NZ718128B2 - Peptidyl nitril compounds as dipeptidyl peptidase i inhibitors - Google Patents
Peptidyl nitril compounds as dipeptidyl peptidase i inhibitors Download PDFInfo
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- NZ718128B2 NZ718128B2 NZ718128A NZ71812814A NZ718128B2 NZ 718128 B2 NZ718128 B2 NZ 718128B2 NZ 718128 A NZ718128 A NZ 718128A NZ 71812814 A NZ71812814 A NZ 71812814A NZ 718128 B2 NZ718128 B2 NZ 718128B2
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- KPGXRSRHYNQIFN-UHFFFAOYSA-N α-Ketoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
Abstract
The invention relates to amino acid derivatives of Formula (I) which possess a bi-phenyl core and 1,4-diazinane substituent. These derivatives are claimed as selective dipeptidyl peptidase I inhibitors for the treatment of, among others, asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, and alpha-1 antitrypsin deficiency. cystic fibrosis, and alpha-1 antitrypsin deficiency.
Description
PEPTIDYL NITRIL COMPOUNDS AS DIPEPTIDYL PEPTIDASE I INHIBITORS
FIELD OF THE INVENTION
The present invention relates to peptidyl nitril compounds and their use as inhibitors of
dipeptidyl peptidase I, pharmaceutical compositions containing the same, and methods of
using the same agents for treatment and/or prevention of inflammatory diseases in which
dipeptidyl peptidase I is involved, especially inflammatory diseases mediated by mast cells
and neutrophil cells, e.g. chronic obstructive pulmonary disease and other respiratory
diseases.
BACKGROUND OF THE INVENTION
Dipeptidyl peptidase I (DPPI; EC 3.4.14.1) also known as cathepsin C is a lysosomal cysteine
peptidase belonging to the papain family. The enzyme is constitutively expressed in many
tissues with highest levels in lung, kidney, liver and spleen. The cDNAs encoding rat, human
and murine DPPI have been cloned and sequenced and it has been shown that the enzyme is
highly conserved. DPPI is synthesized as an inactive precursor (Zymogen), and is activated
by a non-autocatalytic excision of an internal activation peptide within the N-terminal
propeptide. DPPI is the only member of the papain family that is functional as a tetramer,
consisting of four identical subunits. Each is composed of an N-terminal fragment (the
residual propart), a heavy chain and a light chain. Once activated, DPPI catalyzes the
removal of dipeptides from the N-terminal end of polypeptide substrates with broad
specificity. The pH optimum lies in the region of pH 5-7 using human DPPI. Recent data
suggests that, beside of being an important enzyme in lysosomal protein degradation, DPPI
also functions as a key enzyme in the activation of granule serine peptidases in neutrophils
(cathepsin G, proteinase 3, neutrophil serine protease 4 and elastase), mast cells (chymase
and tryptase) and cytotoxic T lymphocytes and natural killer cells (granzymes A and B).
Mast cells are found in many tissues, but are present in greater numbers along the epithelial
linings of the body, such as the skin, respiratory tract and gastrointestinal tract. Mast cells
are also located in the perivascular tissue surrounding small blood vessels. In humans, two
types of mast cells have been identified; the T-type, which expresses only tryptase, and the
MC-type, which expresses both tryptase and chymase. In humans, the T-type mast cells are
located primarily in alveolar tissue and intestinal mucose while the TC-type cells predominate
in skin and conjuctiva. Mast cells can release a range of potent inflammatory mediators
including cytokines, leukotrienes, prostaglandins, histamine and proteoglycans, but among
the most abundant products of mast cell activation are the serine peptidases of the
chymotrypsin family; tryptase and chymase. These peptidases are situated in the mast cell
lysosomes as fully active enzymes. The exact site of tryptase and chymase activation from
zymogen precursors is not known, but the Golgi apparatus might play a role in that regard.
DPPI, which is particular abundant in mast cells, seems to be the key enzyme responsible for
activation of chymase and tryptase. Moreover, tryptase and chymase are emerging as
important mediators of allergic diseases such as asthma, inflammatory bowel disease and
psoriasis. After secretion from activated mast cells, there is evidence that these peptidases
are heavily involved in processes of inflammation, tissue remodelling, bronchoconstriction
and mucus secretion, which have made these peptidases attractive for therapeutic
intervention.
Neutrophils cause considerable damage in a number of pathological conditions. When
activated, neutrophils secrete destructive granular enzymes including elastase and cathepsin
G and undergo oxidative bursts to release reactive oxygen intermediates. Numerous studies
have been conducted on each of these activating agents in isolation. Pulmonary emphysema,
COPD, cystic fibrosis, sepsis and rheumatoid arthritis are just some examples of pathological
conditions associated with the potent enzymes elastase and cathepsin G.
The strong evidence associating tryptase, chymase, elastase, cathepsin G and other similar
inflammatory peptidases with inflammatory diseases, points out DPPI as an attractive target
enzyme for therapeutic intervention against the above mentioned diseases and other similar
inflammatory diseases, due to its central role in activating these peptidases (Adkison et al.
2002, J. Clin. Invest, 109, 363-271; Pham. et al. 2004, J. Immunol, 173,7277-7281).
WO2012130299 and WO2012119941 to PROZYMEX disclose nitrile compounds and use
thereof as dipeptidyl peptidase inhibitors. WO 2009074829A1 to Astrazeneca also discloses
peptidyl nitriles and use thereof as dipeptidyl peptidase inhibitors. WO 2010128324A1,
WO154677A1 and WO 2010142985A1 to Astrazeneca discloses further nitrile compounds and
use thereof as dipeptidyl peptidase inhibitors WO2013041497A1 to Boehringer Ingelheim
International GMBH discloses nitrile compounds as dipeptidyl peptidase inhibitors. Nathalie
Méthot, Daniel Guay, Joel Rubin, Diane Ethier, Karen Ortega, Simon Wong, Denis Normandin,
Christian Beaulieu, T. Jagadeeswar Reddy, Denis Riendeau, and M. David Percival : In Vivo
Inhibition of Serine protease Processing Requires a High Fractional Inhibition of Cathepsin C,
Mol Pharmacol 73:1857-1865, 2008 disclose dipeptide nitrile cathepsin C inhibitors. Nathalie
Méthot, Joel Rubin, Daniel Guay, Christian Beaulieu, Diane Ethier T. Jagadeeswar Reddy,
Denis Riendeau, and M. David Percival: Inhibition of the Activation of Multiple Serine
proteases with a Cathepsin C Inhibitor Requires Sustained Exposure to Prevent Pro-enzyme
Processing J. Biol. Chem., Vol. 282, Issue 29, 20836-20846, July 20, 2007 disclose dipeptide
nitrile cathepsin C inhibitors. Jon Bondebjerg, Henrik Fuglsang, Kirsten Rosendal Valeur, John
Pedersen and Lars Nærum, Dipeptidyl nitriles as human dipeptidyl peptidase I inhibitors,
Bioorganic & Medicinal Chemistry Letters 16 (2006) 3614-3617 disclose compounds having a
dipeptide nitrile scaffold as inhibitors of human dipeptidyl peptidase I.
OBJECT OF THE INVENTION
It is an object of the invention to provide novel compounds being inhibitors of dipeptidyl
peptidase I, suitable for treatment of inflammatory diseases,cancers and infections. An
additional object is that the compounds are potent in cell-based DPPI inhibition assays, and
have good metabolic stability.
FIGURES
Figure 1. Cytotoxicity results for compound PZ1025 analysed at the 24 hour timepoint (Fig.
1a.) and 48 hour timepoint (Fig. 1b.).
Figure 2. Cytotoxicity results for compound PZ1024 analysed at the 24 hour timepoint (Fig.
2a.) and 48 hour timepoint (Fig. 2b.).
