U.S. patent application number 15/267854 was filed with the patent office on 2017-01-05 for cyclopropyl modulators of p2y12 receptor.
The applicant listed for this patent is Auspex Pharmaceuticals, Inc.. Invention is credited to Tadimeti Rao, Chengzhi Zhang.
Application Number | 20170002015 15/267854 |
Document ID | / |
Family ID | 43544862 |
Filed Date | 2017-01-05 |
United States Patent
Application |
20170002015 |
Kind Code |
A1 |
Rao; Tadimeti ; et
al. |
January 5, 2017 |
CYCLOPROPYL MODULATORS OF P2Y12 RECEPTOR
Abstract
The present invention relates to new cyclopropyl modulators of
P2Y12 receptor activity, pharmaceutical compositions thereof, and
methods of use thereof. ##STR00001##
Inventors: |
Rao; Tadimeti; (San Diego,
CA) ; Zhang; Chengzhi; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Auspex Pharmaceuticals, Inc. |
La Jolla |
CA |
US |
|
|
Family ID: |
43544862 |
Appl. No.: |
15/267854 |
Filed: |
September 16, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14977056 |
Dec 21, 2015 |
9498481 |
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15267854 |
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14299782 |
Jun 9, 2014 |
9255104 |
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14977056 |
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12844017 |
Jul 27, 2010 |
8802850 |
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14299782 |
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61228913 |
Jul 27, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 9/06 20180101; C07D 487/04 20130101; A61P 29/00 20180101; C07B
59/002 20130101; A61P 3/14 20180101; C07B 2200/05 20130101; A61P
9/10 20180101; A61P 7/02 20180101; A61K 45/06 20130101; A61K 31/519
20130101; A61P 9/00 20180101; A61P 43/00 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61K 45/06 20060101 A61K045/06; C07B 59/00 20060101
C07B059/00; A61K 31/519 20060101 A61K031/519 |
Claims
1. A compound of Formula A or Formula B: ##STR00162## or a
pharmaceutically acceptable salt thereof, wherein each position
represented as D has deuterium enrichment of no less than about
10%.
2. The compound or salt thereof of claim 1 wherein each position
represented as D has deuterium enrichment of no less than about
50%.
3. The compound or salt thereof of claim 1 wherein each position
represented as D has deuterium enrichment of no less than about
90%.
4. The compound or salt thereof of claim 1 wherein each position
represented as D has deuterium enrichment of no less than about
98%.
5. A method of treating a P2Y12 receptor-mediated disorder
comprising administering to a patient in need thereof, a
therapeutically effective amount of a compound or salt thereof as
recited in claim 1.
6. The method of claim 5, wherein said disorder is arterial
thrombosis or coronary artery disease.
7. The method of claim 5, further comprising administering an
additional therapeutic agent.
8. The method of claim 7 wherein said additional therapeutic agent
is an alpha adrenergic receptor antagonist, a beta adrenergic
receptor antagonist, an angiotensin II receptor antagonist, an
angiotensin-converting enzyme inhibitor, an anti-arrhythmic, an
antithrombotic, an antiplatelet agent, a calcium channel blocker, a
fibrate, or a HMG-CoA reductase inhibitor.
9. The method of claim 8 wherein said alpha adrenergic receptor
antagonist is abanoquil, adimolol, ajmalicine, alfuzosin,
amosulalol, arotinolol, atiprosin, benoxathian, buflomedil,
bunazosin, carvedilol, CI-926, corynanthine, dapiprazole, DL-017,
domesticine, doxazosin, eugenodilol, fenspiride, GYKI-12,743,
GYKI-16,084, indoramin, ketanserin, L-765,314, labetalol,
mephendioxan, metazosin, monatepil, moxisylyte (thymoxamine),
naftopidil, nantenine, neldazosin, nicergoline, niguldipine,
pelanserin, phendioxan, phenoxybenzamine, phentolamine, piperoxan,
prazosin, quinazosin, ritanserin, RS-97,078, SGB-1,534, silodosin,
SL-89.0591, spiperone, talipexole, tamsulosin, terazosin,
tibalosin, tiodazosin, tipentosin, tolazoline, trimazosin,
upidosin, urapidil, zolertine, 1-PP, adimolol, atipamezole,
BRL-44408, buflomedil, cirazoline, efaroxan, esmirtazapine,
fluparoxan, GYKI-12,743, GYKI-16,084, idazoxan, mianserin,
mirtazapine, MK-912, NAN-190, olanzapine, phentolamine,
phenoxybenzamine, piperoxan, piribedil, rauwolscine, rotigotine,
SB-269,970, setiptiline, spiroxatrine, sunepitron, tolazoline, or
yohimbine.
10. The method of claim 8, wherein said beta adrenergic receptor
antagonist is acebutolol, adaprolol, adimolol, afurolol,
alprenolol, alprenoxime, amosulalol, ancarolol, arnolol,
arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol,
bopindolol, bormetolol, bornaprolol, brefonalol, bucindolol,
bucumolol, bufetolol, buftiralol, bufuralol, bunitrolol, bunolol,
bupranolol, burocrolol, butaxamine, butidrine, butofilolol,
capsinolol, carazolol, carpindolol, carteolol, carvedilol,
celiprolol, cetamolol, cicloprolol, cinamolol, cloranolol,
cyanopindolol, dalbraminol, dexpropranolol, diacetolol,
dichloroisoprenaline, dihydroalprenolol, dilevalol, diprafenone,
draquinolol, dropranolol, ecastolol, epanolol, ericolol,
ersentilide, esatenolol, esmolol, esprolol, eugenodilol, exaprolol,
falintolol, flestolol, flusoxolol, hydroxycarteolol,
hydroxytertatolol, ICI-118,551, idropranolol, indenolol,
indopanolol, iodocyanopindolol, iprocrolol, isoxaprolol,
isamoltane, labetalol, landiolol, levobetaxolol, levobunolol,
levocicloprolol, levomoprolol, medroxalol, mepindolol, metalol,
metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nafetolol,
nebivolol, neraminol, nifenalol, nipradilol, oberadilol,
oxprenolol, pacrinolol, pafenolol, pamatolol, pargolol, parodilol,
penbutolol, penirolol, PhQA-33, pindolol, pirepolol, practolol,
primidolol, procinolol, pronethalol, propafenone, propranolol,
ridazolol, ronactolol, soquinolol, sotalol, spirendolol, SR 59230A,
sulfinalol, TA-2005, talinolol, tazolol, teoprolol, tertatolol,
terthianolol, tienoxolol, tilisolol, timolol, tiprenolol,
tolamolol, toliprolol, tribendilol, trigevolol, xibenolol, or
xipranolol.
11. The method of claim 8, wherein said angiotensin II receptor
antagonist is candesartan, eprosartan, irbesartan, losartan,
olmesartan, tasosartan, telmisartan, or valsartan.
12. The method of claim 8, wherein said angiotensin-converting
enzyme inhibitor is captopril, enalapril, lisinopril, perindopril,
ramipril, quinapril, benazepril, cilazapril, fosinopril,
trandolapril, spirapril, delapril, moexipril, temocapril,
zofenopril, or imidapril.
13. The method of claim 8, wherein said anti-arrhythmic is
quinidine, procainamide, disopyramide, sparteine, ajmaline,
prajmaline, lorajmine, lidocaine, mexiletine, tocainide, aprindine,
propafenone, flecainide, lorcainide, encainide, amiodarone,
bretylium tosilate, bunaftine, dofetilide, ibutilidem, tedisamil,
moracizine, or cibenzoline.
14. The method of claim 8, wherein said antithrombotic is
dicoumarol, phenindione, warfarin, phenprocoumon, acenocoumarol,
ethyl biscoumacetate, clorindione, diphenadione, tioclomarol,
heparin, antithrombin III, dalteparin, enoxaparin, nadroparin,
parnaparin, reviparin, danaparoid, tinzaparin, sulodexide,
bemiparin, ditazole, cloricromen, picotamide, clopidogrel,
ticlopidine, acetylsalicylic acid, dipyridamole, carbasalate
calcium, epoprostenol, indobufen, iloprost, abciximab, aloxiprin,
eptifibatide, tirofiban, triflusal, beraprost, treprostinil,
prasugrel, streptokinase, alteplase, urokinase, fibrinolysin,
brinase, reteplase, saruplase, ancrod, drotrecogin alfa
(activated), tenecteplase, protein C, desirudin, lepirudin,
argatroban, melagatran, ximelagatran, bivalirudin, dabigatran
etexilate, defibrotide, dermatan sulfate, fondaparinux, or
rivaroxaban.
15. The method of claim 8, wherein said antiplatelet agent is
abciximab, eptifibatide, tirofiban, clopidogrel, prasugrel,
ticlopidine, ticagrelor, beraprost, prostacyclin, iloprost,
treprostinil, acetylsalicylic acid, aloxiprin, carbasalate calcium,
indobufen, dipyridamole, picotamide, terutroban, cilostazol,
dipyridamole, triflusal, cloricromen, or ditazole.
16. The method as recited in claim 8, wherein said calcium channel
blocker is amlodipine, felodipine, isradipine, nicardipine,
nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine,
nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine,
benidipine, mibefradil, verapamil, gallopamil, diltiazem,
fendiline, bepridil, lidoflazine, or perhexiline.
17. The method of claim 8, wherein said fibrate is clofibrate,
bezafibrate, aluminium clofibrate, gemfibrozil, fenofibrate,
simfibrate, ronifibrate, ciprofibrate, etofibrate, or
clofibride.
18. The method of claim 8, wherein said HMG-CoA reductase inhibitor
is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,
pitavastatin, pravastatin, rosuvastatin, or simvastatin.
19. The method of claim 5, further resulting in at least one effect
which is: a. decreased inter-individual variation in plasma levels
of said compound or a metabolite thereof as compared to the
non-isotopically enriched compound; b. increased average plasma
levels of said compound per dosage unit thereof as compared to the
non-isotopically enriched compound; c. decreased average plasma
levels of at least one metabolite of said compound per dosage unit
thereof as compared to the non-isotopically enriched compound; d.
increased average plasma levels of at least one metabolite of said
compound per dosage unit thereof as compared to the
non-isotopically enriched compound; or e. an improved clinical
effect during the treatment in said subject per dosage unit thereof
as compared to the non-isotopically enriched compound.
20. The method of claim 5, further resulting in at least two
effects which are: a. decreased inter-individual variation in
plasma levels of said compound or a metabolite thereof as compared
to the non-isotopically enriched compound; b. increased average
plasma levels of said compound per dosage unit thereof as compared
to the non-isotopically enriched compound; c. decreased average
plasma levels of at least one metabolite of said compound per
dosage unit thereof as compared to the non-isotopically enriched
compound; d. increased average plasma levels of at least one
metabolite of said compound per dosage unit thereof as compared to
the non-isotopically enriched compound; or e. an improved clinical
effect during the treatment in said subject per dosage unit thereof
as compared to the non-isotopically enriched compound.
21. The method of claim 5, wherein the method effects a decreased
metabolism of the compound per dosage unit thereof by at least one
polymorphically-expressed cytochrome P.sub.450isoform in the
subject, as compared to the corresponding non-isotopically enriched
compound.
22. The method of claim 21, wherein the cytochrome P.sub.450
isoform is CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
23. The method of claim 5, wherein said compound is characterized
by decreased inhibition of at least one cytochrome P.sub.450 or
monoamine oxidase isoform in said subject per dosage unit thereof
as compared to the non-isotopically enriched compound.
24. The method of claim 23, wherein said cytochrome P.sub.450 or
monoamine oxidase isoform is CYP1A1, CYP1A2, CYP1B1, CYP2A6,
CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1,
CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2,
CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12,
CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1,
CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1,
CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO.sub.A, or MAO.sub.B.
25. The method of claim 5, wherein the method reduces a deleterious
change in a diagnostic hepatobiliary function endpoint, as compared
to the corresponding non-isotopically enriched compound.
26. The method of claim 25, wherein the diagnostic hepatobiliary
function endpoint is alanine aminotransferase ("ALT"), serum
glutamic-pyruvic transaminase ("SGPT"), aspartate aminotransferase
("AST," "SGOT"), ALT/AST ratios, serum aldolase, alkaline
phosphatase ("ALP"), ammonia levels, bilirubin, gamma-glutamyl
transpeptidase ("GGTP," ".gamma.-GTP," "GGT"), leucine
aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver
nuclear scan, 5'-nucleotidase, or blood protein.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/977,056, filed Dec. 21, 2015, now allowed,
which is a continuation of U.S. patent application Ser. No.
14/299,782, filed Jun. 9, 2014, now U.S. Pat. No. 9,255,104, which
is a divisional of U.S. patent application Ser. No. 12/844,017,
filed Jul. 27, 2010, now U.S. Pat. No. 8,802,850, which claims the
benefit of priority of U.S. Provisional Patent Application No.
61/228,913, filed Jul. 27, 2009, the disclosures of which are
hereby incorporated by reference as if written herein in their
entireties.
FIELD OF THE INVENTION
[0002] Disclosed herein are new substituted cyclopropyl compounds,
pharmaceutical compositions made thereof, and methods to modulate
P2Y12 receptor activity in a subject are also provided for, for the
treatment of disorders such as arterial thrombosis and coronary
artery disease.
BACKGROUND
[0003] Ticagrelor (AR-C126532, AZD-6140, Brilinta.RTM., CAS
#274693-27-5),
3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-
-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-(1S,2S,3R,5S)-1,-
2-cyclopentanediol, is a P2Y12 receptor antagonist. Ticagrelor is
currently under investigation for the treatment of arterial
thrombosis (Tantry et al., Exp. Opin. Invest. Drugs 2007, 16(2),
225-229; Husted et al., Eur. Heart 1 2006, 27(9), 1038-1047; and WO
2000034283). Ticagrelor has also shown promise in treating coronary
artery disease and other disorders related to platelet aggregation
(Tantry et al., Exp. Opin. Invest. Drugs 2007, 16(2), 225-229;
Husted et al., Eur. Heart J. 2006, 27(9), 1038-1047; and WO
2000034283).
##STR00002##
[0004] Ticagrelor is subject to CYP450-mediated oxidative
metabolism, forming an active metabolite AR-C124910XX (Husted et
al., Eur. Heart J. 2006, 27, 1038-1047). Adverse effects associated
with ticagrelor include excessive bleeding.
Deuterium Kinetic Isotope Effect
[0005] In order to eliminate foreign substances such as therapeutic
agents, the animal body expresses various enzymes, such as the
cytochrome P.sub.450 enzymes (CYPs), esterases, proteases,
reductases, dehydrogenases, and monoamine oxidases, to react with
and convert these foreign substances to more polar intermediates or
metabolites for renal excretion. Such metabolic reactions
frequently involve the oxidation of a carbon-hydrogen (C--H) bond
to either a carbon-oxygen (C--O) or a carbon-carbon (C--C)
.pi.-bond. The resultant metabolites may be stable or unstable
under physiological conditions, and can have substantially
different pharmacokinetic, pharmacodynamic, and acute and long-term
toxicity profiles relative to the parent compounds. For most drugs,
such oxidations are generally rapid and ultimately lead to
administration of multiple or high daily doses.
[0006] The relationship between the activation energy and the rate
of reaction may be quantified by the Arrhenius equation,
k=Ae.sup.-Eact/RT. The Arrhenius equation states that, at a given
temperature, the rate of a chemical reaction depends exponentially
on the activation energy (E.sub.act).
[0007] The transition state in a reaction is a short lived state
along the reaction pathway during which the original bonds have
stretched to their limit. By definition, the activation energy
E.sub.act for a reaction is the energy required to reach the
transition state of that reaction. Once the transition state is
reached, the molecules can either revert to the original reactants,
or form new bonds giving rise to reaction products. A catalyst
facilitates a reaction process by lowering the activation energy
leading to a transition state. Enzymes are examples of biological
catalysts.
[0008] Carbon-hydrogen bond strength is directly proportional to
the absolute value of the ground-state vibrational energy of the
bond. This vibrational energy depends on the mass of the atoms that
form the bond, and increases as the mass of one or both of the
atoms making the bond increases. Since deuterium (D) has twice the
mass of protium (.sup.1H), a C-D bond is stronger than the
corresponding C-.sup.1H bond. If a C-.sup.1H bond is broken during
a rate-determining step in a chemical reaction (i.e. the step with
the highest transition state energy), then substituting a deuterium
for that protium will cause a decrease in the reaction rate. This
phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE).
