WO2014159637A1 - Methods of treating b2-bradykinin receptor mediated angioedema - Google Patents

Methods of treating b2-bradykinin receptor mediated angioedema Download PDF

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WO2014159637A1
WO2014159637A1 PCT/US2014/024540 US2014024540W WO2014159637A1 WO 2014159637 A1 WO2014159637 A1 WO 2014159637A1 US 2014024540 W US2014024540 W US 2014024540W WO 2014159637 A1 WO2014159637 A1 WO 2014159637A1
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attorney docket
subject
pct
compound
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PCT/US2014/024540
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French (fr)
Inventor
Kevin LEACH
Teresa Wright
Brian FELICE
Richard Pfeifer
Pericles Calias
Thomas Mccauley
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Shire Human Genetic Therapies, Inc.
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Priority to KR1020157029035A priority Critical patent/KR20150127718A/en
Priority to AU2014244592A priority patent/AU2014244592A1/en
Priority to CA2904052A priority patent/CA2904052A1/en
Priority to MX2015012650A priority patent/MX2015012650A/en
Priority to JP2016501568A priority patent/JP2016514141A/en
Priority to RU2015138443A priority patent/RU2015138443A/en
Application filed by Shire Human Genetic Therapies, Inc. filed Critical Shire Human Genetic Therapies, Inc.
Priority to EP14776198.5A priority patent/EP2968308A4/en
Priority to BR112015022846A priority patent/BR112015022846A2/en
Priority to CN201480027533.7A priority patent/CN105228623A/en
Priority to US14/776,542 priority patent/US20160030416A1/en
Publication of WO2014159637A1 publication Critical patent/WO2014159637A1/en
Priority to HK16108272.4A priority patent/HK1220136A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • HAE Hereditary angioederaa
  • HAE symptoms include episodes of edema (swelling) in various body parts including the hands, feet, face, intestinal walls and airways.
  • Most HAE patients (those with Type i and Type H HAE) have a defect in the gene that controls the blood protein, CI esterase inhibitor (Cl-INH).
  • the genetic defect results in production of either inadequate (Type 1 HAE) or non-functioning (Type ⁇ HAE) C l - ⁇ protein.
  • Type 1 HAE Type 1 HAE
  • Type ⁇ HAE non-functioning C l - ⁇ protein.
  • the genetic defects related to CI -inhibitor that cause Type I and Type II HAE are autosomal dominant.
  • absence of a family history of HAE does not rule out an HAE diagnosis. It has been reported that as many as 20% of HAE cases result from patients who had a spontaneous mutation of the CI -inhibitor gene at conception.
  • Bradykinin is a vasoactive nonapeptide, H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH (SEQ ID NO:l), formed locally in tissues, often in response to a trauma. Two types of BK receptors are recognized in mammals.
  • Bl and B2 The actions of B mediated by the B2-bradykinin receptor are important physiological functions, such as the increase of vascular permeability, modulation of inflammatory responses and pain, and induction of vasoactive effects (vasodilatation, vasoconstriction).
  • B2-bradykinin receptor The actions of B mediated by the B2-bradykinin receptor are important physiological functions, such as the increase of vascular permeability, modulation of inflammatory responses and pain, and induction of vasoactive effects (vasodilatation, vasoconstriction).
  • Surplus bradykinin results in inflammation, such as swelling, redness, overheating, and pain.
  • Bradykinin is responsible for the clinical symptoms of HAE, causing increased vascular permeability, vasodilation, and contraction of visceral smooth muscle.
  • a quantitative or qualitative deficiency of Cl-MH leads to inadequate regulation of bradykinin production and increased vascular permeability.
  • Extravasation of fluid leads to non-pruritic edema. As high molecular weight kiniaogen is exhausted and bradykinin degraded, the edema begins to subside and the fluid is resorbed by the lymphatic system,
  • Firazyr ® injected icatibant
  • tha is a selective and specific antagonist of Ba-bradykmin receptor and has been used to treat acute attacks of HAE in adults with Cl -esterase inhibitor deficiency.
  • Ecailantide (trade name Attorney Docket " No. 0138.000I-PCT
  • Kalbitor® investigationai name DX-88 is a drug used for the treatment of acute attacks of HAE. It is an inhibitor of the protein kailikrein and a 60-amino acid polypeptide. Also purified (Ci lNH P) or recombinant (rhClINH) human Ci-inhibitor l as been used in the treatment of acute attacks of HAE.
  • Methods of treating B 2 -bradykinin receptor mediated angioedema are desirable. Treatment methods using small molecule B 2 ⁇ bradykinin receptor antagonists are of interest. Also oral therapies for treating Brbradykmin receptor mediated angioedema are desirable.
  • Certain embodiments are drawn to methods of treating a B 2 ⁇ bradyki «in receptor mediated angioedema in a subject comprising administering to the subject in need thereof a therapeutically effective amouni of a composition comprising a compound having formula (1) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof!, wherein plasma extravasation in the subject is reduced upon administration of the compound or the pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof and formula ⁇ is as follows: Aitomey Docket No. 0138.000 ). -PCX
  • R 3 is Ci or CN
  • g is selected from the group consisting of H, a methyl group, an ethyl group, a propyl group, a butyl group, a perstyl group, or a hexyl group.
  • Some embodiments are drawn to methods of treating a 82-bradykmin receptor mediated angioedema in a subject comprising:
  • composition comprising a compound having formula (II) or a pharmaceutically accepLable salt, stereoisomer, hydrate, or solvate thereof Attorney Docket No. 0138.00.01-PCT
  • Embodiments as-e drawn to methods of treating a B 2 -bradykinin receptor mediated angioederaa in a subject comprising:
  • Certain embodiments are drawn to oral formulations comprising a therapeutically effective amount of a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof and a pharmaceutically acceptable carrier, wherein the therapeutically effective amount is between about 0.001 wt % and about 60 wt % of the oral formulation,
  • compositions comprising a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof for the manufacture of a medicament for the treatment and/'or prevention of a Ba-bradyki n receptor mediated angloedema.
  • Figure 1 depicts a synthesis scheme for l-((4-chioro-3-(((4-(4-fluoro»l H-pyrazoi-1 - yl) ⁇ 2-methyIquinolin-8-yl)oxy)m 2- dihydropyridine-3-carbonitrile (JSM 1938/HGT37I I).
  • Figure 2 is a graph showing Evans blue concentration (jig mg) ⁇ SEM (standard error of the mean) of tissue in C57BL/6J (wild-type) mice following intravenous administration of l -((4 ⁇ hloro-3-(((4-(4-fluoro-lH-pyra2oI-l-yl)-2-methyiquinoiin-8-y oxy)methyl)-6- methylpyrk1in-2-yI)methy3)-2-oxo-l , 2-dihydropyridine-3-carbonitrile (JSM1938/HGT3711).
  • Figure 3 is a graph showing Evans blue concentration ⁇ SEM (standard error of the mean) of tissue in C57BL/6J (wild-type) mice following oral administration of l-((4- chloro-3-(((4-(4-fluofo-iH-pyrazol-l-yl 2 > methylquinolin-8-yl)oxy)ra ⁇
  • Figure 4 is a graph showing Evans blue concentration (mg/raL) ⁇ SEM of bladder extract in CHNH mice following oral administration of l-((4-chloro-3-(((4-(4-fiuoro-l.H- pyrazoM-yi)-2-metbylqumolm-8-yl)oxy)m 2- dihydropyridine-3-carbonitrile (JSM1938 HGT3711).
  • Figure 5 is a graph showing Evans blue concentration (mg mL) ⁇ SEM of bladder extract in C 1 -INI ⁇ O (knockout) mice following oral administration of l-((4-chioro-3-(( ⁇ 4- (4-fluoro-1 H-pyrazol-i -yl) ⁇ 2-methylq ⁇
  • Figure 6 is a graph, showing the results of ex vivo efficacy of I ⁇ ((4-chloro-3-(((4*(4- fluoro-lH ⁇ yrazoi ⁇ l -y!)-2-met ⁇
  • JSM I938/I-IGT37H oxo- 1, 2-dihydropyridine-3-carbomtrile
  • Figure 7 Is a graph showing average plasma concentrations versus time following orally administered 1 -((4-chloro-3-(((4-(4-fluoro-l l : i-pyra7.ol-i ⁇ yl)-2-methylquinoiin-8- yl)oxy)methyl)-6-methyipyridin-2-yi)rnet ' hyl)-2-oxo-l, 2-dihydropyridine-3-earbonitrile (HGT371 1) in female CD-I mice.
  • Figure 8 shows average plasma concentration versus time following orally administered l -((4-chloro-3-(((4-(4-fluoro-.Uri-pyra2ol-l-yl)-2-methylquinoltn-8- yl)oxy)methyl)-6-methylpyrid «i-2-yl)methyl)-2-oxo-i, 2-dihydropyridine-3-carbonitrile Attorney Docket No. 05 8.0001 -PC ' T
  • Figure 9 is a graph showing individual plasma concentration (ng/mL) of 1 -((4-chloro- 3 ⁇ (((4 ⁇ (4-fluoro- 11 ⁇ -pyrazol- 1 -yl)-2-methylqumoim-8-yl)oxy)methyl)-6-met3 ⁇ 4y Ipyridin-2- yl)methy l)-2-oxo- 1 , 2-dihydrqpyridine-3-earbonitriie (HGT371 I) versus time following oral administration in female Yucatan mini-pigs at 10 mg kg (Should this be swapped out with a later graph)?
  • FIG. 10 shows representative chromatograms of HGT371 1 incubated for 4 hours with mouse, rat, mini-pig and human hepatocytes. * HPLC retention time of HGT3711 (JSM1 1938) was 35 minutes.
  • Figure I I depicts the structures of metabolites of l -((4-ch1oro ⁇ 3-(((4-(4-fluoro-lH- p>Tazol-l -yl)-2-methy]qumolin-8-yl)ox 2- dihydropyridine-3 -c arborsi tri le.
  • Certain embodiments are drawn to methods of treating a B2-bradykinin receptor mediated angioedema (such as, hereditary angioedema) by administering a therapeutically effective amount of a composition containing a 8-(heteroaryimethoxy)quinolme or 8- (arylniethoxy)quinoline or a pharmaceutically acceptable salt, a stereoisomer, a hydrate, or a solvate thereof.
  • These compounds can act as selective modulators (e.g., antagonists) of B 2 ⁇ bradykinin receptors and can result in reduced plasma extravasation in a subject after they are administered.
  • B?-bradykinin receptor modulators e.g., antagonists
  • can exhibit, high activity on human Bj-bradykinin receptor i.e., an inhibition constant (IC 5 0) for competition with binding of labeled bradykinin (B ) to human Bj-bradykin n receptor of less than about 5 micromolar
  • IC 5 0 an inhibition constant
  • human B2 ⁇ bradykinin receptor i.e., an IC .50 for competition with the binding of labeled BK to human B 2 ⁇ bradykinin receptor of less than about 50 nanomolar
  • such modulators exhibit a high activity on B 2 - Attorney Docket No. 0138.0001 bradykinin receptors of species other than human, e.g., rat, mouse, gerbiL guinea pig. rabbit, dog, cat, pig, or cynomolgus monkey.
  • the activity of the B 2 ⁇ bradykmin receptor modulators can be assessed using appropriate in vitro assays.
  • the ICso values of the modulators for Bi-bradykinm receptor can be determined via a radioligand binding assay.
  • Inhibitor effects of the 31 ⁇ 4- bradykmin receptor modulators provided herein for B bradykinin receptor can be determined, for example, via a calcium mobilization assay.
  • B ⁇ -bradykimn receptor modulators can have an ICso (half-maximal inhibitory concentration) of about 5 mi.crom.okr or less., about 500 n or less, about 50 nM or less, about 10 nM or less, or about 1 nanomolar or less in the assays mentioned above.
  • a compound having formula (I) or (II) can have a half maxima! inhibitory concentration (ICso) for competition with the binding of labeled bradykinin to human B 2 -bradykinin receptor of less than about 50 nanomolar, less than about 10 nanomolar, or less than about 5 nanomolar to B 2 -bradykima receptor,
  • Certain embodiments comprise administering pharmaceutical compositions comprising at least one B ⁇ -bradykinin receptor modulator as described herein, in combination with a physiologically acceptable carrier or excipient. Processes for preparing such pharmaceutical compositions are also provided. Such compositions can be useful in the treatment ofBa-bradykinin receptor mediated angioedema (e.g., HAE).
  • Ba-bradykinin receptor mediated angioedema e.g., HAE
  • Recited compounds are further intended to encompass compounds in which one or .more atoms are replaced with an isotope (i.e., an atom having the same atomic number but a different mass Attorney Docket No. 0138.0001 -PC number).
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include J l €, ,3 C and 14 C.
  • such compounds can have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%, Some embodiments of the compounds have an enantiomeric excess of at least 99%.
  • single enantiomers optically active forms
  • Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiraf HPLC column.
  • Formula (I) is as follows: Attorney Docket No. 0138.0001-PCT
  • Rj can be hydrogen; an optionally substituted alkyl; optionally substituted aJkenyl; 5- mernbered heterocycioalkyi having from 1 to 3 heteroatoros each independently selected from. N, O or S, or cycloalkyl, wherein said 5-raembered heterocycioalkyi or cycloalkyl can be substituted with from 0 to 3 substituents each Independently selected from halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyi, cycloalkyl, heterocycioalkyi, aikyicycloaikyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or a 5-membered heteroaryl having from 1 to 4 heteroatoms each independently selected from N, O or S, wherein said 5-
  • R 5 can be H, a Ct- alkyl (e.g., a methyl group, an ethyl group, a propyl group, a butyl group, a penryl group, or a hexyl group),
  • a Ct- alkyl e.g., a methyl group, an ethyl group, a propyl group, a butyl group, a penryl group, or a hexyl group
  • R can be H or
  • R 2 can be a 6-membered aryl or 6-membered heteroaryl, wherein the 6-membered heteroaryl comprises 1 nitrogen atom.
  • the 6-membered aryl or heteroaryl can Attorney Docket No. 0138.0001-PCT be subsiiutted with ⁇ to 3 subsiituents each independently selected fi-om halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto,.
  • alkyi alkerryl, aikynyl, heteroalkyl, cycioalkyl, .heterc-cycloaikyl, alkylcycloalkyl, heteroalkyicycloa!kyl, aryl, heteroaryl, aralkyl, and heieroaralkyl.
  • R2 can be
  • R 3 , R , Rs, Ri, R 7 , R ⁇ . 9 and R !0 can each be independently selected from a halogen atom, an oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyJ, aikynyl, heteroaikyl, cycioalkyl, heterocycloaikyl, alkylcycloalkyl, heteroaikylcycloalkyl, aryl, heteroaryl, aralkyl, and .heteroaraikyi, and R 3 can also be selected from H in some embodiments.
  • R3 can be a halogen atom (such as. CI), CN or H. In certain embodiments, R3 can be Ci or CN. R s can be a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, in certain embodiments. In certain embodiments, R 5 Is a methyl group. R ⁇ can be a halogen atom (such as, CI) or a Ci-Ca alkyl (such as, CH 3 ), in certain embodiments.
  • R4 can, In certain embodiments, have the formula
  • R 8 can be a halogen or a Cj-Ce alkyl.
  • R 8 can be CI or C3 ⁇ 4 in embodiments, in some embodiments, R9 can be H or a -Ce alkyl.
  • R can be C3 ⁇ 4, in certain embodiments.
  • Certain embodiments are drawn to methods of treating a B 2 -bradykinin receptor mediated angioedema in a subject comprising:
  • composition comprising a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
  • the compound having formula (I) can be as follows:
  • R is selected from the group consisting of H, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyi group, or a hexyf group
  • Plasma extravasation in the subject can be reduced upon administration of the compound of formula (I) or (11) or the pharmaceutically acceptable salt stereoisomer, hydrate, or solvate thereof.
  • the iVbradykinin receptor mediated angioedema treated by embodiments can be hereditary angioedema.
  • Certain treatment methods of embodiments can further comprise administering icatibant, ecailant.de, fresh frozen plasma, CI -inhibitor, or kaliikrem inhibitor to the subject in addition to a therapeutically effective amount of a composition comprising a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
  • Certain embodiments are drawn to methods of treating a Ba-bradykinin receptor mediated angioedema in a subject comprising administering to the subject in need thereof a therapeutically effective amount a composition comprising a compound having Attorney Docket No. 0 i 38.0001 -PCT formula (13) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, thereby reducing plasma extravasation in the subject.
  • compositions comprising l-((4-chloro-3-(((4-(4- flisoro-lH-pyrazoI- i -yl)-2-methyIq ⁇
  • oxo-1, 2-dihydropyridme-3-carborjiianae (HGT37H) or a pharmaceutically acceptable salts, stereoisomers, hydrates, or solvates thereof.
  • 3-i-((4 ⁇ Ch ⁇ oro-3-(((4-(4-fluoro-lH-pyrazoH ⁇ yI)-2 ⁇ nemylqumoUn-8-yi)oxy)methy1)-6-m 2 ⁇ dihydropyridine-3-carbonitriie (HGT371 1) can be orally bioavailable and act as a B 2 - bradykinin receptor antagonist in the treatment of B 2 ⁇ bradykinm receptor mediated angioedema, in embodiments.
  • the 8-(heteroarylmethoxy)quinoline or 8- (arylmethoxy)quinolvne or a pharmaceutically acceptable salt a stereoisomer, a hydrate, or a solvate thereof can be a small molecule.
  • a small molecule is a low molecular weight ( ⁇ 800 Daltons) organic compound that may serve as an enzyme substrate or regulator of biological processes (e.g., Ba-bradykinin receptor antagonist).
  • the upper molecular weight, limit for a small molecule is about 800 Daltons which allows for the possibility to rapidly diffuse across cell membranes so that they can reach intracellular sites of action.
  • this molecular weight cutoff is a necessary but insufficient condition for oral bioavailability.
  • Biopolymers such as nucleic acids, proteins, and polysaccharides (such as starch or cellulose) are not small molecules.
  • Compounds having formula ( ⁇ ) or (H) can have a molecular weight less than about 650 Daltons, less than about 600 Daltons, or less than about 525 Daltons m embodiments.
  • compositions comprising a compound having formula (I) or (II), a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof as an active ingredient in the preparation or manufacture of a medicament for the treatment and/or prevention of a Ba-bradykinjn receptor mediated angioedema.
  • a "pharmaceutically acceptable salt" of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of hum n beings or animals without excessive toxicity or carcinogenicity, and without irritation, allergic response, or other problem or complication, in some embodiments.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Suitable pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycoHc, tumeric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic,, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, iumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacette, alkanoic such as acetic, HOOC— (C3 ⁇ 4) B -COOH where n is any integer from 0 to -4 (i.e., 0, 1, 2, 3, or 4) and the like.
  • acids such as hydroch
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a sioichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • Nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, can be used for preparation of a salt in some embodiments.
  • each compound of formula I can, but need not, be present as a hydrate, solvate or non-covalent complex.
  • the various crystal forms and polymorphs are within the scope of embodiments described herein, as are prodrugs of the compounds of formula (1) or (11) provided herein.
  • a 'prodrug is a compound that differs structurally from 8- (heteroarylmethoxy)quinoline and 8 ⁇ (arylmethoxy)quinoline compounds provided herein Attorney Docket No. 0138.0001-PCT and that is modified in vivo, following administration to a subject or patien to produce a compound of formula I provided herein.
  • a prodrug can be an acyiaied derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryi groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryi group, respectively.
  • prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compoimds provided herein.
  • Prodrugs of the compounds provided herein cars be prepared by modifyin functional groups present m the compounds in suc a way thai the modifications are cleaved in vivo to generate the parent compounds.
  • a "substituent,” as used herein, refers to a molecular moiety that is covalentiy bonded to an atom within a molecule of interest.
  • a "ring substituent” can be a moiety such as a halogen, alkyi group, haioalkyl group, hydroxy, cyano, amino., niiro, mercapto, or other substituent described herein that is covalentiy bonded to an atom thai is a ring member.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated subsiituents, provided thai the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound (ie., a compound thai can be isolated, characterized and tested for biological activity).
  • 2 hydrogens on the atom are replaced.
  • a pyridyi group substituted by oxo is a pyridone.
  • alkyi refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, from 3 to 12 carbon atoms, or from 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, iso-propvL n-butyl, Iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 2,2-dimethylbutyl or n-ocryl group.
  • alkenyi and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, from 2 to 12 carbon atoms, or from 2 to 6 carbon atoms, for example an ethenyl, allyl, acetylenyl, Attorney Docket No. 0138.0001-PCT propargyl, isoprenyi or hex-2-enyl group.
  • Alkenyl groups can have one or two double bonds and alkynyl groups have one or two triple bonds, in certain embodiments.
  • alkyi refers to groups in which one or more hydrogen atoms have been replaced each independently of the others by a halogen atom (such as, F or CI) such as, for example, a 2,2,2 -trichioroethyl or a trifluoromethyi group.
  • a halogen atom such as, F or CI
  • heteroalkyl refers to an alkyl, alkenyl or alkynyl group (for example heteroalkenyl, heteroalkynyl) in which one or more carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulphur atom.
  • heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxy!ic acid such as, for example, acy!, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, earboxyalkylamide, aikylcarbarnoylaikyl, alkylcarbamoyloxyalkyi, a!kyiureidoalkyl, or alkoxycarbonyloxy.