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula (I):
N N R
wherein X represents
wherein y represents 0, 1, 2, 3, 4, 5, 6, 7 or 8
wherein Z represents O (oxygen);
when y is 1 or 2, then R independently represents deuterium; halogen; hydroxyl; cyano;
oxo (=O); mercapto; or C -alkyl; which C -alkyl is optionally substituted with at least one
1-3 1-3
substituent selected from halogen, hydroxyl, cyano and mercapto;
or when y represents 3, 4, 5, 6, 7 or 8, then R represents deuterium;
wherein R represents -C3cycloalkyl, -C1alkyl-C3cycloalkyl or -C1alkyl, which -C1
alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or
amino; and pharmaceutically-acceptable salts, solvates and hydrates thereof.
R may be -C1alkyl, which -C1alkyl is optionally substituted with at least one substituent
selected from hydroxyl, cyano or amino. Suitably, R is -C -alkyl, preferably -C -alkyl,
1-6 1-3
more preferably methyl-, ethyl- or propyl-. Suitably, y = 0 or 1, preferably 0.
The following compound is of particular interest:
The term “DPPI” as used herein is intended to mean dipeptidyl peptidase I (EC 3.4.14.1) also
known as cathepsin C, cathepsin J, dipeptidyl aminopeptidase I and dipeptidyl transferase.
DPPI cleaves a dipeptide Xaa-Xbb from the N terminus of a polypeptide chain Xaa-Xbb-Xcc-
[Xxx] , except when Xaa is Arg or Lys, or when Xbb or Xcc is Pro.
In the formulas, the group –CN is a nitrile group ( ).
The wavy line in depicted substituents as e.g.
is used to indicate the bond, which is connected to the core molecule (formula I) as defined.
In the context of the present specification, unless otherwise stated, an alkyl substituent
group or an alkyl moiety in a substituent group may be linear or branched.
The term “treatment” is defined as the management and care of a patient for the purpose of
combating the disease, condition, or disorder and includes the administration of the
compound of the present invention to prevent the onset of the symptoms or the
complications, or alleviating the symptoms or the complications, or eliminating the disease,
condition, or disorder.
"Half-life" (or "half-lives") refers to the time required for half of a quantity of a substance to
be converted to another chemically distinct specie in vitro or in vivo.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds,
materials, compositions, and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem or complication, and
commensurate with a reasonable benefit/risk ratio.
The compounds according to Formula (I) contain one or more asymmetric centers (also
referred to as a chiral center) and may, therefore, exist as individual enantiomers,
diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers may also
be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral
center present in Formula (I) or in any chemical structure illustrated herein, is not specified
the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus,
compounds according to Formula (I)) containing one or more chiral center may be used as
racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual
stereoisomers.
Individual stereoisomers of a compound according to Formula (I) which contain one or more
asymmetric center may be resolved by methods known to those skilled in the art. For
example, such resolution may be carried out (1) by formation of diastereoisomeric salts,
complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific
reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid
chromatography in a chiral environment, for example, on a chiral support such as silica with
a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate
that where the desired stereoisomer is converted into another chemical entity by one of the
separation procedures described above, a further step is required to liberate the desired
form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using
optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer
to the other by asymmetric transformation. If there is a cycloalkyl group present, some
substituent patterns may result in and axial or an equatorial configuration. Both forms are
included, unless specified otherwise.
All tautomeric forms are also included in Formula (I), whether such tautomers exist in
equilibrium or predominately in one form.
Preferred are the above compounds of formula (I), in their enantiomerically pure form of
formula (II):
N N R
(II)
wherein X and R are as defined above.
The skilled artisan will appreciate that pharmaceutically-acceptable salts of the compounds
according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention,
pharmaceutically-acceptable salts of the compounds according to Formula (I) may be
preferred over the non-salt form because such salts impart greater stability or solubility to
the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is
further directed to pharmaceutically-acceptable salts of the compounds according to Formula
(I).
As used herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the
desired biological activity of the subject compound and exhibit minimal undesired
toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during
the final isolation and purification of the compound, or by separately reacting the purified
compound in its free acid or free base form with a suitable base or acid, respectively.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed
compounds wherein the parent compound is modified by making acid or base salts thereof.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues
such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-
arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol,
diethanolamine (2,2 ′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-
aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine,
magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-
(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2 ′,2 ″-nitrilotris(ethanol)),
tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid,
ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid,
4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphorsulfonic acid, carbonic acid,
cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-
disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid,
ethylenediamonotetraacetic acid, formic acid, fumaric acid, galacaric acid, gentisic acid, D-
glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutantic acid, glutaric
acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid,
hippuric acid, hydrobromic acid, hydrochloric acid isobutyric acid, DL-lactic acid, lactobionic
acid, lauric acid, lysine, maleic acid, ( −)-L-malic acid, malonic acid, DL-mandelic acid,
methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalenesulfonic
acid, 1-hydroxynaphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic
acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid,
( −)-L-pyroglutamic 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 and undecylenic acid. Further pharmaceutically acceptable salts can be formed with
cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc
and the like. (also see Pharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-
19).
The pharmaceutically-acceptable salts of the present invention can be synthesized from the
parent compound which contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or base forms of these
compounds with a sufficient amount of the appropriate base or acid in water or in an organic
diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
Salts of other acids than those mentioned above which for example are useful for purifying or
isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a
part of the invention.
In the solid state, the compound of the invention can exist in crystalline, semi- crystalline
and amorphous forms, as well as mixtures thereof. The skilled artisan will appreciate that
pharmaceutically-acceptable solvates of the compound of the invention may be formed
wherein solvent molecules are incorporated into the solid-state structure during
crystallization. Solvates may involve water or non-aqueous solvents, or mixtures thereof. In
addition, the solvent content of such solvates can vary in response to environment and upon
storage. For example, water may displace another solvent over time depending on relative
humidity and temperature. Solvates wherein water is the solvent that is incorporated into the
solid-state structure are typically referred to as "hydrates." Solvates wherein more than one
solvent is incorporated into the solid-state structure are typically referred to as "mixed
solvates". Solvates include "stoichiometric solvates" as well as compositions containing
variable amounts of solvent (referred to as "non-stoichiometric solvates"). Stoichiometric
solvates wherein water is the solvent that is incorporated into the solid-state structure are
typically referred to as "stoichiometric hydrates", and non-stoichiometric solvates wherein
water is the solvent that is incorporated into the solid-state structure are typically referred to
as "non-stoichiometric hydrates". The invention includes both stoichiometric and non-
stoichiometric solvates.
In addition, crystalline forms of the compounds of the invention, including solvates thereof,
may contain solvent molecules, which are not incorporated into the solid-state structure. For
example, solvent molecules may become trapped in the crystals upon isolation. In addition,
solvent molecules may be retained on the surface of the crystals. The invention includes such
forms.
The compound of the invention may be administered by any suitable route of administration,
including both systemic administration and topical administration. Systemic administration
includes oral administration, parenteral administration, transdermal administration, rectal
administration, and administration by inhalation. Parenteral administration refers to routes of
administration other than enteral, transdermal, or by inhalation, and is typically by injection
or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous
injection or infusion. Inhalation refers to administration into the patient's lungs whether
inhaled through the mouth or through the nasal passages. Topical administration includes
application to the skin as well as intraocular, optic, intravaginal, and intranasal
administration.
The compound of the invention may be administered once or according to a dosing regimen
wherein a number of doses are administered at varying intervals of time for a given period of
time. For example, doses may be administered one, two, three, or four times per day. Doses
may be administered until the desired therapeutic effect is achieved or indefinitely to
maintain the desired therapeutic effect. Suitable dosing regimens for the compound of the
invention depend on the pharmacokinetic properties of that compound, such as absorption,
distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable
dosing regimens, including the amount administered and the duration such regimens are
administered, for the compound of the invention depend on the condition being treated, the
severity of the condition being treated, the age and physical condition of the patient being
treated, the medical history of the patient to be treated, the nature of concurrent therapy,
the particular route of administration chosen, the desired therapeutic effect, and like factors
within the knowledge and expertise of the skilled artisan. It will be further understood by
such skilled artisans that suitable dosing regimens may require adjustment given an
individual patient's response to the dosing regimen or over time as individual patient needs
change. Typical daily dosages range from 1 mg to 1000 mg.