The magnitude of the DKIE can be expressed as the ratio between the
rates of a given reaction in which a C-.sup.1H bond is broken, and
the same reaction where deuterium is substituted for protium. The
DKIE can range from about 1 (no isotope effect) to very large
numbers, such as 50 or more. Substitution of tritium for hydrogen
results in yet a stronger bond than deuterium and gives numerically
larger isotope effects
[0009] Deuterium (.sup.2H or D) is a stable and non-radioactive
isotope of hydrogen which has approximately twice the mass of
protium (.sup.1H), the most common isotope of hydrogen. Deuterium
oxide (D.sub.2O or "heavy water") looks and tastes like H.sub.2O,
but has different physical properties.
[0010] When pure D.sub.2O is given to rodents, it is readily
absorbed. The quantity of deuterium required to induce toxicity is
extremely high. When about 0-15% of the body water has been
replaced by D.sub.2O, animals are healthy but are unable to gain
weight as fast as the control (untreated) group. When about 15-20%
of the body water has been replaced with D.sub.2O, the animals
become excitable. When about 20-25% of the body water has been
replaced with D.sub.2O, the animals become so excitable that they
go into frequent convulsions when stimulated. Skin lesions, ulcers
on the paws and muzzles, and necrosis of the tails appear. The
animals also become very aggressive. When about 30% of the body
water has been replaced with D.sub.2O, the animals refuse to eat
and become comatose. Their body weight drops sharply and their
metabolic rates drop far below normal, with death occurring at
about 30 to about 35% replacement with D.sub.2O. The effects are
reversible unless more than thirty percent of the previous body
weight has been lost due to D.sub.2O. Studies have also shown that
the use of D.sub.2O can delay the growth of cancer cells and
enhance the cytotoxicity of certain antineoplastic agents.
[0011] Deuteration of pharmaceuticals to improve pharmacokinetics
(PK), pharmacodynamics (PD), and toxicity profiles has been
demonstrated previously with some classes of drugs. For example,
the DKIE was used to decrease the hepatotoxicity of halothane,
presumably by limiting the production of reactive species such as
trifluoroacetyl chloride. However, this method may not be
applicable to all drug classes. For example, deuterium
incorporation can lead to metabolic switching. Metabolic switching
occurs when xenogens, sequestered by Phase I enzymes, bind
transiently and re-bind in a variety of conformations prior to the
chemical reaction (e.g., oxidation). Metabolic switching is enabled
by the relatively vast size of binding pockets in many Phase I
enzymes and the promiscuous nature of many metabolic reactions.
Metabolic switching can lead to different proportions of known
metabolites as well as altogether new metabolites. This new
metabolic profile may impart more or less toxicity. Such pitfalls
are non-obvious and are not predictable a priori for any drug
class.
[0012] Ticagrelor is a P2Y12 receptor antagonist. The
carbon-hydrogen bonds of ticagrelor contain a naturally occurring
distribution of hydrogen isotopes, namely .sup.1H or protium (about
99.9844%), .sup.2H or deuterium (about 0.0156%), and .sup.3H or
tritium (in the range between about 0.5 and 67 tritium atoms per
10.sup.18 protium atoms). Increased levels of deuterium
incorporation may produce a detectable Deuterium Kinetic Isotope
Effect (DKIE) that could effect the pharmacokinetic, pharmacologic
and/or toxicologic profiles of ticagrelor in comparison with
ticagrelor having naturally occurring levels of deuterium.
DETAILED DESCRIPTION
[0013] Based on discoveries made in our laboratory, as well as
considering the literature, ticagrelor is likely metabolized in
humans at the 2-hydroxyethoxy group, the S-propyl group, and the
cyclopropyl group. The current approach has the potential to
prevent metabolism at these sites. Other sites on the molecule may
also undergo transformations leading to metabolites with
as-yet-unknown pharmacology/toxicology. Limiting the production of
these metabolites has the potential to decrease the danger of the
administration of such drugs and may even allow increased dosage
and/or increased efficacy. All of these transformations can occur
through polymorphically-expressed enzymes, exacerbating
interpatient variability. Further, some disorders are best treated
when the subject is medicated around the clock or for an extended
period of time. For all of the foregoing reasons, a medicine with a
longer half-life may result in greater efficacy and cost savings.
Various deuteration patterns can be used to (a) reduce or eliminate
unwanted metabolites, (b) increase the half-life of the parent
drug, (c) decrease the number of doses needed to achieve a desired
effect, (d) decrease the amount of a dose needed to achieve a
desired effect, (e) increase the formation of active metabolites,
if any are formed, (f) decrease the production of deleterious
metabolites in specific tissues, and/or (g) create a more effective
drug and/or a safer drug for polypharmacy, whether the polypharmacy
be intentional or not. The deuteration approach has the strong
potential to slow the metabolism of ticagrelor and attenuate
interpatient variability.
[0014] Novel compounds and pharmaceutical compositions, certain of
which have been found to modulate P2Y12 receptor activity have been
discovered, together with methods of synthesizing and using the
compounds, including methods for the treatment of P2Y12
receptor-mediated disorders in a patient by administering the
compounds as disclosed herein.
[0015] In certain embodiments of the present invention, compounds
have structural Formula I:
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0016] R.sub.1-R.sub.28 are independently selected from the group
consisting of hydrogen and deuterium; and
[0017] at least one of R.sub.1-R.sub.28 is deuterium.
[0018] Certain compounds disclosed herein may possess useful P2Y12
receptor modulating activity, and may be used in the treatment or
prophylaxis of a disorder in which P2Y12 receptors play an active
role. Thus, certain embodiments also provide pharmaceutical
compositions comprising one or more compounds disclosed herein
together with a pharmaceutically acceptable carrier, as well as
methods of making and using the compounds and compositions. Certain
embodiments provide methods for modulating P2Y12 receptor activity.
Other embodiments provide methods for treating a P2Y12
receptor-mediated disorder in a patient in need of such treatment,
comprising administering to said patient a therapeutically
effective amount of a compound or composition according to the
present invention. Also provided is the use of certain compounds
disclosed herein for use in the manufacture of a medicament for the
prevention or treatment of a disorder ameliorated by modulating
P2Y12 receptor activity.
[0019] The compounds as disclosed herein may also contain less
prevalent isotopes for other elements, including, but not limited
to, .sup.13C or .sup.14C for carbon, .sup.33S, .sup.34S, or
.sup.36S for sulfur, .sup.15N for nitrogen, and .sup.17O or
.sup.18O for oxygen.
[0020] In certain embodiments, the compound disclosed herein may
expose a patient to a maximum of about 0.000005% D.sub.2O or about
0.00001% DHO, assuming that all of the C-D bonds in the compound as
disclosed herein are metabolized and released as D.sub.2O or DHO.
In certain embodiments, the levels of D.sub.2O shown to cause
toxicity in animals is much greater than even the maximum limit of
exposure caused by administration of the deuterium enriched
compound as disclosed herein. Thus, in certain embodiments, the
deuterium-enriched compound disclosed herein should not cause any
additional toxicity due to the formation of D.sub.2O or DHO upon
drug metabolism.
[0021] In certain embodiments, the deuterated compounds disclosed
herein maintain the beneficial aspects of the corresponding
non-isotopically enriched molecules while substantially increasing
the maximum tolerated dose, decreasing toxicity, increasing the
half-life (T.sub.1/2), lowering the maximum plasma concentration
(C.sub.max) of the minimum efficacious dose (MED), lowering the
efficacious dose and thus decreasing the non-mechanism-related
toxicity, and/or lowering the probability of drug-drug
interactions.
[0022] All publications and references cited herein are expressly
incorporated herein by reference in their entirety. However, with
respect to any similar or identical terms found in both the
incorporated publications or references and those explicitly put
forth or defined in this document, then those terms definitions or
meanings explicitly put forth in this document shall control in all
respects.
[0023] As used herein, the terms below have the meanings
indicated.
[0024] The singular forms "a", "an", and "the" may refer to plural
articles unless specifically stated otherwise.
[0025] The term "about", as used herein, is intended to qualify the
numerical values which it modifies, denoting such a value as
variable within a margin of error. When no particular margin of
error, such as a standard deviation to a mean value given in a
chart or table of data, is recited, the term "about" should be
understood to mean that range which would encompass the recited
value and the range which would be included by rounding up or down
to that figure as well, taking into account significant
figures.
[0026] When ranges of values are disclosed, and the notation "from
n.sub.1 . . . to n.sub.2" or "n.sub.1-n.sub.2" is used, where
n.sub.1 and n.sub.2 are the numbers, then unless otherwise
specified, this notation is intended to include the numbers
themselves and the range between them. This range may be integral
or continuous between and including the end values.
[0027] The term "deuterium enrichment" refers to the percentage of
incorporation of deuterium at a given position in a molecule in the
place of hydrogen. For example, deuterium enrichment of 1% at a
given position means that 1% of molecules in a given sample contain
deuterium at the specified position. Because the naturally
occurring distribution of deuterium is about 0.0156%, deuterium
enrichment at any position in a compound synthesized using
non-enriched starting materials is about 0.0156%. The deuterium
enrichment can be determined using conventional analytical methods
known to one of ordinary skill in the art, including mass
spectrometry and nuclear magnetic resonance spectroscopy.
[0028] The term "is/are deuterium", when used to describe a given
position in a molecule such as R.sub.1-R.sub.28 or the symbol "D",
when used to represent a given position in a drawing of a molecular
structure, means that the specified position is enriched with
deuterium above the naturally occurring distribution of deuterium.
In one embodiment deuterium enrichment is no less than about 1%, in
another no less than about 5%, in another no less than about 10%,
in another no less than about 20%, in another no less than about
50%, in another no less than about 70%, in another no less than
about 80%, in another no less than about 90%, or in another no less
than about 98% of deuterium at the specified position.
[0029] The term "isotopic enrichment" refers to the percentage of
incorporation of a less prevalent isotope of an element at a given
position in a molecule in the place of the more prevalent isotope
of the element.
[0030] The term "non-isotopically enriched" refers to a molecule in
which the percentages of the various isotopes are substantially the
same as the naturally occurring percentages.
[0031] Asymmetric centers exist in the compounds disclosed herein.
These centers are designated by the symbols "R" or "S", depending
on the configuration of substituents around the chiral carbon atom.
It should be understood that the invention encompasses all
stereochemical isomeric forms, including diastereomeric,
enantiomeric, and epimeric forms, as well as D-isomers and
L-isomers, and mixtures thereof. Individual stereoisomers of
compounds can be prepared synthetically from commercially available
starting materials which contain chiral centers or by preparation
of mixtures of enantiomeric products followed by separation such as
conversion to a mixture of diastereomers followed by separation or
recrystallization, chromatographic techniques, direct separation of
enantiomers on chiral chromatographic columns, or any other
appropriate method known in the art. Starting compounds of
particular stereochemistry are either commercially available or can
be made and resolved by techniques known in the art. Additionally,
the compounds disclosed herein may exist as geometric isomers. The
present invention includes all cis, trans, syn, anti, entgegen (E),
and zusammen (Z) isomers as well as the appropriate mixtures
thereof. Additionally, compounds may exist as tautomers; all
tautomeric isomers are provided by this invention. Additionally,
the compounds disclosed herein can exist in unsolvated as well as
solvated forms with pharmaceutically acceptable solvents such as
water, ethanol, and the like. In general, the solvated forms are
considered equivalent to the unsolvated forms.
[0032] The term "bond" refers to a covalent linkage between two
atoms, or two moieties when the atoms joined by the bond are
considered to be part of larger substructure. A bond may be single,
double, or triple unless otherwise specified. A dashed line between
two atoms in a drawing of a molecule indicates that an additional
bond may be present or absent at that position.
[0033] The term "disorder" as used herein is intended to be
generally synonymous, and is used interchangeably with, the terms
"disease", "syndrome", and "condition" (as in medical condition),
in that all reflect an abnormal condition of the human or animal
body or of one of its parts that impairs normal functioning, is
typically manifested by distinguishing signs and symptoms.
[0034] The terms "treat", "treating", and "treatment" are meant to
include alleviating or abrogating a disorder or one or more of the
symptoms associated with a disorder; or alleviating or eradicating
the cause(s) of the disorder itself. As used herein, reference to
"treatment" of a disorder is intended to include prevention. The
terms "prevent", "preventing", and "prevention" refer to a method
of delaying or precluding the onset of a disorder; and/or its
attendant symptoms, barring a subject from acquiring a disorder or
reducing a subject's risk of acquiring a disorder.
[0035] The term "therapeutically effective amount" refers to the
amount of a compound that, when administered, is sufficient to
prevent development of, or alleviate to some extent, one or more of
the symptoms of the disorder being treated. The term
"therapeutically effective amount" also refers to the amount of a
compound that is sufficient to elicit the biological or medical
response of a cell, tissue, system, animal, or human that is being
sought by a researcher, veterinarian, medical doctor, or
clinician.
[0036] The term "subject" refers to an animal, including, but not
limited to, a primate (e.g., human, monkey, chimpanzee, gorilla,
and the like), rodents (e.g., rats, mice, gerbils, hamsters,
ferrets, and the like), lagomorphs, swine (e.g., pig, miniature
pig), equine, canine, feline, and the like. The terms "subject" and
"patient" are used interchangeably herein in reference, for
example, to a mammalian subject, such as a human patient.
[0037] The term "combination therapy" means the administration of
two or more therapeutic agents to treat a therapeutic disorder
described in the present disclosure. Such administration
encompasses co-administration of these therapeutic agents in a
substantially simultaneous manner, such as in a single capsule
having a fixed ratio of active ingredients or in multiple, separate
capsules for each active ingredient. In addition, such
administration also encompasses use of each type of therapeutic
agent in a sequential manner. In either case, the treatment regimen
will provide beneficial effects of the drug combination in treating
the disorders described herein.
[0038] The term "P2Y12 receptor" refers to a G-protein coupled
receptor located on the platelet membrane. The P2Y12 receptor (also
known as P2T, P2YADP, or P2TAC) is primarily involved in mediating
platelet aggregation/activation. The pharmacological
characteristics of this receptor have been described, for example,
by Humphries et al., Br. J. Pharmacology 1994, 113, 1057-1063; and
Fagura et al., Br. J. Pharmacology 1998, 124, 157-164.
[0039] The term "P2Y12 receptor-mediated disorder", refers to a
disorder that is characterized by abnormal P2Y12 receptor activity
or excessive platelet aggregation, or normal platelet aggregation
or normal P2Y12 receptor activity that when modulated ameliorates
other abnormal biochemical processes. A P2Y12 receptor-mediated
disorder may be completely or partially mediated by modulating
P2Y12 receptor activity. In particular, a P2Y12 receptor-mediated
disorder is one in which modulation of P2Y12 receptor activity
results in some effect on the underlying disorder e.g.,
administration of a P2Y12 receptor modulator results in some
improvement in at least some of the patients being treated.
[0040] The term "P2Y12 receptor modulator", refers to the ability
of a compound disclosed herein to alter the function of P2Y12
receptors. A P2Y12 receptor modulator may activate the activity of
a P2Y12 receptor, may activate or inhibit the activity of a P2Y12
receptor depending on the concentration of the compound exposed to
the P2Y12 receptor, or may inhibit the activity of a P2Y12
receptor. Such activation or inhibition may be contingent on the
occurrence of a specific event, such as activation of a signal
transduction pathway, and/or may be manifest only in particular
cell types. The term "P2Y12 receptor modulator", also refers to
altering the function of a P2Y12 receptor by increasing or
decreasing the probability that a complex forms between a P2Y12
receptor and a natural binding partner. A P2Y12 receptor modulator
may increase the probability that such a complex forms between the
P2Y12 receptor and the natural binding partner, may increase or
decrease the probability that a complex forms between the P2Y12
receptor and the natural binding partner depending on the
concentration of the compound exposed to the P2Y12 receptor, and or
may decrease the probability that a complex forms between the P2Y12
receptor and the natural binding partner. In some embodiments,
modulation of the P2Y12 receptor activity may be assessed using the
method described in Husted et al., Eur. Heart J. 2006, 27(9),
1038-1047; WO 2000034283; WO 199905142.
[0041] The term "therapeutically acceptable" refers to those
compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.)
which are suitable for use in contact with the tissues of patients
without excessive toxicity, irritation, allergic response,
immunogenecity, are commensurate with a reasonable benefit/risk
ratio, and are effective for their intended use.