  • heteroalkyl groups are groups of formulae— S--Y a -L,— S ⁇ -Y a — CQ ⁇ R*R ⁇ — Y a — NR°— CO— NR*R b , ⁇ Y* ⁇ NR c -CO--0 ⁇ R c , -Y ⁇ -NR'-CO-R", ⁇ Y a ⁇ 0-- CO ⁇ NR a R ⁇ — Y a -CO-NR a R b , ⁇ 0-Y a "CO ⁇ NR a R b , ⁇ Y a - ⁇ NR c --CO-L, TMY a -L s — Y 9 — O— CO--0-R 0 , ⁇ Y e --0 ⁇ CO--R c , R c ⁇ 0TMY a ⁇ , R c ⁇ S ⁇ Y e , R a ⁇ N(R b )--Y a " R
  • heteroalkyi groups containing at least one carbon atom and it being possible for one or more hydrogen atoms to have been replaced by fluorine or chlorine atoms.
  • Specific examples of heteroalkyi groups are methoxy, trifluororaethoxy, ethoxy.
  • n-propyloxy isopropyloxy, tert-butyloxy, methoxyniethyl, ethoxymethyl, meihoxyethyl, methyiamino, ethylamino, dimethylamino, diethyiamino, iso- propylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyL enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl.
  • heteroalkyi groups are niirile, isonitriie, cyanaie, thiocyanate, isocyanate, isotbiocyanate and alkylnitrile groups.
  • An example of a hetero- alkylene group is a group of formula -CH 2 CH(OH)-- or --CONH— .
  • cycloalkyi refers to a saturated or partially unsaturated cyclic group that contains one or more rings, containing from 3 to 14 ring carbon atoms, from 3 to 10 ring carbon atoms,, or 3 to 6 ring carbon atoms. In an embodiment partially unsaturated cyclic group has one, two or more double bonds, such as a cycloalkenyl group.
  • cycloalkyi group are a cyclopropyi, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl.
  • cyclohexadienyl decalinyl, bicyclo[4.3.OJoon l, tetralin, cyclopentylcyclohexyl, fluorocyciohexyl or cyclohex ⁇ 2-enyl group.
  • heterocycioalky refers to a cycloalkyi group as defined above in which one or more ring carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom.
  • a heterocycioalkyl group has 1 or 2 rings containing from 3 to 1 ring atoms.
  • Examples are a piperidyi, Attorney Docket No. 0138.0001-PCT piperazinyL morpholinyl, urotropinyl, pyrrol tdmyi, tetrahydrothiophenyl, tetxahydropyranyl, tetrahydrofuryl or 2-pyrazolinyi group and also a lactam,, a lactone, a cyclic imide and a cyclic anhydride.
  • alkyicycloalkyi refers to a group containing both cyc!oalkyl and also an alkyl, alkenyl or alkynyl group in accordance with the above definitions, for example alkyi-cycloa!kyi, cycloalkyialkyl, alkylcycloalkenyf, alkenyicycloalkyl and alkynyleycloalky! groups.
  • cyclic group can contain a cycioalkyJ group that contains one or two ring systems having from 3 to 10 carbon atoms, and one or two alkyl, alkenyl or aikynyi groups having i or 2 to 6 carbon atoms, the cyclic groups being optionally substituted.
  • heteroalkylcycloalkyl refers to alkylcycloalkyi groups as defined above in which, one or more carbon atoms have been replaced each independently of the others by an oxygen, nitrogen,, silicon, selenium, phosphorus or sulphur atom.
  • a heteroalkylcycloaikyl group can contain 1 or 2 ring systems having from 3 to 10 ring atoms, and one or two alkyf alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms.
  • Examples of such groups are alkyiheterocycloalkyl, alkylheterocyeloalkenyS, alkenyiheterocyeloalkyl, alkynylheteroeycloalky], heteroaikyicycloalkyl, heteroalkylheterocyeloalkyl and heieroaikylheterocycloaikenyl, the cyclic groups being optionally substituted and saturated or mono-, di ⁇ or tri-unsaturated.
  • aryi refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, or from 6 to 10 ring carbon atoms.
  • aryl refers .furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH 3 ⁇ 4 CN or NC3 ⁇ 4 groups. Examples are a phenyl, naphthyl, bi.phe.ny ' ;, 2 ⁇ fluorophenyl, anilinyl, 3 ⁇ nitrophenyl or 4 -hydroxy henyl group.
  • heteroaryl refers to an aromatic group thai contains one or more rings containing from 5 to 14 ring atoms, or from 5 to 10 ring atoms, and contains one or more oxygen, nitrogen, phosphorus or sulphur ring atoms.
  • Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrroiyl, thiazolyl, oxazolyl, triazolyl, tetrazolyi, isoxazolyl.
  • aralkyf ' refers to a group containing both aryi and also alkyl, aikenyl, alkynyl and/or cycloalkyi groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyi, aryialkynyl. arylcycloalkyl, aryicycloalkenyL . alkylaryicycloalkyl and alkylarylcycloalkenyl groups.
  • Specific examples of aralkyls are toluene, xylene, esitylene, styrene, benzyl chloride, o-fi oroioluene, !
  • An aralkyl group contains one or two aromatic ring systems containing from 6 to 10 carbon atoms and one or two alkyl, aikenyl and or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyi group containing 5 or 6 ring carbon atoms.
  • heterooaralkyl refers to an aralkyl group as defined above in which one or more carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulphur atom, that is to say to groups containing both aryi. or heteroaryl and also alkyl, alkenyi, alkynyl and/of heteroaikyl and/or cycloalkyi and/or heterocycloalkyl groups in accordance with the above definitions.
  • a heteroara!kyl group can contain one or two aromatic ring systems containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, aikenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyi group containing 5 or 6 ring carbon atoms, 1, 2, 3 or 4 of those carbon atoms having been replaced each independently of the others by oxygen, sulphur or nitrogen atoms.
  • heieroaralkyl groups are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloaikenyl, arylaikylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycioalkyl, arylalkylheteroeycloaikenyl, heteroarylalkyl, heteroaryiaikeny!, heteroary!aikynyl, heteroarylheieroalkyl, heteroarylcycloaikyl, heteroaryicycioalkenyl, Attorney Docket No.
  • heteroary!heierocycloalkyi heteroarylheterocycloaikenyl, heteroarylalkylcycloalkyl, heteroarylaikylheterocycloalkeny], heteroarylheteroalky!cyeloalkyl, heteroary Iheteroalky i cycioalkeny 1, heteroalkylheteroaryialky 1 and heteroaiylheteroaO ylheterQcycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsatarated.
  • This expression refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by unsubstituted Ci -Ce alky!., unsubstituted C2-CV, a!kenyl, unsubstituted C1-C0 aikynyi, unsubstituted CVQ heteroalkyJ, unsubstituted C -C JO cycioa!kyl, unsubstituted C2-C9 heterocycioalkyl, unsubstituted C 6 -Cic aryl, unsubstituted C C 9 heteroaryL unsubstituted C 7 ⁇ Ct2 aralkyl or unsubstituted C 2 -Cj] heteroaralkyl groups.
  • a wording defining the limits of a range of length such as, e.g. , "from .1 to 5" means any integer from 1 to 5, i.e., 1, 2, 3. 4 and 5. in other words, any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
  • Certain embodiments can comprise isotopes of atoms of the described compounds.
  • Isotopes are atoms having the same atomic number but different mass numbers.
  • tritium and deuterium are isotopes of hydrogen.
  • Examples for carbon isotopes are "C, 13 C and i C. Attorney Docket No. 0138,0001 -PC!
  • compositions cars comprise at least one compound of formula (i) or (11) and, optionally, one or more carrier substances, excipients and/or adjuvants.
  • Pharmaceutical coin positions can additionally comprise, for example, one or more of water, buffers (e.g., neutral buffered saline or phosphate buffered saline), ethanoi, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), raannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
  • buffers e.g., neutral buffered saline or phosphate buffered saline
  • ethanoi mineral oil
  • vegetable oil dimethylsulfoxide
  • carbohydrates e.g., glucose, mannose, sucrose or dextrans
  • raannitol proteins
  • compositions can comprise one or more of surfactants, tonicity agents (e.g., NaCl), buffers (e.g.. phosphate or citrate buffer), salts, preservatives (e.g., sodium edetate), co-solvent, and viscosity building agents,
  • surfactants e.g., NaCl
  • buffers e.g.. phosphate or citrate buffer
  • salts e.g., sodium edetate
  • preservatives e.g., sodium edetate
  • co-solvent e.g., sodium edetate
  • viscosity building agents e.g., viscosity building agents
  • one or more other active ingredients can (but need not) be included in the pharmaceutical compositions provided herein.
  • the 8- (heteroarylmethoxy)quinoline and 8-(arylmethoxy)quino1one compounds can be employed in combination with icatibant (injectable icatibanHFirazyr), ecallantide, CI -inhibitor, or kaHikrein inhibitor.
  • compositions can be formulated for any appropriate manner of administration, including, for example, topical (e.g., transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique.
  • compositions are in a form suitable for oral use. Such forms include, for example, tablets. Attorney Docket No. 0138.000!
  • compositions provided herein can be formulated as a iyophilizate. Some embodiments include compositions in a form suitable for sublingual administration.
  • the pharmaceutical composition can have a pH of less than about 7, less than about than about 6, less than about 5, less than about 4, less than about 3 or less than about 2 in embodiments.
  • compositions intended for oral or sublingual use can further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations.
  • Tablets contain the active Ingredient in admixture with physioiogically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., com starch or alglnic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or tab).
  • the tablets can be uneoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient can be mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium (e.g., peanut oil, Hquid paraffin or olive oil).
  • an inert solid diluent e.g., calcium carbonate, calcium phosphate or kaolin
  • an oil medium e.g., peanut oil, Hquid paraffin or olive oil
  • oral formulations can comprise a therapeutically effective amount of a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof and a pharmaceutically acceptable carrier, wherein the therapeutically effective amount can be between about 0.001 wt % and about 60 wt %; about 0.01 wt % and about 55 wt %; about 0.1 wt % and about 60 wt %; about 1 wt % and about 50 wt % of the oral formulation.
  • the oral formulation can further comprise hydroxy! propyl methyl cellulose acetate succinate.
  • the oral formulation can be in the form of a spray-dried dispersion in certain embodiments.
  • Aqueous suspensions contain the active gredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents (e.g., sodium carboxymethyicelluiose, methylcelluiose, hydropropylmethylceilulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkyiene oxide with fatty acids such as polyoxyethyiene siearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxyceianol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethyiene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids
  • Aqueous suspensions can also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin.
  • the oily suspensions can contain a thickening agent such as beeswax, hard paraffin or cety! alcohol.
  • Sweetening agents such as those set forth above, and/or flavoring agents can be added to provide palatable oral preparations.
  • Such suspensions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparatio of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent exemplified by those already mentioned above.
  • Additional excipients such as sweetening, .flavoring and coloring agents, can also be present.
  • compositions can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil Attorney Docket No. 013S.0001-PCT
  • Suitable emulsifying agents include naturally- occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides ⁇ e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g., sorbitan monooieate) and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide (e.g., polyoxyethyfene sorbitan monooieate).
  • An emulsion can also comprise one or more sweetening and/or flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations can also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • Compounds can be formulated for local or topical administration, such as for topical application to the skin or mucous membranes, such as in the eye.
  • Formulations for topical administration can comprise a topical vehicle combined with active ageni(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent, that the choice of a vehicle can be adjusted in view of the particular physical form and mode of delivery.
  • Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylcne, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; Hpid-based maieriais such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingo!ipids and waxes; protein- based materials such as collagen and gelatin; siiicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices.
  • organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin
  • glycols e.g.
  • a composition can further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters* gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylcellulose or Attorney Docket No. 0138.0001 -PCX gelatin-microcapsules, liposomes, albumin microspheres, rascroernulsions, nanoparticles or nanocapsuies,
  • a topical formulation can be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches.
  • the physical appearance and viscosity of such forms can be governed by the presence and amount of erau!sifier(s) and viscosity adjusters ⁇ present in the formulation.
  • Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, .moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams can be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity.
  • Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers.
  • Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like poiyox ethylene oleyl ether. PEG-40 stearate, ceteareth-12, ceteareth-20. ceteareth-30, ceteareth alcohol, PEG- 100 stearate and glyceryl stearate.
  • Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, macrocrystalline wax, beeswax, paraffin, and cetyl paSraitate.
  • a gel composition can be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquatemiums, Attorney Docket No, 0138.0001-PCT hydroxyethylcelhilose, hydroxypropylcellulose, hydroxypropylmethyleellulose, carborner or ammomated giycyixhizinate.
  • Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
  • nonionic, amphoteric, ionic and anionic surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
  • dimethicone copoiyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-diraonium chloride, and ammonium lauret sulfate can be used within topical formulations.
  • Suitable preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbaie/ascorbic acid and propyl gallate.
  • Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and batylene glycol.
  • Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
  • Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5.
  • Other suitable additional ingredients that can be included in a topical formulation include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents (e.g., witch hazel, alcohol and herbal extracts such as chamomile extract), bmders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propel lants, opacifying agents, pH adjusters and protectants.
  • Modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing.
  • Controlled release vehicles can also be used, and compositions can be formulated for transdermal administration as a transdermal patch.
  • a pharmaceutical composition can be formulated as inhaled formulations, including sprays, mists, or aerosols. Such formulations are particularly useful for the treatment of asthma or other respiratory conditions.
  • the compounds provided herein can be delivered via any inhalatio methods known to those skilled in the art.
  • Such inhalation methods and devices include, but are not limited to, metered Attorney Docket Mo. 0138.000i dose Inhalers with propeilants such as CFC or HFA or propeilants thai are physiologically and environmentally acceptable.
  • Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers.
  • Aerosol formulations for use in the subject method can include propellants, surfactants and co-solvents and can be filled into conventional aerosol containers that are closed by a suitable metering valve,
  • inhalant compositions can comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and crizrabronchiai use, or aerosol, compositions administered via an aerosol unit dispensing metered doses.
  • Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptabie inhalant solvent e.g., Isotonic saline or bacteriostatic water.
  • the solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the desired dosage amount of the liquid composition to be inhaled into the subject's lungs.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Formulations or compositions suitable for nasal administration include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered by rapid inhalation through the nasal passage from a contai ner of the powder held c lose up to the nose).
  • Suitable powder compositions include, by way of illustration, powdered preparations of the active ingredient thoroughly intermixed with lactose or other inert powders acceptabie for intrabronchial administration.
  • the powder compositions can be administered via an aerosol dispenser or encased in a breakable capsule which can be inserted by the subject into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation.
  • compositions can also be prepared in the form of suppositories (e.g., for rectal administration). Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal Attorney Docket No. 0138.0001 -PCX temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • compositions can be formulated as sustained release formulations (i.e., a formulation such as a capsule that effects a slow release of modulator following administration).
  • sustained release formulations i.e., a formulation such as a capsule that effects a slow release of modulator following administration.
  • Such formulations can generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Carriers for use within such formulations are biocompatible, and can also be biodegradable; in some embodiments the formulation provides a relatively constant level of modulator release.
  • the amount of modulator contained within a sustained release formulation can be based upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • the dose of the biologically active compound disclosed herein can vary within wide limits and can be adjusted to individual requirements.
  • Active compounds compounds of formula (!) or (11), such as, l -((4-chloro-3-(((4-(4-iluoro-lH-pyrazol"I-yi)-2- methylquinolin-8-yl)oxy)methy 2 -d ihy d ropyridine-
  • S-carbonitrile) described herein are generally administered in a therapeutically effective amount.
  • Doses can range from about 0.2 mg to about 50 mg of a compound having formula (I) or (il)/active compound per kilogram body weight, about 0.2 mg to about 35 mg per kilogram body weight, about 0,2 mg to about 20 mg per kilogram of body weight, or about 0.2 mg to about 14.4 mg per kilogram of body weight and can be repeatedly administered every from about 5 hours to about 12 hours, about 10 hours to about 12 hours, or between about 2 and about 5 times per day or between about 2 and about 3 times per day.
  • the daily dose can be administered as a single dose or in a plurality of doses.
  • Dosage unit forms will generally contain between from about 0.5 mg to about 100 nig, about 0.5 mg to about 20 mg, about 0.5 to about 10 mg, or about 0.6 m to about 6 mg of an active ingredient.
  • the specific dose level for any particular subject can be adjusted based upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs being used to treat the subject) and the severity of the particular disease undergoing therapy.
  • Active compounds disclosed herein will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo,
  • B 2 ⁇ bradykinin receptor antagonists can be used to inhibit the binding of Bi-faxadykimn receptor ligands (e.g., bradykinm (BK)) to B 2 -bradykmm receptor in vitro or in vivo.
  • BK bradykinm
  • B 2 - bradykinin receptor moduiator(s) provided herein can be administered to a subject ⁇ e.g., a human) orally or sublingual! ⁇ ', and are present within at least one body fluid or tissue of the subject while modulating B2 ⁇ bradykinin receptor activity.
  • Bj-bradykinin receptor modulators can be useful for the treatment and/or prevention and/or prophylaxis of B 2 -bradykmin receptor mediated angioedema, such as hereditary angioedema (HAE).
  • B 2 -bradykmin receptor mediated angioedema such as hereditary angioedema (HAE).
  • HAE hereditary angioedema
  • Embodiments including compounds having formula (1) or (O) or salts, stereoisomer, hydrates or solvates thereof can be used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of B 2 ⁇ bradykinin receptor mediated angioedema.
  • Compounds of embodiments can be labeled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity label like nanobodies, aptamers, peptides, etc., enzymes or enzyme substrates.
  • These labeled compounds can be useful for mapping; the location of bradykinin receptors in vivo, ex vivo, in vitro and in situ ⁇ e.g., in tissue sections via autoradiography) and as radiotracers for positron Attorney Docket No. 0138.0001 -PCT emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like to characterize those receptors in living subjects or other mater iais.
  • PET emission tomography
  • SPECT single photon emission computerized tomography
  • Embodiments also pertain to methods for altering the signal-transducing activity of bradykinin receptors in vitro arid in vivo.
  • compounds of certain embodiments and labeled derivatives thereof can be used as standard and reagent in determining the ability of a potential pharmaceutical to bind to the B 2 ⁇ bradykinin receptor.
  • Some embodiments can provide methods for localizing or detecting a B 2 ⁇ bradykinin receptor in a tissue ⁇ e.g., a tissue section), which methods involve contactin the tissue sample containing Eb-bradykinin receptor with a detectably labeled compound according to embodiments under conditions that permit binding of the compound to the B 2 - bradykinin receptor and detecting the bound compound.
  • tissue sample containing Eb-bradykinin receptor with a detectably labeled compound according to embodiments under conditions that permit binding of the compound to the B 2 - bradykinin receptor and detecting the bound compound.
  • Such methods and their respective conditions are known to those skilled in the art and include, for example, radioligand binding assays.
  • Some embodiments can provide methods of inhibiting the binding of bradykinin (BK) or any other B 2 ⁇ bradykinin receptor Hgand to a Bi-bradykinin receptor which methods involve contacting a solution containing a B 2 -bradykini ' n receptor antagonist- compound disclosed herein with cells expressing B 2 -bradykinin receptor under conditions and in an amount sufficient to detectably inhibit binding of BK or any other substance to B 2 - bradykmio receptor.
  • BK bradykinin
  • BK bradykinin
  • Certain embodiments can provide methods for treating subjects suffering from Bi-bradykmm receptor mediated aagioedema as mentioned above.
  • treatment encompasses both disease-modifying treatment and symptomatic treatment, either of which can be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.edeem after the onset of symptoms, in order to reduce the severity and/or duration of symptoms).
  • a Bs-bradykim receptor mediated angioedema is "responsive to Bj-bradykinin receptor modulation" if modulation of B 2 -bradykmin receptor activity results in alleviation of the condition or a symptom thereof.
  • Subjects can include but are not limited to primates (especially humans), domesticated companion animals (such as dogs, cats, horses) and livestock (such as cattle, pigs, sheep), with, dosages as described herein,
  • the compounds of formula (I) or (II) according to embodiments can have improved properties when compared to B 2 -bradykinin receptor antagonists known in the state of the art, especially, improved selectivity, low toxicity, low drug-drug interaction, improved bioavailability (especially with regard to oral administration), improved metabolic stability, improved stability in microsomal degradation assay, and improved solubility.
  • Bi-bradykimn receptor antagonists can be used to inhibit the binding of Bj-bradykinin receptor Hgands (e.g., BR) to B -bradykinin receptor in vitro or in vivo.
  • Bj-bradykinin receptor Hgands e.g., BR
  • Ba-bradykinin receptor modii!ator(s) provided herein can be administered to a subject (e.g., a human) orally or topically, and can be present within at least one body fluid or tissue of the subject while modulating B -bradykinin receptor activity, 00192]
  • a subject e.g., a human
  • a subject e.g., a human
  • B -bradykinin receptor activity e.g., B -bradykinin receptor activity
  • the compounds of described embodiments can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of embodiments can be synthesized using synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • reaction step 2 the methyl ether protecting group on 4 ⁇ (4-f1uoro ⁇ lH ⁇ pyrazol-l-yl)-8- methoxy-2-methylquinoline (Ql) was cleaved by aluminum chloride (AlCi 3 ) in toluene leaving the reactive hydroxyqninolme, 4-(4-f!uoro-lH-pyrazol-l-y -2-methylquinolin-8-ol (Q2).
  • reaction step 3 B2 and Q2 are reacted in the presence of potassium carbonate in acetonitrile/water to form an ether linkage between the reactive hydroxyl and chloromethyl groups resulting in the CFMQ.