The compound of the invention may be administered as a prodrug. As used herein, a
"prodrug" of the compound of the invention is a functional derivative of the compound which,
upon administration to a patient, eventually liberates the compound of the invention in vivo.
Administration of the compound of the invention as a prodrug may enable the skilled artisan
to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify
the duration of action of the compound in vivo; (c) modify the transportation or distribution
of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome
or overcome a side effect or other difficulty encountered with the compound. Typical
functional derivatives used to prepare prodrugs include modifications of the compound that
are chemically or enzymatically cleaved in vivo. Such modifications, which include the
preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well
known to those skilled in the art.
In both drug discovery and drug development, prodrugs have become an established tool for
improving physicochemical, biopharmaceutical or pharmacokinetic properties of
pharmacologically active agents that overcome barriers to a drug’s usefulness.
Coupling of short peptides or single amino acids as carriers of a therapeutic agent can be
used as an effective type of prodrug approach. In this approach an amino acid or a di- (or
oligo)peptide moiety is linked to a free (primary or secondary) amino group of the drug
through an amide bond, that can be specifically cleaved by an endogenous peptidase, e.g.
dipeptidyl peptidase IV (DPPIV/CD26), dipeptidyl peptidase I (DPPI/cathepsin C),
aminopeptidase N (APN/CD13), pyroglutamyl aminopeptidase, proline iminopeptidase,
aminopeptidase P, elastase, cathepsin G, proteinase 3, tryptase or chymase.
The amino acid or a di- or oligo-peptide moiety can consist of proteinogenic amino acids (i.e.
amino acids that occur naturally in proteins) or non-proteinogenic amino acids (i.e. non-
proteinogenic amino acids that either occur naturally or are chemically synthesized).
In one aspect, the compound disclosed herein is linked via a free (primary or secondary)
amino group to an amino acid or a di- (or oligo)peptide moiety. These prodrugs may be
converted to the desired active compound by a peptidase catalyzed reaction.
The compounds of general formula I may be used on their own or combined with other active
substances of formula I according to the invention. The compounds of general formula I may
optionally also be combined with other pharmacologically active substances. These include,
B2-adrenoceptor-agonists (short and long-acting), anti-cholinergics (short and long-acting),
anti- inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine,
dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7- inhibitors, LTD4
antagonists, EGFR- inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 derivatives,
FPRLl modulators, LTB4-receptor (BLTl, BLT2) antagonists, Histamine HI receptor
antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3 -receptor antagonists,
PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases as for example LYN, LCK,
SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAP kinases as for example p38, ERK1, ERK2, J
K1, J K2, J K3 or SAP, inhibitors of the NF- κΒ signalling pathway as for example IKK2 kinase
inhibitors, iNOS inhibitors, MRP4 inhibitors or leukotriene biosynthese inhibitors.
The compounds disclosed herein will normally, but not necessarily, be formulated into a
pharmaceutical composition prior to administration to a patient. Accordingly, in another
aspect a pharmaceutical composition comprising, as an active substance, the compound as
disclosed herein or a pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable adjuvant, carrier or diluent, is provided.
The pharmaceutical compositions disclosed herein may be prepared and packaged in bulk
form wherein a safe and effective amount of the compound disclosed herein can be extracted
and then given to the patient such as with powders, syrups, and solutions for injection.
Alternatively, the pharmaceutical compositions disclosed herein may be prepared and
packaged in unit dosage form wherein each physically discrete unit contains a safe and
effective amount of the compound as disclosed herein. When prepared in unit dosage form,
the pharmaceutical compositions disclosed herein typically contain from 1 mg to 1000 mg.
The pharmaceutical compositions disclosed herein typically contain one compound as
disclosed herein. However, in certain embodiments, the pharmaceutical compositions of the
invention may optionally further comprise one or more additional pharmaceutically active
compounds. Conversely, the pharmaceutical compositions of the invention typically contain
more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the
pharmaceutical compositions of the invention contain one pharmaceutically-acceptable
excipient.
As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically
acceptable material, composition or vehicle involved in giving form or consistency to the
pharmaceutical composition. Each excipient must be compatible with the other ingredients of
the pharmaceutical composition when commingled such that interactions which would
substantially reduce the efficacy of the compound of the invention when administered to a
patient and interactions which would result in pharmaceutical compositions that are not
pharmaceutically acceptable are avoided. In addition, each excipient must of course be of
sufficiently high purity to render it pharmaceutically-acceptable. The compound of the
invention and the pharmaceutically-acceptable excipient or excipients will typically be
formulated into a dosage form adapted for administration to the patient by the desired route
of administration. For example, dosage forms include those adapted for (1 ) oral
administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers,
suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such
as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal
administration such as transdermal patches; (4) rectal administration such as suppositories;
(5) inhalation such as aerosols and solutions; and (6) topical administration such as creams,
ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular
dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be
chosen for a particular function that they may serve in the composition. For example, certain
pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the
production of uniform dosage forms. Certain pharmaceutically- acceptable excipients may be
chosen for their ability to facilitate the production of stable dosage forms. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the
carrying or transporting the compound of the invention once administered to the patient from
one organ, or portion of the body, to another organ, or portion of the body. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient
compliance.
Suitable pharmaceutically-acceptable excipients include the following types of excipients:
Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating
agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners,
flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants,
chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives,
stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain
pharmaceutically-acceptable excipients may serve more than one function and may serve
alternative functions depending on how much of the excipient is present in the formulation
and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable
pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In
addition, there are a number of resources that are available to the skilled artisan which
describe pharmaceutically-acceptable excipients and may be useful in selecting suitable
pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical
Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower
Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American
Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and
methods known to those skilled in the art. Some of the methods commonly used in the art
are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule
comprising a safe and effective amount of the compound of the invention and a diluent or
filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch
(e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives
(e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral
solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn
starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic
acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline
cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable
disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and
sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant.
Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc. In
another aspect, the invention is directed to a dosage form adapted for administration to a
patient by inhalation. For example, the compound of the invention may be inhaled into the
lungs as a dry powder, an aerosol, a suspension, or a solution.
Dry powder compositions for delivery to the lung by inhalation typically comprise the
compound of the invention as a finely divided powder together with one or more
pharmaceutically-acceptable excipients as finely divided powders. Pharmaceutically-
acceptable excipients particularly suited for use in dry powders are known to those skilled in
the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides.
The dry powder may be administered to the patient via a reservoir dry powder inhaler (RDPI)
having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry
powder form. RDPIs typically include a means for metering each medicament dose from the
reservoir to a delivery position. For example, the metering means may comprise a metering
cup, which is movable from a first position where the cup may be filled with medicament
from the reservoir to a second position where the metered medicament dose is made
available to the patient for inhalation. Alternatively, the dry powder may be presented in
capsules (e.g. gelatin or plastic), cartridges, or blister packs for use in a multi-dose dry
powder inhaler (MDPI). MDPIs are inhalers wherein the medicament is comprised within a
multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof)
of medicament. When the dry powder is presented as a blister pack, it comprises multiple
blisters for containment of the medicament in dry powder form. The blisters are typically
arranged in regular fashion for ease of release of the medicament therefrom. For example,
the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the
blisters may be elongate in form, for example comprising a strip or a tape.