[0042] The term "pharmaceutically acceptable carrier",
"pharmaceutically acceptable excipient", "physiologically
acceptable carrier", or "physiologically acceptable excipient"
refers to a pharmaceutically-acceptable material, composition, or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent, or encapsulating material. Each component must be
"pharmaceutically acceptable" in the sense of being compatible with
the other ingredients of a pharmaceutical formulation. It must also
be suitable for use in contact with the tissue or organ of humans
and animals without excessive toxicity, irritation, allergic
response, immunogenecity, or other problems or complications,
commensurate with a reasonable benefit/risk ratio. See, Remington:
The Science and Practice of Pharmacy, 21st Edition; Lippincott
Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of
Pharmaceutical Excipients, 5th Edition; Rowe et al., Eds., The
Pharmaceutical Press and the American Pharmaceutical Association:
2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash
and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical
Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca
Raton, Fla., 2004).
[0043] The terms "active ingredient", "active compound", and
"active substance" refer to a compound, which is administered,
alone or in combination with one or more pharmaceutically
acceptable excipients or carriers, to a subject for treating,
preventing, or ameliorating one or more symptoms of a disorder.
[0044] The terms "drug", "therapeutic agent", and "chemotherapeutic
agent" refer to a compound, or a pharmaceutical composition
thereof, which is administered to a subject for treating,
preventing, or ameliorating one or more symptoms of a disorder.
[0045] The term "release controlling excipient" refers to an
excipient whose primary function is to modify the duration or place
of release of the active substance from a dosage form as compared
with a conventional immediate release dosage form.
[0046] The term "nonrelease controlling excipient" refers to an
excipient whose primary function do not include modifying the
duration or place of release of the active substance from a dosage
form as compared with a conventional immediate release dosage
form.
[0047] The term "prodrug" refers to a compound functional
derivative of the compound as disclosed herein and is readily
convertible into the parent compound in vivo. Prodrugs are often
useful because, in some situations, they may be easier to
administer than the parent compound. They may, for instance, be
bioavailable by oral administration whereas the parent compound is
not. The prodrug may also have enhanced solubility in
pharmaceutical compositions over the parent compound. A prodrug may
be converted into the parent drug by various mechanisms, including
enzymatic processes and metabolic hydrolysis. See Harper, Progress
in Drug Research 1962, 4, 221-294; Morozowich et al. in "Design of
Biopharmaceutical Properties through Prodrugs and Analogs," Roche
Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug
in Drug Design, Theory and Application," Roche Ed., APHA Acad.
Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985;
Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al.,
Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm.
Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem.
1996, 671-696; Asgharnejad in "Transport Processes in
Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker,
185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet.
1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999,
39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12;
Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled
Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev.
1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19,
115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381;
Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al.,
J. Chem. Soc., Chem. Commun. 1991, 875-877; Friis and Bundgaard,
Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm.
Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs
1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.
1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et
al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug
Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug
Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug
Delivery Rev. 1999, 39, 63-80; Waller et al., Br. J. Clin. Pharmac.
1989, 28, 497-507.
[0048] The compounds disclosed herein can exist as therapeutically
acceptable salts. The term "pharmaceuticallly acceptable salt," as
used herein, represents salts or zwitterionic forms of the
compounds disclosed herein which are therapeutically acceptable as
defined herein. The salts can be prepared during the final
isolation and purification of the compounds or separately by
reacting the appropriate compound with a suitable acid or base.
Therapeutically acceptable salts include acid and basic addition
salts. For a more complete discussion of the preparation and
selection of salts, refer to "Handbook of Pharmaceutical Salts,
Properties, and Use," Stah and Wermuth, Ed., (Wiley-VCH and VHCA,
Zurich, 2002) and Berge et al., J. Pharm. Sci. 1977, 66, 1-19.
[0049] Suitable acids for use in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic
acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic
acid, benzoic acid, 4-acetamidobenzoic acid, boric acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
cyclohexanesulfamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid.
[0050] Suitable bases for use in the preparation of
pharmaceutically acceptable salts, including, but not limited to,
inorganic bases, such as magnesium hydroxide, calcium hydroxide,
potassium hydroxide, zinc hydroxide, or sodium hydroxide; and
organic bases, such as primary, secondary, tertiary, and
quaternary, aliphatic and aromatic amines, including L-arginine,
benethamine, benzathine, choline, deanol, diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylamine,
ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine,
1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,
isoquinoline, secondary amines, triethanolamine, trimethylamine,
triethylamine, N-methyl-D-glucamine,
2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.
[0051] While it may be possible for the compounds of the subject
invention to be administered as the raw chemical, it is also
possible to present them as a pharmaceutical composition.
Accordingly, provided herein are pharmaceutical compositions which
comprise one or more of certain compounds disclosed herein, or one
or more pharmaceutically acceptable salts, prodrugs, or solvates
thereof, together with one or more pharmaceutically acceptable
carriers thereof and optionally one or more other therapeutic
ingredients. Proper formulation is dependent upon the route of
administration chosen. Any of the well-known techniques, carriers,
and excipients may be used as suitable and as understood in the
art; e.g., in Remington's Pharmaceutical Sciences. The
pharmaceutical compositions disclosed herein may be manufactured in
any manner known in the art, e.g., by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or compression processes. The
pharmaceutical compositions may also be formulated as a modified
release dosage form, including delayed-, extended-, prolonged-,
sustained-, pulsatile-, controlled-, accelerated- and fast-,
targeted-, programmed-release, and gastric retention dosage forms.
These dosage forms can be prepared according to conventional
methods and techniques known to those skilled in the art (see,
Remington: The Science and Practice of Pharmacy, supra;
Modified-Release Drug Deliver Technology, Rathbone et al., Eds.,
Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New
York, N.Y., 2002; Vol. 126).
[0052] The compositions include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous,
intraarticular, and intramedullary), intraperitoneal, transmucosal,
transdermal, rectal and topical (including dermal, buccal,
sublingual and intraocular) administration although the most
suitable route may depend upon for example the condition and
disorder of the recipient. The compositions may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. Typically, these methods
include the step of bringing into association a compound of the
subject invention or a pharmaceutically salt, prodrug, or solvate
thereof ("active ingredient") with the carrier which constitutes
one or more accessory ingredients. In general, the compositions are
prepared by uniformly and intimately bringing into association the
active ingredient with liquid carriers or finely divided solid
carriers or both and then, if necessary, shaping the product into
the desired formulation.
[0053] Formulations of the compounds disclosed herein suitable for
oral administration may be presented as discrete units such as
capsules, cachets or tablets each containing a predetermined amount
of the active ingredient; as a powder or granules; as a solution or
a suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0054] Pharmaceutical preparations which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. Tablets may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with binders, inert diluents, or lubricating, surface active
or dispersing agents. Molded tablets may be made by molding in a
suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent. The tablets may optionally be coated or
scored and may be formulated so as to provide slow or controlled
release of the active ingredient therein. All formulations for oral
administration should be in dosages suitable for such
administration. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, the active
compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols. In
addition, stabilizers may be added. Dragee cores are provided with
suitable coatings. For this purpose, concentrated sugar solutions
may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures. Dyestuffs or pigments may be added to the
tablets or dragee coatings for identification or to characterize
different combinations of active compound doses.
[0055] The compounds may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. The formulations may be presented in
unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in powder form or in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid carrier, for example, saline or sterile pyrogen-free water,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0056] Formulations for parenteral administration include aqueous
and non-aqueous (oily) sterile injection solutions of the active
compounds which may contain antioxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. Suitable lipophilic solvents or vehicles include fatty oils
such as sesame oil, or synthetic fatty acid esters, such as ethyl
oleate or triglycerides, or liposomes. Aqueous injection
suspensions may contain substances which increase the viscosity of
the suspension, such as sodium carboxymethyl cellulose, sorbitol,
or dextran. Optionally, the suspension may also contain suitable
stabilizers or agents which increase the solubility of the
compounds to allow for the preparation of highly concentrated
solutions.
[0057] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0058] For buccal or sublingual administration, the compositions
may take the form of tablets, lozenges, pastilles, or gels
formulated in conventional manner. Such compositions may comprise
the active ingredient in a flavored basis such as sucrose and
acacia or tragacanth.
[0059] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter, polyethylene
glycol, or other glycerides.
[0060] Certain compounds disclosed herein may be administered
topically, that is by non-systemic administration. This includes
the application of a compound disclosed herein externally to the
epidermis or the buccal cavity and the instillation of such a
compound into the ear, eye and nose, such that the compound does
not significantly enter the blood stream. In contrast, systemic
administration refers to oral, intravenous, intraperitoneal and
intramuscular administration.
[0061] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin to the site of inflammation such as gels, liniments,
lotions, creams, ointments or pastes, and drops suitable for
administration to the eye, ear or nose.
[0062] For administration by inhalation, compounds may be delivered
from an insufflator, nebulizer pressurized packs or other
convenient means of delivering an aerosol spray. Pressurized packs
may comprise a suitable propellant such as dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a
metered amount. Alternatively, for administration by inhalation or
insufflation, the compounds according to the invention may take the
form of a dry powder composition, for example a powder mix of the
compound and a suitable powder base such as lactose or starch. The
powder composition may be presented in unit dosage form, in for
example, capsules, cartridges, gelatin or blister packs from which
the powder may be administered with the aid of an inhalator or
insufflator.
[0063] Preferred unit dosage formulations are those containing an
effective dose, as herein below recited, or an appropriate fraction
thereof, of the active ingredient.
[0064] Compounds may be administered orally or via injection at a
dose of from 0.1 to 500 mg/kg per day. The dose range for adult
humans is generally from 5 mg to 2 g/day. Tablets or other forms of
presentation provided in discrete units may conveniently contain an
amount of one or more compounds which is effective at such dosage
or as a multiple of the same, for instance, units containing 5 mg
to 500 mg, usually around 10 mg to 200 mg.
[0065] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
[0066] The compounds can be administered in various modes, e.g.
orally, topically, or by injection. The precise amount of compound
administered to a patient will be the responsibility of the
attendant physician. 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, diets, time of administration, route of
administration, rate of excretion, drug combination, the precise
disorder being treated, and the severity of the disorder being
treated. Also, the route of administration may vary depending on
the disorder and its severity.
[0067] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of the
compounds may be administered chronically, that is, for an extended
period of time, including throughout the duration of the patient's
life in order to ameliorate or otherwise control or limit the
symptoms of the patient's disorder.
[0068] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the compounds may be
given continuously or temporarily suspended for a certain length of
time (i.e., a "drug holiday").
[0069] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
disorder is retained. Patients can, however, require intermittent
treatment on a long-term basis upon any recurrence of symptoms.
[0070] Disclosed herein are methods of treating a P2Y12
receptor-mediated disorder comprising administering to a subject
having or suspected of having such a disorder, a therapeutically
effective amount of a compound as disclosed herein or a
pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0071] P2Y12 receptor-mediated disorders, include, but are not
limited to, arterial thrombosis, coronary artery disease,
myocardial infarction, stroke, atherosclerosis, acute coronary
syndrome, peripheral artery occlusive disease, carotid, vertebral,
or intracerebral artery stenosis, unstable angina, primary arterial
thrombotic complications of atherosclerosis such as thrombotic or
embolic stroke, transient ischaemic attacks, peripheral vascular
disease, myocardial infarction with or without thrombolysis,
arterial complications due to interventions in atherosclerotic
disease such as angioplasty, including coronary angioplasty (PTCA),
endarterectomy, stent placement, coronary and other vascular graft
surgery, thrombotic complications of surgical or mechanical damage
such as tissue salvage following accidental or surgical trauma,
reconstructive surgery including skin and muscle flaps, conditions
with a diffuse thrombotic/platelet consumption component such as
disseminated intravascular coagulation, thrombotic
thrombocytopaenic purpura, haemolytic uraemic syndrome, thrombotic
complications of septicaemia, adult respiratory distress syndrome,
anti-phospholipid syndrome, heparin-induced thrombocytopaenia and
pre-eclampsia/eclampsia, or venous thrombosis such as deep vein
thrombosis, venoocclusive disease, haematological conditions such
as myeloproliferative disease, including thrombocythaemia, sickle
cell disease; or in the prevention of mechanically-induced platelet
activation in vivo, such as cardio-pulmonary bypass and
extracorporeal membrane oxygenation (prevention of
microthromboembolism), mechanically-induced platelet activation in
vitro, such as use in the preservation of blood products, e.g.
platelet concentrates, or shunt occlusion such as in renal dialysis
and plasmapheresis, thrombosis secondary to vascular
damage/inflammation such as vasculitis, arteritis,
glomerulonephritis, inflammatory bowel disease and organ graft
rejection, conditions such as migraine, Raynaud's phenomenon,
conditions in which platelets can contribute to the underlying
inflammatory disease process in the vascular wall such as
atheromatous plaque formation/progression, stenosis/restenosis, in
other inflammatory conditions such as asthma, in which platelets
and platelet-derived factors are implicated in the immunological
disease process, and/or any disorder which can lessened,
alleviated, or prevented by administering a P2Y12 receptor
modulator.
[0072] In certain embodiments, a method of treating a P2Y12
receptor-mediated disorder comprises administering to the subject a
therapeutically effective amount of a compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof,
so as to affect: (1) decreased inter-individual variation in plasma
levels of the compound or a metabolite thereof; (2) increased
average plasma levels of the compound or decreased average plasma
levels of at least one metabolite of the compound per dosage unit;
(3) decreased inhibition of, and/or metabolism by at least one
cytochrome P.sub.450 or monoamine oxidase isoform in the subject;
(4) decreased metabolism via at least one polymorphically-expressed
cytochrome P.sub.450 isoform in the subject; (5) at least one
statistically-significantly improved disorder-control and/or
disorder-eradication endpoint; (6) an improved clinical effect
during the treatment of the disorder, (7) prevention of recurrence,
or delay of decline or appearance, of abnormal alimentary or
hepatic parameters as the primary clinical benefit, or (8)
reduction or elimination of deleterious changes in any diagnostic
hepatobiliary function endpoints, as compared to the corresponding
non-isotopically enriched compound.
[0073] In certain embodiments, inter-individual variation in plasma
levels of the compounds as disclosed herein, or metabolites
thereof, is decreased; average plasma levels of the compound as
disclosed herein are increased; average plasma levels of a
metabolite of the compound as disclosed herein are decreased;
inhibition of a cytochrome P.sub.450 or monoamine oxidase isoform
by a compound as disclosed herein is decreased; or metabolism of
the compound as disclosed herein by at least one
polymorphically-expressed cytochrome P.sub.450 isoform is
decreased; by greater than about 5%, greater than about 10%,
greater than about 20%, greater than about 30%, greater than about
40%, or by greater than about 50% as compared to the corresponding
non-isotopically enriched compound.
[0074] Plasma levels of the compound as disclosed herein, or
metabolites thereof, may be measured using the methods described by
Li et al. Rapid Communications in Mass Spectrometry 2005, 19,
1943-1950; Butler, et al., Drug Metab Rev 2008, 40(Suppl. 3): Abst
280; Husted et al., European Heart Journal 2006, 27(9), 1038-1047;
and any references cited therein and any modifications made
thereof.
[0075] Examples of cytochrome P.sub.450 isoforms in a mammalian
subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1,
CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6,
CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1,
CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11,
CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1,
CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1,
CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.
[0076] Examples of monoamine oxidase isoforms in a mammalian
subject include, but are not limited to, MAO.sub.A, and
MAO.sub.B.
[0077] The inhibition of the cytochrome P.sub.450 isoform is
measured by the method of K.sub.O et al., British Journal of
Clinical Pharmacology 2000, 49, 343-351. The inhibition of the
MAO.sub.A isoform is measured by the method of Weyler et al., J.
Biol Chem. 1985, 260, 13199-13207. The inhibition of the MAO.sub.B
isoform is measured by the method of Uebelhack et al.,
Pharmacopsychiatry, 1998, 31, 187-192.
[0078] Examples of polymorphically-expressed cytochrome P.sub.450
isoforms in a mammalian subject include, but are not limited to,
CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
[0079] The metabolic activities of liver microsomes, cytochrome
P.sub.450 isoforms, and monoamine oxidase isoforms are measured by
the methods described herein.
