR00011## ##STR00012##
[0135] wherein A, Q, Z.sub.1, Z.sub.2, Z.sub.3, R.sup.1 and R.sup.2
are as defined in formula (I);
[0136] Compounds of general formula (I) can easily be prepared from
the alcohols of general formula (IV) by either using the alcohol
directly or pre-forming the alkoxide using a suitable base/reagent
(e.g. NaH) and coupling to a suitably activated A-R or R group (or
protected A-R or R group). Activated A-R or R group functionalities
typically used for the formation of phosphates, esters, carbonates
and carbamates include, but not limited to, phosphoryl chlorides,
acid chlorides, activated carboxylic acids, chloroformates,
activated carbonates and isocyanates. The formation of (la) from
(IV) using dimethylaminoacetyl chloride as an activated R group is
representative of this approach. When the compound of general
formula (I) has an A group defined as --C(R.sup.3)(R.sup.4)O*-- or
C(R.sup.3)(R.sup.4)OC(O)O*-- these may be prepared from compounds
of general formula (IV) using an appropriate alkylating agent which
may include, but not limited to, alkylchlorides, alkylbromides,
alkyliodides, mesylates and tosylates. The formation of (Ib) from
(IV) using NaH to form the sodium alkoxide of (IV) followed by
coupling with bromomethyl acetate as an activated A-R group is
representative of this approach.
##STR00013## ##STR00014##
[0137] wherein A, Q, Z.sub.1, Z.sub.2, Z.sub.3, R.sup.1 and R.sup.2
are as defined in formula (I);
[0138] P.sup.1 is a suitable protecting group or functionality that
can be readily chemically modified/utilised to append R.sup.1.
[0139] Alternatively, compounds of general formula (I) can easily
be prepared in a more step wise manner from the alcohol of general
formula (IV) by using either the alcohol directly or pre-forming
the alkoxide using a suitable base/reagent (e.g. NaH) and coupling
to a suitably activated A-P.sup.1 group. When the compound of
general formula (I) has an A group defined as
--C(R.sup.3)(R.sup.4)O*-- or C(R.sup.3)(R.sup.4)OC(O)O*-- these may
be prepared using activated forms of A-P.sup.1 including, but not
limited to, alkylchlorides, alkylbromides, alkyliodides, mesylates
and tosylates. When the compound of general formula (I) has an A
group defined as --C(O)O*-- or C(O)OC(R.sup.3)(R.sup.4)O*-- these
may be prepared using activated forms of A-P.sup.1 including, but
not limited to, chloroformates and activated carbonates. Then using
methods known to those skilled in the art the intermediates of
general formula (V) can be chemically modified to provide
functionality that facilitates the final coupling step to afford
compounds of general formula (I). The formation of (Ic) from (IV)
via the methylsulfanyl methoxy intermediate (Va) is representative
of this approach.
[0140] The synthesis of Tonabersat, and other structurally related
compounds, is disclosed in WO 95/34545. The present invention
encompasses compounds prepared by applying the pro-drug groups
-AR.sup.1, R.sup.2 and Q taught herein to the specific Examples
disclosed in WO 95/34545. The methods proposed for the synthesis of
compounds of general formula (I) are known to those skilled in the
art, for example in Rautio et al., Nature Reviews Drug Discovery,
7, 255-270, 2008.
[0141] Optionally, a compound of formula (I) can also be
transformed into another compound of formula (I) in one or more
synthetic steps.
