FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"2-0X0-1, 2-DIHYDRO-QUINOLINE
MODULATORS OF IMMUNE FUNCTION"
TEVA PHARMACEUTICAL INDUSTRIES LTD., 5 Basel Street,
P. O. Box 3190, Petach — Tikva 49131, Israel.
The following specification particularly describes the invention and the manner in which
it is to be performed.
WO 2010/028015 PCT/US2009/055692
2-0X0-1,2-DIHYDRO-QUINOLINE MODULATORS OF IMMUNE
FUNCTION
[0001] This application claims the benefit of priority of United States
provisional application No. 61/093,943, filed September 3, 2008, the disclosure of
which is hereby incorporated by reference as if written herein in its entirety.
[0002] Disclosed herein are new substituted 2-oxo-1,2-dihydro-quinoline
compounds, pharmaceutical compositions made thereof, and methods to modulate
immune function activity in a subject are also provided for, for the treatment of
disorders such as multiple sclerosis and autoimmune disorders.
[0003] Laquinimod (ABR 215062; SAIK-MS; ABR-215062; SAIKMS; CAS #
248281-84-7), 5-chloro-4-hydroxy-l-methy1-2-oxo-1,2-dihydro-quinoline-3-
carboxylic acid ethyl-phenyl-amide, is an immune function modulator. Laquinimod
is currently under investigation for the treatment of multiple sclerosis (Burton et al.,
Curr. Neurol. & Neurosc. Reports 2007, 7(3), 223-30; Tuvesson et al., Xenobiotica
2005, 35(3), 293-304; Cohen et al., Int. J. Clin. Pract. 2007, 61(11), 1922-30).
Laquinimod has also shown promise in treating autoimmune disorders (Tuvesson et
al., Xenobiotic:a 2005, 35(3), 293-304).
N 0
CI OH 8
Laquinimod
[0004] Laquinimod is subject to extensive oxidative metabolism by cytochrome
Paso enzymes, particularly by CYP3A4 (Tuvesson et al., Drug Metab. & Disp.
2005, 33(6), 866-72). Primary metabolites include those formed by quinoline
hydroxylation at various sites, quinoline demethylation, aniline de-ethylation, and
aniline hydroxylation at the para position (Tuvesson et al., Xenobiotica 2005, 35(3),
293-304).
WO 2010/028015 PCT/US2009/055692
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 P450 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) 7c-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-Eact/RT. The Arrhenius
equation states that, at a given temperature, the rate of a chemical reaction depends
exponentially on the activation energy (Eau).
[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 Eactfor 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 (1 H), a C-D bond is stronger than the corresponding C-'H
bond. If a C-'H 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
WO 2010/028015 PCT/US2009/055692
reaction in which a C-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 (2H or D) is a stable and non-radioactive isotope of hydrogen
which has approximately twice the mass of protium (1H), the most common isotope
of hydrogen. Deuterium oxide (D20 or "heavy water") looks and tastes like H20,
but has different physical properties.
[0010] When pure D20 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 D20, 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 D20, the animals become excitable. When
about 20-25% of the body water has been replaced with D20, 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
D20, the animals refuse to eat and become comatose. Their body weight drops
sharply and their metal5olic rates drop far below normal, with death occurring at
about 30 to about 35% replacement with D20. The effects are reversible unless
more than thirty percent of the previous body weight has been lost due to D-)0.
Studies have also shown that the use of D20 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
WO 2010/028015 PCT/US2009/055692
different proportions of known metabolites as well as altogether new metabolites.
This new metabolic profile may impart more or less toxicity. Such pitfalls are nonobvious
and are not predictable a priori for any drug class.
[0012] Laquinimod is an immune function modulator. The carbon-hydrogen
bonds of laquinimod contain a naturally occurring distribution of hydrogen
isotopes, namely 1H or protium (about 99.9844%), 2H or deuterium (about
0.0156%), and 3H or tritium (in the range between about 0.5 and 67 tritium atoms
per 1018protium 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 laquinimod in
comparison with laquinimod having naturally occurring levels of deuterium.
[0013] Based on discoveries made in our laboratory, as well as considering the
literature, laquinimod is metabolized in humans at the quinoline ring, the N-methyl
group, the N-ethyl group, and the phenyl ring. 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 laquinimod and
attenuate interpatient variability.
[0014] Novel compounds and pharmaceutical compositions, certain of which
have been found to modulate immune function have been discovered, together with
WO 2010/028015 PCT/US2009/055692
methods of synthesizing and using the compounds, including methods for the
treatment of immune function-mediated disorders in a patient by administering the
compounds.
[0015] In certain embodiments of the present invention, compounds have
structural Formula I:
, R2
rc3,,___ R 1
R4 I Ri
R5 ,y,---1 ,- N,,,..20
I I
—R14
,,,,,,..,..,:,- N \ R8R13
R6 1 \e"---R CI 0, 0 1 9
R7 ,,, V.
1-`12 RAN
,,,
-10 .*
(I)
or a salt, solvate, or prodrug thereof, wherein:
R1-R1 7 are independently selected from the group consisting of hydrogen
and deuterium; and
at least one of R1 -R17is deuterium.
[0016] Certain compounds disclosed herein may possess useful immune
function modulating activity, and may be used in the treatment or prophylaxis of a
disorder in which immune furtction plays 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 immune function. Other
embodiments provide methods for treating a immune function-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 the modulation of immune function.