[0080] Examples of improved disorder-control and/or
disorder-eradication endpoints, or improved clinical effects
include, but are not limited to, bleeding time, platelet
inhibition, inhibition of adenosine-5'-diphosphate-induced platelet
aggregation as measured by optical aggregometry of platelet-rich
plasma, reduced cardiovascular death, reduced myocardial
infarction, reduced stroke, and reduced bleeding events (Tantry et
al., Exp. Opin. Invest. Drugs 2007, 16(2), 225-229; Husted et al.,
Eur. Heart 1 2006, 27(9), 1038-1047; and WO 2000034283).
[0081] Examples of diagnostic hepatobiliary function endpoints
include, but are not limited to, alanine aminotransferase ("ALT"),
serum glutamic-pyruvic transaminase ("SGPT"), aspartate
aminotransferase ("AST" or "SGOT"), ALT/AST ratios, serum aldolase,
alkaline phosphatase ("ALP"), ammonia levels, bilirubin,
gamma-glutamyl transpeptidase ("GGTP," ".gamma.-GTP," or "GGT"),
leucine aminopeptidase ("LAP"), liver biopsy, liver
ultrasonography, liver nuclear scan, 5'-nucleotidase, and blood
protein. Hepatobiliary endpoints are compared to the stated normal
levels as given in "Diagnostic and Laboratory Test Reference",
4.sup.th edition, Mosby, 1999. These assays are run by accredited
laboratories according to standard protocol.
[0082] Besides being useful for human treatment, certain compounds
and formulations disclosed herein may also be useful for veterinary
treatment of companion animals, exotic animals and farm animals,
including mammals, rodents, and the like. More preferred animals
include horses, dogs, and cats.
Combination Therapy
[0083] The compounds disclosed herein may also be combined or used
in combination with other agents useful in the treatment of P2Y12
receptor-mediated disorders. Or, by way of example only, the
therapeutic effectiveness of one of the compounds described herein
may be enhanced by administration of an adjuvant (i.e., by itself
the adjuvant may only have minimal therapeutic benefit, but in
combination with another therapeutic agent, the overall therapeutic
benefit to the patient is enhanced).
[0084] Such other agents, adjuvants, or drugs, may be administered,
by a route and in an amount commonly used therefor, simultaneously
or sequentially with a compound as disclosed herein. When a
compound as disclosed herein is used contemporaneously with one or
more other drugs, a pharmaceutical composition containing such
other drugs in addition to the compound disclosed herein may be
utilized, but is not required.
[0085] In certain embodiments, the compounds disclosed herein can
be combined with one or more alpha adrenergic receptor antagonists,
beta-adrenergic antagonists, angiotensin II receptor antagonists,
angiotensin-converting enzyme inhibitors, anti-arrhythmics,
antithrombotics, antiplatelet agents, calcium channel blockers,
fibrates, and HMG-CoA reductase inhibitors.
[0086] In certain embodiments, the compounds disclosed herein can
be combined with one or more alpha adrenergic receptor antagonists
known in the art, including, but not limited to, abanoquil,
adimolol, ajmalicine, alfuzosin, amosulalol, arotinolol, atiprosin,
benoxathian, buflomedil, bunazosin, carvedilol, CI-926,
corynanthine, dapiprazole, DL-017, domesticine, doxazosin,
eugenodilol, fenspiride, GYKI-12,743, GYKI-16,084, indoramin,
ketanserin, L-765,314, labetalol, mephendioxan, metazosin,
monatepil, moxisylyte (thymoxamine), naftopidil, nantenine,
neldazosin, nicergoline, niguldipine, pelanserin, phendioxan,
phenoxybenzamine, phentolamine, piperoxan, prazosin, quinazosin,
ritanserin, RS-97,078, SGB-1,534, silodosin, SL-89.0591, spiperone,
talipexole, tamsulosin, terazosin, tibalosin, tiodazosin,
tipentosin, tolazoline, trimazosin, upidosin, urapidil, zolertine,
1-PP, adimolol, atipamezole, BRL-44408, buflomedil, cirazoline,
efaroxan, esmirtazapine, fluparoxan, GYKI-12,743, GYKI-16,084,
idazoxan, mianserin, mirtazapine, MK-912, NAN-190, olanzapine,
phentolamine, phenoxybenzamine, piperoxan, piribedil, rauwolscine,
rotigotine, SB-269,970, setiptiline, spiroxatrine, sunepitron,
tolazoline, and yohimbine.
[0087] In certain embodiments, the compounds disclosed herein can
be combined with one or more beta-adrenergic antagonists,
including, but not limited to, acebutolol, adaprolol, adimolol,
afurolol, alprenolol, alprenoxime, amosulalol, ancarolol, arnolol,
arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol,
bopindolol, bormetolol, bornaprolol, brefonalol, bucindolol,
bucumolol, bufetolol, buftiralol, bufuralol, bunitrolol, bunolol,
bupranolol, burocrolol, butaxamine, butidrine, butofilolol,
capsinolol, carazolol, carpindolol, carteolol, carvedilol,
celiprolol, cetamolol, cicloprolol, cinamolol, cloranolol,
cyanopindolol, dalbraminol, dexpropranolol, diacetolol,
dichloroisoprenaline, dihydroalprenolol, dilevalol, diprafenone,
draquinolol, dropranolol, ecastolol, epanolol, ericolol,
ersentilide, esatenolol, esmolol, esprolol, eugenodilol, exaprolol,
falintolol, flestolol, flusoxolol, hydroxycarteolol,
hydroxytertatolol, ICI-118,551, idropranolol, indenolol,
indopanolol, iodocyanopindolol, iprocrolol, isoxaprolol,
isamoltane, labetalol, landiolol, levobetaxolol, levobunolol,
levocicloprolol, levomoprolol, medroxalol, mepindolol, metalol,
metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nafetolol,
nebivolol, neraminol, nifenalol, nipradilol, oberadilol,
oxprenolol, pacrinolol, pafenolol, pamatolol, pargolol, parodilol,
penbutolol, penirolol, PhQA-33, pindolol, pirepolol, practolol,
primidolol, procinolol, pronethalol, propafenone, propranolol,
ridazolol, ronactolol, soquinolol, sotalol, spirendolol, SR 59230A,
sulfinalol, TA-2005, talinolol, tazolol, teoprolol, tertatolol,
terthianolol, tienoxolol, tilisolol, timolol, tiprenolol,
tolamolol, toliprolol, tribendilol, trigevolol, xibenolol, and
xipranolol.
[0088] In certain embodiments, the compounds disclosed herein can
be combined with one or more angiotensin II receptor antagonists,
including, but not limited to, candesartan, eprosartan, irbesartan,
losartan, olmesartan, tasosartan, telmisartan, and valsartan.
[0089] In certain embodiments, the compounds disclosed herein can
be combined with one or more angiotensin-converting enzyme
inhibitors, including, but not limited to, captopril, enalapril,
lisinopril, perindopril, ramipril, quinapril, benazepril,
cilazapril, fosinopril, trandolapril, spirapril, delapril,
moexipril, temocapril, zofenopril, and imidapril.
[0090] In certain embodiments, the compounds disclosed herein can
be combined with one or more anti-arrhythmics, including, but not
limited to quinidine, procainamide, disopyramide, sparteine,
ajmaline, prajmaline, lorajmine, lidocaine, mexiletine, tocainide,
aprindine, propafenone, flecainide, lorcainide, encainide,
amiodarone, bretylium tosilate, bunaftine, dofetilide, ibutilidem,
tedisamil, moracizine, and cibenzoline.
[0091] In certain embodiments, the compounds provided herein can be
combined with one or more antithrombotics, including, but not
limited to, dicoumarol, phenindione, warfarin, phenprocoumon,
acenocoumarol, ethyl biscoumacetate, clorindione, diphenadione,
tioclomarol, heparin, antithrombin III, dalteparin, enoxaparin,
nadroparin, parnaparin, reviparin, danaparoid, tinzaparin,
sulodexide, bemiparin, ditazole, cloricromen, picotamide,
clopidogrel, ticlopidine, acetylsalicylic acid, dipyridamole,
carbasalate calcium, epoprostenol, indobufen, iloprost, abciximab,
aloxiprin, eptifibatide, tirofiban, triflusal, beraprost,
treprostinil, prasugrel, streptokinase, alteplase, urokinase,
fibrinolysin, brinase, reteplase, saruplase, ancrod, drotrecogin
alfa (activated), tenecteplase, protein C, desirudin, lepirudin,
argatroban, melagatran, ximelagatran, bivalirudin, dabigatran
etexilate, defibrotide, dermatan sulfate, fondaparinux, and
rivaroxaban.
[0092] In certain embodiments, the compounds provided herein can be
combined with one or more antiplatelet agents, including, but not
limited to, abciximab, eptifibatide, tirofiban, clopidogrel,
prasugrel, ticlopidine, ticagrelor, beraprost, prostacyclin,
iloprost, treprostinil, acetylsalicylic acid, aloxiprin,
carbasalate calcium, indobufen, dipyridamole, picotamide,
terutroban, cilostazol, dipyridamole, triflusal, cloricromen, and
ditazole.
[0093] In certain embodiments, the compounds disclosed herein can
be combined with one or more beta-adrenergic antagonists,
including, but not limited to, acebutolol, adaprolol, adimolol,
afurolol, alprenolol, alprenoxime, amosulalol, ancarolol, arnolol,
arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol,
bopindolol, bormetolol, bornaprolol, brefonalol, bucindolol,
bucumolol, bufetolol, buftiralol, bufuralol, bunitrolol, bunolol,
bupranolol, burocrolol, butaxamine, butidrine, butofilolol,
capsinolol, carazolol, carpindolol, carteolol, carvedilol,
celiprolol, cetamolol, cicloprolol, cinamolol, cloranolol,
cyanopindolol, dalbraminol, dexpropranolol, diacetolol,
dichloroisoprenaline, dihydroalprenolol, dilevalol, diprafenone,
draquinolol, dropranolol, ecastolol, epanolol, ericolol,
ersentilide, esatenolol, esmolol, esprolol, eugenodilol, exaprolol,
falintolol, flestolol, flusoxolol, hydroxycarteolol,
hydroxytertatolol, ICI-118,551, idropranolol, indenolol,
indopanolol, iodocyanopindolol, iprocrolol, isoxaprolol,
isamoltane, labetalol, landiolol, levobetaxolol, levobunolol,
levocicloprolol, levomoprolol, medroxalol, mepindolol, metalol,
metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nafetolol,
nebivolol, neraminol, nifenalol, nipradilol, oberadilol,
oxprenolol, pacrinolol, pafenolol, pamatolol, pargolol, parodilol,
penbutolol, penirolol, PhQA-33, pindolol, pirepolol, practolol,
primidolol, procinolol, pronethalol, propafenone, propranolol,
ridazolol, ronactolol, soquinolol, sotalol, spirendolol, SR 59230A,
sulfinalol, TA-2005, talinolol, tazolol, teoprolol, tertatolol,
terthianolol, tienoxolol, tilisolol, timolol, tiprenolol,
tolamolol, toliprolol, tribendilol, trigevolol, xibenolol, and
xipranolol.
[0094] In certain embodiments, the compounds disclosed herein can
be combined with one or more calcium channel blockers, including,
but not limited to amlodipine, felodipine, isradipine, nicardipine,
nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine,
nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine,
benidipine, mibefradil, verapamil, gallopamil, diltiazem,
fendiline, bepridil, lidoflazine, and perhexiline.
[0095] In certain embodiments, the compounds provided herein can be
combined with one or more fibrates, including, but not limited to,
clofibrate, bezafibrate, aluminium clofibrate, gemfibrozil,
fenofibrate, simfibrate, ronifibrate, ciprofibrate, etofibrate, and
clofibride.
[0096] In certain embodiments, the compounds disclosed herein can
be combined with one or more HMG-CoA reductase inhibitors,
including, but not limited to, atorvastatin, cerivastatin,
fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,
rosuvastatin, and simvastatin.
[0097] The compounds disclosed herein can also be administered in
combination with other classes of compounds, including, but not
limited to, decongestant treatments; antitussive treatments;
mucolytic treatments; expectorant treatments; antiallergic
non-steroidal treatments; steroidal drugs; antihistamine
treatments; leukotriene receptor antagonists; phosphodiesterase
inhibitors; CYP3A inhibitors; CYP3A inducers; protease inhibitors;
antifungal agents; antibacterials; antimycobacterial agents; sepsis
treatments; steroidal drugs; non-steroidal anti-inflammatory
agents, norepinephrine reuptake inhibitors (NRIs) such as
atomoxetine; dopamine reuptake inhibitors (DARIs), such as
methylphenidate; serotonin-norepinephrine reuptake inhibitors
(SNRIs), such as milnacipran; sedatives, such as diazepam;
norepinephrine-dopamine reuptake inhibitor (NDRIs), such as
bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors
(SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such
as selegiline; hypothalamic phospholipids; endothelin converting
enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as
tramadol; thromboxane receptor antagonists, such as ifetroban;
potassium channel openers; thrombin inhibitors, such as hirudin;
hypothalamic phospholipids; growth factor inhibitors, such as
modulators of PDGF activity; platelet activating factor (PAF)
antagonists; Factor VIIa Inhibitors and Factor Xa Inhibitors; renin
inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase
inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and
gemopatrilat; squalene synthetase inhibitors; bile acid
sequestrants, such as questran; niacin; anti-atherosclerotic
agents, such as ACAT inhibitors; MTP Inhibitors; potassium channel
activators; alpha-muscarinic agents; beta-muscarinic agents, such
as carvedilol and metoprolol; diuretics, such as chlorothlazide,
hydrochiorothiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlorothiazide, trichioromethiazide,
polythiazide, benzothlazide, ethacrynic acid, tricrynafen,
chlorthalidone, furosenilde, musolimine, bumetanide, triamterene,
amiloride, and spironolactone; anti-diabetic agents, such as
biguanides (e.g. metformin), glucosidase inhibitors (e.g.,
acarbose), insulins, meglitinides (e.g., repaglinide),
sulfonylureas (e.g., glimepiride, glyburide, and glipizide),
thiozolidinediones (e.g. troglitazone, rosiglitazone and
pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor
antagonists, such as spironolactone and eplerenone; growth hormone
secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such
as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors
(e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase
inhibitors; antiinflammatories; antiproliferatives, such as
methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil;
chemotherapeutic agents; immunosuppressants; anticancer agents and
cytotoxic agents (e.g., alkylating agents, such as nitrogen
mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and
triazenes); antimetabolites, such as folate antagonists, purine
analogues, and pyrridine analogues; antibiotics, such as
anthracyclines, bleomycins, mitomycin, dactinomycin, and
plicamycin; enzymes, such as L-asparaginase; farnesyl-protein
transferase inhibitors; hormonal agents, such as glucocorticoids
(e.g., cortisone), estrogens/antiestrogens,
androgens/antiandrogens, progestins, and luteinizing
hormone-releasing hormone antagonists, and octreotide acetate;
microtubule-disruptor agents, such as ecteinascidins;
microtubule-stabilizing agents, such as pacitaxel, docetaxel, and
epothilones A-F; plant-derived products, such as vinca alkaloids,
epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;
prenyl-protein transferase inhibitors; and cyclosporins; steroids,
such as prednisone and dexamethasone; cytotoxic drugs, such as
azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as
tenidap; anti-TNF antibodies or soluble TNF receptor, such as
etanercept, rapamycin, and leflunimide; and cyclooxygenase-2
(COX-2) inhibitors, such as celecoxib and rofecoxib; and
miscellaneous agents such as, hydroxyurea, procarbazine, mitotane,
hexamethylmelamine, gold compounds, platinum coordination
complexes, such as cisplatin, satraplatin, and carboplatin.
[0098] Thus, in another aspect, certain embodiments provide methods
for treating P2Y12 receptor-mediated disorders in a human or animal
subject in need of such treatment comprising administering to said
subject an amount of a compound disclosed herein effective to
reduce or prevent said disorder in the subject, in combination with
at least one additional agent for the treatment of said disorder
that is known in the art. In a related aspect, certain embodiments
provide therapeutic compositions comprising at least one compound
disclosed herein in combination with one or more additional agents
for the treatment of P2Y12 receptor-mediated disorders.
General Synthetic Methods for Preparing Compounds
[0099] Isotopic hydrogen can be introduced into a compound as
disclosed herein by synthetic techniques that employ deuterated
reagents, whereby incorporation rates are pre-determined; and/or by
exchange techniques, wherein incorporation rates are determined by
equilibrium conditions, and may be highly variable depending on the
reaction conditions. Synthetic techniques, where tritium or
deuterium is directly and specifically inserted by tritiated or
deuterated reagents of known isotopic content, may yield high
tritium or deuterium abundance, but can be limited by the chemistry
required. Exchange techniques, on the other hand, may yield lower
tritium or deuterium incorporation, often with the isotope being
distributed over many sites on the molecule.