[0142] The following abbreviations have been used:
[0143] Boc tertiary-butyloxycarbonyl
[0144] d day(s)
[0145] DCM dichloromethane
[0146] DIPEA diisopropylethylamine
[0147] DMAP 4-dimethylaminopyridine
[0148] DME dimethoxyethane
[0149] DMF dimethylformamide
[0150] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
[0151] ES+ electrospray ionization
[0152] EtOAc ethyl acetate
[0153] Et.sub.2O diethyl ether
[0154] Et.sub.3N triethylamine
[0155] EtOH ethanol
[0156] h hour(s)
[0157] HOBt Hydroxybenzotriazole
[0158] HPLC High Performance Liquid Chromatography
[0159] HRMS High-Resolution Mass Spectrometry
[0160] IMS Industrial methylated spirit
[0161] LCMS Liquid Chromatography Mass Spectrometry
[0162] Leu Leucine
[0163] M molar
[0164] MeCN acetonitrile
[0165] MeOH methanol
[0166] MTBE methyl tertiary-butyl ether
[0167] [MH].sup.+ protonated molecular ion
[0168] min minute(s)
[0169] MS Mass Spectrometry
[0170] Rt retention time
[0171] TFA trifluoroacetic acid
[0172] THF tetrahydrofuran
EXAMPLES AND INTERMEDIATE COMPOUNDS
Experimental Methods
[0173] Reactions were conducted at room temperature unless
otherwise specified. Preparative chromatography was performed using
a Flash Master Personal system equipped with Isolute Flash II
silica columns or using a CombiFlash Companion system equipped with
GraceResolv silica column. The purest fractions were collected,
concentrated and dried under vacuum. Compounds were typically dried
in a vacuum oven at 40.degree. C. prior to purity analysis.
Compound analysis was performed by HPLC/LCMS using an Agilent 1100
HPLC system/Waters ZQ mass spectrometer connected to an Agilent
1100 HPLC system with a Phenomenex Synergi, RP-Hydro column
(150.times.4.6 mm, 4 .mu.m, 1.5 mL per min, 30.degree. C., gradient
5-100% MeCN (+0.085% TFA) in water (+0.1% TFA) over 7 min, 200-300
nm). The compounds prepared were named using IUPAC
nomenclature.
Intermediate 1
N-[(3S,4S)-6-acetyl-2,2-dimethyl-3-[(methylsulfanyl)methoxy]-3,4-dihydro-2-
H-1-benzopyran-4-yl]-3-chloro-4-fluorobenzamide
##STR00015##
[0175]
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopy-
ran-4-yl]-3-chloro-4-fluorobenzamide (1.00 g, 2.55 mmol) was
dissolved in DME (10 mL) and added to a suspension of sodium
hydride (60% dispersion in oil, 112 mg, 2.81 mmol) in DME (10 mL).
The reaction mixture was stirred for 10 min then sodium iodide (421
mg, 2.81 mmol) was added followed by chloromethyl methyl sulfide
(232 .mu.L, 2.81 mmol). The reaction mixture was stirred for 18 h
then quenched with saturated aqueous ammonium carbonate solution (5
mL), diluted with EtOAc (50 mL), washed with water (3.times.25 mL),
dried (MgSO.sub.4) and concentrated in vacuo. The residue was
purified by column chromatography on normal phase silica eluting
with a gradient of EtOAc in heptane to give the title compound (405
mg, 35.1%) as a white solid. LCMS (ES.sup.+): 452.1 [MH].sup.+.
HPLC: Rt 6.36 min, 86.2% purity.
Intermediate 2
2-{[(tert-Butoxy)carbonyl](propyl)amino}acetic acid
##STR00016##
[0177] Glyoxylic acid monohydrate (4.67 g, 5.08 mmol) and
1-propylamine (1.50 g, 25.4 mmol) were dissolved in DCM (100 mL)
and the reaction mixture was stirred for 18 h and concentrated in
vacuo. 1M aq HCl (125 mL, 125 mmol) was added and the reaction
mixture was heated under reflux overnight, concentrated in vacuo
and crystallised from i-PrOH/Et.sub.2O to give a white solid. The
2-(propylamino)acetic acid hydrochloride intermediate (2.49 g, 16.2
mmol), di-tert-butyl dicarbonate (8.84 g, 40.5 mmol) and Et.sub.3N
(11.3 mL, 81.1 mmol) were dissolved in water (65 mL) and stirred
for 3d. The reaction mixture was washed with hexane and the aqueous
fraction was acidified with 2M aq HCl and extracted into EtOAc,
washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to
give the title compound (3.40 g, 61.9%) as a colourless oil. LCMS
(ES.sup.-): 216.1 [MH].sup.-.
