WO2012093383A1 - Compositions et procédés pour le traitement de la sepsie et d'affections apparentées - Google Patents

Compositions et procédés pour le traitement de la sepsie et d'affections apparentées Download PDF

Info

Publication number
WO2012093383A1
WO2012093383A1 PCT/IL2011/000879 IL2011000879W WO2012093383A1 WO 2012093383 A1 WO2012093383 A1 WO 2012093383A1 IL 2011000879 W IL2011000879 W IL 2011000879W WO 2012093383 A1 WO2012093383 A1 WO 2012093383A1
Authority
WO
WIPO (PCT)
Prior art keywords
ono
linked
ring
carbon atoms
donor group
Prior art date
Application number
PCT/IL2011/000879
Other languages
English (en)
Inventor
Andrew Lurie Salzman
Original Assignee
Radikal Therapeutics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Radikal Therapeutics Inc. filed Critical Radikal Therapeutics Inc.
Publication of WO2012093383A1 publication Critical patent/WO2012093383A1/fr

Links

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/40—Cyclodextrins; 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to use of compounds comprising a nitric oxide (NO) donor and a reactive oxygen species (ROS) degradation catalyst in pharmaceutical compositions and methods for treatment of sepsis and conditions associated therewith.
  • NO nitric oxide
  • ROS reactive oxygen species
  • Sepsis is driven by widespread tissue injury mediated by alterations in the biosynthesis of the free radicals nitric oxide (NO) and superoxide anion (0 " ) (Traber et al, 2007).
  • NO nitric oxide
  • superoxide anion (0 " )
  • the imbalance of these two free radical species produces major changes in the distribution of extracellular water, disrupts epithelial and endothelial tight junctions, impairs endothelial function and vascular smooth muscle tone, chokes off microcirculatory blood flow (Trquelak et al, 2008), triggers pulmonary arterial hypertension, and raises endothelial permeability (Maybauer et al, 2009).
  • sepsis may progress to a state of circulatory collapse, with widespread tissue dysfunction and multiple organ failure prior to death.
  • NO deficiency results both from its consumption by 0 2 " and its diminished synthesis by the endothelial NO synthase (ecNOS) isoform secondary to depletion of its precursor (L-arginine) and synthetic co-factor (tetrahydrobiopterin; BH4) (Luiking and Deutz, 2007; Luiking et al, 2004).
  • 0 2 " is correspondingly elevated due to its excessive production by uncoupled mitochondria and the enzymes NADPH oxidase, xanthine oxidase (XO), and uncoupled ecNOS.
  • the imbalance of NO and 0 2 directly impairs the ability of the arteriolar microcirculation to dilate, producing a biological cascade of ischemia, tissue dysfunction, hemodynamic collapse, and multiple organ failure.
  • a successful treatment of sepsis may require the simultaneous replenishment of NO and removal of 0 2 ⁇
  • US Patent Nos. 6,448,267, 6,455,542 and 6,759,430 herewith incorporated by reference in their entirety as if fully described herein, disclose, inter alia, piperidine, pyrrolidine and azepane derivatives comprising an NO donor and a superoxide scavenger, capable of acting as sources of NO and as ROS degradation catalysts, their preparation, and their use in the treatment of various conditions associated with oxidative stress or endothelial dysfunction such as diabetes mellitus and cardiovascular diseases.
  • the present invention thus relates to a method for treatment of sepsis and conditions associated therewith in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of the general formula I:
  • X 3 is -NO or -ONO 2 , provided that at least one R t group is an NO-donor group;
  • R 2 each independently is selected from (C r Ci 6)alkyl, (C 2 -C) 6 )alkenyl, or (C 2 -C 1 e )alkynyl;
  • n and m each independently is an integer of 1 to 3.
  • the present invention provides a pharmaceutical composition for treatment of sepsis and conditions associated therewith comprising a compound of the general formula I as defined above, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a compound of the general formula I as defined above, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, for use in treatment of sepsis and conditions associated therewith.
  • the present invention relates to use of a compound of the general formula I as defined above, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, for the preparation of a pharmaceutical composition for treatment of sepsis and conditions associated therewith.
  • Fig. 1 shows the percent survival of Balb/c mice exposed to a lethal dose of E. coli lipopolysaccharide (LPS; 10 mg/kg IP), after treatment with compound la ( -100; 0, 20, 40, or 80 mg/kg/day, BID IP), with the initial dose given 1 hr after LPS injection.
  • mortality was 100% for the control group (LPS+vehicle) vs. 0% for the highest dose group (80 mg/kg/day) of compound la treatment (pO.001).
  • the doses (mg/kg) noted in the legend represent the quantity administered via an intraperitoneal route of administration every 12 hrs ( means p ⁇ 0.0 ⁇ ; *** means p ⁇ 0.001).
