WO2016139355A1 - 3,3'-(biphényl-4,4'-diyl)bis-2-aminopropanenitriles n-substitués en tant qu'inhibiteurs de dppi - Google Patents

3,3'-(biphényl-4,4'-diyl)bis-2-aminopropanenitriles n-substitués en tant qu'inhibiteurs de dppi Download PDF

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WO2016139355A1
WO2016139355A1 PCT/EP2016/054683 EP2016054683W WO2016139355A1 WO 2016139355 A1 WO2016139355 A1 WO 2016139355A1 EP 2016054683 W EP2016054683 W EP 2016054683W WO 2016139355 A1 WO2016139355 A1 WO 2016139355A1
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compound
acid
alpha
formula
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Conni Lauritzen
John Pedersen
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Prozymex ApS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
    • C07C255/44—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms at least one of the singly-bound nitrogen atoms being acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to N-substituted 3,3'-(biphenyl-4,4'-diyl)bis-2- aminopropanenitriles in which the biphenyl moiety is substituted with one or more fluorine atoms, and their use as inhibitors of dipeptidyl peptidase I, pharmaceutical compositions containing the same, and methods of using these 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.
  • 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.
  • DPPI also functions as a key enzyme in the activation of granule serine peptidases in neutrophils (cathepsin G, proteinase 3 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.
  • tryptase and chymase are emerging as important mediators of allergic diseases such as asthma, inflammatory bowel disease and psoriasis.
  • allergic diseases such as asthma, inflammatory bowel disease and psoriasis.
  • 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, proteinase 3 and cathepsin G and undergo oxidative bursts to release reactive oxygen intermediates.
  • Pulmonary emphysema, COPD, cystic fibrosis, idiopathic pulmonary fibrosis, alpha-1 antitrypsin deficiency, sepsis, psoriasis and rheumatoid arthritis are just some examples of pathological conditions associated with the potent enzymes elastase, proteinase 3 and cathepsin G.
  • 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, W01154677A1 and WO 2010142985A1 to Astrazeneca discloses further nitrile compounds and use thereof as dipeptidyl peptidase inhibitors.
  • Ingelheim International GMBH discloses nitrile compounds as dipeptidyl peptidase inhibitors. Jon Bondebjerg, Henrik Fuglsang, Kirsten Rosendal Valeur, John Pedersen and Lars Naerum, 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.
  • WO2014/140075 (Boehringer) discloses substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides as inhibitors of cathepsin C.
  • the present invention relates to a compound of the formula (I):
  • X 1 and X 2 independently represent a cyclic alpha amino acid moiety, in which
  • R 1 independently represents
  • Ci-3-alkyl which Q ⁇ -alkyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano and mercapto;
  • X 1 represents
  • m + n 1.
  • m may be 1.
  • m and n in Formula (I) are both 1.
  • F is located at the 2-position and 2'-positions of the biphenyl moiety.
  • the invention also provides a pharmaceutical composition comprising a compound of the formula (I) :
  • a compound or composition as defined herein for use as a medicament is also provided.
  • DPPI 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] bond, except when Xaa is Arg or Lys, or when Xbb or Xcc is Pro.
  • the group -CN is a nitrile group
  • alpha amino acid moiety is defined as an amino acid moiety in which the amine nitrogen atom is attached directly to the alpha carbon atom.
  • alpha amino acid includes alpha amino acids that either occur naturally or are chemically synthesized.
  • cyclic alpha amino acid moiety in which amino acid moiety, the alpha carbon atom forms part of the cyclic structure is intended to mean an amino acid moiety in which the alpha carbon together with side chain atoms forms a mono- or polycyclic ring structure (e.g. bridged, fused or spiro structures), including the situation in which the amine nitrogen atom is included in the ring structure.
  • the cyclic alpha amino acid moiety represented by X 1 and/or X 2 is a monocyclic alpha amino acid moiety.
  • the ring structure can be heterogenic, containing one or more heteroatoms selected from N, O or S, and can include the amine nitrogen of the cyclic alpha amino acid moiety.
  • the ring structure may contain one or more double bonds.