[0100] The compounds as disclosed herein can be prepared by methods
known to one of skill in the art and routine modifications thereof,
and/or following procedures similar to those described in the
Example section herein and routine modifications thereof, and/or
procedures found in Shireman et al., Tetrahedron Letters 2000, 41,
9537-9540; Bioorganic & Medicinal Chemistry Letters 2007, 17,
6013-6018; US 20030148888 and WO 2010030224; WO 2000034283; WO
2001092262; WO 2001092263; WO 199905142, which are hereby
incorporated in their entirety, and references cited therein and
routine modifications thereof. Compounds as disclosed herein can
also be prepared as shown in any of the following schemes and
routine modifications thereof.
[0101] The following schemes can be used to practice the present
invention. Any position shown as hydrogen may optionally be
replaced with deuterium.
##STR00004## ##STR00005##
[0102] Compound 1 is treated with malonic acid in the presence of
an appropriate base, such as piperidine, in an appropriate solvent,
such as pyridine, to give compound 2. Compound 2 is reacted with an
appropriate chlorinating agent, such as thionyl chloride, in the
presence of an appropriate base, such as pyridine, in an
appropriate solvent, such as toluene, to give compound 3. Compound
3 is reacted with compound 4 in the presence of an appropriate
base, such as pyridine, in an appropriate solvent, such as toluene,
to give compound 5. Compound 5 is reacted with compound 6, in the
presence of an appropriate base, such as sodium hydroxide, in an
appropriate solvent, such as an appropriate mixture of dimethyl
sulfoxide and water, to give compound 7. Compound 7 is reacted with
an appropriate hydroxide base, such as sodium hydroxide, in an
appropriate solvent, such as an appropriate mixture of dimethyl
sulfoxide and water, to give compound 8. Compound 8 is reacted with
an appropriate chlorinating agent, such as thionyl chloride, in an
appropriate solvent, such as toluene, to give an acyl chloride
intermediate which is then reacted with an appropriate azide
source, such as sodium azide, in the presence of an appropriate
base, such as sodium carbonate, in the presence of an appropriate
phase-transfer catalyst, such as tetrabutylammonium bromide, to
give compound 9. Compound 9 is reacted at an elevated temperature
in an appropriate solvent, such as toluene, to give compound 10.
Compound 11 is reacted with an appropriate amine protecting
reagent, such as benzyl chloroformate, in the presence of an
appropriate base, such as potassium carbonate, in an appropriate
solvent, such as 4-methyl-2-pentanone, to give compound 12.
Compound 12 is reacted with compound 13 in the presence of an
appropriate base, such as potassium tert-butoxide, in an
appropriate solvent, such as tetrahydrofuran, to give compound 14.
Compound 14 is treated with an appropriate reducing reagent, such
as lithium borohydride, in an appropriate solvent, such as
tetrahydrofuran, to give compound 15. Compound 15 is treated with
an appropriate deprotecting reagent, such as a combination of
hydrogen gas and palladium on carbon, in an appropriate solvent,
such as ethanol, to give compound 16. Compound 17 is reacted with
compound 18 in the presence of an appropriate base, such as sodium
hydroxide, in an appropriate solvent, such as an appropriate
mixture of water and 1-methyl-2-pyrrolidinone, to give compound 19.
Compound 19 is reacted with an appropriate base, such as sodium
hydroxide, and then reacted with an aromatic amine, such as
para-toluidine, in the presence of an appropriate nitrite salt,
such as sodium nitrite, in the presence of an appropriate acid,
such as hydrochloric acid, in an appropriate solvent, such as
water, to give compound 20. Compound 20 is reacted with an
appropriate chlorinating agent, such as phosphorous oxychloride, in
an appropriate solvent, such as toluene, to give compound 21.
Compound 21 is reacted with an appropriate reducing agent, such as
a hydrogen gas, in the presence of an appropriate catalyst, such as
platinum on carbon, in an appropriate solvent, such as 2-propanol,
to give compound 22. Compound 22 is reacted with compound 16, in
the presence of an appropriate base, such as triethylamine, in an
appropriate solvent, such as ethanol, to give compound 23. Compound
23 is reacted with an appropriate nitrite salt, such as sodium
nitrite, in the presence of an appropriate acid, such as acetic
acid, in an appropriate solvent, such as water, to give compound
24. Compound 24 is reacted with compound 10 in the presence of an
appropriate base, such as triethylamine, in an appropriate solvent,
such as acetonitrile, to give compound 25. Compound 25 is treated
with an appropriate ketal deprotecting reagent, such as
hydrochloric acid, in an appropriate solvent, such as a combination
of water and methanol, to give a compound 26 of Formula I.
[0103] Deuterium can be incorporated to different positions
synthetically, according to the synthetic procedures as shown in
Scheme I, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.1-R.sub.4, compound 1 with the corresponding deuterium
substitutions can be used. To introduce deuterium at R.sub.7,
malonic acid with the corresponding deuterium substitutions can be
used. To introduce deuterium at one or more positions of
R.sub.5-R.sub.6, compound 6 with the corresponding deuterium
substitutions can be used. To introduce deuterium at one or more
positions of R.sub.16-R.sub.21, compound 11 with the corresponding
deuterium substitutions can be used. To introduce deuterium at one
or more positions of R.sub.24-R.sub.25, compound 13 with the
corresponding deuterium substitutions can be used. To introduce
deuterium at one or more positions of R.sub.26-R.sub.27, lithium
borodeuteride can be used. To introduce deuterium at one or more
positions of R.sub.9-R.sub.15, compound 18 with the corresponding
deuterium substitutions can be used.
[0104] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the amine N--H and hydroxyl O--Hs, via
proton-deuterium equilibrium exchange. For example, to introduce
deuterium at R.sub.8, R.sub.22-R.sub.23, and R.sub.28, this proton
may be replaced with deuterium selectively or non-selectively
through a proton-deuterium exchange method known in the art.
##STR00006## ##STR00007## ##STR00008## ##STR00009##
[0105] Compound 27 is reacted with compound 28 in the presence of
an appropriate oxidant, such as a combination of oxalyl chloride,
dimethyl sulfoxide, and triethylamine, in an appropriate solvent,
such as a combination of dichloromethane and dimethyl sulfoxide, to
give compound 29. Compound 29 is reacted with an appropriate
oxidizing agent, such as a combination of osmium tetroxide and
N-methylmorpholine N-oxide, in an appropriate solvent, such as a
combination of water and tetrahydrofuran, to give compound 30.
Compound 30 is reacted with an appropriate 1,2-dihydroxy protecting
group, such as 2,2-dimethoxypropane, in the presence of an
appropriate acid, such as p-toluenesulfonic acid, to give compound
31. Compound 31 is reacted with an appropriate reducing agent, such
as sodium borohydride, in an appropriate solvent, such as methanol,
to give compound 32. Compound 32 is treated with an appropriate
reducing agent, such as a combination of hydrogen gas and palladium
on carbon, in an appropriate solvent, such as methanol, to give
compound 33. Compound 33 is reacted with an appropriate amine
protecting reagent, such as benzyl chloroformate, in the presence
of an appropriate base, such as potassium carbonate, in an
appropriate solvent, such as a combination of water and
tetrahydrofuran, to give compound 34. Compound 35 is treated with
an appropriate reducing reagent, such as lithium aluminum hydride,
in an appropriate solvent, such as tetrahydrofuran, to give
compound 36. Compound 36 is reacted with an appropriate alcohol
protecting reagent, such as benzyl bromide, in the presence of an
appropriate base, such as silver oxide, in an appropriate solvent,
such as dichloromethane, to give compound 37. Compound 37 is
reacted with an appropriate brominating agent, such as a
combination of N-bromosuccinimide and triphenylphosphine, in an
appropriate solvent, such as tetrahydrofuran, to give compound 38.
Compound 34 is reacted with compound 38 in the presence of an
appropriate base, such as sodium hydride, in an appropriate
solvent, such as dimethylformamide, to give compound 39. Compound
39 is treated with an appropriate deprotecting reagent, such as a
combination of hydrogen gas and palladium on carbon, in an
appropriate solvent, such as methanol, to give compound 16.
Compound 40 is reacted with compound 41 in the presence of an
appropriate base, such as sodium ethoxide, in an appropriate
solvent, such as ethanol, to give compound 42. Compound 42 is
reacted with an appropriate base, such as triethylamine, at an
elevated temperature, in an appropriate solvent, such as methanol
or d.sub.4-methanol, to give compound 43. Compound 43 is reacted
with an appropriate decarboxylating catalyst, such as sodium
chloride, in an appropriate solvent, such as a combination of water
and dimethylsulfoxide, to give compound 44. Compound 44 is treated
with an appropriate reducing reagent, such as lithium aluminum
hydride, in an appropriate solvent, such as diethyl ether, to give
compound 45. Compound 45 is treated with an appropriate iodinating
reagent, such as hydroiodic acid, to give compound 18. Compound 18
is reacted with compound 17 in the presence of an appropriate base,
such as sodium hydroxide, in an appropriate solvent, such as an
appropriate mixture of water and 1-methyl-2-pyrrolidinone, to give
compound 19. Compound 19 is reacted with an appropriate nitrating
agent, such as nitric acid, to give compound 46. Compound 46 is
reacted with an appropriate chlorinating agent, such as phosphorous
oxychloride, in the presence of an appropriate base, such as
N,N-diethylbenzenamine, to give compound 47. Compound 47 is reacted
with compound 16 in an appropriate solvent, such as
tetrahydrofuran, to give compound 48. Compound 48 is treated with
an appropriate reducing reagent, such as a combination of iron and
acetic acid, in an appropriate solvent, such as a mixture of
ethanol and water, to give compound 23. Compound 23 is reacted with
an appropriate nitrite salt, such as sodium nitrite, in the
presence of an appropriate acid, such as acetic acid, in an
appropriate solvent, such as a combination of toluene and water, to
give compound 24. Compound 2 is reacted with an appropriate
chlorinating agent, such as oxalyl chloride, in the presence of an
appropriate catalyst, such as dimethylformamide, in an appropriate
solvent, such as dichloromethane, to give compound 3. Compound 3 is
reacted with an appropriate chiral auxiliary, such as
(2R)-bornane-10,2-sultam, in the presence of an appropriate base,
such as triethylamine, in an appropriate solvent, such as
dichloromethane, to give compound 49. Compound 49 is reacted with
compound 50, in the presence of an appropriate catalyst, such as
palladium (II) acetate, in an appropriate solvent, such as an
appropriate mixture of diethyl ether and dichloromethane, to give
compound 51. Compound 51 is reacted with an appropriate base, such
as lithium hydroxide, in an appropriate solvent, such as an
appropriate mixture of tetrahydrofuran and water, to give compound
8. Compound 8 is reacted with an appropriate acyl azide-forming
reagent, such as diphenylphosphoryl azide, in the presence of an
appropriate base, such as triethylamine, at elevated temperature,
in an appropriate solvent, such as toluene, to give compound 10.
Compound 24 is reacted with compound 10 in the presence of an
appropriate base, such as diisopropylethylamine, in an appropriate
solvent, such as dichloromethane, to give compound 25. Compound 25
is treated with an appropriate ketal deprotecting reagent, such as
hydrochloric acid, in an appropriate solvent, such as a combination
of water and methanol, to give a compound 26 of Formula I.
[0106] Deuterium can be incorporated to different positions
synthetically, according to the synthetic procedures as shown in
Scheme I, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.16-R.sub.21, compound 28 with the corresponding deuterium
substitutions can be used. To introduce deuterium at
R.sub.13-R.sub.15, compound 41 with the corresponding deuterium
substitutions can be used. To introduce deuterium at R.sub.11,
deuterium oxide and/or d.sub.6-deuterium oxide can be used. To
introduce deuterium at R.sub.12, d.sub.4-methanol can be used. To
introduce deuterium at one or more positions of R.sub.9-R.sub.10 or
R.sub.24-R.sub.27, lithium aluminum deuteride can be used. To
introduce deuterium at one or more positions of R.sub.1-R.sub.4 and
R.sub.7, compound 2 with the corresponding deuterium substitutions
can be used. To introduce deuterium at one or more positions of
R.sub.5-R.sub.6, compound 50 with the corresponding deuterium
substitutions can be used.
[0107] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the amine N--H and hydroxyl O--Hs, via
proton-deuterium equilibrium exchange. For example, to introduce
deuterium at R.sub.8, R.sub.22-R.sub.23, and R.sub.28, this proton
may be replaced with deuterium selectively or non-selectively
through a proton-deuterium exchange method known in the art.
[0108] The invention is further illustrated by the following
examples. All IUPAC names were generated using CambridgeSoft's
ChemDraw 10.0.
Example 1
(1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(pro-
pylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclo-
pentane-1,2-diol (ticagrelor)
##STR00010##
[0109] Step 1
##STR00011##
[0110] (R)-tert-Butyl
1-(hydroxyamino)-1-oxopropan-2-ylcarbamate
[0111] At about 0.degree. C., isopropyl chloroformate (86.05 g,
702.16 mmol, 1.00 equiv.) was added dropwise, over a period of 60
minutes, to a stirred mixture of
(S)-2-(tert-butoxycarbonylamino)propanoic acid (118 g, 623.65 mmol,
1.00 equiv.), tetrahydrofuran (500 mL), and triethylamine (63.63 g,
628.82 mmol, 1.00 equiv.). The resulting mixture was then stirred
at about 0.degree. C. for about 2 hours, and then the solids were
removed by filtration. The resulting filtrate was then added to a
hydroxylamine solution (formed by first stirring a mixture of
sodium hydroxide (37.6 g, 940.00 mmol, 1.50 equiv.), methanol (500
mL), and hydroxylamine hydrochloride (65 g, 935.39 mmol, 1.50
equiv) at about 0.degree. C. for about 2 hours, and then removing
the resulting solids by filtration). The resulting mixture was
stirred at about 0.degree. C. for about 2 hours, the solids were
removed by filtration, and the resulting filtrate was concentrated
in vacuo. The resulting residue was purified by silica gel column
chromatography (ethyl acetate/petroleum ether (1:1)) to give the
title product as a white solid (70 g; yield=55%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.: 5.18 (b, 1H), 4.21 (m, 1H), 2.06 (s, 1H),
1.46 (s, 9H), 1.40 (d, J=7.2 Hz, 3H).
Step 2
##STR00012##
[0112]
tert-Butyl-(R)-1-(3-oxa-2-aza-bicyclo[2.2.1]hept-5-en-2-yl)-1-oxopr-
opan-2-ylcarbamate
[0113] At about -78.degree. C. and under an atmosphere of nitrogen,
oxalyl dichloride (30.43 g, 239.74 mmol, 4.00 equiv.) was added
dropwise, over a period of 20 minutes, to stirred solution of
dimethylsulfoxide (28.1 g, 359.66 mmol, 6.00 equiv.) in
dichloromethane (200 mL). To this mixture was added dropwise, over
a period of about 10 minutes, a solution of (R)-tert-butyl
1-(hydroxyamino)-1-oxopropan-2-ylcarbamate (12.24 g, 59.94 mmol,
1.00 equiv.) and cyclopenta-1,3-diene (4.15 g, 62.78 mmol, 1.05
equiv.) in a mixture of dichloromethane/dimethylsulfoxide (5:1) (60
mL). The resulting mixture was stirred for at about -78.degree. C.
for about 30 minutes, and then triethylamine (66.8 mL) was added.
The resulting mixture was washed with 1M hydrochloric acid
(2.times.200 mL), and extracted with dichloromethane (3.times.100
mL). After the organic layers were combined, the organic phase was
washed with 10% sodium bicarbonate (2.times.200 mL), dried over
anhydrous sodium sulfate, and concentrated in vacuo. The resulting
residue was purified by silica gel column chromatography (ethyl
acetate/petroleum ether (1:10)) to give the desired product as a
white solid (8.6 g; yield=53%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 6.54 (s, 1H), 6.39 (m, 1H), 5.22-5.34 (m, 3H), 4.51 (m,
1H), 2.02 (d, J=8.4 Hz, 1H), 1.86 (d, J=8.7 Hz, 1H), 1.43 (s, 9H),
1.09 (m, 3H).