[0017] The compounds as disclosed herein may also contain less prevalent
isotopes for other elements, including, but not limited to, '3C or 14C for carbon, 33S,
34S, or 36S for sulfur, '5N for nitrogen, and 170 or '80 for oxygen.
[0018] In certain embodiments, the compound disclosed herein may expose a
patient to a maximum of about 0.000005% D90 or about 0.00001% DHO,
R15 R15
WO 2010/028015 PCT/US2009/055692
assuming that all of the C-D bonds in the compound as disclosed herein are
metabolized and released as D20 or DHO. In certain embodiments, the levels of
D20 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
D20 or DHO upon drug metabolism.
[0019] 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 (Tv2), lowering the maximum plasma concentration
. (Cmax) 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.
[0020] 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.
[0021] As used herein, the terms below have the meanings indicated.
[0022] The -singular forms "a," "an," and "the" may refer to plural articles
unless specifically stated otherwise.
[0023] 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.
[0024] When ranges of values are disclosed, and the notation "from ni. . to n2"
or "n1-n2" is used, where n1 and n2are 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.
—6—
WO 2010/628015 PCT/US2009/055692
[0025] 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 nonenriched
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.
[0026] The term "is/are deuterium," when used to describe a given position in a
molecule such as R1-R17 or the symbol "D," when used to represent a given position
in p. 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.
[0027] The term "isotopic enrichnient" 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 pievalent isotope of the element.
[0028] 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.
[0029] 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
WO 2010/028015 PCT/US2009/055692
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.
00304 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.
[0031] The term "disorder" as used herein is intended to be generally
synonymous, and is used interchangeably with, the terms "disease" 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.
[0032] 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.
[0033] 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,
WO 2010/028015 PCTIUS2009/055692
tissue, system, animal, or human that is being sought by a researcher, veterinarian,
medical doctor, or clinician.
[0034] 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.
[0035] 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.
[0036] The term "immune function" refers to the collection of mechanisms
within an organism that protects against disease. Such mechanisms include
macrophages, T-lymphocytes, and B- lymphocytes and their respective activities.
[0037] The term "immune function-mediated disorder," refers to a disorder that
is characterized by abnormal immune function. An immune function-mediated
disorder may be completely or partially mediated by modulating the immune
function in a subject. In particular, an immune function -mediated disorder is one
in which modulation of immune function results in some effect on the underlying
disorder e.g., administration of a immune function modulator results in some
improvement in at least some of the patients being treated.
[0038] The term "immune function modulator," refers to the ability of a
compound disclosed herein to alter immune function activity. An immune function
modulator may stimulate immune function activity, may activate or inhibit immune
function activity depending on the concentration of the compound exposed to the
subject, or may inhibit immune function activity. 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. For
WO 2010/028015 PCT/US2009/055692
example, compounds disclosed herein may modulate immune function by inhibiting
the infiltration of both CD4+T-cells and macrophages into central nervous tissues
and changing the T-lymphocyte population in favour of cells expressing Th2/Th3
cytokines interleukin (IL)-4, IL-10 and transforming growth factor-beta. In some
embodiments, modulation of the immune function may be assessed using the
method described in Karussis et al., Ann. Neurol. 1993, (34), 654-660; Yang, et al.,
Journal of Neuroimmunology 2004, 156(1-2), 3-9; Brunmark et al., J
Neuroimmunol. 2002, 130, 163-172; and Jonsson et al., J. Med. Chem. 2004, 47,
2075-88.
[0039] 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.
[0040] 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, FL, 2004).
[0041] 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.
WO 2010/028015 PCT/US2009/055692
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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. Neuropharmacoi. 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 Enzvmol. 1985, 112,
7,--kr 7 2_
WO 2010/028015 PCT/US2009/055692
360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem.
Soc., Chem. Common. 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.
[0046] The compounds disclosed herein can exist as therapeutically acceptable
salts. The term "therapeutically acceptable salt," as used herein, represents salts or
zwitterionic foims 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., ./.
Pharm. Sci. 1977, 66, 1-19.
[0047] 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, a-oxo-glutaric acid, glycolic acid, hippuric acid,
hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DLlactic
acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid,
(±)-13L-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,
/3
WO 2010/028015 PCT/US2009/055692
phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-aminosalicylic
acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-
L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and
valeric acid.
[0048] 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.
[0049] While it may be possible for the compounds of the subject invention to
be administered as the raw chemical, it is also possible to pre;ent 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: he bcience ana
Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology,
Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.:
New York, NY, 2002; Vol. 126).
[0050] 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.
A pharmaceutical composition of the present invention comprising a compound of
Formula 1, as herein described, in association with a pharmaceutically acceptable carrier
showed unexpected, surprising and enhanced results. Therefore, the said composition is
synagistic composition and not a mere admixture.
[0051] 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 nonaqueous
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.
[0052] 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
WO 2010/028015 PCT/US2009/055692
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.
[0053] 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 rormulatory
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.
[0054] Formulations for parenteral administration include aqueous and nonaqueous
(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
/L
AM&
WO 2010/028015 PCT/US2009/055692
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.
10055] 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.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] Formulations suitable for topical administration include liquid or semiliquid
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.
[0060] 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
dichiorodifluoromethane, 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.
46- /7---
WO 2010/028015 PCT/US2009/055692
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.