  • mice Following CFMQ administration and prior to the terminal time point mice received an IV injection of Evans blue (EB) dye (30 mg/kg) and were sacrificed.
  • EB Evans blue
  • the bladder Attorney Docket No. 0I38.0OO1-PCT was removed, dried and weighed and extracted in formamide (1.0 mL), EB concentration in the formamide extract was determined spectrophotometncaliy and EB content, was calculated as ⁇ ig EB per milligram of tissue weight. Efficacy was determined by inhibiting the accumulation of EB in the bladder.
  • CFMQ doses of 0.001, 0,05, 0.1, 0.25, 0.5, LO, and or 3.0 mg kg were administered as IV bolus injections to WT mice (n ⁇ 8/dose group).
  • a dose-response compared to vehicle controls was demonstrated, with significant inhibition of plasma extravasation at doses of 0.5, LO, and or 3.0 mg kg.
  • CFMQ HCT3711
  • ED 50 effective dose
  • CFMQ CFMQ
  • mice per group received either vehicle or CFMQ (HGT371.1 ) at 1.0, 3,0, .10, or 30 mg/kg by oral gavage.
  • An additional dose group received Firazyr ® (icatibant-0.4 mg/kg) as a subcutaneous (SC) injection.
  • Firazyr ® icatibant-0.4 mg/kg
  • SC subcutaneous
  • the EB concentration of the formamide extract from the bladder demonstrated CFMQ (HGT3711) inhibition of EB absorbanee in a dose dependent manner.
  • An oral dose of 3,0 mg kg was determined to be the minimally-effective dose (MED), and a dose of 10.0 mg kg (plasma value of 267 nM) was found to be equally effective as a 0.4 mg/kg SC dose of Firazyr* (icatibant).
  • MED minimally-effective dose
  • Firazyr* icatibant
  • mice To demonstrate efficacy in a mouse model relevant to the .HAE disease, studies were conducted in a knockout mouse that is deficient in the C-l inhibitor (Cl-INR- KO). These mice contain a simiiar genetic deficit to the HAE patient/subject population and demonstrated increased vascular permeability as compared to wild-type littermates.
  • Cl-INR- KO C-l inhibitor
  • the EB concentration of the formamide extract from the bladder of knockout mice demonstrated CFMQ inhibition of EB absorbance in a dose dependent manner.
  • An oral dose of 3.0 mg kg was determined to be nearly as effective as a 0,4 rag/kg SC dose of Firazyr® (icatibanf) in the knockout mice and both 10 and 30 mg kg doses of CFMQ provided almost 100% inhibition of EB accumu lation in the bladder of knockout mice.
  • CFMQ JSM U938/HGT371 1
  • CFMQ was compared to a diverse set of receptors and reference agents in an in vitro assay using cells from rat heart urinary bladder, cerebral cortex, as well as human recombinant ceils (CHO and HEK 293) and other cell lines.
  • Each assay included a ligand at a specific concentration (concentration ranging from 0.007-10 nM), in addition to a non-specific ligand (concentration ranging from 0J ⁇ -50 nM) for incubation periods ranging from 15 minutes to 6 hours at 4°-37°C.
  • the specific binding to the receptors was defined as the difference between the total binding and the nonspecific binding, determined in the presence of an excess of unlabeled CFMQ.
  • concentration causing a half-maximal inhibition of control specific binding (iC 50 values) and inhibition constants (Kj) were determined, and each reference compound was within the accepted limits of the historic average ⁇ 0.5 log units).
  • CFMQ was found to bind to a small number of off-target (non-bradykmin 2) receptors with ICso values less than 10 ⁇ (Table 4). The levels at which the off-target receptors were bound were greater than ten times higher than the concentrations required to influence efficacy. CFMQ (HGT371 !) was demonstrated to be selective in its binding to the B 2 -bradykimn receptor and to have a strong binding affinity to the i bradykinin receptor.
  • CFMQ was formulated with incubation buffer (containing 2 nM [ 3 H] bradykinin) and brought to concentrations of 0.001, 0.003, 0.01, 0.03, 0.1 , 0.3, 1.0 and 3.0 ⁇ .
  • incubation buffer containing 2 nM [ 3 H] bradykinin
  • concentrations 0.001, 0.003, 0.01, 0.03, 0.1 , 0.3, 1.0 and 3.0 ⁇ .
  • B 10 mM bradykinin
  • HEK 293 cells stably express .recombinant human Bj-bradykinin receptors ( 0 pmo!/mg protein) and were added to 96-welI culture-trays and cultivated for 1-3 days, followed by incubation with 100 ⁇ , of each of the incubation buffers containing [ 3 H]BK. After a 90-minute incubation period and washing (4x PBS (phosphate buffered saline)) supematants of the cell mixtures were transferred to scintillation vials and assayed .for [ 3 H]BK in a beta-counter. Results of counts per minute (cpm) for non-specific binding were subtracted from the total cpm and were used for curve fit and IC 5 o calculation.
  • cpm counts per minute
  • CFMQ activity on the inhibition of calcium mobilization a marker of B2-bradykinin receptor binding was characterized in a cellular assay
  • CFMQ was formulated as a 5 nM stock solution in 100% DMSO and serially diluted to 0.04, 0.12, 0.37, 1.1 1, 3.33, 10 and 30 nM
  • Human fibroblast (BF15) cells, which express the human B2R were loaded with 100 ⁇ calcium dye solution containing 2.5 mM probenicide and were then pre-incubated with CFMQ for 25 minutes at 25°C.
  • the inhibition, effect of CFMQ on bradykinin-mediated calcium mobilization was tested in this system by emission of fluorescence signals, using the height of the resulting peak over the baseline value (relative fluorescence units [RFU] max- min). The percent inhibition for each concentration was used for curve fit and IC 50 calculation.
  • CFMQ was found to have a strong potency to the human B -hradykmin receptor where it inhibited bradykinin-mduced calcium mobilization with an IC5 0 of 2.97 nM.
  • Firazyr® icatibant
  • the inhibition effect of CF Q on bradyki in induced calcium mobilization was examined in an ex vivo functional assay of human umbilical vein contfaetion, which is considered a gold standard for bradykinin activity measurements.
  • the human umbilical cord preparation was comprised of a control condition (no bradykinin. agonist), CFMQ at 10, 30, 100 and 300 nM concentrations and a positive control group with reference to a known B2R antagonist (icatibant; Firazyr®). Following a 30 minute incubation, BK -induced vein contractions were initiated in a cumulative maimer (final concentration of 10 ⁇ ), followed by maxima!
  • CFMQ was examined in an in vitro incubation assay with human small intestinal mucosa (Caco-2 ceil).
  • CFMQ at 5 ⁇ was dosed to the cell monolayers on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37°C with 5% CO 2 for 120 minutes.
  • Permeability of Lucifer Yellow (500 ⁇ ) was measured to ensure no damage was Inflicted to the cell monolayers during the CFMQ flux period. All samples were assayed by LC-MS/MS using eiectrospray ionization.
  • CFMQ HPT37! 1 was administered to fasted female CD-I mice (n-l 8/dose group) by a single oral gavage at 100, 250 and 450 mg/kg in a dose volume of 5 mL kg in a spray-dried dispersion formulation (discussed below). Blood samples were taken via cardioceniesis or abdominal vein prior to administration and at 10, 30. 60 (lhr), 120 (2 hr), 240 (4 hr) and 480 (8 hr) minutes post dose.
  • Plasma concentrations of CFMQ were determined by LC-MS/MS (liquid chromatography mass spectrometry) and concentrations below the limit of quantitation (3 ng/mL) were assigned a value of zero for pharmacokinetic analysis. Nominal dosing concentrations were used in all calculations.
  • Figure 7 illustrates the time-concentration curve at each dose level and Table 5 summarizes the plasma concentration (ng mL) and PK (pharmacokinetic) properties of CFMQ (HGT3711) following oral administration in mice.
  • NMP pyrrolidone
  • PEG400 10% Ethanoi: 30% polyethylene glycol (PEG400): 50% GELUCIRE (lauroyl polyoxylglycerides); and formulation 2; 10% NMP: 0% PEG400: 20% CREMOPHOR EL (Macrogolglycerol ricinoleate): 25% GELUCIRE 44/14 (lauroyl polyoxylglycerides): 25% CAPROYOL 90 (Propylene Glycol Caprylate).
  • Figure 8 illustrates the time-concentration curve of both formulations in both sexes of each species.
  • CFMQ BGT371 1
  • the vehicle formulation utilized in the studies was a spray-dried dispersion formulation of CFMQ (BGT371 I) compiexed with 50% hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) (discussed below).
  • HPMCAS hydroxyl propyl methyl cellulose acetate succinate
  • This stud utilized the spray-dried dispersion (SDD) (50; 50 with polymer; HPMCAS) formulation of CFMQ (HGT3711) (see below).
  • SDD spray-dried dispersion
  • HPMCAS polymer
  • Plasma concentrations of CFMQ (HGT3711) were determined by LC-MS/MS.
  • CFMQ HPT3711
  • CFMQ (HGT37! 1) was administered to fasted female Sprague-Dawley rats by a single intravenous injection at 1.0 mg kg, formulated in 100% PEG200 (Table 2.6.5.X, Study 10SHIR.USP1 1). Blood samples were taken via a jugular vein cannula prior to Attorney Docket No. 0138.0001-PCT administration and at 0.083 (5 min), 0.25 (.15 min), 0.50 (30 min), 1, 2, 4 and 8 hours post dose. Plasma concentrations of CFMQ (HGT3711) were determined by LC-MS/MS and concentrations below the limit of quantitation (1 ng/mL) were assigned a value of zero for pharmacokinetic analysis. Nominal dosing concentrations were used in ail calculations.
  • CFMQ (HGT371 1) was administered to fasted female beagle dogs by a single intravenous injection at 1.0 mg/kg, formulated in 100% PEG200 (Table 10). Blood samples were taken via jugular vein puncture prior to administration and at 0.083 (5 min), 0.25 (15 min), 0.50 (30 min), 1, 4, 8 and 24 hours post dose. Plasma concentrations of CFMQ (HGT371 3) were determined by LC-MS/MS and concentrations below the limit of Attorney Docket No. 013S.0001-PCT quantitation (1.0 ng/mL) were assigned a value of zero for pharmacokinetic analysis. Nominal dosing concentrations were used in all calculations.
  • a cross-over P (pharmacokinetic) analysis was conducted in cynomolgus monkey.
  • Two fasted male monkeys in each dose group received a single 1.0 mg/kg dose of CFMQ (HGT37 I 1) by either IV (intravenous) or PO (oral) administration, with a 7-day washout period between each dose.
  • the dose concentration was 1.0 mg/mL with, a dose volume of 1.0 mL/kg.
  • Blood samples were collected via the femoral vein at 0,083 (5 min), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 3, 4, 6, 8, 18 and 24 hours post-dose.
  • Plasma concentrations of CFMQ (HGT371 1) were determined by LC-MS/MS and concentrations below the limit of quantitation (2.5 ng mL) were assigned a value of zero for pharmacokinetic analysis. Following oral administration of CFMQ (1 mg/kg), the concentration of CFMQ in plasma was below the limit of quantitation (BLQ : - ": ⁇ 2.5ng ml) at each sampling time point, preventing assessment of pharmacokinetic properties of CFMQ Attorney Docket No, 013 ⁇ ,0Q01-PCT after oral administration in monkeys in this study, Table 1 1 summarizes the average PK properties for IV and PC) dosed groups.
  • CFMQ in vitro metabolic stability studies were performed to determine hepatic stability in vivo.
  • CFMQ was incubated in liver microsomal preparations from mouse, rat, dog, mini-pig, and humans, as well as an additional study with monkey and human.
  • CFMQ was incubated with human and animal liver microsomes at 0.3 mg/m ' L at 37°C for 30 or 60 minutes. Additional reference compounds were incubated as controls. Following incubation, samples were analyzed by HPLC-MS/MS.
  • CFMQ HAT3711
  • HAT3711 had variable stability in rodent species with generally increasing stability in higher species, with markedly higher stability in human liver Attorney Docket No. 0138.0001-PCT preparations.
  • Low metabolic stability in the monkey corresponded to low bioavailability and may indicate a unique metabolic pathway. See Table 12.
  • Ml was seen at 10% of parent, while M2 and M3 were formed at 5 % and 3 % of the parent respectively ,
  • A. lipidic formulation of CFMQ was prepared containing 10% N-methyl pyrrofidone (NMP), 10% TRANSCUTOL HP (highly purified 2-(2-ethoxyethoxy)ethanol), 30% polyethylene glycol (PEG400), and 50% GELUCIRE 44/14 (lauroyl polyoxylglycerides).
  • NMP N-methyl pyrrofidone
  • TRANSCUTOL HP highly purified 2-(2-ethoxyethoxy)ethanol
  • 30% polyethylene glycol (PEG400) 30% polyethylene glycol
  • GELUCIRE 44/14 lauroyl polyoxylglycerides
  • CFMQ was milled to have a nano size particle.
  • a spray-dried dispersion approach where CFMQ was complexed with a polymer was also evaluated.
  • CFMQ was spray-dried onto hydroxy! propyl methyl cellulose acetate succinate (HPMCAS)
  • HPMCAS hydroxy! propyl methyl cellulose acetate succinate
  • the spray-drying process consisted of three steps: slurry preparation, spray -drying, and secondary drying.
  • the slurry was prepared by dissolving HPMCAS polymer in. a methanol/water solvent mixture (90 v/10 v), then an equivalent amount of the CFMQ was suspended in the polymer solvent mixture.
  • the slurry was then heated and spray-dried through a flash nozzle into a nitrogen atmosphere in a spray-dryer.
  • the powder output of the spray-dryer retained a small amount of water/methanol, which was removed in a secondary drying step, which occurred in a convection tray dryer at 40°C/15% relative humidity (RH).
  • RH relative humidity
  • a pharmacokinetic extrapolation for a human oral dose was performed using allometric scaling of clearance and volume of distribution.
  • the human pharmacokinetic values were extapolated from in vivo mouse, rat, dog and monkey pharmacokinetic studies. Due to the variability in bioavailability across pre-clinical species a range of bioavailability values from 25% to 50% was modeled.
  • This pharmacokinetic model predicted that at a human equivalent dose of 0.8 mg/kg, plasma levels will stay above the predicted efficacious levels for between greater than 5, 10 and 12 hours when " bioavailability is 25, 50 or 75%.
  • This model was based on the assumption that all of the clearance pathways in the human were captured in the pre-clinical species.
  • ail ranges disclosed herein are to be understood to encompass any and all sub-ranges subsumed therein.
  • a range of "less than 10" can include any and ail sub-ranges between (and including) the minimum value of zero and the maximum value of 10, that is, any and all sub-ranges having a minimum value of equal to or greater than zero and a maximum value of equal to or less than 10, e.g.
  • the numerical values as stated, for the parameter can take on negative values.
  • the example value of range stated as "less than 10" can assume values as defined earlier plus negative values, e.g., -1, -1.2, - 1 ,89, -2, -2.5, -3, -10, -20, and -30, etc.

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Abstract

Methods of treating B2-bradykinin receptor mediated angioedema in a subject by administering a composition containing a 8 - (heteroaryImethoxy)quinolone compound, a 8- (arylmethoxy)quinoline compound, or a salt, a stereoisomer, a hydrate, or a solvate thereof. Oral formulations containing a 8-(heteroaryImethoxy)quinolone compound, a 8- (arylmethoxy)quinoline compound, or a salt, a stereoisomer, a hydrate, or a solvate thereof for the treatment of B2-bradykinin receptor mediated angioedema. Use of a composition containing a 8-(heteroaryImethoxy)quinolone compound, a 8-(arylmethoxy)quinoline compound, or a salt, a stereoisomer, a hydrate, or a solvate thereof for the manufacture of a medicament for the treatment and/or prevention of a B2-bradykinin receptor mediated angioedema.

Description

Attorney Docket No. 0138.0001
METHODS OF TREATING Bj-BRADY ININ RECEPTOR MEDIATED
ANG ί OEDEMA
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of, and relies on the filing date of, U.S. provisional patent application number 61/786, 126, filed 14 March 2013, the entire disclosure of which is incorporated herein by reference.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 1 1, 2014, is named 0138.0001 -PCX. SL.ixt and is 494 bytes in size.
BACKGROUND
[0003] Hereditary angioederaa (HAE) is a rare and potentially life-threatening genetic condition. HAE symptoms include episodes of edema (swelling) in various body parts including the hands, feet, face, intestinal walls and airways. Most HAE patients (those with Type i and Type H HAE) have a defect in the gene that controls the blood protein, CI esterase inhibitor (Cl-INH). The genetic defect results in production of either inadequate (Type 1 HAE) or non-functioning (Type Π HAE) C l -ΪΝΗ protein. The genetic defects related to CI -inhibitor that cause Type I and Type II HAE are autosomal dominant. However, absence of a family history of HAE does not rule out an HAE diagnosis. It has been reported that as many as 20% of HAE cases result from patients who had a spontaneous mutation of the CI -inhibitor gene at conception.
[0004] Normal C -ΓΝΗ protein helps to regulate the complex biochemical interactions of blood-based systems involved in disease fighting, inflammatory response and coagulation. Because defective C l-ΪΝΗ protein does not adequately perform its regulatory function, a biochemical imbalance can occur and produce unwanted peptides that induce the capillaries to release fluids into surrounding tissues, thereby causing edema. Attorney Docket No. 0138,0001-PCT
[0005] Most attacks of HAE occur spontaneously, although anxiety, stress, minor trauma, surgery and illness have been cited as triggers. Untreated, an average HAE attack lasts twenty-four to seventy-two hours, but some residual swelling can persist for up to three or more days. Swelling of the extremities can be painful and debilitating depending on the location of the edema. Attacks that involve the face and/or throat are considered to be a medical emergency, because swelling of the throat can close the airway and lead to death by asphyxiation. Abdominal attacks cause severe pain, nausea, vomiting, dehydration and watery diarrhea. Further, abdominal attacks can mimic a surgical abdomen and many patients have been subjected to unnecessary exploratory surgery.
[0006] Deficienc of CI -inhibitor permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin. Bradykinin (BK) is a vasoactive nonapeptide, H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH (SEQ ID NO:l), formed locally in tissues, often in response to a trauma. Two types of BK receptors are recognized in mammals. Bl and B2, The actions of B mediated by the B2-bradykinin receptor are important physiological functions, such as the increase of vascular permeability, modulation of inflammatory responses and pain, and induction of vasoactive effects (vasodilatation, vasoconstriction). Surplus bradykinin results in inflammation, such as swelling, redness, overheating, and pain.
[0007] Bradykinin is responsible for the clinical symptoms of HAE, causing increased vascular permeability, vasodilation, and contraction of visceral smooth muscle. Thus, after an inciting factor, a quantitative or qualitative deficiency of Cl-MH leads to inadequate regulation of bradykinin production and increased vascular permeability. Extravasation of fluid leads to non-pruritic edema. As high molecular weight kiniaogen is exhausted and bradykinin degraded, the edema begins to subside and the fluid is resorbed by the lymphatic system,
[0008] Peptide and non-peptide antagonists of Ba-bradykinm receptor have been described in the art. Firazyr® (injected icatibant) is a peptidomimetic drug consisting of ten amino acids tha is a selective and specific antagonist of Ba-bradykmin receptor and has been used to treat acute attacks of HAE in adults with Cl -esterase inhibitor deficiency. Ecailantide (trade name Attorney Docket "No. 0138.000I-PCT
Kalbitor®, investigationai name DX-88) is a drug used for the treatment of acute attacks of HAE. It is an inhibitor of the protein kailikrein and a 60-amino acid polypeptide. Also purified (Ci lNH P) or recombinant (rhClINH) human Ci-inhibitor l as been used in the treatment of acute attacks of HAE.
[0009] There are drawbacks with existing treatments. CI -inhibitor replacement products must be reconstituted prior to use and are administered intravenously. Prophylactic therapy with C I -inhibitor products requires intravenous administration twice weekly and only prevents -50% of attacks. Androgens are used for prophylaxis, but there are long-term side effects and they are not recommended for female and pediatric patients. Ecallantide, a subcutaneous (SC.) treatment for acute HAE attacks, has a. documented risk of anaphylaxis and must be administered by a healthcare professional in a hospital setting. Icatibant, which has been approved in the U.S. for subcutaneous self-administration during acute attacks of HAE, produces injection site reactions.
[0010} Methods of treating B2-bradykinin receptor mediated angioedema are desirable. Treatment methods using small molecule B2~bradykinin receptor antagonists are of interest. Also oral therapies for treating Brbradykmin receptor mediated angioedema are desirable.
SUMMARY
[001 1} Certain embodiments are drawn to methods of treating a B2~bradyki«in receptor mediated angioedema in a subject comprising administering to the subject in need thereof a therapeutically effective amouni of a composition comprising a compound having formula (1) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof!, wherein plasma extravasation in the subject is reduced upon administration of the compound or the pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof and formula Ϊ is as follows: Aitomey Docket No. 0138.000 ). -PCX
Figure imgf000005_0001
wherein R3 is Ci or CN;
wherein ¾ is
Figure imgf000005_0002
Attorney Docket No. 0138.0001-PCT
Figure imgf000006_0001
Attorney Docket No. 0138.000I-PCT
Figure imgf000007_0001
wherein g is selected from the group consisting of H, a methyl group, an ethyl group, a propyl group, a butyl group, a perstyl group, or a hexyl group.