Example 1
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-di-
hydro-2H-1-benzopyran-3-yl]oxy}phosphonic acid
##STR00017##
[0179]
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopy-
ran-4-yl]-3-chloro-4-fluorobenzamide (2.00 g, 5.10 mmol) was
dissolved in methylethyl ketone (50 mL). Pyridine (1.62 mL, 20.4
mmol) and POCl.sub.3 (1.50 mL, 16.3 mmol) were added and the
reaction mixture was stirred for 16 h. A precipitate was removed by
filtration, washed with methylethyl ketone (50 mL) and 2M aq HCl
(10 mL) added to the combined methylethyl ketone phases. The
reaction mixture was heated at 65.degree. C. for 1 h. The organic
phase was washed with brine (10 mL), dried (MgSO.sub.4) and
concentrated in vacuo. The residue was dissolved in EtOAc (50 mL)
and stirred for 30 min. The resulting precipitate was collected by
filtration, washed with EtOAc (20 mL) and the solid dried in vacuo
to give the title compound (1.67 g, 69.3%) as a white solid. LCMS
(ES.sup.+): 471.9 [MH].sup.+. HPLC: Rt 4.84 min, 100% purity.
Example 2
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihy-
dro-2H-1-benzopyran-3-yl 2-(dimethylamino)acetate hydrochloride
##STR00018##
[0181]
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopy-
ran-4-yl]-3-chloro-4-fluorobenzamide (100 mg, 0.26 mmol) was
dissolved in THF (10 mL). Et.sub.3N (78.3 .mu.L, 0.56 mmol), DMAP
(3 mg, catalytic) and dimethylaminoacetyl chloride hydrochloride
(40.3 mg, 0.26 mmol) were added and the reaction mixture was
stirred for 16 h. Further Et.sub.3N (78.3 .mu.L, 0.56 mmol) and
dimethylaminoacetyl chloride hydrochloride (40.3 mg, 0.26 mmol)
were added and the reaction mixture was stirred for 1 h. Further
Et.sub.3N (157 .mu.L, 1.12 mmol) and dimethylaminoacetyl chloride
hydrochloride (80.6 mg, 0.52 mmol) were added and the reaction
mixture was stirred for 1 h. The reaction mixture was filtered,
washed with THF (30 mL) and the filtrates diluted with EtOAc (70
mL). The organic phase was washed with saturated aqueous
NaHCO.sub.3 (2.times.30 mL), dried (MgSO.sub.4) and concentrated in
vacuo. The residue was dissolved in Et.sub.2O (10 mL). 2M HCl in
Et.sub.2O (2 mL) was added and the resulting precipitate was
collected by filtration, washed with Et.sub.2O (10 mL) and dried in
vacuo to give the title compound (50.0 mg, 41.1%) as an off-white
solid. LCMS (ES.sup.+): 476.9 [MH].sup.+. HPLC: Rt 5.14 min, 97.9%
purity.
Example 3
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihy-
dro-2H-1-benzopyran-3-yl acetate
##STR00019##
[0183]
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopy-
ran-4-yl]-3-chloro-4-fluorobenzamide (200 mg, 0.51 mmol) was
slurried in toluene (2.0 mL) with acetic anhydride (50 .mu.L, 0.51
mmol), N-hydroxysuccinimide (18 mg, 0.15 mmol) and
4-dimethylaminopyridine (6 mg, 0.05 mmol). The reaction mixture was
heated to 80.degree. C. for 195 min to give a colourless solution
and then cooled to ambient temperature overnight. The reaction
mixture was diluted with toluene (2 mL) and washed with 10% aqueous
citric acid (4 mL) and water (4 mL). The toluene phase was
evaporated in vacuo. The residue was purified by column
chromatography on normal phase silica eluting with heptane/ethyl
acetate mixtures. The product was crystallised from toluene (1
mL)/heptane (3 mL) overnight. The solid was collected by
filtration, washed with heptane (2 mL) and dried in vacuo at
40.degree. C. overnight to give the title compound (88.1 mg, 39.8%)
as a white solid. LCMS (ES.sup.+): 434.0 [MH].sup.+. HPLC: Rt 6.32
min, 97.8% purity.