[0061] Preferred unit dosage formulations are those containing an effective
dose, as herein below recited, or an appropriate fraction thereof, of the active
ingredient.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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.
WO 2010/028015 PCT/US2009/055692
[0066] hi 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").
[0067] 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.
[0068] Disclosed herein are methods of treating an immune function-mediated
disorder comprising administering to a subject having or suspected to have such a
disorder, a therapeutically effective amount of a compound as disclosed herein or a
pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0069] Immune function-mediated disorders, include, but are not limited to,
multiple sclerosis and autoimmune disorders, and/or any disorder which can
lessened, alleviated, or prevented by administering a immune function modulator.
[0070] In certain embodiments, a method of treating a immune functionmediated
disorder comprises administering to the subject a therapeutically effective
amount of a compound or 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 P450 or monoamine oxidase isoform in the
subject; (4) decreased metabolism via at least one polymorphically-expressed
cytochrome P450 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.
[0071] In certain embodiments, inter-individual variation in plasma levels of the
compounds as disclosed herein, or metabolites thereof, is decreased; average
WO 2010/028015 PCT/US2009/055692
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 P450 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 P450 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.
[0072] 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; Sennbro, et al., Rapid
Communications in Mass Spectrometry 2006, 20(22), 3.313-3318; Edman, et al.,
Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life
Sciences 2003, 785(2); and any references cited therein and modifications made
thereof.
[0073] Examples of cytochrome P450 isoforms in a mammalian subject include,
but are not limited to, CYP IA1, CYP1A2, CYPIB1, CYp2A6, CYP2A13,
CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1,
CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2,
CYP3A7, CYP4A 11, CYP4B1, CYP4F2, CYP4F3, CYP4F8; CYP4F11, CYP4F12,
CYP4X1, CYP4Z 1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP1 1 Al,
CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1,
CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.
[0074] Examples of monoamine oxidase isoforms in a mammalian subject
include, but are not limited to, MAOA, and MAOB.
[00751 The inhibition of the cytochrome P450 isoform is measured by the
method of Ko et al., British Journal of Clinical Pharmacology, 2000, 49, 343-351.
The inhibition of the MAOA isoform is measured by the method of Weyler et al., J.
Biol Chem. 1985, 260, 13199-13207. The inhibition of the MAOB isoform is
measured by the method of Uebelhack et al. Pharmacopsychiatrv, 1998, 31, 187-
192.
[0076] Examples of polymorphically-expressed cytochrome P450 isoforms in a
mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19,
and CYP2D6.
--0E-0215
WO 2010/028015 PCT/US2009/055692
[0077] The metabolic activities of liver microsomes, cytochrome 13450 isoforms,
and monoamine oxidase isoforms are measured by the methods described herein.
[0078] Examples of improved disorder-control and/or disorder-eradication
endpoints, or improved clinical effects include, but are not limited to, cumulative
number of active lesions seen at week 24, cumulative and active number of active
and gadolinium-enhancing lesions on MRI every 8 weeks, relapse rate, multiple
sclerosis functional composite, short form 36 quality of life assessment (Burton et
al., Curr. Neurol. Neurosc. Reports 2007, 7(3), 223-30).
[0079] 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," "y-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", 4thedition,
Mosby, 1999. These assays are run by accredited laboratories according to standard
protocol.
[0080] 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•
[0081] The compounds disclosed herein may also be combined or used in
combination with other agents useful in the treatment of immune function-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).
[0082] 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
'NO 2010/028015 PCIMS2009/055692
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.
[0083] In certain embodiments, the compounds disclosed herein can be
combined with one or more immunomodulators, steroidal drugs or cyclosporins.
[0084] In certain embodiments, the compounds provided herein can be
combined with one or more immunomodulators known in the art, including, but not
limited to, filgrastim, molgramostim, sargramostim, lenograstim, ancestim,
pegfilgrastim, interferon gamma, interferon alpha-2a, interferon alpha-2b,
interferon alpha-nl, interferon beta-la, interferon beta-lb, interferon alphacon-1,
peginterferon alpha-2b, peginterferon alpha-2a, interferon omega, aldesleukin,
oprelvekin, lentinan, roquinimex, BCG vaccine, pegademase, pidotimod, Poly I:C,
Poly ICLC, thymopentin, immunocyanin, tasonermin, melanoma vaccine,
glatiramer acetate, histamine dihydrochloride, mifamurtide, plerixafor, muromonabCD3,
antilymphocyte immunoglobulin (horse), antithymocyte immunoglobulin
(rabbit), mycophenolic acid, sirolimus, leflunomide, alefacept, everolimus,
gusperimus, efalizumab, abetimus, natalizumab, abatacept, eculizumab, etanercept,
infliximab, afelimomab, adalimumab, certolizumab pegol, daclizumab, basiliximab,
anakinra, ciclOsporin, tacrolimus, azathioprine, thalidomide, methotrexate, and
lenalidomide.