  • Ring structures of X 1 and/or X 2 suitably contain 4-10 ring atoms (i.e. atoms which constitute the ring structure), including the alpha-carbon atom.
  • Each cyclic alpha amino acid moiety is optionally substituted on a ring carbon, nitrogen or sulfur atom with one or two substituents R 1 .
  • Ring atom(s) are those atoms which form part of the ring structure of the cyclic alpha amino acid moiety. When present, the substituents R 1 may be present on the same ring atom, or different ring atoms.
  • alpha carbon atom forms part of the cyclic structure.
  • alpha carbon atom in an amino acid moiety is defined as the first carbon atom that is attached to the carbonyl group of the moiety.
  • side chains refers to substituents on the alpha carbon atom and on the amine N.
  • Possible cyclic alpha amino acid moieties for X 1 include, but are not limited to:
  • each cyclic structure of X 1 is optionally substituted on a ring carbon, nitrogen or sulfur atom with one or two R 1 .
  • R 1 a ring carbon, nitrogen or sulfur atom
  • Possible cyclic alpha amino acid moieties for X 2 include, but are not limited to:
  • each cyclic structure of X 2 is optionally substituted on a ring carbon, nitrogen or sulfur atom with one or two R 1 .
  • R 1 a ring carbon, nitrogen or sulfur atom
  • cyclic alpha amino acid moieties for X 2 may be substituted or non- substituted.
  • X 1 X 2 .
  • 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
  • Half-life 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.
  • phrases "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 a Iky I 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, enantiomericaily enriched mixtures, or as enantiomericaily 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.
  • 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.
  • the compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. If there is a cycloalkyl or cycloalkenyl group present, some substituent patterns may result in an axial or an equatorial configuration. Both forms are included, unless specified otherwise.
  • X 1 has an enantiomerically pure form selected from:
  • 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).
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired
  • 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.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • 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.
  • 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, lH-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, (+) -camphor- 10-sulfonic
  • ethylenediaminotetraacetic 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, naphtha lene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oct
  • compositions 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
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
  • the compound of the invention in the solid state, can exist in crystalline, semi- crystalline and amorphous forms, as well as mixtures thereof.
  • pharmaceutically-acceptable solvates of the compound of the invention may be formed wherein solvent molecules are incorporated into the solid-state structure during
  • Solvates may involve water or non-aqueous solvents, or mixtures thereof.
  • 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.
  • crystalline forms of the compound of the invention may contain solvent molecules, which are not incorporated into the solid-state structure.
  • solvent molecules may become trapped in the crystals upon isolation.
  • solvent molecules may be retained on the surface of the crystals.
  • the invention includes such forms.
  • an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched.
  • the compounds of the invention may be administered by any suitable route of
  • 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, otic, intravaginal, and intranasal administration.
  • Compounds 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 compounds 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.
  • suitable dosing regimens including the amount administered and the duration such regimens are administered, for compounds 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.
  • a "prodrug" of compounds 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.
  • 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.
  • prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of
  • Coupling of short peptides or single amino acids as carriers of a therapeutic agent can be used as an effective type of prodrug approach.
  • an amino acid or a di- or oligo-peptide moiety is linked to a free 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 (PGAP), 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).
  • the compound disclosed herein is linked via a free 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.
  • Compound PZ1105 can be made essentially as described in the following synthetic scheme, using the appropriate Boc(t-butyloxycarbonyl)-protected amino acid.
  • compounds of the invention wherein the structures of X 1 and X 2 in Formula (I) (including the substitution by R 1 ) are different can be made essentially as described in the following synthetic schemes (exemplified for synthesis of compound PZl lll and PZ1112) by coupling the two compounds PZ1111A and PZ1111B, and PZ1111B and PZ1112A, respectively by a Suzuki coupling followed by deprotection.
  • PZ1111A, PZ1111B and PZ1112A can easily be synthesized by a person skilled in the art of peptide synthesis and medicinal chemistry.
  • Synthesis of compounds of the invention will often involve conversion of an amide to the corresponding nitrite.
  • the conversion may be carried out by use of dehydration agents such as (methoxycarbonylsulfamoyl)triethylammonium hydroxide or cyanuric chloride, in a suitable solvent such as dichloromethane in the case of (methoxycarbonylsulfamoyl)- triethylammonium hydroxide and dimetylformamide in the case of cyanuric chloride.