[0012] Some embodiments are drawn to methods of treating a 82-bradykmin receptor mediated angioedema in a subject comprising:
administering to the subject in need thereof a therapeutically effective amount a composition comprising a compound having formula (II) or a pharmaceutically accepLable salt, stereoisomer, hydrate, or solvate thereof Attorney Docket No. 0138.00.01-PCT
Figure imgf000008_0001
[0013] thereby reducing plasma extravasation in the subject.
[0014] Embodiments as-e drawn to methods of treating a B2-bradykinin receptor mediated angioederaa in a subject comprising:
adrninisiermg to the subject m need thereof a therapeutically effective amount a composition comprising
[0015] 1 } -({4"Cb]oro-3-(((4-(4-iluoro- IH-pyrazol- 1 -yl)~2-n ethylquinoHn-8~y3)oxy)methyl)- 6~methyipyridin-2-yl)methyl)-2-oxo-l, 2~dihydropyridine-3-carbonitrjIe;
Figure imgf000008_0002
y!)oxy3methyl}phenyI)(methyl)amino]-2-oxoeihyl}prop~2-enamide;
[0017] (2E)-3-(6-(Acetylamino)pyridi^^^
yl)oxy]methyl }phenyl)araino] -2-oxoethy! } prop-2-enam kle;
[0018] (2E)-N-{2-[(4-Chloro-2-cyano-3-{[(2-methylquinolin-8- yi)oxy3methyi}phenyl)(metfayI)amm^
enamide;
[0019] N-[4-chloro-2~cyano-3-[(2'methylqinnolin-8-yl)oxy.raethyl]phenyi]~2-
(ethylcarbamoylammo)-N-methylacetamide;
[0020] 2-(4-araiflobutylcarbamoyJamfo^
8~yl)oxymethyi]phenyl]-N-methyiacetam.ide;
[0021 ] 4-[f2-[4-chloro-2~cyano- -methyl-3-[ 2-methylquinolin-8-yl)oxymethyl]
anilino]-2-oxoethyl]carbamoyIarnin6jbutanoic acid;
[0022] (E)-N- 2-|;4-chloro-2-cyano-N-methyl-3-i(2-methy]quinolm-8-yl)oxymethyl] aniiino3-2-oxoethyJ3»3-(3-methoxyphenyl)prop-2 -enamide; Attorney Docket No. 0138.000 S~PCT
[0023] (E)-N~[2 4 ihloro~2-cyano-N-metliyl-3 (2-methyIquino!in-8~yl)oxymethyl] ansimo]~2-oxoethyl]~3-[4~(tr^
[0024] N-[2,4-dichloro-3-[(2-methylquino!in-8-yl)oxymethyl]phenyij-2-[5-(2J
2-dimethylpropanOyl)-.l -methylpyiTol-2-y]]-N--methylaceiamide;
[0025] 4- (E)-3-[[(Z)-3-[2,4-dich}oro-3-[(2-methyiq inoim-8-yl)oxy^
enyl] amino ] - 3 -oxoprop - 1 -enyl] -N-me thy Ibenzam kle ;
[0026] (E)-N~[2-[2,4~dichloro-N^
oxoeihyl]-3-phenylprop-2-enamide hydrochloride;
[0027] 2-(5-ben2oyl-l-meihylpyrrol-2-yl)-N-[2,4-dichloro-3-[(2-me1iiylquinolin-8- yl)oxymcthyi]phenyl]- -methylacetamide;
[0028] {E) -(6-aceiamidopyridio-3~yl)-^
y l)oxymethy !] anilino] -2 -oxoethyl] prop-2-enamide ;
[0029] N-[2,4-dichioro-3-{(2H*K?t^^
methyl-5-(ihiophene-2-carbonyl)pyrroi~2-yl]acetaniide;
[0030] 2-[5-(cyclohexanecarbonyl)-l -metliylpyiTol-2-y j-N-[2,4-dichloro-3-[(2- methylquino].in-8-yl)oxymethyl]phenyl]-N-methylacetaraide;
[0031] 2-[5~(4-cyanobenzoyl)-l~methylpynOl-2-yl3^
yl)oxymethyl]phenyl3acetamide;
[0032] 2-[5-(4-cyanobenx yl)-l H-pyrroi-2-yl]->l-[2,4-dich}oro-3~ {2-meihylqumolin-8- yi)oxyraethyl]phenyl]-N-iT)eihylaceiamide;
[0033] N-[2,4Kliehioro-3-[(2- ethy^
me thy !-5-(2 -phenylac etyl)py rrol-2- Ί jacetami de;
[0034] 2-[5-{4-aiBmobeirzoyl)-l-meihylpy rol-2~yii-N-[2i4-djchloro- yl)oxymethyi]phenyl3- -methylacetamide;
[0035] N 2^dichloro-3- (2-methylqiiittol^
methyl -5 -(pyridine-3 -carbony I )pyrrol -2 -yl]propanamide;
[0036] 4 (E)~3-[[2 2^dich_oro-N-m^
oxoethyi]affiino]~3-oxoprop-l -enyl]~N-methylbenzamide;
[0037] (E)-3-(6-acetamidopyridin-3-y.i)^
8-yI)oxymethyl]anilino]-2-oxoeihyl]prop-2-enamide;
[0038] N-i2,4-djch]oro-3-[(2-mclbylquinoHn-8-y!)oxymethyl]phenyl3-N-raeihyl-3-[l-
.methyi-5-(thiophene-2-carbonyl)pyrrol-2-y!]propanamide; Attorney Docket No. 0 J 38.0001 -PCX
Figure imgf000010_0001
yl)oxyn ethyi]pheny{]-N-methyiacetamide;
[0040] 2~[5-(6-cyanopyridine-3-carbonyl)-l-mei y!p> ro!-2-ylJ-N-[2J4-dicrtloro-3-|(2- mei ylquinolin~8-yl)oxymethyl]phenyl j-N-methylacetarnide;
[0041] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, thereby reducing plasma extravasation in the subject.
[0042] Certain embodiments are drawn to oral formulations comprising a therapeutically effective amount of a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof and a pharmaceutically acceptable carrier, wherein the therapeutically effective amount is between about 0.001 wt % and about 60 wt % of the oral formulation,
[0043] Certain embodiments are drawn to the use of a composition comprising a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof for the manufacture of a medicament for the treatment and/'or prevention of a Ba-bradyki n receptor mediated angloedema.
BRIEF DESCRIPTION OF THE FIGURES
[0044] Figure 1 depicts a synthesis scheme for l-((4-chioro-3-(((4-(4-fluoro»l H-pyrazoi-1 - yl)~2-methyIquinolin-8-yl)oxy)m 2- dihydropyridine-3-carbonitrile (JSM 1938/HGT37I I).
[0045] Figure 2 is a graph showing Evans blue concentration (jig mg) ± SEM (standard error of the mean) of tissue in C57BL/6J (wild-type) mice following intravenous administration of l -((4 ^hloro-3-(((4-(4-fluoro-lH-pyra2oI-l-yl)-2-methyiquinoiin-8-y oxy)methyl)-6- methylpyrk1in-2-yI)methy3)-2-oxo-l , 2-dihydropyridine-3-carbonitrile (JSM1938/HGT3711). * Significant differences to vehicle (p<0.05, Kruskai-Wallis One Way ANOVA with multiple comparisons versus control group (Dunn's Method), a— 8) insert shows the value distribution of single animals. Attorney Docket No. 0138.OOGI-PCT
[0046] Figure 3 is a graph showing Evans blue concentration
Figure imgf000011_0001
± SEM (standard error of the mean) of tissue in C57BL/6J (wild-type) mice following oral administration of l-((4- chloro-3-(((4-(4-fluofo-iH-pyrazol-l-yl 2>methylquinolin-8-yl)oxy)ra^
meihy.l yridin-2- !)niet yl)-2~oxo--i , 2-dihydropyridine-3~carbonitrile (JSMI 938/HGT3711). * *Sigmficant differences to vehicle p<O.05, (Mann- Whitney Rank Sum Test) JSM i 1938 = HGT3711-l -((4-Chioro-3-(((4-(4-flu^^
yl)oxy)methyl)-6-meihyipyridm-2>yl)methyi)-2-oxo-l5 2-dihydropyridine-3-carbonitrile
[0047] Figure 4 is a graph showing Evans blue concentration (mg/raL) ± SEM of bladder extract in CHNH mice following oral administration of l-((4-chloro-3-(((4-(4-fiuoro-l.H- pyrazoM-yi)-2-metbylqumolm-8-yl)oxy)m 2- dihydropyridine-3-carbonitrile (JSM1938 HGT3711).
[0048] Figure 5 is a graph showing Evans blue concentration (mg mL) ± SEM of bladder extract in C 1 -INI Ϊ O (knockout) mice following oral administration of l-((4-chioro-3-(({4- (4-fluoro-1 H-pyrazol-i -yl)~2-methylq^
yI)methyi)-2-oxo-l, 2-dihydropyridine-3-carbonitriie (JSM1938/HGT371 1 ).
[0049] Figure 6 is a graph, showing the results of ex vivo efficacy of I~((4-chloro-3-(((4*(4- fluoro-lH^yrazoi~l -y!)-2-met ^
oxo- 1, 2-dihydropyridine-3-carbomtrile (JSM I938/I-IGT37H) in a human umbilical vein assay.
[0050] Figure 7 Is a graph showing average plasma concentrations versus time following orally administered 1 -((4-chloro-3-(((4-(4-fluoro-l l:i-pyra7.ol-i~yl)-2-methylquinoiin-8- yl)oxy)methyl)-6-methyipyridin-2-yi)rnet'hyl)-2-oxo-l, 2-dihydropyridine-3-earbonitrile (HGT371 1) in female CD-I mice.
[0051] Figure 8 shows average plasma concentration versus time following orally administered l -((4-chloro-3-(((4-(4-fluoro-.Uri-pyra2ol-l-yl)-2-methylquinoltn-8- yl)oxy)methyl)-6-methylpyrid«i-2-yl)methyl)-2-oxo-i, 2-dihydropyridine-3-carbonitrile Attorney Docket No. 05 8.0001 -PC'T
(HGT3711) in male and female Wistar and Sprague-Dawley rats (Formulation 1 -top; Formulation 2 -bottom).
[0052] Figure 9 is a graph showing individual plasma concentration (ng/mL) of 1 -((4-chloro- 3 ~(((4~(4-fluoro- 11 ί-pyrazol- 1 -yl)-2-methylqumoim-8-yl)oxy)methyl)-6-met¾y Ipyridin-2- yl)methy l)-2-oxo- 1 , 2-dihydrqpyridine-3-earbonitriie (HGT371 I) versus time following oral administration in female Yucatan mini-pigs at 10 mg kg (Should this be swapped out with a later graph)?
[0053] Figure 10 shows representative chromatograms of HGT371 1 incubated for 4 hours with mouse, rat, mini-pig and human hepatocytes. * HPLC retention time of HGT3711 (JSM1 1938) was 35 minutes.
[0054] Figure I I depicts the structures of metabolites of l -((4-ch1oro~3-(((4-(4-fluoro-lH- p>Tazol-l -yl)-2-methy]qumolin-8-yl)ox 2- dihydropyridine-3 -c arborsi tri le.
DETAILED DESCRIPTION
[0055] Certain embodiments are drawn to methods of treating a B2-bradykinin receptor mediated angioedema (such as, hereditary angioedema) by administering a therapeutically effective amount of a composition containing a 8-(heteroaryimethoxy)quinolme or 8- (arylniethoxy)quinoline or a pharmaceutically acceptable salt, a stereoisomer, a hydrate, or a solvate thereof. These compounds can act as selective modulators (e.g., antagonists) of B2~ bradykinin receptors and can result in reduced plasma extravasation in a subject after they are administered.
[0056] B?-bradykinin receptor modulators (e.g., antagonists) provided herein can exhibit, high activity on human Bj-bradykinin receptor (i.e., an inhibition constant (IC50) for competition with binding of labeled bradykinin (B ) to human Bj-bradykin n receptor of less than about 5 micromolar) or very high activity on human B2~bradykinin receptor (i.e., an IC.50 for competition with the binding of labeled BK to human B2~bradykinin receptor of less than about 50 nanomolar), in certain embodiments, such modulators exhibit a high activity on B2- Attorney Docket No. 0138.0001 bradykinin receptors of species other than human, e.g., rat, mouse, gerbiL guinea pig. rabbit, dog, cat, pig, or cynomolgus monkey.
[0057] The activity of the B2~bradykmin receptor modulators can be assessed using appropriate in vitro assays. For instance, the ICso values of the modulators for Bi-bradykinm receptor can be determined via a radioligand binding assay. Inhibitor effects of the 3¼- bradykmin receptor modulators provided herein for B bradykinin receptor can be determined, for example, via a calcium mobilization assay. B^-bradykimn receptor modulators can have an ICso (half-maximal inhibitory concentration) of about 5 mi.crom.okr or less., about 500 n or less, about 50 nM or less, about 10 nM or less, or about 1 nanomolar or less in the assays mentioned above. In embodiments, a compound having formula (I) or (II) can have a half maxima! inhibitory concentration (ICso) for competition with the binding of labeled bradykinin to human B2 -bradykinin receptor of less than about 50 nanomolar, less than about 10 nanomolar, or less than about 5 nanomolar to B2-bradykima receptor,
[0058] Certain embodiments comprise administering pharmaceutical compositions comprising at least one B^-bradykinin receptor modulator as described herein, in combination with a physiologically acceptable carrier or excipient. Processes for preparing such pharmaceutical compositions are also provided. Such compositions can be useful in the treatment ofBa-bradykinin receptor mediated angioedema (e.g., HAE).
[0059] Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds can occur in Z- and E-forms, with ail isomeric forms of the compounds being included in embodiments unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Recited compounds are further intended to encompass compounds in which one or .more atoms are replaced with an isotope (i.e., an atom having the same atomic number but a different mass Attorney Docket No. 0138.0001 -PC number). By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include J l€, ,3C and 14C.
[0060] Compounds according to the formulas provided herein, which have one or more siereogerdc centers, have an enantiomeric excess of at least 50%. For example, such compounds can have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%, Some embodiments of the compounds have an enantiomeric excess of at least 99%. it will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiraf HPLC column.
[0061] Certain compounds are described herein using a general formula that includes variables (e.g., Rj-Rp). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R*, the group can be tmsubstituted or substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds (i.e., compounds that can be isolated, characterized and tested for biological activity).
[0062] The terms "8-(arylmethoxy)quinoline" and "8-(heteroaryimeihoxy)qumoline'\ as used herein, refer to compounds of formula (I) or (H) provided herein (described below), as well as pharmaceutically acceptable salts, stereoisomers, hydrates, and solvates thereof. It will be apparent that such compounds can be further substituted as indicated.
[0063] Formula (I) is as follows: Attorney Docket No. 0138.0001-PCT
Figure imgf000015_0001
[0064] Rj can be hydrogen; an optionally substituted alkyl; optionally substituted aJkenyl; 5- mernbered heterocycioalkyi having from 1 to 3 heteroatoros each independently selected from. N, O or S, or cycloalkyl, wherein said 5-raembered heterocycioalkyi or cycloalkyl can be substituted with from 0 to 3 substituents each Independently selected from halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyi, cycloalkyl, heterocycioalkyi, aikyicycloaikyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or a 5-membered heteroaryl having from 1 to 4 heteroatoms each independently selected from N, O or S, wherein said 5-raembered heteroaryl is substituted with from 0 to 3 substituents each independently selected from halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, a!kytiy!, heteroalkyi, optionally substituted ary! or optionally substituted heteroaryl.
[0065] In. certain embodiments, R5 can be H, a Ct- alkyl (e.g., a methyl group, an ethyl group, a propyl group, a butyl group, a penryl group, or a hexyl group),
Figure imgf000015_0002
In some embodiments, R; can be H or
[0067] In embodiments R2 can be a 6-membered aryl or 6-membered heteroaryl, wherein the 6-membered heteroaryl comprises 1 nitrogen atom. The 6-membered aryl or heteroaryl can Attorney Docket No. 0138.0001-PCT be subsiiutted with ί to 3 subsiituents each independently selected fi-om halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto,. alkyi, alkerryl, aikynyl, heteroalkyl, cycioalkyl, .heterc-cycloaikyl, alkylcycloalkyl, heteroalkyicycloa!kyl, aryl, heteroaryl, aralkyl, and heieroaralkyl.
[0068 ] In certain embodiments, R2 can be
Figure imgf000016_0001
[0069] R3, R , Rs, Ri, R7, R§. 9 and R!0 can each be independently selected from a halogen atom, an oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyJ, aikynyl, heteroaikyl, cycioalkyl, heterocycloaikyl, alkylcycloalkyl, heteroaikylcycloalkyl, aryl, heteroaryl, aralkyl, and .heteroaraikyi, and R3 can also be selected from H in some embodiments.
[0070] In some embodiments, R3 can be a halogen atom (such as. CI), CN or H. In certain embodiments, R3 can be Ci or CN. Rs can be a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, in certain embodiments. In certain embodiments, R5 Is a methyl group. R§ can be a halogen atom (such as, CI) or a Ci-Ca alkyl (such as, CH3), in certain embodiments.
[0071 R4 can, In certain embodiments, have the formula
[0072] Attorney Docket No. 0138.0G0.1~PC
Figure imgf000017_0001
Attorney Docket No. 013 S.OOOl -PCX
Figure imgf000018_0001
Attorney Docket No. 01.38.0001-PCT
Figure imgf000019_0001
Attorney Docket No, 0138.0001-PCT
Figure imgf000020_0001
Attorney Docket No. 0138.0001 -PCX
{00 93 ¾ certain embodiments, R8 can be a halogen or a Cj-Ce alkyl. R8 can be CI or C¾ in embodiments, in some embodiments, R9 can be H or a -Ce alkyl. R can be C¾, in certain embodiments.
[00100] Rio can be selected from
[00101] Certain embodiments are drawn to methods of treating a B2-bradykinin receptor mediated angioedema in a subject comprising:
administering to the subject in need thereof a therapeutically effective amount of a composition comprising a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
In certain embodiments the compound having formula (I) can be as follows:
Figure imgf000021_0002
Attorney Docket No.0138.0001-PCT wherein R2 is
Figure imgf000022_0001
wherein 3 is Ci or CN;
Figure imgf000022_0002
Attorney Docket No. 0138.0001-PCT
Figure imgf000023_0001
Attorney Docket No. 0138.0001
Figure imgf000024_0001
[00102] wherein Rs is selected from the group consisting of H, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyi group, or a hexyf group
[00103] Plasma extravasation in the subject can be reduced upon administration of the compound of formula (I) or (11) or the pharmaceutically acceptable salt stereoisomer, hydrate, or solvate thereof. The iVbradykinin receptor mediated angioedema treated by embodiments can be hereditary angioedema. Certain treatment methods of embodiments can further comprise administering icatibant, ecailant.de, fresh frozen plasma, CI -inhibitor, or kaliikrem inhibitor to the subject in addition to a therapeutically effective amount of a composition comprising a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
[00104] Some specific examples of compounds that can be used hi embodiments encompassed by formula (I) or (11) include:
[00105] l l-((4-Chloro-3-{((4-(4-flaoro-lH-pyrazol-l -yl)-2~mefhyiquino!in-8- y3)oxy)methyl)-6-metfayipyrid!ii-2-yl)rnethy3)-2-oxo-l? 2-dihydropyridme~3-carbomtrile;
[00.106] (2E) -[6-(Acetylamino)pyridi^^
methylquinolin~8~yl)oxy]methyl}ph
[00107] (2E)-3-[6-(Aeetylamino)pyrid^
methylquinoHn~8~yl)oxy]methyl}phenyi)amino]-2-oxoethyl}prop-2-enamide; Attorney Docket No. 0138.0001-PCT
[00108} (2E)- 2-((4-Chloro-2-cyano-3-{[(2-methylqi{inolin-8- yl}oxy3metfayl}phenyl)(methyl)ammo^
enamide;
[00109] N-[4-ohloro-2^yano-3-[(2-rnethylquino!j«-8-yI)oxymeAyljphenyl]-2-
(ethykarbamoylamino)-N-methyiacetamide;
[001 10] 2~(4-ammobutyIcarbamo to
S-yi)oxymeiihyl3phenyl]-N-methylacetan\ide;
[00111 ] 4-[[2-[4K;hloro~2-cyano-N~methyI-3~|^
aiiilmoj-2-oxoethyl3carbamoyiamSno)butaBoic acid;
[001 12] (E)-N-[2 4-chloro-2-cyaMO-N~methyl-3-[(2~methylqiijnolin
anilino]-2-oxoethyi]-3-(3-methoxyphenyl)prop-2 -enamide;
[001133 (E)-N 2~[4~ch3oro~2-cyano-N~mei^
ani!mo]-2-oxoethyl]~3-[4-(trifluoromethyl)phenyl3prop-2-enamide;
[001 14] N 2!4~dichloro-3 (2-methylqiimolm-8-> }oxymethyl]phenyl]-2-[5-(2,
2-dimetbyipropanoyl)-l-methylpyrrol-2-yl3- -raethylacetamide;
[00 15] 4-[(E) -[E(Z)-3-[2,4-dichIoro-3-[(2-methylquinolin-8- yl)oxymethyi3phefiyi]prop-2-e^
[001163 (E)-N-[2-[2,4-dichloro-N-methy!-3-[(2-methyiqumoIin-8- yi)oxymefhyl]aniiino3~2~oxoethyi3^
[00117] 2-(5-benzoyl-l -methylpyrroI-2-y!)- -[234-dIchloro-3-[(2-methylqi3molin-8- yl)oxymethyl3phenyl]-N-methylacetemide;
[00118] (E)-3-(6-acetamidopyrid^
y3)oxyraethyl3anUino]-2-oxoethyl]prop-2-enamide;
[0011 3 N-[2,4~dichlorc>-3-[(2-methylquinol ^ - methyl-5-(thiop ene-2-carboayl)pyrroi-2-yl]acetamide;
[00120] 2-[5-{cyclohexanecarbonyI)-l -met ylpynOl-2-yl3-N~[2J4-dichloiO-3-[(2- methylquinoiin-8-yi)oxymethyi]phenyl]-N-methylacetamide;
[00121] 2-[5^ ^ anobenz» l)-l-me& l^^
rnethylquinolin-8-yl)oxymethyi]phenyl]acetarnide;
[00122] 2-{5^4-cyanobenzoylHH-pyr^
8~yi)oxymethyl]phenyl]-N-methylacetamide;
[00123] N- 2,4-dichloro~3-[(2-me lquinoi^ Attorney Docket No. 0138.0001-PCT meil yl-5-(2-phenylacei}rl)pyrrol-2-yi]acetamide;
[00124] 2 5-(4-ammob£nzoyi} -meihyip>TTol-2~yl]-N 2,4-dichloro-3-[(2-- met yiquinoHn-8-yl)oxymethy!3phenyl3-N-methyiacetamide;
[00125] -[2,4-dichloro-3-[(2-m<ithyIquinolm-8-yl)oxymethyl3ph^
methyi-5-(pynd.me-3-carbonyl)pyrroI-2-yl3propaiiamide;
[001263 4-[(E)-3^I2-[2,4-dichloro-N^^
yl)oxyreethyl]afi.Uino]~2~oxoeihyi3a
[001271 (E)«3-(6^cetamidopyridm-3-y])-N^
roethylquinolin-8-yl)oxymethyI]anih½io3-2-oxoeihyI]prop-2-enamkIe;
[001283 N~[2,4-dichloro-3-[(2-methy}qumolm^
methyl-5-(thiophene-2-carbony3}pyrroI~2-yI]propanamide
[00 ί 29) 2-[5-<4-cyanobenzoy -raethylpyrrol-2-yl]-N-[2,4-dichloro-3-[(2-
Tnefeylqainolin-8-yl)oxymethy!]pheny3]-N-ineihylacetaniide;
[001303 2-[5-(6-cyanopyridine-3-carbonyl)- 1 -methylpynOl-2-yl ]-N-[2,4-dich]oro~3~
[{2-methylquinolin-8-y!)oxymeihyl3phenyl3-N-raeihylaceia.mide;
[00131 ] or pharmaceutically acceptable sails, stereoisomers, hydrates, or solvates thereof.