[0085] The compounds disclosed herein can also be administered in
combination with other classes of compounds, including, but not limited to,
norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake
inhibitors (DARls), such as methylphenidate; serotonin-norepinephrine reuptake
inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham;
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; anti-platelet agents, such as
GPII13/Bla blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC)
WO 2010/028015 PCT/US2009/055692
antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants,
such as warfarin; low molecular weight heparins, such as enoxaparin; Factor VIIa
Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP)
inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat
ancrgetriopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin,
atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and
ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene
synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; antiatherosclerotic
agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel
blockers, such as amlodipine besylate; potassium channel activators; alpha-
.
muscarinic agents; beta-muscarinic agents, such as carvedilol and metoprolol;
antiarrhythmic agents; diuretics, such as chlorothlazide, hydrochiorothiazide,
flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,
trichioromethiazide, polythiazide, benzothlazide, ethacrynic acid, tricrynafen,
chlorthalidone, furosenilde, musolimine, bumetanide, triamterene, amiloride, and
spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA),
recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated
plasminogen streptokinase activator complex (APSAC); 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
AO.
WO 2010/028015 PCT/1S2009/055692
hormone-releasing hormone anatagonists, and octreotide acetate; microtubuledisruptor
agents, such as ecteinascidins; microtubule-stablizing agents, such as
pacitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca
alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenylprotein
transferase inhibitors; and cyclosporins; steroids, such as prednisone and
dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNFalpha
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.
[0086]. Thus, in another aspect, certain embodiments provide methods for
treating immune function-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 immune
function-mediated disorders.
General Synthetic Methods for Preparing Compounds
[0087] 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.
[0088] 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
R4
NH2
OH
CI 0
1
R6
CI 0
WO 2010/028015 PCT/US2009/055692
procedures similar to those described in the Example section herein and routine
modifications thereof, and/or procedures found in Wennerberg et al., Org. Proc.
Res. & Dev. 2007, 11(4), 674-80; Wang et al., Bioorganic & Medicinal Chemistry
Letters 2007, 17(10), 2817-2822; Jansson et al., J Org. Chem. 2006, 71(4), 1658-
67; Joensson et al., J Med. Chem. 2004, 47(8), 2075-88; US 201)77088050; US
2005/215586; US 2005/192315; US 2004/034227; WO 2005/74899; WO
2003106424; and WO 1999/55678, 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.
[0089] The following schemes can be used to practice the present invention.
Any position shown as hydrogen may be optionally substituted with deuterium.
Scheme I
[0090] Compound 1 is reacted with an appropriate chloroformate or phosgene
equivalent, such as isopropyl carbonochloridate, in the presence of an appropriate
dehydrating agent, such as acetyl chloride, in an appropriate solvent, such as 1,4-
dioxane, at an elevated temperature to give compound 2. Compound 2 is reacted
with compound 3 in the presence of an appropriate base, such as sodium hydride, in
an appropriate solvent, such as dimethylformamide, under an inert atmosphere,
such as nitrogen, to give compound 4. Compound 4 is reacted with an appropriate
- CI 0Na 0
1 I
WO 20t0/028015 PCT/US2009/055692
malonate derivative, such as diethyl malonate, in the presence of an appropriate
base, such as sodium hydride, in an appropriate solvent, such as
dimethylformamide, at an elevated temperature, to give compound 5. Compound 5
is reacted with compound 6 in an appropriate solvent, such as n-heptane, at an
elevated temperature, to givt compound 7 of Formula I.
[0091] 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 R4-R6, compound 1 with the corresponding deuterium substitutions can
be used. To introduce deuterium at one or more positions of R1-R3, compound 3
with the corresponding deuterium substitutions can be used. To introduce deuterium
at one or more positions of R8-R17, compound 6 with the corresponding deuterium
substitutions can be used.
[0092] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the hydroxyl 0-H, via proton-deuterium equilibrium
exchange. For example, to introduce deuterium at R7, this proton may be replaced
with deuterium selectively or non-selectively through a proton-deuterium exchange
method known in the art.
[0093] The invention is further illustrated-by the following examples. All
IUPAC names were generated using CambridgeSoft's ChemDraw 10.0.
EXAMPLE 1
Sodium 5-c hlo ro-3-(ethyl(p henyl)ca rba m oy1)-1-m ethy1-2-oxo-1,2-
dihydroquinolin-4-olate
WO 2010/028015 PCT/US2009/055692
Step 1
CI 0 CI 0
I
OH 0
,
NH2 0
[0094] 5-Chloro-1H-benzold111,31oxazine-2,4-dione: Under an atmosphere of
nitrogen, isopropyl carbonochloridate (50 ml, 4.50 equiv) was added dropwise to a
suspension of 2-amino-6-chlorobenzoic acid (20 g, 116.56 mmol, 1.00 equiv) in
1,4-dioxane (150 m1). The resulting solution was maintained at about 90 °C for 30
minutes, and then cooled to about 50 °C. Acetyl chloride (50 ml, 6.00 equiv) was
added in one portion, and the solution was maintained at about' 50 °C for about 30
minutes. The resulting solids were collected by filtration and purified by silica gel
chromotagraphy (ethyl acetate/petroleum ether 10:1) to afford the title product as a
gray white solid (17.6g, yield: 76%).
Step 2
CI 0
0
I N
CH3
[0095] 5-Chloro-l-methy1-1H-benzordlf1,31oxazine-2,4-dione: Under an
atmosphere of nitrogen, 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (10 g, 50.61
mmol, 1.00 equiv) was dissolved in N,N-dimethylformamide (100 ml) at about 5
°C. Sodium hydride (2.8 g, 121.5 mmol, 2.4 equiv) and methyl iodide (5.7 ml, 2
equiv) were then added, and the resulting mixture was stirred at ambient
temperature for about 16 hours. The mixture was purged with nitrogen for about 1
hour to give the title product as a yellow solid, which was used directly in the next
step without any purification.