  • 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, FPRLI modulators, LTB4- receptor (BLTI, BLT2) antagonists, Histamine HI receptor
  • Histamine H4 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 Kl, J K2, J K3 or SAP, inhibitors of the NF- ⁇ signalling pathway as for example IKK2 kinase inhibitors, iNOS inhibitors, MRP4 inhibitors or leukotriene biosynthese inhibitors.
  • 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, ERK
  • compositions comprising, as an active substance, a compound as disclosed herein or a pharmaceutically acceptable salt thereof together with a
  • 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.
  • 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.
  • the pharmaceutical compositions disclosed herein typically contain from 1 mg to 1000 mg.
  • 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.
  • 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.
  • 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.
  • dosage forms include those adapted for (1 ) oral
  • administration such as tablets, capsules, cap lets, pills, troches, powders, syrups, elixirs, 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.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • 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.
  • 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, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • 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, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, hemectants, chel
  • 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).
  • 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.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch giycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • the invention is directed to a dosage form adapted for administration to a patient by inhalation.
  • 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.
  • 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.
  • 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).
  • MDPI multi-dose dry powder inhaler
  • 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.
  • the dry powder 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.
  • 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,
  • Aerosols comprising the compound of the invention will typically be administered to a patient via a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • the aerosol may contain additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, co-solvents 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
  • 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.
  • 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.
  • 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.
  • organic acids e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
  • compositions 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.
  • 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 compound according to Formula I is prepared using conventional organic syntheses. Suitable synthetic routes are depicted below in the following general reaction schemes.
  • the compound disclosed herein may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydro bromide,
  • 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.
  • the compound disclosed herein is in the form of a pharmaceutically acceptable salt thereof.
  • the compound disclosed herein is for use in medicine such as for use as a dipeptidyl peptidase I (DPPI) inhibitor.
  • DPPI dipeptidyl peptidase I
  • 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;
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • bronchitis including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; alpha-1 antitryps
  • lung fibrosis including, idiopathic pulmonary fibrosis, 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
  • vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension include 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; pyodermatitis
  • glomerulonephritis 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 following 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-lgE 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 (HIV), 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,
  • virus diseases such as genital wart
  • Pneumocystis camii cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis; congestive heart failure; atherosclerosis; coronary artery disease;
  • the compound disclosed herein is for use as a dipeptidyl peptidase I inhibitor.
  • the compound or pharmaceutical composition disclosed herein is for use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, 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.
  • the compound or pharmaceutical composition disclosed herein is for for use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, 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.
  • the compound or pharmaceutical composition disclosed herein is for use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, idiopathic pulmonary fibrosis, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic
  • cardiomyopathy gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the pharmaceutical composition in unit dosage form comprised from about 1 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.
  • the pharmaceutical composition disclosed herein is for oral, nasal, transdermal, pulmonal or parenteral administration.
  • 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
  • a method for the treatment of ailments 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.
  • an effective amount of the compound as disclosed herein is in a range of from about 1 ⁇ to about 1000 mg such as, e.g., from about 10 jig to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg per day.
  • the use of the compound or pharmaceutical composition as disclosed herein for the preparation of a medicament is provided.
  • 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.
  • said DPPI is inhibited.
  • agents independently selected from: a non-steroidal glucocorticoid receptor agonist; a selective ⁇ 2 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.
  • the medical condition is selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis.
  • a compound of the formula (I) is a compound of the formula (I) :
  • the amino acid moiety of said cyclic alpha amino acid moiety is optionally substituted on a ring carbon, nitrogen or sulfur atom with one or two substituents R 1 ;
  • R 1 independently represents Ci-3-alkyl; which C 1 3 -alkyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano and mercapto;
  • Aspect 2 The compound according to any one of the preceding aspects, wherein the cyclic alpha amino acid moiety represented by X 1 and/or X 2 comprises 3-10 ring atoms, preferably 4-10 ring atoms.
  • Aspect 3 The compound according to any one of the preceding aspects, wherein the cyclic alpha amino acid moiety represented by X 1 and/or X 2 is a monocyclic alpha amino acid moiety.