  • FIG. 2 shows histological analysis of the ileum of mice 16 hrs after administration of LPS (10 mg/kg IP; upper panels), indicating massive confluent infiltration by neutrophils, macrophages, and plasma cells; and the effect of compound la (R-100; 80 mg/kg/day, BID IP) administered 1 hr and 13 hrs after LPS administration (left lower panel) as compared to control (Sham; right lower panel).
  • LPS 10 mg/kg IP
  • FIG. 2 shows histological analysis of the ileum of mice 16 hrs after administration of LPS (10 mg/kg IP; upper panels), indicating massive confluent infiltration by neutrophils, macrophages, and plasma cells; and the effect of compound la (R-100; 80 mg/kg/day, BID IP) administered 1 hr and 13 hrs after LPS administration (left lower panel) as compared to control (Sham; right lower panel).
  • Fig. 3 shows that mice treated with LPS (10 mg/kg IP) showed a marked reduction in mean arterial pressure when compared to the control untreated group (Sham+Vehicle); and administration of compound la (R-100; 10 mg/kg, IP) 1 hr and 6 hrs after LPS administration significantly increased blood pressure when compared with the LPS-treated controls.
  • Figs. 4A-4H show the effect of compound la (R-100; 80 mg/kg/day, IV) on the Pa0 2 /FiO 2 ratio (4A), the peak airway pressure (4B), pause airway pressure (4C), pulmonary artery pressure (4D), activated clotting time (4E), fluid balance after 24 hours (4F), mean arterial pressure (4G) and systemic vascular resistance index (4H) in an ovine Pseudomonas aer ginosa-s&ptic shock model. Measurements were taken at baseline and every 3 hrs during the 24 hrs study period. Data are expressed as mean ⁇ SEM, Statistical analysis: two-way ANOVA and Bonferroni post hoc comparison. /? ⁇ 0.05 was considered as statistically significant.
  • the present invention provides a method for treatment of sepsis and conditions associated therewith, by administration of piperidine, pyrrolidine, or azepane derivatives of the general formula I as defined above, comprising one to four NO donor groups and a reactive oxygen species (ROS) degradation catalyst, i.e., a superoxide scavenger.
  • ROS reactive oxygen species
  • alkyl typically means a straight or branched saturated hydrocarbon radical having 1-16 carbon atoms and includes, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2,2- dimethylpropyl, n-hexyl, n-hepty], n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, and the like.
  • (C r C 6 )alkyl groups Preferred are (C r C 6 )alkyl groups, more preferably (C r C 4 )alkyl groups, most preferably methyl and ethyl.
  • alkenyl and “alkynyl” typically mean straight and branched hydrocarbon radicals having 2-16 carbon atoms and 1 double or triple bond, respectively, and include ethenyl, propenyl, 3-buten-l-yl, 2-ethenylbutyl, 3-octen-l- yl, 3-nonenyl, 3-decenyl, and the like, and ropynyl, 2-butyn-l-yl, 3-pentyn-l-yl, 3- hexynyl, 3-octynyl, 4-decynyl, and the like.
  • C 2 -C 6 alkenyl and alkynyl radicals are preferred, more preferably C 2 -C 4 alkenyl
  • alkylene typically means a divalent straight or branched hydrocarbon radical having 1-20 carbon atoms and includes, e.g., methylene, ethylene, propylene, butylene, 2-methylpropylene, pentylene, 2-methyibutylene, hexylene, 2-methylpentylene, 3-methylpentylene, 2,3-dimethylbutylene, heptylene, octylene and the like.
  • Preferred are (Ci-Cg)alkylene, more preferably (C r C 4 )alkylene, most preferably (C
  • cycloalkyl as used herein means a cyclic or bicyclic hydrocarbyl group having 3-12 carbon atoms such as cyciopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyi, adamantyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, and the like.
  • Preferred are (C 5 -Ci 0 )cycloalkyls, more preferably (C 5 -C 7 )cycloalkyls.
  • aryl denotes an aromatic carbocyclic group having 6-14 carbon atoms consisting of a single ring or multiple rings either condensed or linked by a covalent bond such as, but not limited to, phenyl, naphthyl, phenanthryl, and biphenyl.
  • heterocyclic ring denotes a mono- or poly-cyclic non-aromatic ring of 4-12 atoms containing at least one carbon atom and one to three heteroatoms selected from sulfur, oxygen or nitrogen, which may be saturated or unsaturated, i.e., containing at least one unsaturated bond. Preferred are 5- or 6-membered heterocyclic rings.
  • heterocyclyl refers to any univalent radical derived from a heterocyclic ring as defined herein by removal of hydrogen from any ring atom. Examples of such radicals include, without limitation, piperidino, 4-morpholinyl, or pyrrolidinyl.
  • NO-donor group refers to any group of the formula -X r X 2 -X 3 , wherein X ! may be absent or is selected from -0-, -S- or -NH-; X 2 may be absent or is (C
  • Preferred NO-donor groups are those in which Xi is absent or is -O-; X 2 is absent or is -(C r C 6 )alkylene, preferably -(C r C4)alkylene, more preferably methylene; and X 3 is -NO or -ONO 2 , preferably - ONO 2 , and said alkylene is optionally substituted as defined hereinabove.
  • the compound of the general formula I may comprise one NO-donor group or more than one identical or different NO-donor groups.