Step 3
CI 0
0 L
0
/0
`.<
0 CI OH 0
I H
0 11
CI OH 0
+ 0
NO
-
+
CI 0 Na 0
N0
WO 2010/028015 PCT/1152009/055692
[0096] Ethyl 5-chloro-4-hydroxy-l-methv1-2-oxo-1,2-dihydroquinoline-3-
carboxylate: Sodium hydride (1.9 g, 79.17 mmol, 1.60 equiv) was added in several
portions to the mixture of 5-chloro-1-methy1-1H-benzo[d][1,3]oxazine-2,4-dione in
N,N-dimethylformamide from Step 2. Diethyl malonate (7 7 g, 48.07 mmol, 1.00
equiv) was then added dropwise to the stirred mixfure over a period of about 30
minutes. The resulting solution was stirred at about 85 °C for about 1 hour, water
(800 ml) was added, and the pH of the solution was adjusted to 2 with a solution of
hydrochloric acid (5 mol/L). The resulting crude product was collected by filtration
and then re-crystallized in ethanol to give the title product as a light yellow solid
(2.5 g, yield: 18% 2 steps).
Step 4
[0097] 5-Chloro-N-ethv1-4-hydroxv-l-methyl-2-oxo-N-phenv1-1,2-
dihydroquinoline-3-carboxarnide: N-ethylbenzenamine (430 mg, 3.55 mmol, 2.00
equiv) was added dropwise to ethyl 5-chloro-4-hydroxy-1-methy1-2-oxo-1,27
dihydroquinoline-3-carboxylate (500 mg, 1.78 mmol, 1.00 equiv) dissolved in
heptane (10 ml). The resulting mixture was heated about 100 °C and the volatiles
were removed by distillation over a period of about 7 hours. After cooling to
ambient temperature, the resulting crystals were collected by filtration, washed with
heptane, and purified by by silica gel chromotagraphy (ethyl acetate/petroleum
ether 1:3) to afford the title product as a white solid (0.38g, yield: 60%).
[0098] Sodium 5-chloro-3-(ethyl(phenvl)carbamov1)-1-methvI-2-oxo-1.2-
dihydroquinolin-4-olate: The pH value of a solution of 5-chloro-N-ethy1-4-
hydroxy-l-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide (170 mg,
0
CI O
O + - CD3
N"--
CD3
0 9 9H 9
0 0
0--‘
0
11 0
CD3
WO 2010/028015 PCT/US2009/055692
0.48 mmol, 1.00 equiv) in ethanol (5 ml) was adjusted to 9-10 with a solution of
5M sodium hydroxide. The mixture then was stirred for about 30 min at ambient
temperature. The resulting solids were collected by filtration and washed with
ethanol to give the title compound as a white solid (70 mg, yield: 39%). iH NMR
(300 MHz., DMSO) 8: 6.84-7.31(m, 8H), 3.68(q, 2H), 3.34(s, 3H), 1.02(t, 3H). LCMS
: m/z= 357 (M-Na.+2H) +
EXAMPLE 2
Sodium 5-chloro-3-(ethyl(phenyl)carbamoy1)-1-d3-methyl-2-oxo-1,2-
dihydroquinolin-4-olate
Step 1
[0099] d -Eth 15-chloro-4-h 1-2-oxo-1 2-dih Arb uinoline-3-
carboxylate: The procedure of Example 1, Step 2 was followed, but substituting d3-
methyl iodide for methyl iodide. The resulting product, a yellow solid, was used
directly in the next step without any purification.
[001001 dl-Ethyl 5-chloro-4-hvdroxy-l-methy1-2-oxo-1,2-dihvdroquinoline-3-
carboxylate: The procedure of Example 1, Step 3 was followed, but substituting d3-
ethyl 5-chloro-4-hydroxy-l-methy1-2-oxo-1,2-dihydroquinoline-3-carboxylate for
CI OH 0
N 0 L
CD3
Step 4
CI OH 0
+
N 0
CD3
CI 0 Na0
I II
N
0
Step 5
CI OH 0
I
CD3
WO 2010/028015 PCT/US2009/055692
ethyl 5-chloro-4-hydroxy-l-methy1-2-oxo-1,2-dihydroquinoline-3-carboxylate. The
title product was isolated as a yellow solid (5.8 g, yield: 57% 2 steps).
[00101] c1-5-Chloro-N-ethy1-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-
dihydroquinoline-3-carboxamide: The procedure of Example 1, Step 4 was
followed, but substituting d3-ethyl 5-chloro-4-hydroxy-l-methyl-2-oxo-1,2-
dihydroquinoline-3-carboxylate for ethyl 5-chloro-4-hydroxy-l-methy1-2-oxo-1,2-
dihydroquinoline-3-carboxylate. The title product was isolated as a white solid (1.0
g, yield: 79%).
CD3
[00102] Sodium 5-chloro-3-(ethyl(phenyl)carbamoy1)-1-d 1-2-oxo-1 a:
dihydroquinolin-4-olate: The procedure of Example 1, Step 5 was followed, but
substituting d3-5-chloro-N-ethy1-4-hydroxy-I-methy1-2-oxo-N-phenyl-1,2-
dihydroquinoline-3-carboxamide for 5-chloro-N-ethy1-4-hydroxy-l-methyl-2-oxoN-phenyl-1,2-dihydroquinoline-3-carboxamide.