[00.1323 One example of a compound encompassed by formula (!) has formula II
Figure imgf000026_0001
1 ~((4-chk>ro-3-(((4-(4-fiuoro- 1 H-pyrazoi-1 ~yl> met ylqui«oHn-8-yl)oxy)methyi)^-methyIpyridin-2-yl)methyI)-2-oxo-l 5 2-dihydropyridine- 3-carbonftfiJe. Certain embodiments are drawn to methods of treating a Ba-bradykinin receptor mediated angioedema in a subject comprising administering to the subject in need thereof a therapeutically effective amount a composition comprising a compound having Attorney Docket No. 0 i 38.0001 -PCT formula (13) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, thereby reducing plasma extravasation in the subject.
[00133] Certain embodiments include compositions comprising l-((4-chloro-3-(((4-(4- flisoro-lH-pyrazoI- i -yl)-2-methyIq^
oxo-1, 2-dihydropyridme-3-carborjiiriie (HGT37H) or a pharmaceutically acceptable salts, stereoisomers, hydrates, or solvates thereof. 3-i-((4~Ch{oro-3-(((4-(4-fluoro-lH-pyrazoH~ yI)-2^nemylqumoUn-8-yi)oxy)methy1)-6-m 2~ dihydropyridine-3-carbonitriie (HGT371 1) can be orally bioavailable and act as a B2- bradykinin receptor antagonist in the treatment of B2~bradykinm receptor mediated angioedema, in embodiments.
[00134] In embodiments, the 8-(heteroarylmethoxy)quinoline or 8- (arylmethoxy)quinolvne or a pharmaceutically acceptable salt a stereoisomer, a hydrate, or a solvate thereof (e.g., a compound having formula (!) or (II)) can be a small molecule. A small molecule is a low molecular weight (<800 Daltons) organic compound that may serve as an enzyme substrate or regulator of biological processes (e.g., Ba-bradykinin receptor antagonist). The upper molecular weight, limit for a small molecule is about 800 Daltons which allows for the possibility to rapidly diffuse across cell membranes so that they can reach intracellular sites of action. In addition, this molecular weight cutoff is a necessary but insufficient condition for oral bioavailability. Biopolymers such as nucleic acids, proteins, and polysaccharides (such as starch or cellulose) are not small molecules. Compounds having formula (Ϊ) or (H) can have a molecular weight less than about 650 Daltons, less than about 600 Daltons, or less than about 525 Daltons m embodiments.
[00135] Certain embodiments are drawn to the therapeutic use of (a) compounds of formula (I) or (II), their pharmaceutically acceptable salts, stereoisomers, solvates or hydrates and also (b) formulations and pharmaceutical compositions containing the same. Some embodiments also relate to the use of compositions comprising a compound having formula (I) or (II), a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof as an active ingredient in the preparation or manufacture of a medicament for the treatment and/or prevention of a Ba-bradykinjn receptor mediated angioedema. Attorney Docket No. 0138.0001 -FCT
[00136] A "pharmaceutically acceptable salt" of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of hum n beings or animals without excessive toxicity or carcinogenicity, and without irritation, allergic response, or other problem or complication, in some embodiments. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
[00137] Suitable pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycoHc, tumeric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic,, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, iumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacette, alkanoic such as acetic, HOOC— (C¾)B-COOH where n is any integer from 0 to -4 (i.e., 0, 1, 2, 3, or 4) and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a sioichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, can be used for preparation of a salt in some embodiments.
[00138] It will be apparent that each compound of formula I can, but need not, be present as a hydrate, solvate or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of embodiments described herein, as are prodrugs of the compounds of formula (1) or (11) provided herein.
[00139] A 'prodrug" is a compound that differs structurally from 8- (heteroarylmethoxy)quinoline and 8~(arylmethoxy)quinoline compounds provided herein Attorney Docket No. 0138.0001-PCT and that is modified in vivo, following administration to a subject or patien to produce a compound of formula I provided herein. For example, a prodrug can be an acyiaied derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryi groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryi group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compoimds provided herein. Prodrugs of the compounds provided herein cars be prepared by modifyin functional groups present m the compounds in suc a way thai the modifications are cleaved in vivo to generate the parent compounds.
[00140] A "substituent," as used herein, refers to a molecular moiety that is covalentiy bonded to an atom within a molecule of interest. For example, a "ring substituent" can be a moiety such as a halogen, alkyi group, haioalkyl group, hydroxy, cyano, amino., niiro, mercapto, or other substituent described herein that is covalentiy bonded to an atom thai is a ring member. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated subsiituents, provided thai the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound (ie., a compound thai can be isolated, characterized and tested for biological activity). When a substituent is oxo (i.e., =0), then 2 hydrogens on the atom are replaced. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH— to -0 =0)- and a loss of aromaticity. For example a pyridyi group substituted by oxo is a pyridone.
[00141] The expression "alkyi" refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, from 3 to 12 carbon atoms, or from 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, iso-propvL n-butyl, Iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 2,2-dimethylbutyl or n-ocryl group.
[00142] The expressions "aJkenyi" and "alkynyl" refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, from 2 to 12 carbon atoms, or from 2 to 6 carbon atoms, for example an ethenyl, allyl, acetylenyl, Attorney Docket No. 0138.0001-PCT propargyl, isoprenyi or hex-2-enyl group. Alkenyl groups can have one or two double bonds and alkynyl groups have one or two triple bonds, in certain embodiments.
[00143] Furthermore, the terms "alkyi", "alkenyl" and "alkynyl" refer to groups in which one or more hydrogen atoms have been replaced each independently of the others by a halogen atom (such as, F or CI) such as, for example, a 2,2,2 -trichioroethyl or a trifluoromethyi group.
[00144] The expression "heteroalkyl" refers to an alkyl, alkenyl or alkynyl group (for example heteroalkenyl, heteroalkynyl) in which one or more carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulphur atom. The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxy!ic acid such as, for example, acy!, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, earboxyalkylamide, aikylcarbarnoylaikyl, alkylcarbamoyloxyalkyi, a!kyiureidoalkyl, or alkoxycarbonyloxy.
[00145] Examples of "heteroalkyl" groups are groups of formulae— S--Ya-L,— S~-Ya— CQ~ R*R\— Ya— NR°— CO— NR*Rb, ~Y*~NRc-CO--0~Rc, -Y^-NR'-CO-R", ~Ya~0-- CO~NRaR\ — Ya-CO-NRaRb, ~0-Ya"CO~NRaRb, ~Ya-~NRc--CO-L, ™Ya-Ls — Y9— O— CO--0-R0, ~Ye--0~CO--Rc, Rc~0™Ya~, Rc~S~Ye, Ra~N(Rb)--Ya" Rc-CO~Ya~s Rc~0~ CO-YS Rc.-CO--0-YS R ---CO-N(Rh)--Ya--s Ra--N(R:b)~CO-Ya-~, Rc»SO-Y*-, RcS02-Ya--; -Yft~NRc-S02~NRaRb, -Ya— S02— NR*Rb, ~Ya~NRc--SOr-Rc, R ~0~CO~ N(Rb)-Ya-s Ra-N(Rb)-C(^ Rd)"N(R£)-Ya-, c-.S-CO~~Ya-5 Rc~CO--S--Y8--, Rc-S- CO~N( Y ~, Ra-~N(Rb)--CO-S-~Ya--, Rc~S-CO~0~Ya~, Rc~0-CO-S-«Ys™, Rc--S-- CO— S-Ya— Ra being a hydrogen atom, a C i, alkyl, a C2~Q alkenyl, a C2-C6 alkynyl, or is joined to Rb to form a 4- to iO-membered eycloalkyi or heterocycioalkyl: Rh being a hydrogen atom., a C Ce alkyl, a C2-C6 alkenyl or a C2~C6 alkynyl, or taken together with Ra to form a 4~ to ίθ-membered eycloalkyi or heterocycioalkyl; Rc being a hydrogen atom, an optionally substituted CrG$ alkyl, an optionally substituted C2-C6 alkenyl or an optionally substituted Cj-Cg alkynyl; Rd being a hydrogen atom, a C]-C6 alkyl, a C2-C6 alkenyl or a C2- Cg alkynyl; L being a eycloalkyi, heterocycioalkyl, a!ky!eyc!oalkyl, heteroalkylcycloalkyl, aryl, optionally substituted heteroaryl, aralkyl, or heteroaralk l; and Ya being a bond, a Cj-Q Attorney Docket No. 0I38.0001-PCT alkylene, a C2-C6 alkenylene or a C2-C6 alkynylene group; each heteroalkyi group containing at least one carbon atom and it being possible for one or more hydrogen atoms to have been replaced by fluorine or chlorine atoms. Specific examples of heteroalkyi groups are methoxy, trifluororaethoxy, ethoxy. n-propyloxy, isopropyloxy, tert-butyloxy, methoxyniethyl, ethoxymethyl, meihoxyethyl, methyiamino, ethylamino, dimethylamino, diethyiamino, iso- propylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyL enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl. butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, isobutyjrylam o-methyl, N-etj yl-N-fliethylcarbamoyl and N-methylcarbamoyL Further exampies of heteroalkyi groups are niirile, isonitriie, cyanaie, thiocyanate, isocyanate, isotbiocyanate and alkylnitrile groups. An example of a hetero- alkylene group is a group of formula -CH2CH(OH)-- or --CONH— .
[00146] The expression "cycloalkyi" refers to a saturated or partially unsaturated cyclic group that contains one or more rings, containing from 3 to 14 ring carbon atoms, from 3 to 10 ring carbon atoms,, or 3 to 6 ring carbon atoms. In an embodiment partially unsaturated cyclic group has one, two or more double bonds, such as a cycloalkenyl group. The expression cycloalkyi refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by Oil, =0. SH, ==S, NH2, =NH, CN or N02 groups, thus, for example, cyclic ketones such as, for example, cyciohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of a cycloalkyi group are a cyclopropyi, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl. cyclohexadienyl, decalinyl, bicyclo[4.3.OJoon l, tetralin, cyclopentylcyclohexyl, fluorocyciohexyl or cyclohex~2-enyl group.
[00147] The expression "heterocycioalky!" refers to a cycloalkyi group as defined above in which one or more ring carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom. A heterocycioalkyl group has 1 or 2 rings containing from 3 to 1 ring atoms. The expression heterocycioalky! refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, — S, NH¾™NH, CN or NC¾ groups. Examples are a piperidyi, Attorney Docket No. 0138.0001-PCT piperazinyL morpholinyl, urotropinyl, pyrrol tdmyi, tetrahydrothiophenyl, tetxahydropyranyl, tetrahydrofuryl or 2-pyrazolinyi group and also a lactam,, a lactone, a cyclic imide and a cyclic anhydride.
[00148] The expression "alkyicycloalkyi" refers to a group containing both cyc!oalkyl and also an alkyl, alkenyl or alkynyl group in accordance with the above definitions, for example alkyi-cycloa!kyi, cycloalkyialkyl, alkylcycloalkenyf, alkenyicycloalkyl and alkynyleycloalky! groups. An alkyicyeioalky! group can contain a cycioalkyJ group that contains one or two ring systems having from 3 to 10 carbon atoms, and one or two alkyl, alkenyl or aikynyi groups having i or 2 to 6 carbon atoms, the cyclic groups being optionally substituted.
[00149] The expression "heteroalkylcycloalkyl" refers to alkylcycloalkyi groups as defined above in which, one or more carbon atoms have been replaced each independently of the others by an oxygen, nitrogen,, silicon, selenium, phosphorus or sulphur atom. A heteroalkylcycloaikyl group can contain 1 or 2 ring systems having from 3 to 10 ring atoms, and one or two alkyf alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkyiheterocycloalkyl, alkylheterocyeloalkenyS, alkenyiheterocyeloalkyl, alkynylheteroeycloalky], heteroaikyicycloalkyl, heteroalkylheterocyeloalkyl and heieroaikylheterocycloaikenyl, the cyclic groups being optionally substituted and saturated or mono-, di~ or tri-unsaturated.
[00150] The expression "aryi" refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, or from 6 to 10 ring carbon atoms. The expression aryl refers .furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH¾ CN or NC¾ groups. Examples are a phenyl, naphthyl, bi.phe.ny';, 2~ fluorophenyl, anilinyl, 3~nitrophenyl or 4 -hydroxy henyl group.
[00151 j The expression "heteroaryl" refers to an aromatic group thai contains one or more rings containing from 5 to 14 ring atoms, or from 5 to 10 ring atoms, and contains one or more oxygen, nitrogen, phosphorus or sulphur ring atoms. The expression heteroaryl refers Attorney Docket No. 0138.0Q0KPCT furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, H2,™NH, CN or N<½ groups. Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrroiyl, thiazolyl, oxazolyl, triazolyl, tetrazolyi, isoxazolyl. indazolyl, mdolyl, benzirnidazolyl, pyn'dazinyl, quinolinyl, purinyl, carbazo!yL acridinyi, pyrfmidyL 2,3'-bifliryh 3-pyrazolyl and isoquinolmyi.
[00152] The expression "aralkyf ' refers to a group containing both aryi and also alkyl, aikenyl, alkynyl and/or cycloalkyi groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyi, aryialkynyl. arylcycloalkyl, aryicycloalkenyL. alkylaryicycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, esitylene, styrene, benzyl chloride, o-fi oroioluene, ! H~mdene, tetralin, dihydronaphthalene, indanone, phenyicyclopentyl cumene, cyclohexylpbenyi, fluorene and indan. An aralkyl group contains one or two aromatic ring systems containing from 6 to 10 carbon atoms and one or two alkyl, aikenyl and or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyi group containing 5 or 6 ring carbon atoms.
[00553] The expression "heieroaralkyl" refers to an aralkyl group as defined above in which one or more carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulphur atom, that is to say to groups containing both aryi. or heteroaryl and also alkyl, alkenyi, alkynyl and/of heteroaikyl and/or cycloalkyi and/or heterocycloalkyl groups in accordance with the above definitions. A heteroara!kyl group can contain one or two aromatic ring systems containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, aikenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyi group containing 5 or 6 ring carbon atoms, 1, 2, 3 or 4 of those carbon atoms having been replaced each independently of the others by oxygen, sulphur or nitrogen atoms.
[00154] Examples of heieroaralkyl groups are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloaikenyl, arylaikylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycioalkyl, arylalkylheteroeycloaikenyl, heteroarylalkyl, heteroaryiaikeny!, heteroary!aikynyl, heteroarylheieroalkyl, heteroarylcycloaikyl, heteroaryicycioalkenyl, Attorney Docket No. 0138.0001-PCT heteroary!heierocycloalkyi, heteroarylheterocycloaikenyl, heteroarylalkylcycloalkyl, heteroarylaikylheterocycloalkeny], heteroarylheteroalky!cyeloalkyl, heteroary Iheteroalky i cycioalkeny 1, heteroalkylheteroaryialky 1 and heteroaiylheteroaO ylheterQcycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsatarated. Specific examples are a tetrahydroisoqumoiiny!, benzoyl, 2- or 3- ethylindolyl, 4-methyipyridino, 2-, 3- or 4-methoxyphenyi, 4-ethoxyphenyI, and 2-, 3- or 4- carboxyphenylalkyl groups,
[00155] ne expressions cycioalky.l, heterocycloalkyl, alkylcycloalkyl, heteroalkyicycloalkyl, aryl, heteroaryL aralkyl and heteroai'alkyl refer to groups in which one or more hydrogen atom s of such groups have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, N¾ =NH, CN or N(¾ groups.
[00156] The expression "optionally substituted" refers to groups in which one or more hydrogen atoms have been replaced each independently of the others by hydrogen, fluorine, chlorine, bromine or iodine atoms or by OH, =Os SH, **S, N¾, =N¾ CN or ΝΌ2 groups. This expression refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by unsubstituted Ci -Ce alky!., unsubstituted C2-CV, a!kenyl, unsubstituted C1-C0 aikynyi, unsubstituted CVQ heteroalkyJ, unsubstituted C -C JO cycioa!kyl, unsubstituted C2-C9 heterocycioalkyl, unsubstituted C6-Cic aryl, unsubstituted C C9 heteroaryL unsubstituted C7~Ct2 aralkyl or unsubstituted C2-Cj] heteroaralkyl groups.
[00157] As used herein a wording defining the limits of a range of length such as, e.g. , "from .1 to 5" means any integer from 1 to 5, i.e., 1, 2, 3. 4 and 5. in other words, any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
[00158] Certain embodiments can comprise isotopes of atoms of the described compounds. Isotopes are atoms having the same atomic number but different mass numbers. For example, tritium and deuterium are isotopes of hydrogen. Examples for carbon isotopes are "C, 13C and i C. Attorney Docket No. 0138,0001 -PC!
[00159] The therapeutic use of compounds of formula (Ϊ) or (II), their pharmaceutically acceptable salts, stereoisomers, solvates or hydrates and also formulations and pharmaceutical compositions can be used in embodiments for treating a Ba-bradykmin receptor mediated angioedema in a subject. Certain embodiments are drawn to the use of those compounds of formula (I) or (II) as active ingredients in the preparation or manufacture of a medicament.
[00160] The pharmaceutical compositions cars comprise at least one compound of formula (i) or (11) and, optionally, one or more carrier substances, excipients and/or adjuvants. Pharmaceutical coin positions can additionally comprise, for example, one or more of water, buffers (e.g., neutral buffered saline or phosphate buffered saline), ethanoi, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), raannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives. In embodiments the pharmaceutical compositions can comprise one or more of surfactants, tonicity agents (e.g., NaCl), buffers (e.g.. phosphate or citrate buffer), salts, preservatives (e.g., sodium edetate), co-solvent, and viscosity building agents,
[00161] Furthermore, one or more other active ingredients can (but need not) be included in the pharmaceutical compositions provided herein. For instance, the 8- (heteroarylmethoxy)quinoline and 8-(arylmethoxy)quino1one compounds can be employed in combination with icatibant (injectable icatibanHFirazyr), ecallantide, CI -inhibitor, or kaHikrein inhibitor.
[00162] Pharmaceutical compositions can be formulated for any appropriate manner of administration, including, for example, topical (e.g., transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions are in a form suitable for oral use. Such forms include, for example, tablets. Attorney Docket No. 0138.000! -PCX pills, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules,, solutions, or syrups or elixirs. Within yet other embodiments, compositions provided herein can be formulated as a iyophilizate. Some embodiments include compositions in a form suitable for sublingual administration. The pharmaceutical composition can have a pH of less than about 7, less than about than about 6, less than about 5, less than about 4, less than about 3 or less than about 2 in embodiments.