Example 4
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-di-
hydro-2H-1-benzopyran-3-yl]oxy}methyl acetate
##STR00020##
[0185]
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopy-
ran-4-yl]-3-chloro-4-fluorobenzamide (229 mg, 0.58 mmol) was
stirred in DMF (4.0 mL) with NaH (60% dispersion, 45 mg, 0.68 mmol)
for 20 min. Bromomethyl acetate (69 .mu.L, 0.70 mmol) was added and
the mixture stirred at room temperature for 90 min. The reaction
mixture was quenched with water (8 mL) and extracted with EtOAc
(2.times.5 mL). The combined organic extracts were washed with
water (5 mL) and the organic phase evaporated in vacuo. The residue
was purified by column chromatography on normal phase silica
eluting with 4:1 heptane:EtOAc to give the title compound (88 mg;
32.5%) as a white solid. LCMS (ES.sup.+): 464.0 [MH].sup.+. HPLC:
Rt 6.52 min, 97.3% purity.
Example 5
{[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-di-
hydro-2H-1-benzopyran-3-yl]oxy}methyl 2-(dimethylamino)acetate
##STR00021##
[0187] Intermediate 1 (261 mg, 0.58 mmol) was dissolved in DCM (7
mL) and treated with sulfuryl chloride (51.5 .mu.L, 0.64 mmol). The
reaction mixture was stirred for 10 min. N,N-Dimethylglycine (298
mg, 2.89 mmol) and DIPEA (1.00 mL, 5.78 mmol) were dissolved in DCM
(3 mL) and added to the reaction mixture. After 30 min the reaction
mixture was poured into 1M aqueous Na.sub.2CO.sub.3 (50 mL) and
extracted with DCM (2.times.50 mL). The combined organic layers
were dried (MgSO.sub.4) and concentrated in vacuo. The residue was
purified by column chromatography on normal phase silica eluting
with a gradient of EtOAc in heptane. The pure fractions were
combined and dried in vacuo overnight to give the title compound
(114 mg, 38.9%) as a white solid. LCMS (ES.sup.+): 507.1
[MH].sup.+. HPLC: Rt 4.99 min, 98.3% purity.
Example 6
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihy-
dro-2H-1-benzopyran-3-yl 2-aminoacetate hydrochloride
##STR00022##
[0189]
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopy-
ran-4-yl]-3-chloro-4-fluorobenzamide (400 mg, 1.02 mmol) was
dissolved in DCM (8 mL) at room temperature. Boc-Gly-OSu (full
name: 2,5-dioxopyrrolidin-1-yl
2-{[(tert-butoxy)carbonyl]amino}acetate) (556 mg, 2.04 mmol), DIPEA
(391 L, 2.25 mmol) and DMAP (12 mg, 0.10 mmol) were added. The
reaction mixture was stirred overnight. The DCM was evaporated in
vacuo and the residue suspended between EtOAc (15 mL) and 10%
aqueous citric acid solution (10 mL). The organic phase was washed
with water (10 mL) and concentrated in vacuo. The residue was
purified by column chromatography on normal phase silica eluting
with heptane/EtOAc mixtures. The
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl 2-{[(tert-butoxy)carbonyl]amino}acetate
intermediate was dissolved in 4M HCl in dioxane (4 mL) and stirred
at room temperature for 90 min. The solvents were removed in vacuo
and the residue partitioned between EtOAc (10 mL) and saturated
aqueous Na.sub.2CO.sub.3 solution (5 mL). The aqueous layer was
extracted with EtOAc (10 mL) and the combined organic phases
concentrated in vacuo. The residue was purified by column
chromatography on normal phase silica eluting with heptane/ethyl
acetate mixtures. To each pure fraction was added 1.25M HCl in EtOH
(200 .mu.L). The pure fractions were combined and dried in vacuo to
give the title compound (93 mg, 18.8%) as a white foam. LCMS
(ES.sup.+): 449.0 [MH].sup.+. HPLC: Rt 4.95 min, 96.9% purity.