  • Aspect 4 The compound according to any one of the preceding aspects, wherein the cyclic alpha amino acid moiety represented by X 1 and/or X 2 is a cyclic alpha amino acid moiety in which one ring atom is nitrogen, which cyclic alpha amino acid moiety contains a bridge between two carbon ring atoms of X 1 and/or X 2 , said bridge having the general
  • Aspect 5 The compound according to any one of the preceding aspects, wherein X 1 represents: optionally substituted on a ring carbon atom with one or two R 1 , wherein R 1 is as defined in aspect 1.
  • Aspect 6 The compound according to any one of aspects 1-5, wherein X 2 represents
  • each cyclic structure of X 2 is optionally substituted on a ring carbon, nitrogen or sulfur atom with one or two R 1 , and wherein R 1 is defined in aspect 1.
  • Aspect 7 The compound according to any one of aspects 1 -6, wherein unsubstituted or substituted X 2 represents
  • Aspect 9 The compound according to any one of aspects 1-8, wherein R 1 independently represents C 1-3 -alkyl .
  • Aspect 14 The compound according to any one of aspects 1-9, wherein X 1 optionally substituted on a ring carbon atom with one or two substituents Rl, and wherein R 1 is as defined in any one of aspects 1-9.
  • Aspect 16 A compound according to any one of aspects 1- 15, selected from:
  • a pharmaceutical composition comprising a compound of the formula (I):
  • Aspect 28 The method according to aspect 27, wherein the medical condition is selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, psoriasis, rheumatoid arthritis or sepsis.
  • the medical condition is selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy,
  • Aspect 29 Use of a compound of formula (I) according to any one of aspects 1 - 22 for the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, 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,
  • Aspect 30 The use according to aspect 29, wherein the medicament is for the treatment of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, psoriasis, rheumatoid arthritis or sepsis.
  • MATERIALS AND METHODS MATERIALS AND METHODS
  • Pd(PPh 3 ) Tetrakis(triphenylphosphine)palladium
  • Fmoc-Osu N-(9-Fluorenylmethoxycarbonyloxy)succinimide
  • HATU l-[Bis(dimethylamino)methylene]- lW-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • 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.
  • 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 ⁇ _ at 37°C, and absorbance was measured 8 times during 21-35 minutes using a plate reader. IC 50 was determined using a 4-parameter logistic equation in a nonlinear curve fitting routine.
  • 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.
  • 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 ⁇ _ at 37°C, and absorbance was measured 8 times during 21 minutes using a plate reader. IC 50 was determined using a 4-parameter logistic equation in a non-linear curve fitting routine. Human DPPI inhibition assay 1
  • the IC 50 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 NaCI (4.4 g NaCI) and 2 mM EDTA (370 mg EDTA) was dissolved in 500 mL H 2 0, and pH was adjusted to 4.5 with HCI.
  • Substrate Gly-Phe-paranitroanilide (Sigma Aldrich; Cat. No G0142) was used as the substrate for determination of IC 50 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 Horsholm, Denmark) was stored at -20 °C in a buffer containing 2.5 mM Na-phosphate, 150 mM NaCI, 2 mM cysteamine, 50% glycerol, pH 7.0 at a concentration of 1-2 mg/mL (5-10 ⁇ ). 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 pL) was added to the well, followed by 25 pL of test substance in varying concentrations, and the solution was mixed. The plate was incubated at 37 °C for 5 minutes, followed by addition of 150 pL of 1 mM substrate prewarmed to 37 °C (corresponding to a substrate concentration of 750 ⁇ in the assay). The absorption was measured at 405 nm at 37 °C for every 90 seconds for 12 minutes or every 20 seconds for 4 minutes. Each measurement was made in duplicate. IC 50 was determined using a 4-parameter logistic equation in a non-linear curve fitting routine.
  • Human DPPI inhibition assay 2 Using this assay, the IC 50 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 NaCI (4.4 g NaCI) and 2 mM EDTA (370 mg EDTA) was dissolved in 500 mL H 2 0, and pH was adjusted to 4.5 with HCI.