[00163] Compositions intended for oral or sublingual use can further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active Ingredient in admixture with physioiogically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., com starch or alglnic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or tab). The tablets can be uneoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient can be mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium (e.g., peanut oil, Hquid paraffin or olive oil). In embodiments oral formulations can comprise a therapeutically effective amount of a compound having formula (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof and a pharmaceutically acceptable carrier, wherein the therapeutically effective amount can be between about 0.001 wt % and about 60 wt %; about 0.01 wt % and about 55 wt %; about 0.1 wt % and about 60 wt %; about 1 wt % and about 50 wt % of the oral formulation. In some embodiment the oral formulation can further comprise hydroxy! propyl methyl cellulose acetate succinate. The oral formulation can be in the form of a spray-dried dispersion in certain embodiments. Attorney Docket No. 0138.0001-PCT
[00164] Aqueous suspensions contain the active gredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (e.g., sodium carboxymethyicelluiose, methylcelluiose, hydropropylmethylceilulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkyiene oxide with fatty acids such as polyoxyethyiene siearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxyceianol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethyiene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate). Aqueous suspensions can also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[00165] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent such as beeswax, hard paraffin or cety! alcohol. Sweetening agents such as those set forth above, and/or flavoring agents can be added to provide palatable oral preparations. Such suspensions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
[00166] Dispersible powders and granules suitable for preparatio of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, .flavoring and coloring agents, can also be present.
[00167] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil Attorney Docket No. 013S.0001-PCT
(e.g., liquid paraffin) or a mixture thereof Suitable emulsifying agents include naturally- occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides {e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g., sorbitan monooieate) and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide (e.g., polyoxyethyfene sorbitan monooieate). An emulsion can also comprise one or more sweetening and/or flavoring agents.
[00168] Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
[00169] Compounds can be formulated for local or topical administration, such as for topical application to the skin or mucous membranes, such as in the eye. Formulations for topical administration can comprise a topical vehicle combined with active ageni(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent, that the choice of a vehicle can be adjusted in view of the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylcne, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; Hpid-based maieriais such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingo!ipids and waxes; protein- based materials such as collagen and gelatin; siiicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices.
[00170] A composition can further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters* gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale-The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.). Remington's Pharmaceutical Sciences. Formulations can comprise microcapsules, such as hydroxymethylcellulose or Attorney Docket No. 0138.0001 -PCX gelatin-microcapsules, liposomes, albumin microspheres, rascroernulsions, nanoparticles or nanocapsuies,
[ 00171] A topical formulation can be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches. The physical appearance and viscosity of such forms can be governed by the presence and amount of erau!sifier(s) and viscosity adjusters} present in the formulation. Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, .moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams can be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations- like those of lotions and creams, can also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
[00172] Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like poiyox ethylene oleyl ether. PEG-40 stearate, ceteareth-12, ceteareth-20. ceteareth-30, ceteareth alcohol, PEG- 100 stearate and glyceryl stearate. Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, macrocrystalline wax, beeswax, paraffin, and cetyl paSraitate. A gel composition can be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquatemiums, Attorney Docket No, 0138.0001-PCT hydroxyethylcelhilose, hydroxypropylcellulose, hydroxypropylmethyleellulose, carborner or ammomated giycyixhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, one or more of dimethicone copoiyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-diraonium chloride, and ammonium lauret sulfate can be used within topical formulations.
[00173] Suitable preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbaie/ascorbic acid and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and batylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils. Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that can be included in a topical formulation include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents (e.g., witch hazel, alcohol and herbal extracts such as chamomile extract), bmders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propel lants, opacifying agents, pH adjusters and protectants.
[00174] Modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing. Controlled release vehicles can also be used, and compositions can be formulated for transdermal administration as a transdermal patch.
[00175] A pharmaceutical composition can be formulated as inhaled formulations, including sprays, mists, or aerosols. Such formulations are particularly useful for the treatment of asthma or other respiratory conditions. For inhalation formulations, the compounds provided herein can be delivered via any inhalatio methods known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered Attorney Docket Mo. 0138.000i dose Inhalers with propeilants such as CFC or HFA or propeilants thai are physiologically and environmentally acceptable. Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers. Aerosol formulations for use in the subject method can include propellants, surfactants and co-solvents and can be filled into conventional aerosol containers that are closed by a suitable metering valve,
[00176] inhalant compositions can comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and iritrabronchiai use, or aerosol, compositions administered via an aerosol unit dispensing metered doses. Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptabie inhalant solvent e.g., Isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the desired dosage amount of the liquid composition to be inhaled into the subject's lungs. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
[00177] Formulations or compositions suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered by rapid inhalation through the nasal passage from a contai ner of the powder held c lose up to the nose). Suitable powder compositions include, by way of illustration, powdered preparations of the active ingredient thoroughly intermixed with lactose or other inert powders acceptabie for intrabronchial administration. The powder compositions can be administered via an aerosol dispenser or encased in a breakable capsule which can be inserted by the subject into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation.
[00178] Pharmaceutical compositions can also be prepared in the form of suppositories (e.g., for rectal administration). Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal Attorney Docket No. 0138.0001 -PCX temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
[00179] Pharmaceutical compositions can be formulated as sustained release formulations (i.e., a formulation such as a capsule that effects a slow release of modulator following administration). Such formulations can generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and can also be biodegradable; in some embodiments the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation can be based upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
[00180] For the prevention and or treatment of B2-bradykinm receptor mediated angioedema (e.g.. HAE), the dose of the biologically active compound disclosed herein can vary within wide limits and can be adjusted to individual requirements. Active compounds (compounds of formula (!) or (11), such as, l -((4-chloro-3-(((4-(4-iluoro-lH-pyrazol"I-yi)-2- methylquinolin-8-yl)oxy)methy 2 -d ihy d ropyridine-
S-carbonitrile) described herein are generally administered in a therapeutically effective amount. Doses can range from about 0.2 mg to about 50 mg of a compound having formula (I) or (il)/active compound per kilogram body weight, about 0.2 mg to about 35 mg per kilogram body weight, about 0,2 mg to about 20 mg per kilogram of body weight, or about 0.2 mg to about 14.4 mg per kilogram of body weight and can be repeatedly administered every from about 5 hours to about 12 hours, about 10 hours to about 12 hours, or between about 2 and about 5 times per day or between about 2 and about 3 times per day. The daily dose can be administered as a single dose or in a plurality of doses. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form can be based upon the subject treated and the particular mode of administration. Dosage unit forms will generally contain between from about 0.5 mg to about 100 nig, about 0.5 mg to about 20 mg, about 0.5 to about 10 mg, or about 0.6 m to about 6 mg of an active ingredient.
-4Ϊ- Attorney Docket No. 013 S.0001 -PCT
[00181 ] It will be understood, however, that the specific dose level for any particular subject can be adjusted based upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs being used to treat the subject) and the severity of the particular disease undergoing therapy.
[00182] Active compounds disclosed herein will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo,
[00183] 8-{aryimethoxy)qumoiines and 8~{heteroarylmethoxy)q inoimes provided herein can be used as antagonists of B2-bradykinin receptors. B2~bradykinin receptor antagonists according to embodiments can be used to inhibit the binding of Bi-faxadykimn receptor ligands (e.g., bradykinm (BK)) to B2-bradykmm receptor in vitro or in vivo. B2- bradykinin receptor moduiator(s) provided herein can be administered to a subject {e.g., a human) orally or sublingual!}', and are present within at least one body fluid or tissue of the subject while modulating B2~bradykinin receptor activity.
[00184] Bj-bradykinin receptor modulators can be useful for the treatment and/or prevention and/or prophylaxis of B2-bradykmin receptor mediated angioedema, such as hereditary angioedema (HAE). Embodiments including compounds having formula (1) or (O) or salts, stereoisomer, hydrates or solvates thereof can be used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of B2~bradykinin receptor mediated angioedema.
[00185] Compounds of embodiments can be labeled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity label like nanobodies, aptamers, peptides, etc., enzymes or enzyme substrates. These labeled compounds can be useful for mapping; the location of bradykinin receptors in vivo, ex vivo, in vitro and in situ {e.g., in tissue sections via autoradiography) and as radiotracers for positron Attorney Docket No. 0138.0001 -PCT emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like to characterize those receptors in living subjects or other mater iais.
[00186] Embodiments also pertain to methods for altering the signal-transducing activity of bradykinin receptors in vitro arid in vivo. For instance, compounds of certain embodiments and labeled derivatives thereof can be used as standard and reagent in determining the ability of a potential pharmaceutical to bind to the B2~ bradykinin receptor.
[00187] Some embodiments can provide methods for localizing or detecting a B2~ bradykinin receptor in a tissue {e.g., a tissue section), which methods involve contactin the tissue sample containing Eb-bradykinin receptor with a detectably labeled compound according to embodiments under conditions that permit binding of the compound to the B2- bradykinin receptor and detecting the bound compound. Such methods and their respective conditions are known to those skilled in the art and include, for example, radioligand binding assays.
[00188] Some embodiments can provide methods of inhibiting the binding of bradykinin (BK) or any other B2~bradykinin receptor Hgand to a Bi-bradykinin receptor which methods involve contacting a solution containing a B2-bradykini'n receptor antagonist- compound disclosed herein with cells expressing B2 -bradykinin receptor under conditions and in an amount sufficient to detectably inhibit binding of BK or any other substance to B2- bradykmio receptor. Such methods and their respective conditions are known to those skilled in the art and include, for example, calcium mobilization assays.
[00189] Certain embodiments can provide methods for treating subjects suffering from Bi-bradykmm receptor mediated aagioedema as mentioned above. As used herein, the term "treatment" encompasses both disease-modifying treatment and symptomatic treatment, either of which can be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e„ after the onset of symptoms, in order to reduce the severity and/or duration of symptoms). A Bs-bradykim receptor mediated angioedema is "responsive to Bj-bradykinin receptor modulation" if modulation of B2-bradykmin receptor activity results in alleviation of the condition or a symptom thereof. Attorney Docket No. 0138.000 -PCT
Subjects can include but are not limited to primates (especially humans), domesticated companion animals (such as dogs, cats, horses) and livestock (such as cattle, pigs, sheep), with, dosages as described herein,
( 0190J The compounds of formula (I) or (II) according to embodiments can have improved properties when compared to B2-bradykinin receptor antagonists known in the state of the art, especially, improved selectivity, low toxicity, low drug-drug interaction, improved bioavailability (especially with regard to oral administration), improved metabolic stability, improved stability in microsomal degradation assay, and improved solubility.
[00191] 8-(heteroaryimethoxy)quinolines provided herein can be used as agonists or antagonists of B2-bradykinin receptors in a variety of applications, both in vitro and in vivo, Bi-bradykimn receptor antagonists according to certain embodiments can be used to inhibit the binding of Bj-bradykinin receptor Hgands (e.g., BR) to B -bradykinin receptor in vitro or in vivo. Ba-bradykinin receptor modii!ator(s) provided herein can be administered to a subject (e.g., a human) orally or topically, and can be present within at least one body fluid or tissue of the subject while modulating B -bradykinin receptor activity, 00192] The following Examples further define and describe embodiments herein. Unless otherwise indicated,, all parts and percentages are by weight.
EXAMPLES
[00193] The compounds of described embodiments can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of embodiments can be synthesized using synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
[00194] The compounds shown in the following Table 1 are representative examples of compounds of formula (I) or (Π) of embodiments. "Die CID (Chemical Identification number) listed in the table below can be used to retrieve chemical and biological information available regarding a given compound in the PybChem database at pubchem.ncbi.nlm.nih.gov. Compounds in Table .1 have been shown to at least have Attorney Docket No, 0138.0001-PCT binding/antagonist activity with regard to the Bj-bradykmin receptor and information relating to biological activity of the compounds cm be found herein and in the PubChem database (based on the€ID). The compounds are share a similar core structure (e.g., formula (Ϊ))
Attorney Docket No. OL18.000I -PCT
[00195] Table
Figure imgf000047_0002
Figure imgf000047_0001
Attorney Docket No. 0138.00.01-PCT
Figure imgf000048_0001
rney Docket No. 0138.0G01-PCT
Figure imgf000049_0001
Aitorney Docket No, 0138.0001-PCT
Figure imgf000050_0001
Attorney Docket No. 0138.000I-PCT
Figure imgf000051_0001
Attorney Docket No, 0138.0G01-PCT
Example Structure Name Weight Citation/
CID
U 2-(5-benzoyl-S-metJjylpyrroi~2-yi)-N- 572,5 442767 Π 2,4-diehioro- 3 -[{2-rnettiyl quino] in-8- yI)oxyrnethyI]ptoyl]- - I methylacctamide
Figure imgf000052_0001
14 (f;)-3-(6-Hcetati!jdooyridin-3-yI)-N- 578.4 10555202
[2-[2,4-dicb!oro-3-ii2- meftylquinoUn-S- i)oxyffiethyi]aniiinoj~2.
oxoethy! prop-
2-ena!Tiide
Figure imgf000052_0002
Attorney Docket No. 0B8.00QI-PCT
Figure imgf000053_0001
Attorney Docket No. Gi38.000I >CT
Figure imgf000054_0001
Attorney Docket No. 0138.0001 -PCT
Structure Weight
Mame Citation/
CiD
N-{2,4-die ioro-3~[(2- 586.5 44276375 rnethySquiiioiin-S- yI)oxysset yl]pheriy]J -N-methyi -?.-[ J - met¾yi-5-(2-phenyiacetyl)pynOl-2- yrjacetamide
2-[5 -(4-msiisoben2oy5)- 1 - 587.5 22288562 methy]pyrrol-2-yi]~N~[2,4-dichioro-3- [(2-me!hyiquiiiolin-S- yi)oxymethyl] beayl]-N- meihy!acei amide
Attorney Docket No. 0138,0001
Figure imgf000056_0001
Attoraey Docket No. QI38.0001-PCT
Figure imgf000057_0001
Attorney Docket No. 0138.0001 -PCT
Figure imgf000058_0001
Attorney Docket No. 0338.O0G1-PCT
Figure imgf000059_0001
[001%] Example 29 Synthesis of U(4-Chioro~3 (f4-f4-fluoro-1H^
methylq.iijnojj.n-8 2-dihydropyridme- 3 -carbon itrile
[00197] l-{(4 :hioro-3 ({4 4-iluoro-l H-pyrazoI-l -yl)--2-meihyk| inoIin-8- yi)oxy)methyl)-6-methylpyridin-2-yj)methyl)-2-oxo-l, 2~dihydropy.rIdine-3-carbonitrile (CFMQ) was synthesized using starting materials Bl and Ql shown in Figure 1. In reaction step 1 , i~((4-chIorQ-6-methyi-3-(((tetrah^
yl)methyl)~2-oxo-l ,2-dihydropyridine-3-carboniirile (B l ) was deprotected under acidic conditions in the presence of thionyl chloride to remove the ietrahydropyranyl ether protecting group and replace the alcohol with a chlorine (CI) atom forming !-({4-chforo-3-
Figure imgf000059_0002
In reaction step 2, the methyl ether protecting group on 4~(4-f1uoro~lH~pyrazol-l-yl)-8- methoxy-2-methylquinoline (Ql) was cleaved by aluminum chloride (AlCi3) in toluene leaving the reactive hydroxyqninolme, 4-(4-f!uoro-lH-pyrazol-l-y -2-methylquinolin-8-ol (Q2). In the final step (reaction step 3), B2 and Q2 are reacted in the presence of potassium carbonate in acetonitrile/water to form an ether linkage between the reactive hydroxyl and chloromethyl groups resulting in the CFMQ. Attorney Docket No. 0138. OG01. -PCX
[00198] Example 30 Physicochemical Properties of CFMO
[00199] The physicochemical properties of l-({4-Chloro-3-(((4~(4-fluoro-lH-pyrazol- l~yl)-2-me&ylquinoiin-8~yl)oxy)methy3)~^ 2- dihydropyridme-3-carboiiitrile (CFMQ) were determined using standard methods. See Tables 2 and 3, below. CFMQ was a free base with a molecular weight of 514.9 Da and was a nonhygroscopic, crystalline powder with a melting point of about 21 °C. While CFMQ had slight solubility in aqueous medium, its solubility was greatly enhanced in acidic environments.
[00200] Table 2 Summary of Physicochemical Properties of CFMQ
Figure imgf000060_0001
H-bond Donors
Attorney Docket No. 0138.0001-PCT
Table 3 Summary of Solubility Properties of CFMQ
Figure imgf000061_0002
[00202] Example 31 Efficacy of CFMQ
[00203] In vivo experiments in both wild-type (WT) C578L/5J mice and CI -inhibited knock out (CI !NH KO) mice measured pharmacodynamic efficacy by the ability of CFMQ to block plasma extravasation, which is causative to edema, the most important symptom requiring treatment in HAE subjects.. This plasma extravasation model has been used extensively in the literature to investigate the efficacy of bradykinin receptor antagonists. (Han et ai, "Increased vascular permeability in CI inhibitor-deficient mice mediated by the bradykinin type 2 receptor," J Clin Invest 2002 Apr; 109(8); 1057-1063.)
[00204] Determination of ED in Mice
[00205] Intravenous Study in Wild-Type Mice
[00206] The uptake and effective blocking of plasma extravasation of CFMQ was examined following IV (intravenous) bolus administration in wild-type (WT) C57/BL6" male mice
Figure imgf000061_0001
and/or 6 mg/kg. Following CFMQ administration and prior to the terminal time point mice received an IV injection of Evans blue (EB) dye (30 mg/kg) and were sacrificed. The bladder Attorney Docket No. 0I38.0OO1-PCT was removed, dried and weighed and extracted in formamide (1.0 mL), EB concentration in the formamide extract was determined spectrophotometncaliy and EB content, was calculated as ^ig EB per milligram of tissue weight. Efficacy was determined by inhibiting the accumulation of EB in the bladder.
[00207] Doses of 1.0 and or 100 ^ig kg did not inhibit extravasation, showing similar levels of EB in the bladder as controls., with the 1.0 [tg/kg dose giving a value of 0.7602 EB mg kg tissue, compared to controls (0.7927 EB mg/kg tissue). However, the 6 mg/kg dose achieved significant inhibition of extravasation compared to the control group, with a value of 0.0701 EB mg/kg tissue.
[00208] CFMQ doses of 0.001, 0,05, 0.1, 0.25, 0.5, LO, and or 3.0 mg kg were administered as IV bolus injections to WT mice (n~8/dose group). As illustrated in Figure 2, a dose-response compared to vehicle controls was demonstrated, with significant inhibition of plasma extravasation at doses of 0.5, LO, and or 3.0 mg kg. When dosed intravenously in the WT model, CFMQ (HGT3711) blocked plasma extravasation completely at high doses (500 ^g/kg) and showed an effective dose (ED50) of 460 g kg (Figure 2).
[00209] Oral Administration Study in Wild-Type Mice
[00210] The uptake and effective blocking of plasma extravasation of CFMQ (HGT3711) was examined following oral administration, in wild-type (WT) C57/BL6 male mice (n-4/dose group). Mice received a single oral gavage of CFMQ (HGT3711) (ΙΟμ-L/g) at 3.0 or 10 mg/kg. Blood samples were taken at 20 and 60 minutes post-dose. Following oral administration CFMQ (HGT3711) administration and prior to the terminal time point mice received an IV injection of Evans blue (EB) dye (30 mg/kg ) and were sacrificed. Similar to the IV study, EB concentration in the formamide extract was determined spectrophotornetricaliy (^tg EB per milligram of tissue) and efficacy was determined by inhibiting the accumulation of EB in the bladder.
[0021 1] As illustrated in Figure 3, both doses of CFMQ (HGT371 1) had an inhibitory effect on plasma extravasation, with significant differences seen at 10 and 30 mg/kg (4 minutes) and at 10 mg/kg (24 minutes) post-dose, compared to vehicle controls. At 3.0 Attorney Docket No. 0138.000I-PCT mg kg inhibition to 56% and 58% at 4 and 24 minutes post dose were observed. A dose of 10 mg/kg showed greater inhibition of extravasation to 14% and 21% at 4 and 24 minutes, respectively. After 64 minutes, inhibition was at 72% and 75% fo the 3.0 and 10 mg/kg doses, respectively. These results supported that oral administration of CFMQ (HGT3711) demonstrated rapid pharmacodynamic effects in the mouse,
[00212] The efficacy of CFMQ (HGT3711) following orally administration was studied in female WT mice. Eight mice per group received either vehicle or CFMQ (HGT371.1 ) at 1.0, 3,0, .10, or 30 mg/kg by oral gavage. An additional dose group received Firazyr® (icatibant-0.4 mg/kg) as a subcutaneous (SC) injection. Similar to the previous studies, inhibition ofEB content in the dried bladder EB per milligram of tissue weight) was utilized as measurement of efficacy.
[00213] The EB concentration of the formamide extract from the bladder demonstrated CFMQ (HGT3711) inhibition of EB absorbanee in a dose dependent manner. An oral dose of 3,0 mg kg was determined to be the minimally-effective dose (MED), and a dose of 10.0 mg kg (plasma value of 267 nM) was found to be equally effective as a 0.4 mg/kg SC dose of Firazyr* (icatibant). The results illustrated in Figure 4 show that both 10 and 30 mg/kg doses of CFMQ (HGT37H) provided almost 100% inhibition of EB accumulation in the bladder.
[00214] Oral Administration Study in Knockout Mice
[00215] To demonstrate efficacy in a mouse model relevant to the .HAE disease, studies were conducted in a knockout mouse that is deficient in the C-l inhibitor (Cl-INR- KO). These mice contain a simiiar genetic deficit to the HAE patient/subject population and demonstrated increased vascular permeability as compared to wild-type littermates.