Aerosols may be formed by suspending or dissolving the compound of the invention in a
liquified propellant. Suitable propellants include halocarbons, hydrocarbons, and other
liquified gases. Representative propellants include: trichlorofluoromethane (propellant 11 ),
dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114),
tetrafluoroethane (HFA-134a), 1 ,1-difluoroethane (HFA-152a), difluoromethane (HFA-32),
pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane,
perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols comprising the
compound of the invention will typically be administered to a patient via a metered dose
inhaler (MDI). Such devices are known to those skilled in the art.
The aerosol may contain additional pharmaceutically-acceptable excipients typically used with
MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical
stability of the formulation, to improve valve performance, to improve solubility, or to
improve taste.
Suspensions and solutions comprising the compound of the invention may also be
administered to a patient via a nebulizer. The solvent or suspension agent utilized for
nebulization may be any pharmaceutically-acceptable liquid such as water, aqueous saline,
alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene
glycol, etc. or mixtures thereof. Saline solutions utilize salts which display little or no
pharmacological activity after administration. Both organic salts, such as alkali metal or
ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as
potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid,
acetic acid, tartaric acid, etc. may be used for this purpose.
Other pharmaceutically-acceptable excipients may be added to the suspension or solution.
The compound of the invention may be stabilized by the addition of an inorganic acid, e.g.,
hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid; an organic acid, e.g.,
ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA
or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or
ascorbic acid. These may be used alone or together to stabilize the compound of the
invention. Preservatives may be added such as benzalkonium chloride or benzoic acid and
salts thereof. Surfactant may be added particularly to improve the physical stability of
suspensions. These include lecithin, disodium dioctylsulphosuccinate, oleic acid and sorbitan
esters.
The compounds according to Formula I are prepared using conventional organic syntheses.
Suitable synthetic routes are depicted below in the following general reaction schemes.
Starting materials and reagents depicted below in the general reaction schemes are
commercially available or can be made from commercially available starting materials using
methods known by those skilled in the art.
The compounds disclosed herein may be converted to a pharmaceutically acceptable salt
thereof, preferably an acid addition salt such as a hydrochloride, hydro bromide,
trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate,
pyruvate, succinate, oxalate, methane sulphonate or p-toluenesulphonate. The compound of
formula (1) and pharmaceutically acceptable salts thereof may exist in solvated, for example
hydrated, as well as unsolvated forms, and the present invention encompasses all such
solvated forms. In a further aspect, the compound disclosed herein is in the form of a
pharmaceutically acceptable salt thereof.
In a further aspect, the compounds disclosed herein are for use in medicine such as for use
as a dipeptidyl peptidase I (DPPI) inhibitor. In one aspect, they have activity as
pharmaceuticals, in particular as inhibitors of dipeptidyl peptidase I activity, and thus may be
used in the treatment of:
Obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic,
extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-
induced asthma, both intermittent and persistent and of all severities, and other causes of
airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); acute lung
injury; acute respiratory distress syndrome; bronchitis, including infectious and eosinophilic
bronchitis; emphysema; bronchiectasis; cystic fibrosis; alpha-1 antitrypsin deficiency;
sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis,
including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis
complicating anti-neoplastic therapy and chronic infection, including tuberculosis and
aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and
thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive
activity including treatment of chronic cough associated with inflammatory and secretory
conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis
medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including
rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold,
and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and
adenovirus; psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses,
and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic
dermatitis; dermatitis herpetiformis, lichen planus; lichen sclerosus et atrophica; pyoderma
gangrenosum; skin sarcoid; discoid lupus erythematosus; pemphigus; pemphigoid;
epidermolysis bullosa; urticaria; angioedema; vasculitides; toxic erythemas; cutaneous
eosinophilias; alopecia areata; male-pattern baldness; Sweet's syndrome; Weber-Christian
syndrome; erythema multiforme; cellulitis, both infective and non-infective; panniculitis;
cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced
disorders including fixed drug eruptions; blepharitis; conjunctivitis, including perennial and
vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune,
degenerative or inflammatory disorders affecting the retina; ophthalmitis including
sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial; sepsis;
nephritis including interstitial and glomerulonephritis; nephritic syndrome; cystitis including
acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis,
prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease;
erectile dysfunction (both male and female); acute and chronic implications following, for
example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or
following blood transfusion; or chronic graft versus host disease; rheumatoid arthritis;
irritable bowel syndrome; inflammatory bowel disease; gout; pseudogout; Alzheimer’s
disease; systemic lupus erythematosus; multiple sclerosis; Hashimoto's thyroiditis; Graves'
disease; Addison's disease; diabetes mellitus, including type-1 diabetes mellitus; idiopathic
thrombocytopaenic purpura; eosinophilic fasciitis; hyper-1gE syndrome; antiphospholipid
syndrome and Sazary syndrome; cancers with neutrophil involvement; treatment of common
cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin
and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and
lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the
prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic
syndromes; virus diseases such as genital warts, common warts, plantar warts, hepatitis B,
hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency
virus (H1V), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus
(VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such
as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as
malaria, fungal diseases, chlamydia, candida, aspergillus, cryptococcal meningitis,
pneumocystis camii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection
and leishmaniasis; congestive heart failure; atherosclerosis; coronary artery disease;
myocardial infarction; reperfusion injury; abdominal aortic aneurysms (AAA); diabetic
cardiomyopathy (DCM); hypertension; peripheral artery disease; cardiac arrhythmia; stroke
and cardiomegaly.
In a further aspect, the compounds disclosed herein are for use as a dipeptidyl peptidase I
inhibitor.
In a further aspect, the compounds or pharmaceutical compositions disclosed herein are for
use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis,
alpha-1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome,
congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal
aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus
infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis,
malaria, Alzheimer’s disease or sepsis.
In a further aspect, the compounds or pharmaceutical compositions disclosed herein are for
use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis,
alpha-1 antitrypsin deficiency, acute lung injury; acute respiratory distress syndrome,
congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic
aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection,
inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis or sepsis.
In yet a further aspect, the compounds or pharmaceutical compositions disclosed herein are
for use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic
fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction,
reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout,
respiratory syncytial virus infection, rheumatoid arthritis or sepsis.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with
the compound employed, the mode of administration, the treatment desired and the disorder
indicated.
In a further aspect, the pharmaceutical composition in unit dosage form, comprises from
about 1 g to about 1000 mg such as, e.g., from about 10 g to about 500 mg, from about
0.05 to about 100 mg or from about 0.1 to about 50 mg, of the active substance.
In yet a further aspect, disclosed herein is a compound which 24 hours after a single
subcutaneous animal dosing at a concentration of 10 µmol/kg, has a concentration in bone
marrow of 250 nM or more, such as 500 nM or, 750 nM or more or 1000 nM or more.
In yet a further aspect, disclosed herein is a compound which 12 hours after a single
subcutaneous animal dosing at a concentration of 10 µmol/kg, has a concentration in bone
marrow of 1000 nM or more, such as 1500 nM or more, 2000 nM or more, 3000 nM or more,
or 5000 nM or more.
In a further aspect, the pharmaceutical composition disclosed herein is for oral, nasal,
transdermal, pulmonal or parenteral administration.
In one aspect, a method of treating an obstructive airways disease in a patient suffering
from, or at risk of, said disease, which comprises administering to the patient a
therapeutically effective amount of the compound of formula (I) or a pharmaceutically
acceptable salt thereof, is provided herein.
In one aspect, a method for the treatment of ailments, the method comprising administering
to a subject in need thereof an effective amount of the compound as disclosed herein or of a
composition as disclosed herein, is provided.
In a further aspect, an effective amount of the compound as disclosed herein is in a range of
from about 1 g to about 1000 mg such as, e.g., from about 10 g to about 500 mg, from
about 0.05 to about 100 mg or from about 0.1 to about 50 mg per day.
In one aspect, the use of the compound or pharmaceutical composition as disclosed herein
for the preparation of a medicament, is provided.