Example 7
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihy-
dro-2H-1-benzopyran-3-yl 2-(methylamino)acetate hydrochloride
##STR00023##
[0191]
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopy-
ran-4-yl]-3-chloro-4-fluorobenzamide (200 mg, 0.51 mmol) was
dissolved in THF (4 mL) at room temperature. Boc-Sar-OSu (full
name: tert-butyl
N-{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-hydroxyethyl}-N-methylcarbamate)
(292 mg, 1.02 mmol), DIPEA (196 .mu.L, 1.12 mmol) and DMAP (6 mg,
0.05 mmol) were added and the reaction mixture was stirred
overnight at 70.degree. C. The THF was evaporated in vacuo and the
residue suspended between EtOAc (10 mL) and 10% aqueous citric acid
solution (5 mL). The organic phase was washed with water (10 mL)
and concentrated in vacuo. The residue was purified by column
chromatography on normal phase silica eluting with heptane/EtOAc
mixtures. The
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl
2-{[(tert-butoxy)carbonyl](methyl)amino}acetate intermediate was
dissolved in 4M HCl in dioxane (2 mL) and stirred at room
temperature for 1 h. The solvents were removed in vacuo. The
residue was triturated in EtOAc/MTBE mixture and then stirred with
ice bath cooling for 1 h. The solid was collected by filtration,
washed with MTBE (2 mL) and dried in vacuo at 50.degree. C. to give
the title compound (110 mg, 43.2%) as a white solid. LCMS
(ES.sup.+): 463.1[MH].sup.+. HPLC: Rt 5.06 min, 98.6% purity.
Example 8
({[(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-d-
ihydro-2H-1-benzopyran-3-yl]oxy}methoxy)phosphonic acid diamine
##STR00024##
[0193] Intermediate 1 (600 mg, 1.33 mmol) was dissolved in THF (12
mL) and treated with phosphoric acid (85%, 911 mg, 9.29 mmol) and
powdered 4 .ANG. molecular sieves (1.80 g) at room temperature. The
reaction mixture was cooled in an ice bath and N-iodosuccinimide
(478 mg; 2.12 mmol) added. The reaction mixture was stirred in an
ice bath for 5 min. After overnight at room temperature the
reaction mixture was diluted with EtOAc (30 mL). The molecular
sieves were removed by filtration and washed with EtOAc (10 mL).
The combined organic filtrates were washed with 5% aqueous sodium
thiosulfate solution (25 mL). The product was extracted into 10%
aqueous sodium carbonate solution (30 mL). The aqueous phase was
separated, adjusted to pH1-2 with 2N HCl in ice and the product
extracted into EtOAc (15 mL). The organic phase was washed with
water (3.times.10 mL) until pH 4 and then concentrated in vacuo.
The residue was partitioned between EtOAc (20 mL) and 5% aqueous
sodium carbonate solution (20 mL). The aqueous phase was separated,
adjusted to pH 1 with 2N HCl in ice, loaded onto a preconditioned
column of Amberlite XAD-4 resin (5 g) and the product eluted with
water/MeCN mixtures. The solvents were removed in vacuo and the
residue triturated in EtOAc/MTBE mixture. The solid was collected
by filtration, washed with MTBE and dried. The solid was
partitioned between water (10 mL) and EtOAc (5 mL). 7N Ammonia in
MeOH (1 mL) was added. The aqueous phase was separated,
concentrated in vacuo, triturated with EtOAc (2.times.5 mL) and
dried in vacuo at 40.degree. C. to give the title compound (44 mg,
6.18%) as a white solid. HPLC: Rt 4.88 min, 98.5% purity.
Example 9
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihy-
dro-2H-1-benzopyran-3-yl (2S)-2-amino-4-methylpentanoate
hydrochloride
##STR00025##
[0195] Boc-Leu-OH (full name:
(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanoic acid) (555
mg, 2.40 mmol), HOBt hydrate (429 mg, 2.80 mmol), EDC.HCl (537 mg,
2.80 mmol) and DMAP (733 mg, 6.00 mmol) were dissolved in DCM (15
mL) and the reaction mixture was stirred for 15 min.
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4--
yl]-3-chloro-4-fluorobenzamide (784 mg, 2.00 mmol) was added and
the reaction mixture was stirred for 4d, diluted with EtOAc, washed
with 10% aq citric acid, 10% aq NaHCO.sub.3 and brine, dried
(MgSO.sub.4) and concentrated in vacuo. This procedure was repeated
on the same scale and the combined reaction products were purified
by column chromatography on normal phase silica eluting with
hexane/EtOAc mixtures. The
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl
(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanoate
intermediate (520 mg, 0.86 mmol) was dissolved in DCM (10 mL) and
4N HCl in dioxane (4.3 mL) was added. The reaction mixture was
stirred until completion, diluted with EtOAc, washed with 1M aq
NaOH, water and brine, dried (MgSO.sub.4) and concentrated in
vacuo. The residue was dissolved in Et.sub.2O and acidified with 2M
HCl in Et.sub.2O, and the resulting precipitate was collected by
filtration, washed with Et.sub.2O and dried in vacuo at 40.degree.