[00216] In a simiiar study design as described above, oral administration of CFMQ (HGT3711) demonstrated a similar efficacy profile as observed in the WT mice, with dose-dependent inhibition of EB dye extravasation in the bladder of CFMQ (HGT3711) dosed animals (Figure 5). Attorney Docket No, 0138.0001--PCT
[00217] The EB concentration of the formamide extract from the bladder of knockout mice demonstrated CFMQ inhibition of EB absorbance in a dose dependent manner. An oral dose of 3.0 mg kg was determined to be nearly as effective as a 0,4 rag/kg SC dose of Firazyr® (icatibanf) in the knockout mice and both 10 and 30 mg kg doses of CFMQ provided almost 100% inhibition of EB accumu lation in the bladder of knockout mice.
[00218} Example 32 Potency of H(4-Chloro-3-(((4-(4-fiuoro^
.mefflylquinolin-8-yl)oxy 2-d.ihydropvridine- 3-earbonitrile
[00219] The potency of CFMQ (JSM U938/HGT371 1) was determined in B2- bradykinin receptor binding and functional cellular and ex vivo assays, CFMQ was potent in assays that assessed binding to the B2-bradykinin receptor and functional assays that measured calcium mobilization as a marker of Bj-bradykinin receptor binding.
[00220] Receptor Binding and Selectivity
[00221] To determine the affinity to the Ba-hradykimn receptor, CFMQ was compared to a diverse set of receptors and reference agents in an in vitro assay using cells from rat heart urinary bladder, cerebral cortex, as well as human recombinant ceils (CHO and HEK 293) and other cell lines. Each assay included a ligand at a specific concentration (concentration ranging from 0.007-10 nM), in addition to a non-specific ligand (concentration ranging from 0J μΜ-50 nM) for incubation periods ranging from 15 minutes to 6 hours at 4°-37°C. The specific binding to the receptors was defined as the difference between the total binding and the nonspecific binding, determined in the presence of an excess of unlabeled CFMQ. The concentration causing a half-maximal inhibition of control specific binding (iC50 values) and inhibition constants (Kj) were determined, and each reference compound was within the accepted limits of the historic average {± 0.5 log units).
[00222] CFMQ was found to bind to a small number of off-target (non-bradykmin 2) receptors with ICso values less than 10 μΜ (Table 4). The levels at which the off-target receptors were bound were greater than ten times higher than the concentrations required to influence efficacy. CFMQ (HGT371 !) was demonstrated to be selective in its binding to the B2-bradykimn receptor and to have a strong binding affinity to the i bradykinin receptor. Attorney Docket No. 0138.O0OJ-PCT
[00223] Table 4 Receptors >50% inhibited by CFMQ at Ι ΟμΜ
Figure imgf000065_0001
[00224] In a competition assay, CFMQ was formulated with incubation buffer (containing 2 nM [3H] bradykinin) and brought to concentrations of 0.001, 0.003, 0.01, 0.03, 0.1 , 0.3, 1.0 and 3.0 μΜ. For determination of non-specific binding 1.25 μί, of a 10 mM bradykinin (B ) solution was added to 248.8 L incubation buffer {containing 2 nM [¾]BK). For determination of total binding, CFMQ was not added. Appropriate controls were prepared in the same method.
[00225] Human embryonic kidney (HEK) 293 cells stably express .recombinant human Bj-bradykinin receptors ( 0 pmo!/mg protein) and were added to 96-welI culture-trays and cultivated for 1-3 days, followed by incubation with 100 ί, of each of the incubation buffers containing [3H]BK. After a 90-minute incubation period and washing (4x PBS (phosphate buffered saline)) supematants of the cell mixtures were transferred to scintillation vials and assayed .for [3H]BK in a beta-counter. Results of counts per minute (cpm) for non-specific binding were subtracted from the total cpm and were used for curve fit and IC5o calculation.
[00226] Results showed that CFMQ (HGT37I 1) bound to and competed away bradykinin with an 1C50 of 3.3 nM. The reference compound Firazyr® (icatibant) exhibited similar affinity for B2-bradykinitt receptor with an IC5<> of 2 nM. Attorney Docket No. 0138.0001 -PCX
[00227] The results of these studies demonstrated that CFMQ (HGT3711) has selective and strong binding affinity to the B -bradyki n receptor.
[00228] Calcium Mobilization Assays
[00229] CFMQ activity on the inhibition of calcium mobilization, a marker of B2-bradykinin receptor binding was characterized in a cellular assay, CFMQ was formulated as a 5 nM stock solution in 100% DMSO and serially diluted to 0.04, 0.12, 0.37, 1.1 1, 3.33, 10 and 30 nM, Human fibroblast (BF15) cells, which express the human B2R were loaded with 100 Τ calcium dye solution containing 2.5 mM probenicide and were then pre-incubated with CFMQ for 25 minutes at 25°C, The inhibition, effect of CFMQ on bradykinin-mediated calcium mobilization was tested in this system by emission of fluorescence signals, using the height of the resulting peak over the baseline value (relative fluorescence units [RFU] max- min). The percent inhibition for each concentration was used for curve fit and IC50 calculation.
[00230] CFMQ was found to have a strong potency to the human B -hradykmin receptor where it inhibited bradykinin-mduced calcium mobilization with an IC50 of 2.97 nM. In a previou study the reference compound Firazyr® (icatibant) exhibited an ICso of 4.0 nM. (Data not shown.)
Attorney Docket No. 0138.000 t-PCT
[00231] Umbilical Vein Contraction Assays
[00232] The inhibition effect of CF Q on bradyki in induced calcium mobilization was examined in an ex vivo functional assay of human umbilical vein contfaetion, which is considered a gold standard for bradykinin activity measurements. The human umbilical cord preparation was comprised of a control condition (no bradykinin. agonist), CFMQ at 10, 30, 100 and 300 nM concentrations and a positive control group with reference to a known B2R antagonist (icatibant; Firazyr®). Following a 30 minute incubation, BK -induced vein contractions were initiated in a cumulative maimer (final concentration of 10 μΜ), followed by maxima! calibration contraction induction by 10 μΜ serotonin, The tension increase for each dose response was calculated in relation to the (maximal) response towards serotonin, graphed as a dose-response curve and used to calculate an effective concentration at 50% (EC5o) value (Figure 6)
[00233] in this unctional umbilical vein assay, an EC50 of 73 nM for CFMQ (Figure 6) was found to be comparable to Firazyr® (icatibant), which had an EC50 of 2,5 nM,
[00234] Permeability
[00235] To determine bidirectional permeability, CFMQ was examined in an in vitro incubation assay with human small intestinal mucosa (Caco-2 ceil).. CFMQ at 5 μ was dosed to the cell monolayers on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37°C with 5% CO2 for 120 minutes. Permeability of Lucifer Yellow (500 μΜ) was measured to ensure no damage was Inflicted to the cell monolayers during the CFMQ flux period. All samples were assayed by LC-MS/MS using eiectrospray ionization.
[00236] The result was a permeability coefficient of 34 to 38 cm/s (A-to-B; B-to-A) respectively, whic was considered highly permeable with no significant efflux in the Caco-2 cells. This absorption in humans was not expected to be permeability limited, and was a favorable predictor for both rapid absorption and time to onset of action of an orally administered molecule. Attorney Docket No. OS 38.0001 -PCT
[00237] Example 33 Pharmacokinetics of CFMQ in Mouse, Rat. Dog. Monkey and Micro Yucatan Miniature Swine
[00238] Absorption in Mice
[00239] CFMQ (HGT37! 1) was administered to fasted female CD-I mice (n-l 8/dose group) by a single oral gavage at 100, 250 and 450 mg/kg in a dose volume of 5 mL kg in a spray-dried dispersion formulation (discussed below). Blood samples were taken via cardioceniesis or abdominal vein prior to administration and at 10, 30. 60 (lhr), 120 (2 hr), 240 (4 hr) and 480 (8 hr) minutes post dose. Plasma concentrations of CFMQ (HGT371 1 ) were determined by LC-MS/MS (liquid chromatography mass spectrometry) and concentrations below the limit of quantitation (3 ng/mL) were assigned a value of zero for pharmacokinetic analysis. Nominal dosing concentrations were used in all calculations.
[00240] Figure 7 illustrates the time-concentration curve at each dose level and Table 5 summarizes the plasma concentration (ng mL) and PK (pharmacokinetic) properties of CFMQ (HGT3711) following oral administration in mice.
[00241 ] Table 5 Average Plasma Concentration (ng/mL) and PK Properties of CFMQ (HGT3711) Following IV Administration in CD- I Mice
Figure imgf000068_0001
Attorney Docket No. 0138.0001 -PCT
[00242] There was a dose proportional increase in the exposure profile of fee mouse followiag oral administration of CFMQ (HGT371 1), Absorption was rapid with the time of maximum plasma concentration (Tmax) valises at or near the first time point collected. The peak serum concentration. (Cmax) was seen to compress as the doses got larger, owever the exposure (area under the concentration curve; AUC„) continued to increase proportionally. This may reflect a maximum in absorption rate at doses higher than 250 mg/kg with this formulation.
[00243] Absorption in Rats
[00244] Pharmacokinetics and gender differences were evaluated with 2 different formulations of CFMQ (HGT3711) in 2 different types of rat models. These attributes were investigated in a single oral gavage study, Male and female Wistar rats (n-3 per dose group) received CFMQ (HGT3711) at 15, 75 75, and or 150 mg/'kg. Mak Sprague-Dawley (S-D) rats (n=3 per dose group) received a single dose level, 75 mg kg. The two vehicle formulations evaluated were formulation 1: 10% N-methy! pyrrolidone (NMP): 10% Ethanoi: 30% polyethylene glycol (PEG400): 50% GELUCIRE (lauroyl polyoxylglycerides); and formulation 2; 10% NMP: 0% PEG400: 20% CREMOPHOR EL (Macrogolglycerol ricinoleate): 25% GELUCIRE 44/14 (lauroyl polyoxylglycerides): 25% CAPROYOL 90 (Propylene Glycol Caprylate).
[00245] Blood samples were taken via cardiac puncture prior to administration and at 0.25 (ISmin). 0.50 (30 min), 1, 2, 4, 8 and 24 hours post dose. Plasma concentrations of CFMQ (HGT3711) were determined by LC-MS/MS and nominal dosing concentrations were used in all calculations.
[00246] No adverse reactions were observed in any rats in this study. Figure 8 illustrates the time-concentration curve of both formulations in both sexes of each species.
[00247] Based on average dose normalized AUG values and similar dose concentration, oral exposure to CFMQ (HGT37I 1) was 20-40 times higher in female rats compared to male rats of both species (Table 6). This gender difference was observed in both S-D and Wistar rats. In both dose formulations in the Wistar rat, the average AUG values Attorney Docket No. 0I38.0O01-PCT decreased with increasing dose, showing that CF Q (HGT371 1) exposure was not dose proportional; however, this was likely due to precipitation of the molecule at the higher concentrations.
[00248] Table 6 Average Pharmacokinetic Properties of CFMQ (HGT371 1 } Following Oral Administration of 2 Formulations in Maie and Female Wistar and Sprague Dawley Rats
Figure imgf000070_0001
S-D (Male) 75 193 0.67 3^43 673 745
[00249] Within both formulations, CFMQ (BGT371 1) demonstrated large differences in exposure between sexes, with females showing greater than a 5-foid increase in exposure compared to males. The vehicle formulation utilized in the studies was a spray-dried dispersion formulation of CFMQ (BGT371 I) compiexed with 50% hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) (discussed below). Attorney Docket No. 0138.0001-PCT
[00250] Absorption in Micro Yucatan Miniature Swine
[00251 ] CFMQ (HGT371 1) was administered to female Yucatan Miniature Swine (mini-pig; n=3) by a single oral .gavage at 10 mg kg (concentration 2 mg mL) at a dose volume of 5.0 mg mL. This stud utilized the spray-dried dispersion (SDD) (50; 50 with polymer; HPMCAS) formulation of CFMQ (HGT3711) (see below). Blood samples were taken via jugular or other suitable vein puncture prior to administration and at 0.083 (5 mm), 0.25 (15 mm), 0.50 (30 min), 1, 2, 4, 8, 12 and 24 hours post dose. Plasma concentrations of CFMQ (HGT3711) were determined by LC-MS/MS.
[00252] There were no test articles related to mortality/morbidity and no abnormal clinical observations noted during the course of the study.
[00253] The average plasma concentration time curve is seen in Figure 9 and pharmacokinetic properties and plasma concentrations of CFMQ (HGT371 1) are summarized in Table 7.
[00254] Table 7 Average Plasma Concentration (ng mL) and P Profile of CFMQ (HGT371 1 ) Following PO Administration in Female Yucatan mini-pig at 10 mg kg
Figure imgf000071_0001
ND: Not Determined; Extrapolated to H>.
[00255] following oral administration in mini-pig, averaged plasma levels of CFMQ (HGT371 1 ) had a half-life of 57 hours and an extrapolated AUC of 11 1 15 hrng rnL.
[00256] Plasma. Kinetics Following intravenous Exposure in Mice
[00257] CFMQ (HGT3711) was administered to fasted female CD- mice by a single intravenous injection at 1.0 mg/kg, formulated in 100% PEG200. Blood samples were taken via cardiac puncture prior to administration and at 0.083 (5 min), 0.25 (15 min), 0.50 (30 Attorney Docket No. 0138.0001-PCT min), L 2. 4, and 8 hours post dose. Plasma concemraiions of CFMQ (HGT3711) were determined by LC-MS MS and concentrations below the limit of quantitation (BLOQ = <lng/ml) were assigned a value of zero for pharmacokinetic analysis. Nominal dosing concentrations were used in all calculations.
[00258] No adverse reactions were observed after the IV (intravenous) administration CFMQ (HGT37U). Table 8 summarizes the. average plasma concentration and calculated pharmacokinetic properties of CFMQ in the mouse. By 4 hours post-dose CFMQ (HGT3711) plasma concentration was below the BLOQ.
[00259] Table 8 Average Plasma Concentration (ng mL) and PK Properties of CFMQ (HGT37 1) Following IV Administration in Female CD-I Mice at 1 trig/kg
Average Concentration of HGT37U (ag mL) ±SD at SampHug Time points (hr)
Ϊ.0 2.0 4.0
12.6 ± 3.48 + ND ND 8.59 ND
Figure imgf000072_0001
Pharmacokinetic Properties
CL V65 (L/kg) AUCiast AUC»
(krf (L hr kg) irng/mL) ± SE (hrrsg/mL)
214 0 0.56 14.1 6.3 68.1 ± 10.8 70.9
NDT OT Determined; Extrapolated to t=0
[00260] Following IV administration, averaged plasma levels of CFMQ (HGT371 1) had a half-life (tm) of 0.56 hours and a clearance (CL) rate of 14.1 L hr/kg, which is greater than liver blood flow in a typical mouse (5.40 L/hr/kg). (D vies and Morris, "Physiological parameters in laboratory animals and humans," Pharm Res, 1993 July; 10(7): 1093-5.) The average volume of distribution (Vss) was 6.3 L/kg, whic is greater than total body water in mouse (0.73 L/kg), This suggested that CFMQ (HGT371 1) was extensively distributed in the mouse.
[00261 1 Plasma Kinetics Followin Intravenous Exposure in Rats
[00262] CFMQ (HGT37! 1) was administered to fasted female Sprague-Dawley rats by a single intravenous injection at 1.0 mg kg, formulated in 100% PEG200 (Table 2.6.5.X, Study 10SHIR.USP1 1). Blood samples were taken via a jugular vein cannula prior to Attorney Docket No. 0138.0001-PCT administration and at 0.083 (5 min), 0.25 (.15 min), 0.50 (30 min), 1, 2, 4 and 8 hours post dose. Plasma concentrations of CFMQ (HGT3711) were determined by LC-MS/MS and concentrations below the limit of quantitation (1 ng/mL) were assigned a value of zero for pharmacokinetic analysis. Nominal dosing concentrations were used in ail calculations.
[00263] There were no adverse reactions observed after the intravenous administration of CFMQ (HGT373 1). Table 9 summarizes the average plasma concentration and calculated pharmacokinetic properties of CFMQ in the rat.
[00264] Table 9 Average Plasma Concentration (ng mL) and PK Properties of CFMQ (HGT371 1) Following IV Administration in Female Sprague-Dawley Rats at I mg kg
Figure imgf000073_0001
[00265] .Following IV administration in rat, averaged plasma levels of C.F.MQ (HGT371 1) had a half-life of 2.86 ± 2.54 hours and a clearance rate of 0.95 d 0.68 L/hr/kg, which is approximately 30% of liver blood flow in rat (3.3 L/Ttr/kg) (Davies and Morris, 1.993). The average volume of distribution was 2.6 ± L i L/kg. which was high and greater than total body water in rat (0.7 L kg) (Davies and Morris, 1993) suggesting that CFMQ was extensively distributed in the rat.
[00266] Plasma Kinetics Following Intravenous Exposure in Dogs
[00267] CFMQ (HGT371 1) was administered to fasted female beagle dogs by a single intravenous injection at 1.0 mg/kg, formulated in 100% PEG200 (Table 10). Blood samples were taken via jugular vein puncture prior to administration and at 0.083 (5 min), 0.25 (15 min), 0.50 (30 min), 1, 4, 8 and 24 hours post dose. Plasma concentrations of CFMQ (HGT371 3) were determined by LC-MS/MS and concentrations below the limit of Attorney Docket No. 013S.0001-PCT quantitation (1.0 ng/mL) were assigned a value of zero for pharmacokinetic analysis. Nominal dosing concentrations were used in all calculations.
[00268] Table 10 Average Plasma Concentration (ng/mL) and Pharmacokinetic Properties for CFMQ (HGT3711) Following IV Administration in Femal Beagle Dogs at 1 mg kg
Figure imgf000074_0001
ND: Mot Determined; xtrapoiated to t~0
[00269] Following IV administration in dogs, average plasma levels of CFMQ (HGT3711) demonstrated a half-life of 2.69 hours and clearance rate of 0.25 L/hr/kg, which is approximately 14% of liver blood flow in dog (1.85 L/hr/kg) (Davies and Morris 1993). The average volume of distribution was 0.75 L kg, similar to total body water in dog (0.6 L/kg), (Davies and Morris 1993). This suggested that CFMQ is not extensively distributed in dogs.
[00270] Plasma Kinetics Following Intravenous Exposure in Monkeys
[00271] A cross-over P (pharmacokinetic) analysis was conducted in cynomolgus monkey. Two fasted male monkeys in each dose group received a single 1.0 mg/kg dose of CFMQ (HGT37 I 1) by either IV (intravenous) or PO (oral) administration, with a 7-day washout period between each dose. The dose concentration was 1.0 mg/mL with, a dose volume of 1.0 mL/kg. Blood samples were collected via the femoral vein at 0,083 (5 min), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 3, 4, 6, 8, 18 and 24 hours post-dose. Plasma concentrations of CFMQ (HGT371 1) wer determined by LC-MS/MS and concentrations below the limit of quantitation (2.5 ng mL) were assigned a value of zero for pharmacokinetic analysis. Following oral administration of CFMQ (1 mg/kg), the concentration of CFMQ in plasma was below the limit of quantitation (BLQ:-":<2.5ng ml) at each sampling time point, preventing assessment of pharmacokinetic properties of CFMQ Attorney Docket No, 013§,0Q01-PCT after oral administration in monkeys in this study, Table 1 1 summarizes the average PK properties for IV and PC) dosed groups.
[00272] Table 11 Selected Pharmacokinetic Properties of CFMQ (HGT3711) in Male Cynomolgus Monkeys Following IV and Oral Administration
Figure imgf000075_0002
Figure imgf000075_0003
Figure imgf000075_0001
[00283] Following IV (intravenous) administration in monkeys, the average plasma levels of CFMQ (HGT3711) demonstrated a systemic clearance (CL) of 1.51 ± 0.41 L/hr/kg, which coiTesponds to 57.63% of monkey hepatic blood flow (2.62 L/hr/kg)(Davies and Morris 1993). The mean half-life (i ), :r,iX and AUC(0-*) values were 1.40 ± 0.24 hr, 410 ± 107.14 ^tg/L and 693,99 ± 15.1.48 hr^g/L, respectively. CFMQ administered intravenous iy distributes extensively into the tissues of the monkey, with a mean volume of distribution (Vz) at terminal phase of 2.98 ± 0.55 L/kg, which corresponds to 4.32-fold of the total body- water (0.69 L/kg) in the monkey.(Davies and Morris 1 93)
[00284] A late Tmsxwas observed in Monkey 2 and 4 following intravenous injection, which may have been due to the utilization of 50% PEG200, which has a delayed-response effect and may have made the solution viscous, limiting the solution at the injection site and slowing blood dispersal Attorney Docket No. 0138.0001 -PCT
[00285] Following oral administration of CFMQ (HGT3711) at 1 mg kg there was no bioavailability in the monkey, as plasma concentrations of CFMQ were below the limit of quantification (BLQ), However, bioavailability following an oral dose of CFMQ was observed in all other species tested.
[00286] Based on in vitro metabolism studies across species the lack of exposure in the monkey may be due to low metabolic stability and/or a unique clearance or transport mechanism in the primate that is not expected in other species, including humans. When CFMQ was dosed, to monkeys by the intravenous route it demonstrated moderate to high clearance values, and this may indicate that the lack of bioavailability may in part be due to a lack of absorption. Low absorption could be the result of an interaction with a transporter in the liver or intestine that limits the systemic exposure of CFMQ in monkeys.
[00287] Metabolism
[00288] The metabolic pathway of CFMQ (HGT371 I) was explored in liver microsomes and primary hepatocytes, as well as in an in vivo mini-pig biodistribution study.