In one aspect, the use of the compound, a pharmaceutically acceptable salt thereof or
pharmaceutical composition as disclosed herein for the preparation of a medicament for
treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-
1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive
heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic
aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection,
inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria,
Alzheimer’s disease or sepsis, is provided.
In one aspect, the use of the compound, a pharmaceutically acceptable salt thereof or
pharmaceutical composition as disclosed herein in the manufacture of a medicament for
treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-
1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive
heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic
cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel
diseases, psoriasis, rheumatoid arthritis, multiple sclerosis or sepsis, is provided.
In one aspect, the use of the compound, a pharmaceutically acceptable salt thereof or
pharmaceutical composition as disclosed herein in the manufacture of a medicament for
treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-
1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury,
abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory
syncytial virus infection, rheumatoid arthritis or sepsis is provided.
In one aspect, a method for modulating DPPI levels in a subject in need thereof comprising
administering to said subject an amount of the compound or a pharmaceutically acceptable
salt thereof as disclosed herein or a composition as disclosed herein in an amount effective to
modulate said DPPI levels in said subject, is provided.
In one aspect, said DPPI is inhibited.
In one aspect, a combination of the compound or a pharmaceutically acceptable salt thereof
as disclosed herein and one or more agents independently selected from: a non-steroidal
glucocorticoid receptor agonist; a selective β2 adrenoceptor agonist; a phosphodiesterase
inhibitor; a peptidase inhibitor; a glucocorticoid; an anticholinergic agent; a modulator of
chemokine receptor function; and an inhibitor of kinase function, is provided.
In another aspect, a method for treatment of a medical condition selected from the group
selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis,
alpha-1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome,
congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal
aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus
infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis,
malaria, Alzheimer’s disease or sepsis, is provided, said method comprising administration of
a pharmaceutically effective amount of a compound of formula (I) or the composition
according to the invention. Suitably, in this method, the medical condition is selected from
the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis,
cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction,
reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout,
respiratory syncytial virus infection, rheumatoid arthritis or sepsis.
The invention relates to the following numbered aspects:
Aspect 1: A compound of the formula (I)
N N R
wherein X represents
wherein y represents 0, 1, 2, 3, 4, 5, 6, 7 or 8;
wherein Z represents O (oxygen);
when y is 1 or 2, then R independently represents deuterium; halogen; hydroxyl; cyano;
oxo (=O); mercapto; or C1alkyl; which C1alkyl is optionally substituted with at least one
substituent selected from halogen, hydroxyl, cyano and mercapto;
or when y represents 3, 4, 5, 6, 7 or 8, then R represents deuterium;
wherein R represents -C3cycloalkyl, -C1alkyl-C3cycloalkyl or -C1alkyl, which -C1
alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or
amino as well as pharmaceutically-acceptable salts, solvates and hydrates thereof.
Aspect 2: The compound according to aspect 1, wherein R is -C1alkyl, which -C1alkyl is
optionally substituted with at least one substituent selected from hydroxyl, cyano or amino.
Aspect 3: The compound according to any one of the preceding aspects, wherein R is -C -
alkyl, preferably -C1alkyl, more preferably methyl-, ethyl- or propyl-.
Aspect 4: The compound according to any one of the preceding aspects, wherein y = 0 or 1,
preferably 0.
Aspect 5: The compound according to any one of the preceding aspects, being:
Aspect 6: The compound according to any one of the preceding aspects, in the
enantiomerically pure form of formula (II):
N N R
(II)
wherein X and R are as defined in any one of the preceding aspects.
Aspect 7: A pharmaceutical composition comprising a compound of the formula (I) according
to any one of aspects 1-6, or a pharmaceutically acceptable salt thereof, together with at
least one pharmaceutically-acceptable adjuvant, carrier or diluent.
Aspect 8: The compound according to any one of aspects 1-6 or composition according to
aspect 7 for use as a medicament.
Aspect 9: A compound according to any one of aspects 1-6 or composition according to
aspect 7 for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic
fibrosis, alpha-1 antitrypsin deficiency,, acute lung injury, acute respiratory distress
syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury,
abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory
syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis,
multiple sclerosis, malaria, Alzheimer’s disease or sepsis.
Aspect 10: A compound according to any one of aspects 1-6 or composition according to
aspect 7 for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic
fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction,
reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout,
respiratory syncytial virus infection, rheumatoid arthritis or sepsis.
Aspect 12: A method for treatment of a medical condition selected from the group selected
from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1
antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive
heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic
aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection,
inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria,
Alzheimer’s disease or sepsis, said method comprising administration of a pharmaceutically
effective amount of a compound of formula (I) according to any one of aspects 1-6 or
composition according to aspect 7.
Aspect 12: The method according to aspect 11, wherein the medical condition is selected
from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis,
cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction,
reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout,
respiratory syncytial virus infection, rheumatoid arthritis or sepsis.
Aspect 13: Use of a compound of formula (I) according to any one of aspects 1-6 or
composition according to aspect 7 for the manufacture of a medicament for the treatment of
asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1
antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive
heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic
aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection,
inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria,
Alzheimer’s disease or sepsis.
Aspect 14: Use according to aspect 13, wherein the medicament is for the treatment of
asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1
antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury,
abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory
syncytial virus infection, rheumatoid arthritis or sepsis.
MATERIALS AND METHODS
Cell based DPPI inhibition assay
The herein described compounds are DPPI inhibitors, which indirectly inhibit the activity of
serine peptidases that are activated by DPPI, such as elastase. Using the cell based assay
described below, the biological activity of the compounds of the invention or other DPPI
inhibitors may be determined.
Neutrophil elastase enzymatic activities in U937 cells grown in the presence of DPPI
inhibitors were measured by methods modified from Méthot N; Rubin J; Guay D; Beaulieu C;
Ethier D; Reddy TJ; Riendeau D and Percival MD (2007) J Biol Chem, 282, 20836-20846.
U937 cells were propagated in culture media (RPMI 1640, supplemented with 10% FBS, 10
mM Hepes, 1 mM sodium pyrovate, 100 units/ml of each of penicillin and streptomycin). Cells
were seeded in 12-well plates at 0.4 x 10 cells/ml in volumes of 1.5 ml per well in the
presence of no or increasing concentrations of DPPI inhibitor. 12 points in duplicate in the
range of 0.1 nM to 50 µM inhibitor were tested. After 24 hours cells were harvested, washed
with PBS and lysed in 20 mM Tris-HCl, pH 7.5, 100 mM NaCl, 0.2% Triton X-100. Debris was
removed by centrifugation and supernatants were retained. The extracts were mixed with
assay buffer (50 mM Tris, 0.1% Triton X-100, 0.5 M NaCl, pH 8.0) supplemented with
substrate (MetOSuc-Ala-Ala-Pro-Val-pNA; Bachem; Cat. No. L-1335) to a final concentration
of 0.9 mM.
The activity of neutrophil elastase was determined by measuring the enzymatic release of
chromogenic p-nitroaniline from the substrate MetOSuc-Ala-Ala-Pro-Val-pNA, which leads to
an increase in absorbance at 405 nm. Assays were carried out in 96-well plates in a final
volume of 200 µL at 37°C, and absorbance was measured 8 times during 21-35 minutes
using a plate reader. IC was determined using a 4-parameter logistic equation in a non-
linear curve fitting routine.
Human DPPI inhibition assay
Using this assay, the IC value of the compound of the invention may be determined using
Gly-Phe-paranitroanilide as a DPPI specific substrate.
Assay buffer: 20 mM citric acid (2.1 g citric acid), 150 mM NaCl (4.4 g NaCl) and 2 mM EDTA
(370 mg EDTA) was dissolved in 500 mL H2O, and pH was adjusted to 4.5 with HCl.