The title product was isolated as a
white solid (0.17 g, yield: 80%). 1H NMR (300 MHz, DMS0)13: 6.83-7.32(m, 8H),
3.68(q, 2H), 1.03(t, 3H). LC-MS : m/z= 360 (M-Na+2H) +.
Step 1
NH2 0
.+ >c4)-L0jLO
WO 2010/028015 PCT/US2009/055692
EXAMPLE 3
Sodium 5-chloro-3-(ds-ethyl(phenyl)carbamoy1)-1-methy1-2-oxo-1,2-
dihydroquinolin-4-olate
_
+
Na
CI. 0
1
0
11
D
I
D D
[00103] tert-butyl phenylcarbamate: Aniline (2.3 g, 25 mmol, 1 equiv) was
dissolved in tetrahydrofuran (25 ml) at about 5°C. A solution of di-tert-butyl
dicarbonate (6.0 g, 27.5 mmol) in tetrahydrofuran (10 ml) was added to the
solution, and the resulting mixture was heated at reflux for about 2 hours. The
solvent was removed in vacuo and the resulting residue was dissolved in ethyl
acetate (50 ml). The resulting solution was washed with a 1M citric acid solution
(2 x50m1) and brine (1x50m1). The organic phase was dried over sodium sulfate and
evaporated in vacuo to give the title product as a white solid (4.3g, yield: 83%).
Step 2
D
R
D +
0
0
[OM 04] A:Ethyl- lmry_ 11-carbamic acid tert-butyl ester: Potassium 2-
methylpropan-2-olate (790 mg, 7.05 mmol, 2.50 equiv) and d5-iodoethane (500 mg,
3.11 mmol, 1.10 equiv) were added to tert-butyl phenylcarbamate (540 mg, 2.80
mmol, 1.00 equiv) dissolved in N,N-dimethylformamide (100 mL). The resulting
mixture was stirred at about 55 °C for about 16 hours, and then deuterium oxide
was added (10m1). The pH of the mixture was then adjusted to about 6-7 with IN
hydrochloric acid. Standard extractive workup with ethyl acetate gave the title
3
WO 2010/028015 PCT/US2009/055692
product as a crude residue, which was used in the next step without further
purification.
Step 3
D
H D
N, 0
0 [00105j N-sh:Ethylbenzenamine: Over a period of 1 hour and maintaining the
temperature at around 25 °C, hydrochloric gas was introduced to d5-ethyl-phenyl-
• carbamic acid tert-butyl ester dissolved in ethyl acetate (5 ml). The pH of the
solution was then adjusted to 6-7 with a sodium hydroxide solution(10 mol/L).
Standard extractive workup with ethyl acetate gave the title product as yellow oil
(0.33 g, yield: 93%).
Step 4
CI OH 0
N
D.
[001061 5-Chloro-N-d5-ethy1-4-hydroxv-1-methyl-2-oxo-N-phenyl-1,2-
dihydroquinoline-3-carboxamide: The procedure of Example 1, Step 4 was
followed, but substituting N-ds-ethylbenzenamine for N-ethylbenzenamine. The
title product was isolated as a white solid (0.4 g, yield: 58%).
Step 5
N
D
[00107] Sodium 5-chloro-3- d5-eth 1 hei Ieth 1-2-oxo-I 2-
dihydroquinolin-4-olate: The procedure of Example 1, Step 5 was followed, but
substituting 5-chloro-N- d5-ethy1-4-hydroxy-l-methyi-2-oxo-N-phenyl-1,2-
dihydroquinoline-3-carboxamide for 5-chloro-N-ethy1-4- hydroxy-1 -methy1-2- oxo-
H D
N
D D
CD3•
D
WO 2010/028015 PCT/US2009/055692
N-phenyl-1,2-dihydroquinoline-3-carboxamide. The title product was isolated as a
white solid (90mg, yield: 40.5%). 1H NMR (300 MHz, DMSO) 6: 6.84-7.32(m,
8H), 3.34(s, 3H)LC-MS : m/z= 362 (M-Na+2H) 4 .
EXAMPLE 4
Sodium 5-chloro-3-(d5-ethyl(phenyl)carbamoy1)-1-d3-methy1-2-oxo-1,2-
dihydroquinolin-4-olate
_
CI 0 0
Sten 1
CI OH 0
'N 0
CD3
[00108j 5-chloro-N-d8-ethyl-4-1 1-2-oxo-N- hen 1-1 2-
dihydroquinOline-3-carboxamide: The procedure of Exatnple 2, Step 4 was
followed, but substituting N-d5-ethylbenzenamine for N-ethylbenzenamine. The
title product was isolated as a white solid.
Step 2
_ ÷Na
CI 0
DMK- 1 D D D
CD3
[00109] Sodium 5-chloro-3- cis-oh 1 -methy1-2-oxo-1,2._z
dihydroquinolin-4-olate: The procedure of Example 2, Step 5 was followed, but
substituting N-d5-ethylbenzenamine for N-ethylbenzenamine. The title product was
isolated as a white solid ( 0.1 g, yield :70%). 1H NMR (300 MHz, DMSO) 6:
6.83-7.31 (m, 8H). LC-MS : mlz= 365 (M-Na'-2H)+.
WO 2010/028015 PCT/US2009/055692
[00110} 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.