Step 3
##STR00013##
[0114] tert-Butyl
(R)-1-(5,6-dihydroxy-3-oxa-2-aza-bicyclo[2.2.1]heptan-2-yl)-1-oxopropan-2-
-ylcarbamate
[0115] A solution of
tert-butyl-(R)-1-(3-oxa-2-aza-bicyclo[2.2.1]hept-5-en-2-yl)-1-oxopropan-2-
-ylcarbamate (27.3 g, 101.75 mmol, 1.00 equiv.) in tetrahydrofuran:
water (5:1) (600 mL), osmium tetroxide (230 mg, 0.90 mmol, 0.01
equiv.), and N-methylmorpholine-N-oxide (25.26 g, 215.62 mmol, 2.10
equiv.) was stirred at about 20.degree. C. for about 50 minutes.
After adding sodium thiolsulfate (22 g), the resulting solution was
extracted with ethyl acetate (3.times.200 mL) and the organic
layers combined. The organic phase was washed with a saturated
sodium bicarbonate solution (1.times.250 mL) and then concentrated
in vacuo to give the desired product as a yellow liquid (30.1 g;
yield=98%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 5.29 (b,
1H), 4.36-4.74 (m, 3H), 3.76-4.09 (m, 4H), 2.67 (m, 1H), 1.90 (m,
1H), 1.43 (s, 9H), 1.30 (d, J=6.9 Hz, 3H).
Step 4
##STR00014##
[0117]
(2-(4,4-Dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.0.sup.2,b]dec-9--
yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester: A
solution of tert-butyl
(R)-1-(5,6-dihydroxy-3-oxa-2-aza-bicyclo[2.2.1]heptan-2-yl)-1-oxopropan-2-
-ylcarbamate (30.1 g, 99.56 mmol, 1.00 equiv.) in
2,2-dimethoxypropane (600 mL) and p-toluenesulfonic acid (1.1 g,
6.39 mmol, 0.06 equiv.) was stirred at about 22.degree. C. for
about 50 minutes. After adding a saturated solution of sodium
bicarbonate (450 mL), the mixture was extracted with ethyl acetate
(3.times.300 mL). The organic layers were combined and concentrated
in vacuo to give the title product as a white solid (33.5 g;
yield=98%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 5.22 (b,
1H), 4.89 (s, 1H), 4.70 (s, 1H), 4.61 (b, 1H), 4.33 (s, 2H), 2.24
(d, J=11.4 Hz, 1H), 1.82 (m, 1H), 1.52 (s, 3H), 1.46 (s, 9H), 1.32
(d, J=6.9 Hz, 3H), 1.27 (s, 3H).
Step 5
##STR00015##
[0118]
4,4-Dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.0.sup.2,6]decane
[0119] A mixture of
[2-(4,4-dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.0.sup.2,b]dec-9-yl)-1--
methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (33.5 g, 97.84
mmol, 1.00 equiv.), methanol (500 mL), and sodium borohydride
(14.67 g, 388.10 mmol, 4.00 equiv) was stirred at about 20.degree.
C. for about 50 minutes. The pH value of the mixture was then
adjusted to 3 by adding 1M hydrochloric acid. After extracting the
mixture with ethyl acetate (200 mL), the aqueous layers were
combined and the pH was adjusted to 10 by adding a 10% sodium
bicarbonate solution. Standard extractive workup with ethyl acetate
(3.times.300 mL) gave the title product as a white solid (16.7 g;
yield=99.8%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 4.80 (b,
1H), 4.69 (s, 1H), 4.29 (d, J=5.4 Hz, 1H), 4.22 (d, J=5.4 Hz, 1H),
3.77 (s, 1H), 2.28 (d, J=11.1 Hz, 1H), 1.65 (d, J=11.4 Hz, 1H),
1.50 (s, 3H), 1.27 (s, 3H).
Step 6
##STR00016##
[0120]
(3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1-
,3]dioxol-4-ol
[0121] Under a pressurized hydrogen atmosphere (3 atm), a
suspension of
4,4-dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.0.sup.2,6]decane
(16.7 g, 97.55 mmol, 1.00 equiv.), 10% palladium on carbon (1.67
g), and methanol (250 mL) was stirred at about 20.degree. C. for
about 60 minutes. After filtering the solution, the resulting
filtrate was concentrated in vacuo to give the title product as a
white solid (16.8 g; yield=99%). MS: m/z=174 (MH).sup.+.
Step 7
##STR00017##
[0122] Benzyl
(3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]d-
ioxol-4-ylcarbamate
[0123] At about 0.degree. C., benzyl carbonochloridate (18.4 g,
107.86 mmol, 1.05 equiv.) was added to the solution of
(3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dio-
xol-4-ol (17.0 g, 98.15 mmol, 1.00 equiv.) and sodium carbonate
(20.8 g, 196.24 mmol, 2.00 equiv) in tetrahydrofuran:water (5:1)
(600 mL). Standard extractive workup with ethyl acetate
(3.times.200 mL) gave the title product as a white solid (20.5 g;
yield=68%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.30-7.39
(m, 5H), 5.20 (s, 2H), 4.60 (d, J=5.4 Hz, 1H), 4.50 (d, J=5.4 Hz,
1H), 4.27 (s, 1H), 4.19 (d, J=5.7 Hz 1H), 2.26 (m, 1H), 1.71 (d,
J=14.4 Hz, 1H), 1.47 (s, 3H), 1.28 (s, 3H).
Step 8
##STR00018##
[0124] Ethyl
2-((3aR,4S,6R,6aS)-6-(benzyloxycarbonyl)-2,2-dimethyl-tetrahydro-3aH-cycl-
openta[d][1,3]dioxol-4-yloxy)acetate
[0125] Benzyl
(3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]d-
ioxol-4-ylcarbamate (12.29 g, 39.99 mmol, 1.00 equiv.) was added to
a solution of sodium hydride (70%) (1.44 g, 60.00 mmol, 1.05
equiv.) in dimethylformamide (200 mL). The solution was stirred at
about -30.degree. C. for about 30 minutes, and then ethyl
2-bromoacetate (7.68 g, 45.99 mmol, 1.20 equiv) was added. The
resulting solution was stirred at ambient temperature for about 5.5
hours, and then water was added (500 mL). Following standard
extractive workup with ethyl acetate (3.times.200 mL), the
resulting residue was purified by silica gel column chromatography
(ethyl acetate: petroleum ether (1:10)) to afford the title product
as a colorless solid (0.9 g; yield=69%). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.: 7.30-7.35 (m, 5H), 5.07 (s, 2H), 4.60 (d,
J=5.7 Hz, 1H), 4.51 (d, J=5.7 Hz, 1H), 4.12-4.29 (q, J=16.5 Hz,
2H), 4.10-4.22 (q, J=7.2 Hz, 2H), 4.00 (d, J=5.7 Hz, 1H), 3.92
(J=4.3 Hz, 1H), 2.17-2.19 (m, 1H), 1.84 (d, J=14.7 Hz, 1H), 1.38
(s, 3H), 1.26 (s, 3H), 1.11-1.22 (t, J=7.2 Hz, 3H).
Step 9
##STR00019##
[0127] Ethyl
2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-
dioxol-4-yloxy)acetate: Under an atmosphere of hydrogen, a
suspension of ethyl 2-((3
aR,4S,6R,6aS)-6-(benzyloxycarbonyl)-2,2-dimethyl-tetrahydro-3aH-cyclopent-
a[d][1,3]dioxol-4-yloxy)acetate (150 mg, 0.38 mmol, 30.00 equiv.)
and 10% palladium on carbon (16 mg, 0.15 mmol, 1.00 equiv) in
methanol (10 mL) was stirred at ambient temperature for about 80
minutes. After filtering, the resulting filtrate was concentrated
in vacuo to give the title product as a yellow solid (80 mg;
yield=82%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 4.64 (s,
1H), 4.42 (s, 1H), 4.08-4.20 (m, 4H), 3.87 (s, 1H), 3.31 (s, 1H),
2.17 (m, 1H), 1.76 (m, 1H), 1.36 (s, 3H), 1.21-1.29 (m, 6H).
Step 10
##STR00020##
[0129]
2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d-
][1,3]dioxol-4-yloxy)ethanol: A solution of ethyl
2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-
dioxol-4-yloxy)acetate (4.2 g, 16.2 mmol, 1.00 equiv.) in dry
tetrahydrofuran (50 mL) was slowly added to a suspension of lithium
aluminum hydride (1.23 g, 32.4 mmol, 2.00 equiv.) in
tetrahydrofuran (50 mL). The mixture was heated at reflux for about
1 hour, and then water was added (2 mL). After the solids were
collected by filtration, the solids were washed with
tetrahydrofuran (50 mL) and then dried in vacuo to give the title
product as a yellow oil (2.3 g, 65%). MS: m/z=218(MH).sup.+.
Step 11
##STR00021##
[0130] 2-(Propylthio)pyrimidine-4,6-diol
[0131] A solution of 2-mercaptopyrimidine-4,6-diol (25 g, 173.61
mmol, 1.00 equiv.), sodium hydroxide (15.8 g, 395.00 mmol, 2.27
equiv.), 1-methylpyrrolidin-3-one (50 mL), and 1-iodopropane (30.6
g, 180.00 mmol, 1.05 equiv.) dissolved in water (60 mL) was stirred
at ambient temperature for about 48 hours. The pH value of the
solution was adjusted to 2-3 by adding hydrochloric acid. The
solids were then collected by filtration to give the product as an
off-white solid (35 g; (crude)). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.: 11.78 (b, 1H), 10.30 (b, 1H), 5.13 (s, 1H),
3.07 (t, J=7.2 Hz, 2H), 1.58-1.70 (m, 2H), 0.96 (t, J=7.2 Hz,
2H).
Step 12
##STR00022##
[0132] 5-Nitro-2-(propylthio)pyrimidine-4,6-diol
[0133] A solution of 2-(propylthio)pyrimidine-4,6-diol (3 g, 16.11
mmol, 1.00 equiv.) in nitric acid (65%) (10 mL) was stirred at
ambient temperature for about 2 hours. After adding water (10 mL),
the mixture was stirred at about 0.degree. C. for about 30 minutes.
The resulting solids were collected by filtration to afford the
title product as a yellow solid (1.8 g; yield=48%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta.: 3.17 (t, J=7.2 Hz, 2H), 1.62-1.75
(m, 2H), 0.95-1.02, (t, J=7.2 Hz, 3H).
Step 13
##STR00023##
[0134] 4,6-Dichloro-5-nitro-2-(propylthio)pyrimidine
[0135] A solution of 5-nitro-2-(propylthio)pyrimidine-4,6-diol (1.8
g, 6.71 mmol, 1.00 equiv.), phosphoryl chloride (15 mL) and
N,N-diethylbenzenamine (2 mL) was stirred at reflux for about 3
hours in an oil bath. After cooling the mixture to about 20.degree.
C. with a water/ice bath, the mixture was concentrated in vacuo.
The resulting residue was purified by silica gel column
chromatography (ethyl acetate/petroleum ether (1:100)) to give the
title product as a yellow oil (1.1 g; yield=61%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.: 3.15 (t, J=7.2 Hz, 2H), 1.73-1.87 (m,
2H), 1.07-1.13 (J=7.2 Hz, 3H).
Step 14
##STR00024##
[0136]
2-((3aR,4S,6R,6aS)-6-(6-Chloro-5-nitro-2-(propylthio)pyrimidin-4-yl-
amino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethano-
l
[0137] A solution of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine
(1.07 g, 3.99 mmol, 1.00 equiv.), and
2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-
dioxol-4-yloxy)ethanol (570 mg, 4.41 mmol, 1.20 equiv.) in
tetrahydrofuran (20 mL) was stirred at 0-10.degree. C. for about 2
hours and then water (20 mL) was added. Standard extractive workup
with ethyl acetate (3.times.20 mL) afforded the title product as a
yellow oil (800 mg; yield=45%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 8.65 (b, 1H), 4.66-4.76 (m, 2H), 4.56 (m, 1H), 3.99 (d,
J=7.5 Hz, 1H), 3.70-3.87 (m, 3H), 3.64-3.67 (m, 1H), 3.07-3.20 (m,
2H), 2.34 (m, 1H), 1.97 (m, 1H), 1.76-1.82 (m, 2H), 1.46 (s, 3H),
1.27 (s, 3H), 1.07 (t, J=7.5 Hz, 3H).
Step 15
##STR00025##
[0138]
2-((3aR,4S,6R,6aS)-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl-
amino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethano-
l
[0139] A suspension of
2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4-ylamino)-
-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol
(800 mg, 1.78 mmol, 1.00 equiv.), iron powder (800 mg, 14.29 mmol,
8.00 equiv.), acetic acid (860 mg, 14.33 mmol, 8.00 equiv.) and
water/ethanol (10 mL) was stirred at about 60.degree. C. for about
20 minutes in an oil bath. After the solids were removed by
filtration, the resulting filtrate was extracted with
dichloromethane (3.times.10 mL). The organic layers were combined,
dried over anhydrous sodium sulfate, and concentrated in vacuo to
give the title product as a yellow oil (780 mg; yield=93%). MS:
m/z=419 (MH).sup.+.
Step 16
##STR00026##
[0140]
2-((3aR,4S,6R,6aS)-6-(7-Chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,-
5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-
-yloxy)ethanol
[0141] A solution of sodium nitrite (148 mg, 2.14 mmol, 1.12
equiv.) in water (1 mL) was added to a solution of
2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-
-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol
(800 mg, 1.91 mmol, 1.00 equiv.) and acetic acid (680 mg, 11.33
mmol, 5.90 equiv.) in toluene (9 mL). The resulting solution was
stirred at about 20.degree. C. for about 30 minutes, and then the
pH value of the solution was adjusted to 8-9 by adding potassium
carbonate. Following standard extractive workup with ethyl acetate
(3.times.10 mL), the resulting residue was purified by silica gel
column (ethyl acetate/petroleum ether (1:10)) to give the title
product as a yellow oil (370 mg; yield=45%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.: 5.54-5.56 (q, J.sub.1=2.4 Hz, J.sub.2=6.3 Hz,
1H), 5.21-5.25 (m, 1H), 4.90 (d, J=6.3 Hz, 1H), 4.05-4.09 (m, 1H),
3.50-3.66 (m, 4H), 3.23 (t, J=7.5 Hz, 2H), 2.68-2.72 (m, 1H), 2.58
(m, 1H), 1.81-1.89 (m, 2H), 1.57 (s, 3H), 1.39 (s, 3H), 1.12, (t,
J=7.5 Hz, 3H).
Step 17
##STR00027##
[0143] 3-(3,4-Difluoro-phenyl)-acryloyl chloride: At 0-5.degree.
C., oxalyl dichloride (25.7 g, 202.36 mmol, 3.00 equiv.) was added
to a mixture of (E)-3-(3,4-difluorophenyl)acrylic acid (12.4 g,
67.38 mmol, 1.00 equiv.), N,N-dimethylformamide (1 mL), and
dichloromethane (150 mL). The solution was stirred at ambient
temperature for about 2 hours, and then concentrated in vacuo to
give the title product, which was used in the next step without any
further purification.
Step 17
##STR00028##
[0144]
[3aS-[1(E),3a,6,7a]]-1-[3-(3,4-Difluorophenyl)-1-oxo-2-propenyl]-he-
xahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide
[0145] At 0-5.degree. C., a solution of
343,4-difluoro-phenyl)-acryloyl chloride in dichloromethane (30 mL)
was added to a mixture of (2R)-bornane-10,2-sultam (14.5 g, 67.35
mmol, 1.00 equiv), triethylamine (20.4 g, 201.98 mmol, 3.00 equiv),
and dichloromethane (120 mL). The resulting solution was stirred at
ambient temperature for about 3 hours and then water (40 mL) was
added. Standard extractive workup with dichloromethane (2.times.40
mL) gave the title product as an off-white solid (18.5 g;
yield=72%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.68 (d,
J=15.6 Hz, 1H), 7.15-7.45 (m, 3H), 7.19 (d, J=15.6 Hz, 1H), 4.00
(m, 1H), 3.55 (q, J.sub.1=13.8 Hz, J.sub.2=24.0 Hz), 2.18 (m, 2H),
1.93 (m, 2H), 1.37-1.48 (m, 2H), 1.22 (s, 3H), 0.96 (s, 3H).