Substrate: Gly-Phe-paranitroanilide (Sigma Aldrich; Cat. No G0142) was used as the
substrate for determination of IC50 values. Km was 2.2 mM. The substrate was solubilized in
dimethylformamid to give a 0.2-0.5 M stock solution, which was then further diluted with
stirring in assay buffer to a final concentration of 1 mM.
DPPI: Human DPPI (obtained from UNIZYME Laboratories A/S, DK-2970 Hørsholm, Denmark)
was stored at –20 ºC in a buffer containing 2.5 mM Na-phosphate, 150 mM NaCl, 2 mM
cysteamine, 50% glycerol, pH 7.0 at a concentration of 1-2 mg/mL (5-10 µM). This stock
solution was diluted 500-1000 times in assay buffer to a concentration of 10-20 nM.
Assay conditions: The assay was performed in 96-well plates. Diluted enzyme (25 μL) was
added to the well, followed by 25 µL of test substance in varying concentrations, and the
solution was mixed. The plate was incubated at 37 ºC for 5 minutes, followed by addition of
150 μL of 1 mM substrate prewarmed to 37 ºC (corresponding to a substrate concentration of
750 μM in the assay). The absorption was measured at 405 nm at 37 ºC for every 90
seconds for 12 minutes or every 20 seconds for 4 minutes. Each measurement was made in
duplicate. IC50 was determined using a 4-parameter logistic equation in a non-linear curve
fitting routine.
Test for metabolic stability
The test for metabolic stability was performed by Absorption System, Exton, PA 19341, USA.
The test compound (DPPI inhibitor) was dissolved in 100% DMSO at a concentration of 10
mM. The reaction mixture, consisted of Mouse or Human Liver Microsomes (1.0 mg/mL), 1
mM NADPH, 100 mM Potassium Phosphate, pH 7.4, 10 mM Magnesium Chloride and test
compound at a concentration of 5 μM.
An aliquot of the reaction mixture (without cofactors) was incubated in a shaking water bath
at 37 °C for 3 minutes. Another aliquot of the reaction mixture was prepared as the negative
control. The test compound was added into both the reaction mixture and the negative
control at a final concentration of 5 μM.
The reaction was initiated by the addition of NADPH to 1 mM (not into the negative controls)
and then incubated in a shaking water bath at 37 °C. Aliquots (100 μL) were withdrawn at 0,
, 20, 30, and 60 minutes or at 0, 15, 30 and 60 minutes and combined with 900 μL of ice-
cold 50/50 acetonitrile/dH O to terminate the reaction. A control (testosterone) was run
simultaneously with the test compound in a separate reaction. LC/MS/MS is used to
determine the peak area response ratio (peak area corresponding to test compound or
control divided by that of an analytical internal standard). The natural log of the percent
remaining was plotted versus time. A linear fit was used to determine the rate constant. The
fit was truncated if the percent remaining of test compound was less than 10%. The
elimination half-lives associated with the disappearance of the test and control compounds
were determined to compare their relative metabolic stability.
Test for inhibition of CYP2C9, CYP2D6 and CYP3A4 enzymes
The test for inhibition of CYP2C9, CYP2D6 and CYP3A4 enzymes was performed by Absorption
System, Exton, PA 19341, USA according to the procedure described below.
The IC50 values of Example 1 of WO2012119941 (PZ1024) and the compound of the present
invention (PZ1025) for CYP enzymes (CYP2C9, CYP2D6, and CYP3A4) in Human Liver
Microsomes were measured. The test compounds, at eight concentration levels (0, 0.137,
0.412, 1.23, 3.70, 11.1, 33.3 and 100 μM), were incubated with pooled Human Liver
Microsomes (0.25 mg protein/mL) at 37ºC in the presence of phosphate buffer (100 mM, pH
7.4), MgCl2 (5 mM), NADPH (1 mM), and CYP-specific probe substrate at approximately Km
(6 μM diclofenac, 7 μM bufuralol and 75 µM testosterone for CYP2C9, CYP2D6, and CYP3A4,
respectively). After a period of incubation, the samples were treated by the addition of
protein precipitation solvent and centrifuged. CYP enzyme activities were measured by
determining the formation of the CYP probe metabolites by LC-MS/MS, and the IC50 (the
concentration of an inhibitor causing 50% inhibition) was estimated using GraphPad Prism®
software by fitting the experimental data (percent of control activity remaining at each
concentration of test compound) to a sigmoidal model and non-linear regression analysis.
The CYP enzyme activities in the Human Liver Microsomes were verified in parallel by
determining the inhibition of positive inhibitors on the CYP enzyme activities (sulfaphenazole,
quinidine and ketoconazole for CYP2C9, CYP2D6, and CYP3A4, respectively). All CYP enzymes
showed expected inhibitions by positive inhibitors, indicating that the human liver
microsomes used in this study were metabolically active and responsive.
Test for cytotoxicity
The test for cytotoxicity was performed by Cyprotex Discovery Ltd.15 Beech lane,
Macclesfield, Cheshire, SK10 2DR, UK.
Two strains of cultured human lymphoblastoid TK6 cells was used, GenM-T01 and GenM-
C01. A dilution series of each test compound was generated in a 96-well, black
microplate with an optically clear base. The plates was analysed at 24 hour and 48 hour
time points using a microplate reader, that provides measurements of light absorbance
for cells and solutions in the microplates wells.
Cytotoxicity was assessed using relative cell proliferation, quantified using optical
absorbance. Cytotoxic compounds are those which reduce relative cell density below a
significance threshold set at 80% compared to the vehicle-treated control, at one or
more test concentrations.
EXAMPLE 1. (S)amino-N-(1-cyano(4'-((4-methylpiperazin
yl)methyl)biphenylyl)ethyl)tetrahydro-2H-pyrancarboxamide (PZ1025)
PZ1025
Synthetic scheme
Procedure
(S)-tert-Butyl 1-amino(4-bromophenyl)oxopropanylcarbamate (1)
A solution of (S)(4-bromophenyl)(tert-butoxycarbonylamino)propanoic acid (20.0 g,
58.3 mol) in DCM (400 mL) was cooled in an ice-water bath and DMTMM (24.2 g, 87.5 mol)
was added. The mixture was stirred at 0 C for 1 h before addition of 25% NH3-H2O (6 g, 87.5
mol). The reaction mixture was allowed to warm to room temperature and stirred for 12 h.
The mixture was extracted with ethyl acetate three times and the combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford compound
1 (19.0 g, yield 95%) as a white solid.
(S)-tert-Butyl 2-(4-bromophenyl)cyanoethylcarbamate (2)
A solution of compound 1 (14.73 g, 43 mmol) in anhydrous pyridine (150 mL) was cooled in
an ice-water batch and POCl3 (8 mL, 77.4 mmol) was added dropwise over 30 min. The
reaction mixture was stirred at 0 C for 2 h and then allowed to warm to room temperature
and stirred overnight. The mixture was treated with ice-water and extracted with ethyl
acetate. The combined organic layers were washed with 1 M HCl solution, saturated aqueous
NaHCO and brine, respectively. The organic layer was dried over anhydrous Na SO and
3 2 4
concentrated. The residue was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc = 50:1 to 10:1) to give compound 2 (9.67 g, yield 69.3%) as a
white solid.
1-(4-Bromobenzyl)methylpiperazine (3)
1-Methylpiperazine (37.4 g, 0.374 mol) was added dropwise to a mixture of 1-bromo
(bromomethyl)benzene (78.0 g, 0.312 mol) and K CO (86.1 g, 0.624 mol) in DMF (400 mL)
and the reaction mixture was stirred for 4 h at room temperature. The mixture was poured
into water (1500 mL) and then extracted with EtOAc three times. The combined extracts
were washed with brine, dried over anhydrous Na2SO4 and concentrated to give compound 3
(50.0 g, yield 59.5%) as a yellow oil.
Methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzyl)piperazine (4)
To a stirred solution of compound 3 (35.0 g, 130 mmol) in 1,4-dioxane (500 mL) at room
temperature were added potassium acetate (38.3 g, 390 mmol) and pinacolatodiboron (33.0
g, 130 mmol). The mixture was evacuated and refilled with nitrogen (three times).
Pd(dppf)Cl2 (3.0 g, 1.3 mmol) was added and the reaction mixture was stirred at 110 C
under nitrogen for 12 h. The mixture was cooled to room temperature and the solid was
filtered off. The filtrate was concentrated and the residue was diluted with ethyl acetate and
water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue
was purified by flash column chromatography on silica gel (DCM/MeOH = 50:1 to 10:1) to
give compound 4 (37.0 g, yield 90%) as a brown solid.
(S)-tert-Butyl 1-cyano(4'-((4-methylpiperazinyl)methyl)biphenylyl) ethyl
carbamate (5)
To a stirred solution of compound 4 (5.0 g, 15.4 mmol) and compound 2 (4.4 g, 14.0 mmol)
in 1,4-dioxane (200 mL) at room temperature was added sodium carbonate (3.7 g, 35
mmol). The mixture was evacuated and refilled with nitrogen (three times). Pd(dppf)Cl (0.5
g, 0.22 mmol) was added and the reaction mixture was stirred at 90 C under nitrogen for 12
h. The mixture was cooled to room temperature and the solid was filtered off. The filtrate was
concentrated and the residue was diluted with ethyl acetate and water. The organic layer was
dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column
chromatography on silica gel (DCM/MeOH = 50:1 to 10:1) to afford compound 5 (3.4 g, yield
50.7%) as a brown solid.
(S)Amino(4'-((4-methylpiperazinyl)methyl)biphenylyl)propanenitrile
Compound 5 (1.0 g, 2.3 mmol) was dissolved in 88% HCOOH (20 mL) and the reaction
mixture was stirred at room temperature for 12 h. Saturated aqueous NaHCO was added
dropwise and the resulting mixture was extracted with DCM. The combined organic layers
were washed with brine, dried over anhydrous Na SO and concentrated. The residue was
purified by flash column chromatography on silica gel (DCM/MeOH = 100:1 to 20:1) to afford
compound 6 (300 mg, yield 38%) as a white solid.
4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyrancarboxylic acid (7)
To a suspension of dihydro-2H-pyran-4(3H)-one (5.0 g, 50 mmol) and (NH ) CO (24.5 g,
4 2 3
255 mmol) in ethanol/water (1:1, 100 mL) was added sodium cyanide (2.5 g, 51 mmol). The
reaction mixture was heated at 50 C for 12 h and then heated to 80 C to decompose an
excess of (NH ) CO Ethanol was removed and sodium hydroxide (8.16 g, 0.76 mmol) was
4 2 3.
added. The reaction mixture was refluxed overnight and then cooled to room temperature.
The mixture was adjusted to pH=10 with 2 N HCl solution and Boc2O (11.1 g, 51 mmol) and
acetonitrile (50 mL) were added. The reaction mixture was stirred overnight at room
temperature and ethyl acetate was added. The resulting mixture was adjusted to pH=3-4
with 2 N HCl solution carefully and the organic layer was separated and concentrated. The
residue was purified by flash column chromatography on silica gel (DCM/MeOH = 100:1) to
afford compound 7 (3.0 g, yield 24% over three steps) as a white solid.
Boc-(S)amino-N-(1-cyano(4'-((4-methylpiperazinyl) methyl)
biphenylyl)ethyl)tetrahydro-2H-pyrancarboxamide (Boc-PZ1025)
To a solution of compound 6 (4.5 g, 13.51 mmol) in DCM (90 mL) in an ice-water bath was
added DMTMM (7.5 g, 27 mmol). The mixture was stirred at 0 C for 0.5 h and compound 7
(4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyrancarboxylic acid; 4.0 g, 16.22 mmol)
was added. The reaction mixture was allowed to warm to room temperature and stirred for
12 h. The mixture was extracted with EtOAc three times and the combined organic layers
were washed with brine, dried over anhydrous Na SO and concentrated. The residue was
purified by flash column chromatography on silica gel (DCM/MeOH = 20:1) to afford
compound Boc-PZ1025 (6.3 g, yield 83.1%) as a light yellow solid.
(S)amino-N-(1-cyano(4'-((4-methylpiperazinyl) methyl)
biphenylyl)ethyl)tetrahydro-2H-pyrancarboxamide (PZ1025)
A solution of Boc-PZ1025 (8.5 g, 15.16 mmol) in 88% HCOOH (150 ml) was stirred for 3 h
at room temperature. The mixture was poured into saturated aqueous NaOH (200 mL) and
the resulting mixture was extracted with DCM twice. The organic layers were combined,
washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified
by flash column chromatography on silica gel (DCM/MeOH = 40:1 to 20:1) to afford
compound PZ1025 (3.9 g, 55.9% yield) as a white solid. H NMR (300 MHz, CDCl ): δ 8.25
(d, 1H, J = 9.0 Hz), 7.61-7.53 (m, 4H), 7.42-7.33 (m, 4H), 5.14 (m, 1H), 3.95-3.85 (m, 2H),
3.67-3.62 (m, 2H), 3.60- 3.57 (m, 2H), 3.16 (d, J = 6.9 Hz, 2H), 2.56 (m, 8H), 2.35 (s, 3H),
2.32-2.18 (m, 2H), 1.33 (m, 1H), 1.21 (m, 1H); MS (ESI): m/z 446.4 [M+H] .
PZ1025 was found to have an IC50 of ≈ 11 nM in the cell based DPPI inhibition assay and a
half-life in human liver microsomes of more than 300 minutes. The combination of a good
potency in a cell based DPPI inhibition assay and a good metabolic stability is particularly
relevant in relation to achieve a pharmacological effect of a DPPI inhibitor during therapy in
humans, as pharmacokinetic studies (see reference) have shown, that in vivo inhibition of
elastase and cathepsin G require a high fractional and sustained level of DPPI inhibition,
probably as high as 90% or more.
Reference. Méthot N, Guay D, Rubin J, Ethier D, Ortega K, Wong S, Normandin D, Beaulieu
C, Reddy TJ, Riendeau D, Percival MD. In vivo inhibition of serine protease processing
requires a high fractional inhibition of cathepsin C. Mol Pharmacol. 2008 Jun;73(6):1857-65.
COMPARATIVE EXAMPLES
COMPARATIVE EXAMPLE A: Comparison with WO2012119941
Table 1 below compares PZ1025 (Example 1) and Example 1 of WO2012119941. The
difference between Example 1 of WO2012119941 (PZ1024) and the compound of the present
invention (PZ1025) is the oxygen in PZ1025 vs. the carbon in PZ1024. As shown in the table,
the potency of PZ1025 and PZ1024 (Example 1 of WO2012119941) is nearly the same.
Metabolic stability Metabolic stability
CYP inhibition
IC50
Structure human mouse
microsomes microsomes IC50 µM
PZ1025
CYP2C9: > 100
NCN 34 t½ > 300 min t½ ≈ 65 min CYP2D6: > 100
CYP3A4: > 100
CYP2C9: > 100
37 t½ ≈ 55 min t½ ≈ 10 min CYP2D6: 18
CYP3A4: > 100
Example 1 of
WO2012119941
(PZ1024)
Table 1
Table 1 also shows the metabolic stability of PZ1025 and PZ1024 (Example 1 of
WO2012119941) in human and mouse liver microsomes. The metabolic stability was
determined as measured by the elimination half-lives (t½). The half-life of PZ1024 in human
liver microsomes is ≈ 55 minutes, however the half-life of PZ1025 in human liver microsomes
is more than 5 times higher (> 300 minutes). The half-life of PZ1024 in mouse liver
microsomes is ≈ 10 minutes, however the half-life of PZ1025 in mouse liver microsomes is
more than 6 times higher ( ≈ 65 minutes).