CD3
CI OH 0 n
N •
WO 2010/028015 PCT/US2009/055692
CI OH 0 CI OH 0
0
, and
0
CI OH 0
CD3
CI OH 0
[00111] 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
[00112] Liver microsomal stability assays are conducted at 2 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 are
WO 2010/028015 PCT/US2009/055692
prepared as solutions in 20% acetonitrile-water and added to the assay mixture
(final assay concentration 5 microgram per mL) and incubated at 37 °C. Final
concentration of acetonitrile in the assay should be <1%. Aliquots (504) are taken
out at times 0, 30, 60, 90, and 120 minutes, and diluted with ice cold acetonitrile
(200 !IL) 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. The degradation half-lives of Examples 1 through 4 (laquinimod and
isotopically enriched drugs) are shown in Table 1.
Results of in vitro human liver microsornal LIVI stability assay
% increase of HLM degradation half-life
-20% - 0% 0% - 20% 20% -100% >100%
Example 1 +
Example 2 +
Example 3 +
Example 4 +
Table 1
In vitro metabolism using human cytochrome P450 enzymes
[001131 The cytochrome P450 enzymes are expressed from the corresponding
human cDNA using a baculovirus expression system (BD Biosciences, San Jose,
CA). A 0.25 milliliter--reaction mixture containing 0.8 milligrams per milliliter
protein, 1.3 millimolar NAD13±, 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 of Formula I, the corresponding non-isotopically
enriched compound or standard or control in 100 millimolar potassium phosphate
(pH 7.4) is incubated at 37 °C for 20 min. 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 min. The
supernatant is analyzed by HPLC/MS/MS.
WO 2010/028015 PC-I./US2009/055692
Cytochrome Paso Standard
CYP1A2 Phenacetin
CYP2A6 Coumarin
CYP2B6 [13C]-(S)-mephenytoin
CYP2C8 Paclitaxel
CYP2C9 Diclofenac
CYP2C19 [13C]-(S)-mephenytoin
CYP2D6 (+/-)-Bufuralol
CYP2E1 Chlorzoxazone
CYP3A4 Testosterone
CYP4A [13C]-Lauric acid
Monoamine Oxidase A Inhibition and Oxidative Turnover
[00114} The procedure is carried out using the methods described by Weyler,
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 kynummine with formation of 4-hydroxyquinoline. The
measurements are carried out, at 30 °C, in 50mM 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
[00115] The procedure is carried out as described in Uebelhack,
Pharmacopsychiatry 1998, 31(5), 187-192, which is hereby incorporated by
reference in its entirety.
Determining Laquinimod in plasma by coupled-column liquid chromatography with
ultraviolet absorbance detection
[00.116] The procedure is carried out as described in Edman, et al., Journal of
Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences
2043, 785(2), which is hereby incorporated by reference in its entirety.
WO 2010/028015 PCT/US2009/055692
Determining laquinimod in human plasma by liquid chromatography/tandem mass
spectrometry
[00117] The procedure is carried out as described in Sennbro, et al., Rapid
Communications in Mass Spectrometry 2006, 20(22), 3313-3318, which is hereby
incorporated by reference in its entirety.
Measuring laquinimod's effect on Thl/Th2 balance, and Th3 cytokine and TGF-13
cytokine production in Lewis rats.
[00118] The procedure is carried out as described in Yang, et al., Journal of
Neuroimmunology 2004, 156(1-2), 3-9, which is hereby incorporated by reference
in its entirety.
Experimental Autoimmune Encephalomyelitis Model
[00119] The procedure is carried out as described in Karussis et al., Ann. Neurol.
1993, 34, 654-660, which is hereby incorporated by reference in its entirety.
[00120] 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.
.49
R16
rc
n. 15
R14
WO 2010/028015 PCT/US2009/055692
1. A compound of structural Formula I
R
R3
2
R1
R4 R17
R5
R6 R8 R13 9
CI O. 0
R7
R12 D R10
(I)
or a salt thereof, wherein:
R1-R17are independently selected from the group consisting of hydrogen
and deuterium; and
at least one of Ri-R17 is deuterium.
2. The compound as recited in Claim 1 wherein at least one of R1-R17
independently has deuterium enrichment of no less than about 10%.
3. The compound as recited in Claim 1 wherein at least one of R1-R17
independently has deuterium enrichment of no less than about 50%.
4. The compound as recited in Claim 1 wherein at least one of RI-RI7
independently has deuterium enrichment of no less than about 90%.
5. The compound as recited in Claim 1 wherein at least one of RI-RI7
independently has deuterium enrichment of no less than about 98%.
6. The compound as recited in Claim 1 wherein said compound has a structural
formula selected from the group consisting of:
D
0' 0 'D CI OH 0 Dom`
D
I
ND
D
CD3
CI
0
CD3
4F 2,1
WO 2010/028015 PCT/US2009/055692
N 0 D CD3
CD3
N O p N 0
CD3 CD3
CI OH 0 CI OH 0 CI OH 0
CI OH 0
WO 2010/028015 PCT/US2009/055692
CI OH 0
and
7. The compound as recited in Claim 1 wherein said compound has a structural
formula selected from the group consisting of
CI OH 0
CD3
, and
8. The compound as recited in Claim 7 wherein each position represented as D has
deuterium enrichment of no less than about 10%.
9. The compound as recited in Claim 7 wherein each position represented as D has
deuterium enrichment of no less than about 50%.