C. to give the title compound (273 mg, 12.9%) as a white solid.
LCMS (ES.sup.+): 505.1 [MH].sup.+. HPLC: Rt 5.57 min, 99.2%
purity.
Example 10
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihy-
dro-2H-1-benzopyran-3-yl 2-(propylamino)acetate hydrochloride
##STR00026##
[0197] Intermediate 2 (478 mg, 2.20 mmol), HOBt hydrate (429 mg,
2.80 mmol), EDC.HCl (537 mg, 2.80 mmol) and DMAP (733 mg, 6.00
mmol) were dissolved in DCM (15 mL) and the reaction mixture was
stirred for 15 min.
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4--
yl]-3-chloro-4-fluorobenzamide (784 mg, 2.00 mmol) was added and
the reaction mixture was stirred for 24 h, diluted with EtOAc,
washed with 1M aq HCl, 10% aq NaHCO.sub.3 and brine, dried
(MgSO.sub.4) and concentrated in vacuo. The residue was purified by
column chromatography on normal phase silica eluting with
hexane/EtOAc 3:1. The
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl
2-{[(tert-butoxy)carbonyl](propyl)amino}acetate intermediate (360
mg, 0.61 mmol) was dissolved in DCM (6 mL) and 4N HCl in dioxane (3
mL) was added. The reaction mixture was stirred until completion,
diluted with EtOAc, washed with 1M aq NaOH, water and brine, dried
(MgSO.sub.4) and concentrated in vacuo. The residue was dissolved
in Et.sub.2O and acidified with 2M HCl in Et.sub.2O, and the
resulting precipitate was collected by filtration, washed with
Et.sub.2O and dried in vacuo at 40.degree. C. to give the title
compound (261 mg, 25.9%) as a white solid. LCMS (ES.sup.+): 491.1
[MH].sup.+. HPLC: Rt 5.35 min, 98.7% purity.
Example 11
(3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihy-
dro-2H-1-benzopyran-3-yl 2-[(propan-2-yl)amino]acetate
hydrochloride
##STR00027##
[0199] N-Boc-N-isopropylamino-acetic acid (520 mg, 2.39 mmol), HOBt
hydrate (441 mg, 2.88 mmol), EDC.HCl (552 mg, 2.88 mmol) and DMAP
(733 mg, 6.00 mmol) were dissolved in DCM (10 ml) and the reaction
mixture was stirred for 30 min.
N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4--
yl]-3-chloro-4-fluorobenzamide (784 mg, 2.00 mmol) was added and
the reaction mixture was stirred for 20 h and concentrated in
vacuo. The residue was purified by column chromatography on normal
phase silica eluting with hexane/EtOAc 3:1. The
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dih-
ydro-2H-1-benzopyran-3-yl
2-{[(tert-butoxy)carbonyl](propan-2-yl)amino}acetate intermediate
(820 mg, 1.39 mmol) was dissolved in MeOH (3 mL) and 4N HCl in
dioxane (20 mL) was added. The reaction mixture was stirred for 2 h
and concentrated in vacuo. The residue was suspended in diisopropyl
ether (50 mL) and EtOAc (1 mL), stirred overnight and collected by
filtration. The residue was partitioned between aq NaHCO.sub.3 (20
mL) and DCM (20 mL) and the aqueous fraction was extracted with DCM
(2.times.20 mL). The combined organic fractions were concentrated
in vacuo and the residue was purified by normal phase silica
eluting with hexane/EtOAc 1:2. The residue was suspended in
Et.sub.2O (6 mL) and 2M HCl in Et.sub.2O (2 mL), stirred for 1 h
and the precipitate was collected by filtration and washed with
Et.sub.2O (2.times.2 mL) to give the title compound (451 mg, 43.2%
in two batches) as a white solid. LCMS (ES.sup.+): 491.1
[MH].sup.+. HPLC: Rt 5.23-5.24 min, 99.5-100% purity.
Preparation of Compounds of Formula (II)
##STR00028##
##STR00029##
[0201] wherein Q, Z.sub.1, Z.sub.2, Z.sub.3 and R.sup.2 are as
defined in the section entitled "detailed description of the
invention" and P.sup.2 is a suitable protecting group.