The higher metabolic stability of PZ1025 (a compound of the present invention) is very
beneficial, as the improved metabolic stability will increase the bioavailabity of PZ1025 as
compared to the bioavailability of PZ1024. This is particularly relevant in relation to achieve a
pharmacological effect of a DPPI inhibitor in both animal studies and during therapy in
humans, as pharmacokinetic studies (see reference) have shown, that in vivo inhibition of
elastase and cathepsin G require a high fractional and sustained level of DPPI inhibition,
probably as high as 90% or more.
Table 1 also shows the selectivity of PZ1025 and PZ1024 (Example 1 of WO2012119941)
with respect to CYP2C9, CYP2D6 and CYP3A4, which are some of the most important
metabolizing CYP enzymes. Both PZ1025 and PZ1024 have a satisfactory selectivity (> 100
µM) over CYP2C9 and CYP3A4, but only PZ1025 have a satisfactory selectivity (> 100 µM)
over CYP2D6.
Reference. Méthot N, Guay D, Rubin J, Ethier D, Ortega K, Wong S, Normandin D, Beaulieu
C, Reddy TJ, Riendeau D, Percival MD. In vivo inhibition of serine protease processing
requires a high fractional inhibition of cathepsin C. Mol Pharmacol. 2008 Jun;73(6):1857-65.
COMPARATIVE EXAMPLE B: Comparison with WO2012119941
Figures 1 and 2 compare PZ1025 (Example 1) and Example 1 of WO2012119941 (PZ1024)
with respect to cytotoxicity. Figure 1 shows compound PZ1025 analysed at the 24 hour
timepoint (Fig. 1a.) and 48 hour timepoint (Fig. 1b.). Figure 2 shows cytotoxicity results for
compound PZ1024 analysed at the 24 hour timepoint (Fig. 2a.) and 48 hour timepoint (Fig.
2b.). Horizontal axis in each case is M.
The highest concentration (µM) that does not cross the significance threshold is 150 µM for
PZ1025 and 15 µM for PZ1024. It can therefore be concluded that PZ1025 is at least 5 times
less toxic than PZ1024.
COMPARATIVE EXAMPLE C: Comparison with WO2010128324
Table 2 below compares PZ1025 (Example 1) and Example 29 of WO2010128324. Example
29 of WO2010128324 (PZ1032) differs from the compound of the present invention (PZ1025)
in the sulfonyl, instead of the methylene, bridging moiety between the phenyl and the
piperazinyl ring (se structures in Table 2 below). As shown in Table 2, the potency of PZ1025
and PZ1032 measured in the cell based DPPI inhibition assay is essential the same.
Cell based DPPI Metabolic Metabolic
Structure inhibition assay stability - stability
IC50 Human MS Mouse MS
≈ 11 nM t½ > 300 min t½ ≈ 65 min
PZ1025
≈ 11 nM t½ ≈ 50 min t½ ≈ 35 min
Example 29 of WO2010128324
(PZ1032)
Table 2
Table 2 also shows the metabolic stability of PZ1025 and PZ1032 (Example 29 of
WO2010128324) in human and mouse liver microsomes (MS). The metabolic stability were
determined as measured by the elimination Half-Lives (t½). The Half-Life of PZ1032 in
human liver microsomes is ≈ 50 minutes, however the Half-Life of PZ1025 in human liver
microsomes is more than 5 times higher (> 300 minutes). The Half-Life of PZ1032 in mouse
liver microsomes is ≈ 35 minutes, however the Half-Life of PZ1025 in mouse liver
microsomes is about 2 times higher ( ≈ 65 minutes).
The higher metabolic stability of PZ1025 (a compound of the present invention) is very
beneficial, as the improved metabolic stability will increase the bioavailabity of PZ1025 as
compared to the bioavailability of PZ1032. This is particularly relevant when attempting to
achieve a pharmacological effect of a DPPI inhibitor in both animal studies and during therapy
in humans, as pharmacokinetic studies (see reference) have shown that in vivo inhibition of
elastase and cathepsin G require a high fractional and sustained level of DPPI inhibition,
probably as high as 90% or more.
Reference.
Méthot N, Guay D, Rubin J, Ethier D, Ortega K, Wong S, Normandin D, Beaulieu C, Reddy TJ,
Riendeau D, Percival MD. In vivo inhibition of serine protease processing requires a high
fractional inhibition of cathepsin C. Mol Pharmacol. 2008 Jun;73(6):1857-65.
COMPARATIVE EXAMPLE D: Structural comparison with WO2012119941
The compounds of the present invention are inter alia characterized by a tetrahydro-pyranyl
ring adjacent to the carboxamide moiety. illustrates different structures
comprising a bridged or fused oxygen-containing saturated ring system adjacent to the
carboxamide moiety (cf. the fourth compound on page 57 and the fifth compound on page
58). No synthetic routes have been made available for these two compounds, and thus no
biological tests have been carried out.
The tetrahydro-pyranyl ring represents a flexible structure known to adapt to various three-
dimensional conformations. In contrast hereto, each of the two particular compounds of WO
2012/119941 represent structures wherein the bridging or fusing of the ring(s) hinder the
conformational flexibility. This means that such bridged or fused oxygen-containing saturated
ring systems have significantly different steric properties compared to a tetrahydro-pyranyl
ring.
Claims (9)
1. A compound of the formula (I) N N R wherein X represents wherein y represents 0, 1, 2, 3, 4, 5, 6, 7 or 8; 10 wherein Z represents O (oxygen); when y is 1 or 2, then R independently represents deuterium; halogen; hydroxyl; cyano; oxo (=O); mercapto; or C1alkyl; which C1alkyl is optionally substituted with at least one of the following substituents: halogen, hydroxyl, cyano, or mercapto; or when y represents 3, 4, 5, 6, 7 or 8, then R represents deuterium; 15 wherein R represents -C3cycloalkyl, -C1alkyl-C3cycloalkyl or -C1alkyl, which -C1 alkyl is optionally substituted with at least one of the following substituents:hydroxyl, cyano or amino; or a pharmaceutically-acceptable salt thereof.
2. The compound according to claim 1, being:
3. The compound according to claim 1, wherein R is -C -alkyl, which -C -alkyl is 1-6 1-6 5 optionally substituted with at least one of the following substituents: hydroxyl, cyano or amino.
4. The compound according to any one of claims 1 or 3, wherein R is -C1alkyl, preferably -C -alkyl, more preferably methyl-, ethyl- or propyl-.
5. The compound according to any one of claims 1, 3 or 4, wherein y represents 0, 1, 2, 10 3 or 4, such as e.g. 0 or 1, preferably 0.
6. A pharmaceutical composition comprising a compound of the formula (I) according to any one of claims 1-5; or a pharmaceutically-acceptable salt thereof, together with at least one pharmaceutically-acceptable adjuvant, carrier or diluent.
7. A pharmaceutical composition according to claim 6 comprising a compound of the 15 formula: or a pharmaceutically-acceptable salt thereof.
8. Use of a compound of formula (I) according to any one of claims 1-5 or a composition according to any one of claims 6-7 for the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive 5 heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer’s disease or sepsis.
9. Use according to claim 8, wherein the medicament is for the treatment of 10 asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13183519 | 2013-09-09 | ||
EP13183519.1 | 2013-09-09 | ||
EP14151979 | 2014-01-21 | ||
EP14151979.3 | 2014-01-21 | ||
PCT/EP2014/069088 WO2015032945A1 (en) | 2013-09-09 | 2014-09-08 | Peptidyl nitril compounds as dipeptidyl peptidase i inhibitors |
Publications (2)
Publication Number | Publication Date |
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NZ718128A NZ718128A (en) | 2021-04-30 |
NZ718128B2 true NZ718128B2 (en) | 2021-08-03 |
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