10. The compound as recited in Claim 7 wherein each position represented as D has
deuterium enrichment of no less than about 90%.
11. The compound as recited in Claim 7 wherein each position represented as D has
deuterium enrichment of no less than about 98%.
12. The compound as recited in Claim 7 wherein said compound has the structural
formula:
WO 2010/028015 PCT/US2009/055692
13. The compound as recited in Claim 7 wherein said compound has the structural
formula:
14. The compound as recited in Claim 7 wherein said compound has the structural
formula:
15. A pharmaceutical composition comprising a compound as recited in Claim 1
together with a pharmaceutically acceptable carrier.
16. A method of treatment of a immune function-mediated disorder comprising the
administration of a therapeutically effective amount of a compound as recited in
Claim 1 to a patient in need thereof.
17. The method as recited in Claim 16 wherein said disorder is multiple sclerosis
and autoimmune disorders.
18. The method as recited in Claim 16 further comprising the administration of an
additional therapeutic agent.
19. The method as recited in Claim 18 wherein said additional therapeutic agent is
selected from the group consisting of immunomodulators and cyclosporins.
20. The method as recited in Claim 19 wherein said immunomodulator is selected
from the group consisting of filgrastim, molgramostim, sargramostim,
lenograstim, ancestim, pegfilgrastim, interferon gamma, interferon alpha-2a,
interferon alpha-2b, interferon alpha-n1, interferon beta-la, interferon beta-lb,
interferon alphacon-1, peginterferon alpha-2b, peginterferon alpha-2a,
interferon omega, aldesleukin, oprelvekin, lentinan, roquinimex, BCG vaccine,
pegademase, pidotimod, Poly I:C, Poly ICLC, thymopentin, immunocyanin,
WO 2010/028015 PCT/US2009/055692
tasonermin, melanoma vaccine, glatiramer acetate, histamine dihydrochloride,
mifamurtide, plerixafor, muromonab-CD3, antilymphocyte immunoglobulin
(horse), antithymocyte immunoglobulin (rabbit), mycophenolic acid, sirolimus,
leflunomide, alefacept, everolimus, gusperimus, efalizumab, abetimus,
natalizumab, abatacept, eculizumab, etanercept, infliximab, afelimomab,
adalimumab, certolizumab pegol, daclizumab, basiliximab, anakinra,
ciclosporin, tacrolimus, azathioprine, thalidomide, methotrexate, and
lenalidomide.
21. The method as recited in Claim 16, further resulting in at least one effect
selected from the group consisting of:
a. decreased inter-individual variation in plasma levels of said
compound or a metabolite thereof as compared to the nonisotopically
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 nonisotopically
enriched compound;
d. increased average plasma levels of at least one metabolite of said
compound per dosage unit thereof as compared to the nonisotopically
enriched compound; and
e. an improved clinical effect during the treatment in said subject per
dosage unit thereof as compared to the non-isotopically enriched
compound.
22. The method as recited in Claim 16, further resulting in at least two effects
selected from the group consisting of:
a. decreased inter-individual variation in plasma levels of said
compound or a metabolite thereof as compared to the nonisotopically
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 nonisotopically
enriched compound;
WO 2010/028015 PCT/US2009/055692
d. increased average plasma levels of at least one metabolite of said
compound per dosage unit thereof as compared to the nonisotopically
enriched compound; and
e. an improved clinical effect during the treatment in said subject per
dosage unit thereof as compared to the non-isotopically enriched
compound.
23. The method as recited in Claim 16, wherein the method effects a decreased
metabolism of the compound per dosage unit thereof by at least one
polymorphically-expressed cytochrome P450 isoform in the subject, as
compared to the corresponding non-isotopically enriched compound.
24. The method as recited in Claim 23, wherein the cytochrome P450 isoform is
selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and
CYP2D6.
25. The method as recited Claim 16, wherein said compound is characterized by
decreased inhibition of at least one cytochrome P450 or monoamine oxidase
isoform in said subject per dosage unit thereof as compared to the nonisotopically
enriched compound.
26. The method as recited in Claim 25, wherein said cytochrome P450 or
monoamine oxidase isoform is selected from the group consisting of 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, MAOA, and MAOB.
27. The method as recited in Claim 16, wherein the method reduces a deleterious
change in a diagnostic hepatobiliary function endpoint, as compared to the
corresponding non-isotopically enriched compound.
28. The method as recited in Claim 27, wherein the diagnostic hepatobiliary
function endpoint is selected from the group consisting of 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
ji
WO 2010/028015 PCT/US2009/055692
transpeptidase ("GGTP," "y-GTP," "GGT"), leucine aminopeptidase ("LAP"),
liver biopsy, liver ultrasonography, liver nuclear scan, 5'-nucleotidase, and
blood protein.
29. A compound as recited in Claim 1 for use as a medicament.
30. A compound as recited in Claim 1 for use in the manufacture of a medicament
for the prevention or treatment of a disorder ameliorated by the modulation of
immune function.
Datid this the day of , 20 Ly-.'•-
Amrish Tiwari
Of K & S Partners
Attorney for the Applicant
ABSTRACT
Title : "2-0X0-1, 2-DIHYDRO-QUINOLINE MODULATORS OF IMMUNE
FUNCTION"
The present invention relates to new 2-oxo-1,2-dihydro-quinoline modulators of immune
function, pharmaceutical compositions thereof and methods of use thereof
4