  • Substrate Gly-Phe-paranitroanilide (Sigma Aldrich; Cat. No G0142) was used as the substrate for determination of IC 50 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 Horsholm, Denmark) was stored at -20 °C in a buffer containing 2.5 mM Na-phosphate, 150 mM NaCI, 2 mM cysteamine, 50% glycerol, pH 7.0 at a concentration of 2.2 mg/mL ( « 12 pM). This stock solution was diluted 800-3200 times in assay buffer to a concentration of about 4-15 nM. Assay conditions: The assay was performed in 96-well plates. Diluted enzyme (25 pL) was added to the well, followed by 25 pL of test substance in varying concentrations, and the solution was mixed.
  • the plate was incubated at 37 °C for 5 minutes, followed by addition of 150 pL of 1 mM substrate prewarmed to 37 °C (corresponding to a substrate concentration of 750 ⁇ in the assay).
  • the absorption was measured at 405 nm at 37 °C for every 90 seconds for 12 minutes or every 20 seconds for 4 minutes. Each measurement was made in duplicate.
  • IC 50 was determined using a 4-parameter logistic equation in a non-linear curve fitting routine.
  • PZ1125 was found to have an IC 50 of ⁇ 16 nM in the Human DPPI inhibition assay 2 and an IC 50 of « 15 nM in the cell based DPPI inhibition assay 2.
  • PZ1105 was found to have an IC 50 of « 1 nM in the Human DPPI inhibition assay 2 and an IC 50 of « 15 nM in the cell based DPPI inhibition assay 2
  • PZ1102 was found to have an IC 50 of « 6 nM in the Human DPPI inhibition assay 2.
  • Example 4 A/,/V'-((lS, l , S)-(2,2 , ,3,3 , -tetrafluoro-[ l, l , -biphenyl]-4,4'-diyl)bis(l- cyanoethane-2, l-diyl))bis(4-aminotetrahydro-2W-pyran-4-carboxamide) (PZ1127)

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Abstract

L'invention concerne un composé de Formule (I) et son utilisation en tant qu'inhibiteur sélectif de la dipeptidyl peptidase I, ainsi que des compositions pharmaceutiques comprenant ledit composé, et des méthodes de traitement impliquant ledit composé.
PCT/EP2016/054683 2015-03-05 2016-03-04 3,3'-(biphényl-4,4'-diyl)bis-2-aminopropanenitriles n-substitués en tant qu'inhibiteurs de dppi Ceased WO2016139355A1 (fr)

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WO2022042591A1 (fr) * 2020-08-26 2022-03-03 四川海思科制药有限公司 Dérivé de nitrile agissant comme inhibiteur de la dipeptidyle peptidase 1 et son utilisation
WO2023160541A1 (fr) 2022-02-22 2023-08-31 四川海思科制药有限公司 Procédé de préparation d'un composé hétérocyclique contenant de l'azote
WO2023160579A1 (fr) 2022-02-22 2023-08-31 四川海思科制药有限公司 Polymorphe d'inhibiteur de la dipeptidyl peptidase 1, son procédé de préparation et son utilisation

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US11807635B2 (en) 2020-08-26 2023-11-07 Haisco Pharmaceuticals Pte. Ltd. Nitrile derivative that acts as inhibitor of dipeptidyl peptidase 1 and use thereof
EP4497473A3 (fr) * 2020-08-26 2025-04-23 Haisco Pharmaceuticals Pte. Ltd. Dérivé de nitrile qui agit en tant qu'inhibiteur de la dipeptidyl peptidase 1 et son utilisation
US12365673B2 (en) 2020-08-26 2025-07-22 Haisco Pharmaceuticals Pte. Ltd. Nitrile derivative that acts as inhibitor of dipeptidyl peptidase 1 and use thereof
WO2023160541A1 (fr) 2022-02-22 2023-08-31 四川海思科制药有限公司 Procédé de préparation d'un composé hétérocyclique contenant de l'azote
WO2023160579A1 (fr) 2022-02-22 2023-08-31 四川海思科制药有限公司 Polymorphe d'inhibiteur de la dipeptidyl peptidase 1, son procédé de préparation et son utilisation

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