[00289] In Vitro Metabolism Studies
[00290] in vitro metabolite identification was performed in CD-I mice, Sprague- Dawley rats, Yucatan mini-pigs and human hepatocytes. Observed metabolites were confirmed by comparison against synthetic reference standards.
[00291] in vitro metabolic stability studies were performed to determine hepatic stability in vivo. CFMQ was incubated in liver microsomal preparations from mouse, rat, dog, mini-pig, and humans, as well as an additional study with monkey and human. CFMQ was incubated with human and animal liver microsomes at 0.3 mg/m'L at 37°C for 30 or 60 minutes. Additional reference compounds were incubated as controls. Following incubation, samples were analyzed by HPLC-MS/MS.
[00292] CFMQ (HGT3711) had variable stability in rodent species with generally increasing stability in higher species, with markedly higher stability in human liver Attorney Docket No. 0138.0001-PCT preparations. Low metabolic stability in the monkey corresponded to low bioavailability and may indicate a unique metabolic pathway. See Table 12.
[00293] Table 12 Summary of In Vitro Microsomal S ability of CFMQ (HGT3711)
Figure imgf000077_0001
[00294] Bcpatocvtc Metabolism
[00295] In vitro metabolism of a tritiated labeled form of CFMQ (HGT37H) was assessed in cryopreserved male and female rat and mini-pig hepatocytes, as well as in male and female mouse hepatocytes. Human .hepatocytes (mixed-gender) were also examined.
[00296] 3H~CFMQ1 (concentration of 5 μΜ or 10 uM; approximately 1.0 mCi/xnL) was incubated with 1 x 106 cells (hepatoc>tes)/niL hepatocytes for up to four hours. Hepatocyies from all species were characterized for both Phase I and Phase II metabolizing capacity by incubation with positive controls (s*C-7-ethoxycoumarin and ! C-testosterone) at 2 and 4 hours. At time points of 0.5, 1 , 1.5, 2, and 4 hours, Incubation samples were extracted by the addition of acetonitrile and analyzed by liquid scintillation (LSC) counting followed by H'PLC (high performance liquid chromatography) radiodeteetion. Selected samples (4 hr) underwent further analysis by LC-MS/MS (liquid chromatography mass spectrometry) to identify those metabolites representing >5% of sample radioactivity.
[00297] Within both studies a total of 16 main radioactive regions of interest were detected in incubations of 3H-CFMQ with cryopreserved hepatocytes. Some of these Aitoniey Docket No. 0138,0001-PCT components were multi-component in nature. A summary of the major metabolites observed are listed in Table 13.
Tabic 13 In Vitro Metabolite identification and Related Species of CPMQ (HGT37 1 ί )
Figure imgf000079_0001
a MET numbers were assigned 3H-radiochromatograro of various hepatocyte incubation samples
component detected during LC-MS/MS analyses and >1% of sample radioactivity in 3H~radiochromatogram
vft component tentatively present (insufficient MRM transitions present to definitively confirm presence)
V* component not confirmed by LC-MS MS due to low sensitivity in negative ion polarity, however a peak in the SB-radiochromatogram indicates that component is present X - Not determined
Attorney Docket No. 0138.0001 -PCT
[00298] Parent ¾-CF Q was shown to be stable in the absence of hepatocytes and the rate of metabolism of JH-CFMQ was similar m mouse, female rat, mini-pig and human (Figure
10). In vitro metabolism of 3H-CFMQ at 5μΜ was most extensive in male rat hepatocytes, with approximately 95% of the parent metabolized by 4 hours. 'The rate of metabolism was markedly lower in female rat (approximately 32%) as well as both sexes of other species (mini -pig 52-57% and human 25-35%). At a higher concentration (!OuM), metabolism in the male and female mouse and human, by 4 hours was 22% and 21%, respectively.
[00299] Incubations of CFMQ (HGT3711) in human hepatocytes produced one main metabolite, METl, and was a mono-oxygenated structure which formed to levels of 10-11%, or 7-8% of parent METl was also the main metabolite observed in incubations with mouse (2,0- 3.7%) and mini-pig (18-20.56%) hepatocytes, and was observed in incubations with rat. Other minor metabolites were detected in human hepatocytes as well as in animal species. Numerous minor metabolite fragments were also detected in some species, however these were produced at levels below the deemed limit of accurate quantification (<!% of sample radioactivity) and therefore were not further detailed. There was no evidence for a human specific metabolite.
[00300] The 4 hour samples incubated with 3H-CFMQ (5 and 10 uM) were further analyzed by LC-MS/MS to identif metabolites. These studies demonstrated that both Phase I and Phase II metabolites were observed in all species including mono- and di-hydroxylated metabolites (METl), acid metabolites, glucuronic acid and sulphate conjugates of Phase I metabolites of CFMQ. In addition glutathione conjugates of de -chlorinated and mono-hydroxy, de-chlorinated and a glutathione conjugates were observed only in the mouse hepatocytes.
[00301] The major metabolites identified from each species (including mini-pig) were mono-oxidation products with smaller amounts of di-oxidation products. Metabolism by human, liver hepatocytes was much less extensive than that seen in rats and mini-pigs, as was expected based on previous metabolic stability assays. Attorney Docket No. 0138.0001-PCT
[00302] There were three major human metabolites, ML M2 and M3 (Figure 11). Ml was seen at 10% of parent, while M2 and M3 were formed at 5 % and 3 % of the parent respectively ,
[00303] Results of these two studies showed that the major human hepatic metabolites of 3H-CFMQ were mono-hydroxy and di~oxygenated molecules that importantly, are produced in all other animal species examined. There may be a marked sex difference in the metabolism of CFMQ, which was also seen in the blood pharmacokinetic profile of the rat. In general the quantity of metabolites formed was greater in the nonclinical species likely due to lower stability in liver preparations. Overall, these studies suggested similar metabolism in the different species as compared to human. Importantly, each of these metabolites formed hi human liver hepatocytes was also observed in the mouse and mini-pig incubations, which qualify them as a relevant nonclinical species for safety studies.
[00304] Formulations
[00305] , Various formulations of CFMQ were prepared.
[00306] A. lipidic formulation of CFMQ was prepared containing 10% N-methyl pyrrofidone (NMP), 10% TRANSCUTOL HP (highly purified 2-(2-ethoxyethoxy)ethanol), 30% polyethylene glycol (PEG400), and 50% GELUCIRE 44/14 (lauroyl polyoxylglycerides). The formulation was found to give solubility, stability and exposure parameters that would allow for animal dosing experiments. Additionally, an in vivo study was conducted in Yucatan mini-pigs that demonstrated toierability of the formulation up to 5mL kg. The results of that study showed that the formulation was well tolerated in mini-pigs in terras of food consumption, body weight and clinical observations.
[00307] in addition to the lipidic formulation several other approaches to formulation were taken. Three salts of CFMQ were prepared: l}2-ethane disulfonic acid (hemi) salt, 1,5- Attorney Docket No. 0? 38.000 i -PCT napthalene disulfonic acid salt and 1,2-ethane disulfonic acid (mono) salt. The 1,2 ethane disulfonic (mono) salt greatly increased the solubility of CFMQ.
[00308] Additionally, CFMQ was milled to have a nano size particle.
[00309] A spray-dried dispersion approach where CFMQ was complexed with a polymer was also evaluated. When CFMQ was spray-dried onto hydroxy! propyl methyl cellulose acetate succinate (HPMCAS), the combination was found to have excellent solubility. The spray-drying process consisted of three steps: slurry preparation, spray -drying, and secondary drying. The slurry was prepared by dissolving HPMCAS polymer in. a methanol/water solvent mixture (90 v/10 v), then an equivalent amount of the CFMQ was suspended in the polymer solvent mixture. The slurry was then heated and spray-dried through a flash nozzle into a nitrogen atmosphere in a spray-dryer. The powder output of the spray-dryer retained a small amount of water/methanol, which was removed in a secondary drying step, which occurred in a convection tray dryer at 40°C/15% relative humidity (RH). A 50:50 solid dispersion of the active ingredient in HPMCAS, was used in the animal studies described herein.
[00310] Example .3.4. .. Extrapo lation of CFMQ Oral Dose by interspecies and
Pharrnacokineti c Simi ation
[00311] A pharmacokinetic extrapolation for a human oral dose was performed using allometric scaling of clearance and volume of distribution. The human pharmacokinetic values were extapolated from in vivo mouse, rat, dog and monkey pharmacokinetic studies. Due to the variability in bioavailability across pre-clinical species a range of bioavailability values from 25% to 50% was modeled. This pharmacokinetic model predicted that at a human equivalent dose of 0.8 mg/kg, plasma levels will stay above the predicted efficacious levels for between greater than 5, 10 and 12 hours when "bioavailability is 25, 50 or 75%. This model was based on the assumption that all of the clearance pathways in the human were captured in the pre-clinical species. Attorney Docket No. 0138.0001-PCT
[00312] While the present teachings have been illustrated with respect to one or more implementations, alterations and/or modifications can be made to the disclosed embodiments without departing from the spirit, and scope of the appended claims, in addition, while a particular feature of the present teachings can. have been disclosed with respect to only one of several implementations, such feature can be combined with one or more other features of the other implementations as can be desired and advantageous for any given or particular function.
[00313] To the extent that the terms "containing," "including," "includes," "having," "has," "with," or variants thereof are used in either the detailed description and the claims, such terms are intended to be inclusive in a manner similar to the term "comprising.5' As used herein, the term "one or more of with respect to a listing of items suc as, for example, A and B, means A alone, B alone, or A and B. The term "at least one of is used to mean one or more of the listed items can be selected.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present teachings are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, ail ranges disclosed herein are to be understood to encompass any and all sub-ranges subsumed therein. For example, a range of "less than 10" can include any and ail sub-ranges between (and including) the minimum value of zero and the maximum value of 10, that is, any and all sub-ranges having a minimum value of equal to or greater than zero and a maximum value of equal to or less than 10, e.g. 1 to 5, In certain cases, the numerical values as stated, for the parameter can take on negative values. In this case, the example value of range stated as "less than 10" can assume values as defined earlier plus negative values, e.g., -1, -1.2, - 1 ,89, -2, -2.5, -3, -10, -20, and -30, etc.

Claims

Attorney Docket No. 0138.0001 -PCX
What is claimed hi
L A method of treating a Ba-bradykmin receptor mediated angioedema in a subject comprising:
administering to the subject in need thereof a therapeutically effective amouni of a composition comprising a compound having formula (i) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof
Figure imgf000084_0001
wherein R$ is CI or CN;
wherein is
Figure imgf000084_0002
Aiiorney Docket No. 0138,000 i -PCT
Figure imgf000085_0001
Figure imgf000085_0002
Attorney Docket No. 0138.0001-PCT
Figure imgf000086_0001
Attorney Docket No. OI 38.0001-PCT wherein R5 is selected from the group consisting of Hs a methyl group, an ethyl group, a propyl group, a butyl group, a petityl group, or a hexyl group, and
wherein plasma extravasation in the subject is reduced upon administration of the compound or the pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
2. The .method of claim 1, wherein the Brbradykmin receptor mediated angioedema is hereditary angioedema (HAE).
3. The method of claim 1, wherein the composition is administered to the subject orally or sublinguall .
4. The method of claim 1, wherein the composition further comprises a pharmaceutical earner substance, excipient, and/or an adjuvant.
5. The method of claim I, wherein the composition is administered to the subject at about. 3.0 mg of the compound having formula (i) kg to about 35 mg of the compound having formula (I)/kg per dose and the dose is repeated within about 5 hours to about 12 hours after the initial dose.
6. The method of claim 1 , wherein the method further comprises administering icatibant, ecai!antide, fresh frozen plasma, CI -inhibitor, or kallikrein inhibitor to fee subject.
7. The method of claim I , wherein the compound having formula (I) has a half maximal inhibitory concentration (IC50) o competition with the binding of labeled bradykinin to human B2"bradykinin receptor of iess than about 50 nanomolar.
8. The method of claim 1, wherein composition further comprises one or more of surfactants, tonicity agents, buffers, salts, preservatives, co-solvents, and viscosity building agents. Attorney Docket No. OB8.0GO1-PCT
9. The method of claim. 1, wherein composition in the form an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, or a transdermal patch.
Ϊ 0. The method of c!afra 1 , wherein the composition has a pH of less than about 5.
1 1. The method of claim 1, wherein the compound lias a molecular weight less than about 650.
12. A method of treating a B2~bradykinin receptor mediated angioedema in a subject, comprising:
administering to the subject in need thereof a therapeutically effective amount a composition comprising a compound having formula (II) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or sol vate thereof
Figure imgf000088_0001
thereb reducing plasma extravasation in the subject.
13. The method of claim 12, wherein the Bs-bradykmm receptor mediated angioedema is hereditary angioedema (HAE).
14. The method of claim 12, wherein the composition is administered to the subject orally or subiingualiy. Attorney Docket No. O138.0OO1-PCT
15. The method of claim 12, wherein the composition is administered to the subject at about 3.0 mg of the compound having formula (il)/kg to about 35 mg of the compound having formula (il) kg per dose and the dose is repeated within about 5 hours to about 12 hours after the initial dose,
16. The method of claim 12, wherein the method further comprises administering icatibant, ecallaniide, fresh frozen plasma, C! -inhibitor, or kallikrein inhibitor to the subject
17. A method of treating a B2-bradykinin receptor mediated angioedema in a subject comprising:
administering to the subject in need thereof a therapeutically effective amount a composition comprising
! l-((4-CMoro-3-(({4-(4-fluoro
meth.yipyridin-2-yl)methyi)-2-Oxo-l, 2-dihydropyridine-3-carbonitrile;
(2E)-3-[6-(Acetylammo)pyridin-3-yl3^
y l)oxy]methyl } pberry i)(methyl)amino ] -2-oxoet hy i } prop-2-enamide ;
(2E)-3-[6-(Acetylammo)pyridm~3~yl]-N^
yl)oxy jmethyl } phen.yl)amino] -2-oxoethyl}prop-2-enamide ;
(2E)-M-{2-[(4~Chloro-2-cyano~3-{[(2.~me^
2-oxoethyi}-3-[4-(irii]uoromethyl)phenyi]prop-2"enamide
N-[4-ehloro-2-cyano-3-[(2-ttiethyIqumolin-8-yI)oxyrnethyl]phenyl]-2-
(eihylcar'bamoylamino)- -methyiacetainide;
2-(4-aminobutylcarbamoylamino)-N- 4-chioro-2-cyanO"3-[(2-methylquinolin-- 8-y i )oxymethy Ijpheny ! j -N-methy 3 acetami de ;
4-[[2-[4-cMoro-2-cyano-N-metliyl-3-[(2-methylquinoIin-8-yl)oxymethyl3
ani [ino]-2-oxoethyl jcarbamoylaminojbutanoic acid;
(E)~N-[2-[4 Woro-2-c a«o^^
anilino]-2-oxoethyl]-3-(3-methoxyphenyl)prop-2-eiiamide; Attorney Docket No, 0138.0001 -PCX
(E)~N-[2-[4-c oro-2-cyano-N^^
anilino]~2-oxoe&yl]~3-[4-(t^^
-[2,4^ichlotO-3-[(2-metjiyLquiiiolm-8-yl)oxymethyljphenyl]-2~[5-(2,
2-dimethy Ipropanoy 1)~ 1 -methy lpyrrol-2 -y 1 ] -N-methy lacetainide ;
4- (E)~3~[[CZ)~3-[2,4-dichloro~3-[(2-^^
3 -oxoprop- 1 -eny i] -N-methy 1 benzamide;
(B)-N-[2- 2s4-dI Joro-N~me^
oxoethyl j~3 -pheaylprop-2-enamide hydrochloride;
Figure imgf000090_0001
yl)oxymethyi]phenyl]-N-methylacetamide;
(E)~3-(6-acetamidopyridin-3-yl)-^
yl)oxymethyijainlinoj-2-oxoethyl]prop-2-enai»ide;
N~[2J4-dichIoro~3~[(2-meihylqumoSJR-8-yl)oxynieihyl]phenyl]
methy!-5-(tkiopbene-2-carbonyl)pyrrol-2-yl]acetamide;
2-[5-(cyclohexanecarbonyl)-l-methy!py
yi)oxymethyl]phet\yI]-N-meihylacetaraide;
2-[S-(4~cyaiiobenzoyI)"l-methylpy
yl)oxy methyl] phenyl] acetamide ;
2-[S-(4-cyaBobenzoylHH-pym>I-2~yl]~N ^
yl)oxymethy I jphenyij -N-methy 1 acetamide;
N - [2,4-dichloro-3 - f (2-methylquinolin-8~yl)oxyineihyl]phenyl] -N-methy 1-2- f 1 - meil yi-5-(2-phenylacet>d)pyrrol-2-yl]acetainide;
2 5-(4~ammoben2oyl}-i-methylpyrro^^
yl)oxymethyl]phenyl]-N-methylacetamide;
N~(2,4-dichloro~3 - [(2-meihylquinolin-8-yl)oxymethyl]pheny 1] -N-methyl-3 - { 1 - methyl~5-(pyridine-3-carbonyI)pyrrol-2~yl]propanainide;
4-[(E)-3- [2-[2,4- ichloro-N-methyl-3-^
oxoethyl] amino j-3 -oxoprop- 1 -enyl] -N-methy Ibenzamide ; Attorney Docket No. 0138.0001 -PCX
(E)-3-(6-acetamidopvrid -3-yl)- ^
y 1) oxymetry!] ani lino] -2-oxoethy 1] prop~2~enam ide;
N»[2 ,4-di chloro-3 - [(2-methyiquinolin- 8-yl)oxymethyl]pheny.l]~N-methyl-3-fl- methyl-5-(thiophene-2-carbonyl)pynOl-2-yl]propanamide;
2 5~(4-eyanobenzoyl)-l-methylpy^
yl)oxymethyl phenyl]-N-methylaceiamide;
2~[5-(0-cyanopyridine-3~earbony^
8-yl)oxymetliyl|p3ienyl]-N-methyIacetamide;
or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, thereby reducing plasma extravasation in the subject.
18. The method of claim 17, wherein the composition is administered to the subject orally or sublinguaily.
19. An oral formulation comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof and a pharmaceutically acceptable carrier, wherein the therapeutically effective amount is between about 60 wt % of the oral formulation and formula (Ϊ) is as follows:
Figure imgf000091_0001
wherein Rj is
H or
Figure imgf000091_0002
Attorney Docket No. O138.O00I-PCT wherein R2 is
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000092_0003
Attorney Docket No. 0138,0001-PCT
Figure imgf000093_0001
Attorney Docket No. 0138.0001 -PCT
Figure imgf000094_0001
wherein R¾ is selected from the group consisting of H, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group.
20. The oral formulation of clai 19, further comprising hydroxy! propyl metliyl cellulose acetate succinate.
21. The oral formulation of claim 19. wherein the oral formulation is in the form of a spray- dried dispersion.
22. Use of a composition comprising a compound having formula (!) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof for the manufacture of a medicament for the treatment and/or prevention of a Ba-bradykinin receptor mediated angioedema, wherein formula (!) is as follows:
Attorney Docket No. 0138.0001·
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000095_0003
Figure imgf000095_0004
Figure imgf000096_0001
Figure imgf000096_0002
-95- Attorney Docket No. OI 38.0001-PCT
Figure imgf000097_0001
wherein R5 is selected from the group consisting of H, a metliyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group.
23. An oral formulation comprising a therapeuticaUy effective amount of a compound having formula (Π) or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof and a Attorney Docket No. 0138.000 l-PCT pharmaceutically acceptable carrier, wherein the therapeutically effective amount is between about 0.001 wt % and about 60 wt % of the oral formulation and formula (II) is as follows;
Figure imgf000098_0001
24. The oral ibrmiilation of claim 23, further comprising hydroxy! propyl methyl cellulose acetate succinate.
25. The oral formulation of claim 23, wherein the oral formulation is in the form of a spray- dried dispersion.
PCT/US2014/024540 2013-03-14 2014-03-12 Methods of treating b2-bradykinin receptor mediated angioedema WO2014159637A1 (en)

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MX2015012650A MX2015012650A (en) 2013-03-14 2014-03-12 Methods of treating b2-bradykinin receptor mediated angioedema.
JP2016501568A JP2016514141A (en) 2013-03-14 2014-03-12 B2-bradykinin receptor mediated angioedema treatment method
RU2015138443A RU2015138443A (en) 2013-03-14 2014-03-12 METHODS FOR TREATMENT OF ANGIONEUROTIC Edema Mediated by Bradykinin B2 Receptors
KR1020157029035A KR20150127718A (en) 2013-03-14 2014-03-12 Methods of treating b2-bradykinin receptor mediated angioedema
EP14776198.5A EP2968308A4 (en) 2013-03-14 2014-03-12 Methods of treating b2-bradykinin receptor mediated angioedema
BR112015022846A BR112015022846A2 (en) 2013-03-14 2014-03-12 use of a compound to treat or prevent a bradykinin b2 receptor mediated angioedema and formulation comprising the same
CN201480027533.7A CN105228623A (en) 2013-03-14 2014-03-12 The angioedematous method for the treatment of B2-bradykinin receptor mediation
US14/776,542 US20160030416A1 (en) 2013-03-14 2014-03-12 Methods of treating b2-bradykinin receptor mediated angioedema
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WO2023180577A1 (en) 2022-03-25 2023-09-28 Pharvaris Gmbh Therapeutic uses of bradykinin b2-receptor antagonists
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