Step 18
##STR00029##
[0146]
[3aS-[1(1R,2R),3a,6,7a]]-1-[[2-(3,4-Difluorophenyl)cyclopropyl]carb-
onyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxi-
de
[0147] At 0-5.degree. C., 1-methyl-1-nitrosourea (39.1 g, 379.61
mmol, 2.50 equiv.) was added in portions to a mixture of 50%
aqueous sodium hydroxide (150 mL) and ethyl ether (300 mL). After
the solid was dissolved, the aqueous phase was removed. At
0-5.degree. C., a solution of
[3aS-[1(E),3a,6,7a]]-1-[3-(3,4-difluorophenyl)-1-oxo-2-propenyl]-hexah-
ydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide
(48.2 g, 126.51 mmol, 1.00 equiv.), palladium(II) acetate (200 mg,
1.04 mmol) in dichloromethane (300 mL) was then added to the
mixture. The mixture was stirred at ambient temperature for about 1
hour, acetic acid (100 mL) was added, and then water (500 mL) was
added. Standard extractive workup with dichloromethane (2.times.100
mL) afforded the title product as a light-yellow oil (48 g;
yield=80%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 6.97-7.09
(m, 3H), 3.91-3.95 (m, 1H), 3.44-3.57 (q, J.sub.1=13.8 Hz,
J.sub.2=24.9 Hz), 2.56 (m, 2H), 2.15 (m, 2H), 1.90-1.95 (m, 3H),
1.76-1.82 (m, 1H), 1.22-1.47 (m, 3H), 1.20 (s, 3H), 1.00 (s,
3H).
Step 19
##STR00030##
[0148] (1R,2R)-2-(3,4-Difluorophenyl)cyclopropanecarboxylic
acid
[0149] A mixture of
[3aS-[1(1R,2R),3a,6,7-a]]-1-[[2-(3,4-difluorophenyl)cyclopropyl]carbonyl]-
-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide
(48 g, 121.52 mmol, 1.00 equiv.) in 10% lithium hydroxide (200 mL)
and tetrahydrofuran (200 mL) was stirred at about 50.degree. C. for
about 0.5 hours. The mixture was cooled to ambient temperature, and
washed ether (2.times.100 mL). The pH value of the aqueous layer
was adjusted to 3 by adding 12N hydrochloric acid. Following
standard extractive workup with ether (3.times.200 mL), the crude
residue was purified by silica gel column chromatography (ethyl
acetate/petroleum ether (1:4)) to give the title product as a white
solid (16.0 g; yield=66%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 7.05-7.14 (m, 1H), 6.85-6.96 (m, 2H), 2.54-2.60 (m, 1H),
1.84-1.90 (m, 1H), 1.65-1.72 (m, 1H), 1.30-1.40 (m, 1H).
Step 20
##STR00031##
[0150] (1R,2S)-2-(3,4-Difluorophenyl)cyclopropanamine
[0151] A solution of
(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (8.0 g,
40.40 mmol, 1.00 equiv.), diphenylphosphoryl azide (11.2 g, 40.73
mmol, 1.00 equiv.), triethylamine (6.2 g, 61.39 mmol, 1.50 equiv.)
in toluene (60 mL) was heated at reflux for about 1 hour and then
refluxing 6N hydrogen chloride was added. The mixture was kept at
reflux for 16 hours, and then cooled to ambient temperature. The
resulting mixture was concentrated in vacuo, and the resulting
residue was dissolved in water/ether (1:1) 200 mL). Following
standard extractive workup with ether (3.times.100 mL), the
resulting residue was purified by silica gel column chromatography
(ethyl acetate/petroleum ether (1:4.about.1:0)) to give the title
product as a light-brown solid (6.2 g; yield=91%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.: 6.98-7.07 (m, 1H), 6.72-6.81 (m, 2H),
2.40 (m, 1H), 1.82-1.87 (m, 1H), 1.05-1.11 (m, 1H), 0.85-0.96 (m,
1H).
Step 21
##STR00032##
[0152]
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyla-
mino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-
-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol
[0153] A solution of
2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]py-
rimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy-
)ethanol (370 mg, 0.86 mmol, 1.00 equiv) (15 mL),
(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (145.6 mg, 0.86
mmol, 1.00 equiv.) and N,N-diisopropylethylamine (155.7 mg, 1.21
mmol, 1.20 equiv.) in dichloromethane was stirred at ambient
temperature for about 16 hours, and then water (10 mL) was added.
Standard extractive workup with dichloromethane (3.times.10 mL)
gave the title product as a yellow oil (450 mg; yield=93%). m/z=563
(MH).sup.+.
Step 22
##STR00033##
[0154]
(1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-
-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethox-
y) cyclopentane-1,2-diol (ticagrelor-d.sub.0)
[0155] A solution of
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)--
5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetra-
hydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (450 mg, 0.80
mmol, 1.00 equiv.) in methanol (4 mL) and 12N hydrochloric acid
(1.5 mL) was stirred at ambient temperature for about 3 hours. The
pH value of the solution was adjusted to 8-9 by adding potassium
carbonate. Following standard extractive workup with ethyl acetate
(3.times.20 mL), the resulting crude residue was purified by silica
gel column chromatography (dichloromethane/methanol (50:1)) to give
a semi-crude product (200 mg; yield=48%). The semi-crude product,
which contained about 5% of other diastereoisomers, was then
further purified by chiral-prep HPLC (column: Chiralpak
IA2.times.25 cm, 5umChiral-P(IA)004IA00CJ-MB003) to afford the
title compound (100 mg). [.alpha.].sub.D.sup.24.1 -43.2.degree. (c,
0.2 g/100 mL in MeOH). LC-MS: m/z=523.0 (MH).sup.+, Retention time:
1.58 minute. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 7.08-7.23
(m, 3H), 5.13 (q, 1H), 4.75-4.79 (m, 1H), 4.17-4.20 (m, 1H),
3.91-3.95 (m, 1H), 3.63-3.73 (m, 4H), 3.06-3.26 (m, 2H), 2.90-3.00
(m, 1H), 2.70-2.80 (m, 1H), 2.05-2.29 (m, 2H), 1.60-1.88 (m, 2H),
1.38-1.59 (m, 2H), 0.94 (t, J=7.5 Hz, 3H).
Example 2
(1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(pro-
pylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxy-d.sub.4-eth-
oxy)cyclopentane-1,2-diol (ticagrelor-d.sub.4)
##STR00034##
[0156] Step 1
##STR00035##
[0157] d.sub.4-Ethane-1,2-diol
[0158] A solution of diethyloxalate (6.5 g, 44.48 mmol, 1.00
equiv.) in dry tetrahydrofuran (100 mL) was slowly added to a
slurry of lithium aluminum deuteride (1.87 g, 44.48 mmol, 1.00
equiv) in tetrahydrofuran (100 mL). The mixture was heated at
reflux for about 3 hours, and then water (4 mL) was added. The
solids were removed by filtration, and the resulting filtrate was
then washed with tetrahydrofuran (100 mL). The solvent was removed
in vacuo to give the title product as a colorless oil (2.1 g;
yield=71%).
Step 2
##STR00036##
[0159] 2-(Benzyloxy)-d.sub.4-ethanol
[0160] Silver oxide (11.05 g, 47.72 mmol, 1.50 equiv.), and
benzylbromide (5.98 g, 34.99 mmol, 1.10 equiv.) were added to a
stirred solution of d.sub.4-ethane-1,2-diol (2.1 g, 31.81 mmol,
1.00 equiv.) in dichloromethane (40 mL). The mixture was stirred at
ambient temperature for about 16 hours, and then filtered through a
small pad of silica gel. Following standard extractive workup with
ethyl acetate, the crude residue was purified by silica gel column
chromatography (ethyl acetate: petroleum ether (1:10)) to give the
title product as a colorless oil (2.85 g; yield=57%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta.: 7.29-7.42 (m, 5H), 4.59 (s, 2H).
Step 3
##STR00037##
[0161] 1((2-Bromo-d.sub.4-ethoxy)methyl)benzene
[0162] At about -20.degree. C., triphenylphosphine (5.73 g, 21.87
mmol, 1.20 equiv.) was added in portions, over a period of 15
minutes, to a solution of d.sub.4-2-(benzyloxy)ethanol (2.85 g,
18.24 mmol, 1.00 equiv), and N-bromosuccinimide (4.85 g, 27.25
mmol, 1.50 equiv.) in tetrahydrofuran (80 mL). The resulting
solution was stirred at 15-25.degree. C. for about 30 minutes.
Following standard extractive workup with ethyl acetate, the
resulting crude residue was purified by silica gel column
chromatography (ethyl acetate/petroleum ether (1:5)) to give the
title product as a colorless liquid (2.64 g; yield=66%). .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta.: 7.31-7.40 (m, 5H), 4.62 (s,
2H)
Step 4
##STR00038##
[0163] Benzyl
(3aS,4R,6S,6aR)-6-(2-benzyloxy)-d.sub.4-ethoxy-2,2-dimethyl)-tetrahydro-3-
aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate
[0164] At about -10.degree. C., benzyl
(3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]d-
ioxol-4-ylcarbamate (3.25 g, 10.57 mmol, 1.00 equiv.) was added to
a solution of 70% sodium hydride (0.38 g, 11.11 mmol, 1.05 equiv.)
in N,N-dimethylformamide (50 mL). The solution was stirred at about
-10.degree. C. for about 30 minutes, and then
1-((2-bromo-d.sub.4-ethoxy)methyl)benzene (2.64 g, 12.04 mmol, 1.14
equiv.) was added. The resulting solution was stirred at ambient
temperature for about 24 hours, and then water (50 mL) was added.
Following standard extractive workup with ethyl acetate (3.times.50
mL), the resulting crude product was purified by silica gel column
chromatography (ethyl acetate: petroleum ether (1:10)) to give
title product as a colorless solid (2.25 g; yield=48%).
Step 5
##STR00039##
[0165]
2-((3aR,4S,6R,6aS)-6-Amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d-
][1,3]dioxol-ethanol
[0166] Under an atmosphere of hydrogen, a suspension of benzyl (3
aS,4R,6S,6aR)-6-(2-(benzyloxy)-d.sub.4-ethoxy)-2,2-dimethyl-tetrahydro-3
aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate (2.25 g, 5 mmol, 3.30
equiv.), 10% palladium on carbon (1.6 g, 1.5 mmol, 1.00 equiv.),
and methanol (50 mL) was stirred at ambient temperature for about
10 hours. The suspension was filtered, and the resulting filtrate
was concentrated in vacuo to give the title product as a yellow
solid (0.95 g; yield=86%). MS: m/z=222 (MH).sup.+.
Step 6
##STR00040##
[0167]
2-((3aR,4S,6R,6aS)-6-(6-Chloro-5-nitro-2-(propylthio)pyrimidin-4-yl-
amino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub-
.4-ethanol
[0168] The procedure of Example 1, Step 14 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-
dioxol-4-yloxy)-d.sub.4-ethanol for
2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-
dioxol-4-yloxy)ethanol. The title product was isolated as a yellow
oil (680 mg; yield=47.39%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 8.66 (b, 1H), 4.65-4.76 (m, 2H), 4.56 (m, 1H), 3.99 (d,
J=7.5 Hz, 1H), 3.07-3.21 (m, 2H), 2.34 (m, 1H), 1.98 (m, 1H),
1.77-1.82 (m, 2H), 1.46 (s, 3H), 1.27 (s, 3H), 1.06 (t, J=7.5 Hz,
3H).
Step 7
##STR00041##
[0169]
2-((3aR,4S,6R,6aS)-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl-
amino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub-
.4-ethanol
[0170] The procedure of Example 1, Step 15 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4-ylamino)-
-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub.4-eth-
anol for
2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4--
ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)etha-
nol. The title product was isolated as a yellow oil (700 mg
(crude)). MS: m/z=423 (MH).sup.+.
Step 8
##STR00042##
[0171]
2-((3aR,4S,6R,6aS)-6-(7-Chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,-
5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-
-yloxy)-d.sub.4-ethanol
[0172] The procedure of Example 1, Step 16 was followed but
substituting
2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-
-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub.4-eth-
anol for
2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4--
ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)etha-
nol. The title product was isolated as a yellow oil (800 mg;
(crude)). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 5.53-5.57 (q,
J.sub.1=2.4 Hz, J.sub.2=6.3 Hz, 1H), 5.22-5.25 (m, 1H), 4.91 (d,
J=6.3 Hz, 1H), 4.05-4.09 (m, 1H), 3.25 (t, J=7.5 Hz, 2H), 2.68-2.72
(m, 1H), 2.57 (m, 1H), 1.81-1.88 (m, 2H), 1.57 (s, 3H), 1.39 (s,
3H), 1.11, (t, J=7.5 Hz, 3H).
Step 9
##STR00043##
[0173]
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyla-
mino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-
-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub.4-ethanol
[0174] The procedure of Example 1, Step 21 was followed but
substituting
2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]py-
rimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy-
)-d.sub.4-ethanol for
2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]py-
rimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy-
)ethanol. The title product was isolated as a yellow oil (450 mg;
yield=43%). MS: m/z=567 (MH).sup.+.
Step 10
##STR00044##
[0175]
(1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino)-
-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxy-d.su-
b.4-(ethoxy)cyclopentane-1,2-diol (ticagrelor-d.sub.4)
[0176] The procedure of Example 1, Step 22 was followed but
substituting 2-((3
aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-
-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetr-
ahydro-3 aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub.4-ethanol for
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)--
5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetra-
hydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol. The title
product was first isolated as an semi-pure off-white solid (300 mg)
that was then further purified by chiral-prep HPLC (column:
Chiralpak IA2.times.25 cm, 5umChiral-P(IA)004IA00CJ-MB003) to give
the title compound as a nearly pure product (210 mg; yield=50%).
[.alpha.].sub.D.sup.24.1 -19.0.degree. (c, 0.1 g/100 mL in MeOH).
LC-MS: m/z=527.0 (MH).sup.+, Retention time: 1.58 minute. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta.: 7.09-7.24 (m, 3H), 5.14 (q, 1H),
4.75-4.80 (m, 1H), 4.17-4.20 (m, 1H), 3.90-3.95 (m, 1H), 3.06-3.26
(m, 2H), 2.90-3.00 (m, 1H), 2.70-2.81 (m, 1H), 2.05-2.30 (m, 2H),
1.61-1.88 (m, 2H), 1.38-1.59 (m, 2H), 0.94 (t, J=7.5 Hz, 3H).
Example 3
(1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino)-5-(d.s-
ub.7-propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyetho-
xy)cyclopentane-1,2-diol (ticagrelor-d.sub.7)
##STR00045##
[0177] Step 1
##STR00046##
[0178] d.sub.3-Diethyl 2-methylmalonate
[0179] Sodium metal (7.59 g, 330.00 mmol, 1.05 equiv.) was slowly
added to ethanol (500 mL) and stirred at ambient temperature until
all the sodium metal was consumed. At about 0.degree. C., diethyl
malonate (50 g, 312.50 mmol, 1.00 equiv.) was added dropwise, over
a period of 30 minutes, to the stirred solution. At about 0.degree.
C., iodomethane-d.sub.3 (47.85 g, 330.00 mmol, 1.05 equiv) was then
added dropwise, over a period of about 2 hours, to the stirred
solution. The solution was stirred at ambient temperature for about
3 hours and then concentrated in vacuo. After adding water (500
mL), standard extractive workup with ethyl acetate (3.times.300 mL)
afforded the title product as a light yellow liquid (48 g;
yield=87%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 4.15 (q,
J=7.2 Hz, 2H), 2.30 (s, 1H), 1.28 (t, J=7.2 Hz, 3H).
Step 2
##STR00047##
[0180] d.sub.4-Diethyl 2-methylmalonate
[0181] A solution of d.sub.3-diethyl 2-methylmalonate (48 g, 271.19
mmol, 1.00 equiv.) and triethylamine (27.4 g, 271.29 mmol, 1.00
equiv.) in d.sub.4-methanol (240 mL) was stirred at about
25.degree. C. for about 16 hours. The resulting mixture was then
concentrated in vacuo to give the title product as a light yellow
liquid (48 g; yield=99%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 4.16 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Step 3
##STR00048##
[0182] d.sub.5-Ethyl propionate
[0183] A mixture of d.sub.4-diethyl 2-methylmalonate (42 g, 235.69
mmol, 1.00 equiv.), sodium chloride (27.5 g, 470.57 mmol, 2.00
equiv.), deuterium oxide (4.8 g, 240.00 mmol, 1.00 equiv.) and
dimethylsulfoxide-d.sub.6 (200 mL) was stirred at 150-160.degree.