[0202] Compounds of general formula (IIa) can easily be prepared
from the alcohols of general formula (IVa) by protecting the
hydroxyl functionality with a suitable protecting group P.sup.2 to
give compounds of general formula (VI) and then coupling the
prodrug functionality onto the amide nitrogen atom in one or more
steps using synthetic strategies analogous to those used for the
synthesis of compounds of general formula (I). The final step is to
remove the protecting group P.sup.2 to give compounds of general
formula (IIa).
Preparation of Compounds of Formula (IIIa) and (IIIb)
##STR00030##
##STR00031##
[0204] wherein A, Z.sub.1, Z.sub.2, Z.sub.3, R.sup.1 and R.sup.2
are as defined in the section entitled "detailed description of the
invention"
[0205] Compounds of general formula (IIIa) can easily be prepared
from the ketones of general formula (Id) by either using an alcohol
or diol in the presence of an acid and removal of the water
generated to prepare acyclic or cyclic ketals respectively. Such
methods proposed for the synthesis of compounds of general formula
(IIIa) are known to those skilled in the art, for example in T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis
(2nd edition) J. Wiley & Sons, 1991 and P. J. Kocienski,
Protecting Groups, Georg Thieme Verlag, 1994.
##STR00032##
[0206] wherein A, Q, Z.sub.1, Z.sub.2, Z.sub.3, R.sup.1, R.sup.2,
and R.sup.43 are as defined in the section entitled "detailed
description of the invention"
[0207] Compounds of general formula (IIIb) can easily be prepared
from the ketones of general formula (I) where Q=O by using the
appropriate hydroxylamine and removal of the water generated to
prepare the ketoxime. Such methods proposed for the synthesis of
compounds of general formula (IIIb) are known to those skilled in
the art, for example in T. W. Greene & P. G. M. Wuts,
Protective Groups in Organic Synthesis (2nd edition) J. Wiley &
Sons, 1991
[0208] Biological Rational
[0209] Without wishing to be bound by theory, the general mode of
action of the claimed pro-drugs is as follows. For IV
administration the high solubility conferred by the solubilising
pro-moiety to the parent Tonabersat-like drug is expected to allow
a rapid bolus injection whereupon the pro-drug will be quickly
cleaved by in vivo esterases/phosphatases to reveal the parent
drug. For PO administration the preferred mode of action is where
the solubilising pro-drug is predominantly cleaved in the gut by
esterases/phosphatases prior to absorption of the parent drug into
the systemic circulation.
[0210] Pharmacokinetics
[0211] Example prodrugs were dosed either intravenously or orally
to fasted male Sprague Dawley rats. The rats underwent surgery for
jugular vein cannulation 48 hrs prior to dosing. Following dosing,
0.25 mL blood samples were taken via the cannulae at 0, 5, 10, 20,
30, 45, 60, 120, 240 & 360 minutes in EDTA coated tubes. Tubes
were spun at 13,000 rpm for 4 minutes and 100 ul of supernatant
taken immediately and stored at -80.degree. C. prior to analysis.
Plasma samples were analysed by LC-MS/MS following extraction by
protein precipitation, and levels of parent prodrug and tonabersat
were measured by MRM (Multiple Reaction Monitoring) analysis
against an extracted calibration curve of plasma samples spiked
with the Example prodrug and tonabersat.
[0212] Example 2 was dosed according to this protocol at 0.95 mg/kg
IV. Plasma levels of Example 2 were found to decline from 730 ng/mL
at 5 min to <5 ng/mL at 6 hrs. Plasma levels of tonabersat were
determined to be 130 ng/mL at 5 min and 115 ng/mL at 6 hrs clearly
showing conversion of the prodrug to tonabersat over this
timecourse following intravenous dosing.
[0213] Example 2 was dosed according to this protocol at 6.10 mg/kg
PO. Plasma levels of Example 2 were found to decline from 38 ng/mL
at 5 min to <5 ng/mL at 6 hrs. Plasma levels of tonabersat were
determined to be 63 ng/mL at 5 min and 900 ng/mL at 6 hrs clearly
showing conversion of the prodrug to tonabersat over this
timecourse following oral dosing.
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