C. for about 3 hours. The solvent was then removed by distillation.
Standard extractive workup with ethyl ether (250 mL) gave the title
product, which was used in the next step without further
purification (15 g; yield=59%), .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 4.13 (q, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
Step 4
##STR00049##
[0185] d.sub.5-Propan-1-ol: At 0-5.degree. C., lithium aluminum
deuteride (5.8 g, 138.10 mmol, 0.80 equiv.) was added to a solution
of d.sub.5-ethyl propionate (18.6 g, 173.83 mmol, 1.00 equiv.) in
ethyl ether (200 mL). The resulting solution was stirred at ambient
temperature for about 3 hours, and then deuterium oxide (50 mL) was
added. The solution was stirred at ambient temperature for about 1
hour, and then the pH value of the solution was adjusted to 4-5 by
adding 10% sulfuric acid. The crude product was purified by
distillation. The fraction collected was at 70-88.degree. C. to
give the title product (19.8 g; (crude, contained water and
ethanol)) as a colorless liquid, which was used in the next step
without more purification.
Step 5
##STR00050##
[0186] d.sub.7-1-Iodopropane
[0187] A solution of d.sub.5-propan-1-ol (19.8 g, 295.52 mmol, 1.00
equiv.) in 45% hydroiodic acid (180 mL) was heated at reflux for
about 17 hours. The organic phase was separated and washed with
sodium sulfate (1.times.10 mL) and brine (1.times.10 mL). The
resulting crude product was then purified by distillation (1 atm).
The fraction collected was at 95-101.degree. C. to give the title
product as a colorless liquid (5.1 g; yield=26%).
Step 6
##STR00051##
[0188] 2-(d.sub.7-Propylthio)pyrimidine-4,6-diol
[0189] The procedure of Example 1, Step 11, was followed but
substituting d.sub.7-1-iodopropane for 1-iodopropane. The title
product was isolated as an off-white solid (3.5 g; yield=64%).
Step 7
##STR00052##
[0190] 5-Nitro-2-(d.sub.7-propylthio)pyrimidine-4,6-diol
[0191] The procedure of Example 1, Step 12 was followed, but
substituting 2-(propyl-d.sub.7-thio)pyrimidine-4,6-diol for
2-(propylthio)pyrimidine-4,6-diol. The title product was isolated
as a yellow solid (3.2 g; yield=51%).
Step 8
##STR00053##
[0192] 4,6-Dichloro-5-nitro-2-(d.sub.7-propylthio)pyrimidine
[0193] The procedure of Example 1, Step 13 was followed, but
substituting 5-nitro-2-(d.sub.7-propylthio)pyrimidine-4,6-diol for
5-nitro-2-(propylthio)pyrimidine-4,6-diol. The title product was
isolated as a yellow oil (1.8 g; yield=49%).
Step 9
##STR00054##
[0194]
2-((3aR,4S,6R,6aS)-6-(6-Chloro-5-nitro-2-(d.sub.7-propylthio)pyrimi-
din-4-ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylox-
y)ethanol
[0195] The procedure of Example 1, Step 14 was followed, but
substituting 4,6-dichloro-5-nitro-2-(d.sub.7-propylthio)pyrimidine
for 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine. The title
product was isolated as a yellow oil (800 mg; yield=57%). .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta.: 8.66 (b, 1H), 4.66-4.77 (m, 2H),
4.56 (m, 1H), 3.99 (d, J=7.5 Hz, 1H), 3.71-3.87 (m, 3H), 3.64-3.66
(m, 1H), 2.33 (m, 1H), 1.97 (m, 1H), 1.45 (s, 3H), 1.26 (s,
3H).
Step 10
##STR00055##
[0196]
2-((3aR,4S,6R,6aS)-6-(5-Amino-6-chloro-2-(d.sub.7-propylthio)pyrimi-
din-4-ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylox-
y)ethanol
[0197] The procedure of Example 1, Step 15 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(d.sub.7-propylthio)pyrimidin-4--
ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)etha-
nol for
2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4-y-
lamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethan-
ol. The title product was isolated as a yellow oil (700 g;
yield=93%).
Step 11
##STR00056##
[0198]
2-((3aR,4S,6R,6aS)-6-(7-Chloro-5-(d.sub.7-propylthio)-3H[1,2,3]tria-
zolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]d-
ioxol-4-yloxy)ethanol
[0199] The procedure of Example 1, Step 16 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(d.sub.7-propylthio)pyrimidin-4--
ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)etha-
nol for
2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-y-
lamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethan-
ol. The title product was isolated as a yellow oil (320 mg;
yield=45%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 5.54-5.57
(q, J.sub.1=2.4 Hz, J.sub.2=6.3 Hz, 1H), 5.21-5.25 (m, 1H), 4.91
(d, J=6.3 Hz, 1H), 4.05-4.08 (m, 1H), 3.50-3.65 (m, 4H), 2.68-2.72
(m, 1H), 2.58 (m, 1H), 1.57 (s, 3H), 1.38 (s, 3H).
Step 12
##STR00057##
[0200]
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyla-
mino)-5-(d.sub.7-propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2--
dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol
[0201] The procedure of Example 1, Step 21 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]py-
rimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy-
)ethanol for
2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(d.sub.7-propylthio)-3H-[1,2,3]triazolo[-
4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-
-4-yloxy)ethanol. The title product was isolated as a yellow oil
(600 mg; yield=58%).
Step 13
##STR00058##
[0202]
(1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino)-
-5-(d.sub.7-propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydr-
oxyethoxy)cyclopentane-1,2-diol (ticagrelor-d.sub.7)
[0203] The procedure of Example 1, Step 22 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)--
5-(d.sub.7-propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimeth-
yl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol for
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)--
5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetra-
hydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol. The title
product was isolated as a semi pure off-white solid (350 mg) that
was further purified by chiral-prep HPLC (column: Chiralpak
IA2.times.25 cm, 5umChiral-P(IA)004IA00CJ-MB003) to give the nearly
pure product (220 mg; yield=40%). [.alpha.].sub.D.sup.26.3
-26.8.degree. (c, 0.31 g/100 mL in MeOH). LC-MS: m/z=530.0
(MH).sup.+, Retention time: 1.58 minute. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.: 7.08-7.23 (m, 3H), 5.13 (q, 1H), 4.75-4.79 (m,
1H), 4.17-4.20 (m, 1H), 3.91-3.95 (m, 1H), 3.63-3.73 (m, 4H), 3.14
(m, 1H), 2.70-2.80 (m, 1H), 2.15-2.29 (m, 2H), 1.38-1.50 (m,
2H).
Example 4
(1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(d.s-
ub.7-propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxy-d.s-
ub.4ethoxy)cyclopentane-1,2-diol (ticagrelor-d.sub.11)
##STR00059##
[0204] Step 1
##STR00060##
[0205]
2-((3aR,4S,6R,6aS)-6-(6-Chloro-5-nitro-2-(d.sub.7-propylthio)pyrimi-
din-4-ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylox-
y)-d.sub.4-ethanol
[0206] The procedure of Example 3, Step 9 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-
dioxol-4-yloxy)-d.sub.4-ethanol for
2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-
dioxol-4-yloxy)ethanol. The title product was isolated as a yellow
oil (800 mg; yield=57%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.:
8.65 (b, 1H), 4.66-4.77 (m, 2H), 4.56 (m, 1H), 3.99 (d, J=7.5 Hz,
1H), 2.34 (m, 1H), 1.98 (m, 1H), 1.45 (s, 3H), 1.27 (s, 3H).
Step 2
##STR00061##
[0207]
d.sub.11-2-(3aR,4S,6R,6aS)-6-(5-Amino-6-chloro-2-(d.sub.7-propylthi-
o)pyrimidin-4-ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxo-
l-4-yloxy)-d.sub.4-ethanol
[0208] The procedure of Example 3, Step 10 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(d.sub.7-propylthio)pyrimidin-4--
ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.s-
ub.4-ethanol for
2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(d.sub.7-propylthio)pyrimidin-4--
ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)etha-
nol. The title product was isolated as a yellow oil (560 mg;
yield=81%).
Step 3
##STR00062##
[0209]
2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propyl-d.sub.7-thio)-3H-[1,2,3]tr-
iazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3-
]dioxol-4-yloxy)-d4-ethanol
[0210] The procedure of Example 3, Step 11 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(d.sub.7-propylthio)pyrimidin-4--
ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.s-
ub.4-ethanol for
2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(d.sub.7-propylthio)pyrimidin-4--
ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)etha-
nol. The title product was isolated as a yellow oil (460 mg;
yield=80%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 5.54-5.58
(q, J.sub.1=2.4 Hz, J.sub.2=6.3 Hz, 1H), 5.21-5.25 (m, 1H), 4.92
(d, J=6.3 Hz, 1H), 4.06-4.09 (m, 1H), 2.67-2.73 (m, 1H), 2.58 (m,
1H), 1.57 (s, 3H), 1.38 (s, 3H).
Step 4
##STR00063##
[0211]
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyla-
mino)-5-(d.sub.7-propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2--
dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub.4-ethanol
[0212] The procedure of Example 3, Step 12 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propyl-d.sub.7-thio)-3H-[1,2,3]triazolo-
[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3
aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub.4-ethanol for
2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propyl-d.sub.7-thio)-3H-[1,2,3]triazolo-
[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxo-
l-4-yloxy)ethanol. The title product was isolated as a yellow oil
(400 mg; yield=67%).
Step 5
##STR00064##
[0213]
(1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-
-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethox-
y)cyclopentane-1,2-diol (ticagrelor-d.sub.11)
[0214] The procedure of Example 3, Step 13 was followed, but
substituting
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)--
5-(d.sub.7-propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimeth-
yl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)-d.sub.4-ethanol
for
2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)--
5-(d.sub.7-propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimeth-
yl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol. The
title product was isolated as an semi-pure off-white solid (350 mg)
that was further purified by chiral-prep-HPLC (column: Chiralpak
IA2.times.25 cm, 5umChiral-P(IA)004IA00CJ-MB003) to give pure
product 260 mg (70%). [.alpha.].sub.D .sup.26.1 -23.2.degree. (c,
0.21 g/100 mL in MeOH). LC-MS: m/z=534.0 (MH).sup.+, Retention
time: 1.58 minute. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.:
7.09-7.26 (m, 3H), 5.14 (q, 1H), 4.75-4.79 (m, 1H), 4.17-4.20 (m,
1H), 3.91-3.95 (m, 1H), 3.14 (m, 1H), 2.76-2.84 (m, 1H), 2.15-2.29
(m, 2H), 1.43-1.51 (m, 2H).
[0215] The following compounds can generally be made using the
methods described above. It is expected that these compounds when
made will have activity similar to those described in the examples
above.
##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069##
##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##
##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079##
##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084##
##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089##
##STR00090## ##STR00091## ##STR00092## ##STR00093##
##STR00094##
##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099##
##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104##
##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109##
##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114##
##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119##
##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124##
##STR00125## ##STR00126##
##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131##
##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136##
##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141##
##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146##
##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151##
##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156##
##STR00157## ##STR00158## ##STR00159## ##STR00160##
##STR00161##
[0216] Changes in the metabolic properties of the compounds
disclosed herein as compared to their non-isotopically enriched
analogs can be shown using the following assays. Compounds listed
above which have not yet been made and/or tested are predicted to
have changed metabolic properties as shown by one or more of these
assays as well.
Biological Activity Assays
In Vitro Liver Microsomal Stability Assay
[0217] Liver microsomal stability assays were conducted at 1 mg per
mL liver microsome protein with an NADPH-generating system in 2%
sodium bicarbonate (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6
units per mL glucose 6-phosphate dehydrogenase and 3.3 mM magnesium
chloride). Test compounds were prepared as solutions in 20%
acetonitrile-water (20 .mu.M stock solutions) and added to the
assay mixture (final assay concentration 1 .mu.M). Final
concentration of acetonitrile in the assay should be <1%. The
reactions were incubated at 37.degree. C. Aliquots (50 .mu.L) were
taken out at times 0, 15, 30, 45, and 60 minutes, and diluted with
ice cold acetonitrile (200 .mu.L) to stop the reactions. Samples
are centrifuged at 12,000 RPM for 10 minutes to precipitate
proteins. Supernatants are transferred to microcentrifuge tubes and
stored for LC/MS/MS analysis of the degradation half-life of the
test compounds. It has thus been found that certain
isotopically-enriched compounds disclosed herein that have been
tested in this assay showed an increased degradation half-life as
compared to the non-isotopically enriched drug. In certain
embodiments, the increase in degradation half-life is at least 5%;
at least 10%; at least 15%; at least 20%; at least 25%; or at least
30%.
In Vitro Metabolism Using Human Cytochrome P.sub.450 Enzymes
[0218] The cytochrome P.sub.450 enzymes are expressed from the
corresponding human cDNA using a baculovirus expression system (BD
Biosciences, San Jose, Calif.). A 0.25 milliliter reaction mixture
containing 0.8 milligrams per milliliter protein, 1.3 millimolar
NADP.sup.+, 3.3 millimolar glucose-6-phosphate, 0.4 U/mL
glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium
chloride and 0.2 millimolar of a compound as disclosed herein, the
corresponding non-isotopically enriched compound or standard or
control in 100 millimolar potassium phosphate (pH 7.4) is incubated
at 37.degree. C. for 20 minutes. After incubation, the reaction is
stopped by the addition of an appropriate solvent (e.g.,
acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial
acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial
acetic acid) and centrifuged (10,000 g) for 3 minutes. The
supernatant is analyzed by HPLC/MS/MS.
TABLE-US-00001 Cytochrome P.sub.450 Standard CYP1A2 Phenacetin
CYP2A6 Coumarin CYP2B6 [.sup.13C]-(S)-mephenytoin CYP2C8 Paclitaxel
CYP2C9 Diclofenac CYP2C19 [.sup.13C]-(S)-mephenytoin CYP2D6
(+/-)-Bufuralol CYP2E1 Chlorzoxazone CYP3A4 Testosterone CYP4A
[.sup.13C]-Lauric acid
Monoamine Oxidase A Inhibition and Oxidative Turnover
[0219] The procedure is carried out using the methods described by
Weyler et al., Journal of Biological Chemistry 1985, 260,
13199-13207, which is hereby incorporated by reference in its
entirety. Monoamine oxidase A activity is measured
spectrophotometrically by monitoring the increase in absorbance at
314 nm on oxidation of kynuramine with formation of
4-hydroxyquinoline. The measurements are carried out, at 30.degree.
C., in 50 mM sodium phosphate buffer, pH 7.2, containing 0.2%
Triton X-100 (monoamine oxidase assay buffer), plus 1 mM
kynuramine, and the desired amount of enzyme in 1 mL total
volume.
Monooamine Oxidase B Inhibition and Oxidative Turnover
[0220] The procedure is carried out as described in Uebelhack et
al., Pharmacopsychiatry 1998, 31(5), 187-192, which is hereby
incorporated by reference in its entirety.
Inhibition of Platelet Aggregation
[0221] The procedure is carried out as described in Husted et al.,
Eur. Heart J. 2006, 27(9), 1038-1047, which is hereby incorporated
by reference in its entirety.
Measuring Pharmacokinetics, and Safety of Ticagrelor
[0222] The procedure is carried out as described in Husted et al.,
European Heart Journal 2006, 27(9), 1038-1047, which is hereby
incorporated by reference in its entirety.
Detecting Ticagrelor and Ticagrelor Metabolites in Humans
[0223] The procedure is carried out as described in Butler, et al.,
Drug Metab Rev 2008, 40(Suppl. 3): Abst 280, which is hereby
incorporated by reference in its entirety.
Bleeding Time
[0224] The procedure is carried out as described in Husted et al.,
Eur. Heart J. 2006, 27(9), 1038-1047, which is hereby incorporated
by reference in its entirety.
Inhibition of Platelet Aggregation
[0225] The procedure is carried out as described in WO 2000034283,
which is hereby incorporated by reference in its entirety.
Inhibition of Platelet Aggregation
[0226] The procedure is carried out as described in WO 199905142,
which is hereby incorporated by reference in its entirety.
[0227] From the foregoing description, one skilled in the art can
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
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