  • the compound used according to the method of the present invention is a compound of the general formula I, wherein Rj each independently is selected from H, -COOR 3 , -CON(R 3 ) 2 , or an NO-donor group; and R 3 is H.
  • the compound used according to the method of the present invention is a compound of the general formula I, wherein R 2 each independently is (C r C 8 )alkyl, preferably more preferably (C r C 2 )a!kyl, most preferably methyl.
  • R 2 each independently is (C r C 8 )alkyl, preferably more preferably (C r C 2 )a!kyl, most preferably methyl.
  • Preferred embodiments are those in which all the R 2 groups in the formula I are identical.
  • the compound used according to the method of the present invention is a compound of the general formula I, wherein in said NO-donor group, X
  • the compound used according to the method of the present invention is a compound of the general formula I, wherein n is 1 , 2 or 3, preferably 1 or 2.
  • the compound used according to the method of the present invention has the general formula I, wherein n is 1 , i.e., a 1 -pyrrolidinyloxy derivative of the formula la (see Table 1).
  • the compound used according to this method has the general formula la, wherein either the carbon atom at position 3 of the pyrrolidine ring or the carbon atom at position 4 of the pyrrolidine ring, or both, are each linked to an NO-donor group.
  • the compound used according to the method of the present invention has the general formula I, wherein n is 2, i.e., a 1- piperidinyloxy derivative of the formula lb (see Table 1).
  • the compound used according to this method has the genera! formula lb, wherein one, two or three of the carbon atoms at positions 3 to 5 of the piperidine ring are each linked to an NO-donor group.
  • the carbon atom at position 3 of the piperidine ring and optionally one or more of the carbon atoms at positions 4 or 5 of the piperidine ring are each linked to an NO-donor group;
  • the carbon atom at position 4 of the piperidine ring and optionally one or more of the carbon atoms at positions 3 or 5 of the piperidine ring are each linked to an NO-donor group; or
  • the carbon atom at position 5 of the piperidine ring and optionally one or more of the carbon atoms at positions 3 or 4 of the piperidine ring are each linked to an NO-donor group.
  • the compound used according to the method of the present invention has the general formula I, wherein n is 3, i.e., a 1- azepanyloxy derivative of the formula Ic (see Table 1).
  • the compound used according to this method has the general formula Ic, wherein one, two, three or four of the carbon atoms at positions 3 to 6 of the azepane ring are each linked to an NO-donor group.
  • the carbon atom at position 3 of the azepane ring and optionally one or more of the carbon atoms at positions 4 to 6 of the azepane ring are each linked to an NO-donor group;
  • the carbon atom at position 4 of the azepane ring and optionally one or more of the carbon atoms at positions 3, 5 or 6 of the azepane ring are each linked to an NO-donor group;
  • the carbon atom at position 5 of the azepane ring and optionally one or more of the carbon atoms at positions 3, 4 or 6 of the azepane ring are each linked to an NO-donor group; or
  • the carbon atom at position 6 of the azepane ring and optionally one or more of the carbon atoms at positions 3 to 5 of the azepane ring are each linked to an NO-donor group.
  • the compound used according to the method of the invention is a 1-pyrrolidinyloxy derivative of the formula la, 1 -piperidinyloxy derivative of the formula lb, or 1-azepanyloxy derivative of the formula Ic, and each one of the NO-donor groups in said compound independently is of the formula -(C r C 6 )alkylene-ONO 2 , preferably -(Cj-C 4 )alkylene-ONO 2 , more preferably -CH 2 - ONO 2s or -O-(C]-C 6 )alkylene-ONO 2 , wherein said alkylene is optionally substituted by one or more -ONO 2 groups, or is -ONO 2 .
  • Tabic 1 Structures la, lb and Ic, indicating 1 -pyrrolidinyloxy, 1 -piperidinyloxy and 1 -azepanyloxy derivatives, respectively
  • Table 2 Compounds of the general formulas la, lb and Ic, identified la- 15a
  • the compound used according to the method of the invention is the compound of formula la, i.e., a compound of the general formula I in which n is 1 , wherein R 2 each is methyl; and (i) the Rj group linked to the carbon atom at position 3 of the pyrrolidine ring is the NO-donor group -CH 2 - ONO 2 or ON0 2 ; and the R[ group linked to the carbon atom at position 4 of the pyrrolidine ring is H, i.e., 3-nitratomethyl-2,2,5,5-tetramethylpyrrolidinyloxy (compound la; R-100) or 3-nitrato-2,2,5,5-tetramethylpyrrolidinyIoxy (compound lb), respectively; or (ii) each one of the R t groups linked to the carbon atoms at positions 3 and 4 of the pyrrolidine ring is the NO-donor group -CH 2 -ONO 2 or ONO 2 ,
  • the compound used according to the method of the invention is the compound of formula lb, i.e., a compound of the general formula I wherein n is 2, wherein R 2 each is methyl; and (i) the R ⁇ group linked to the carbon atom at position 3 of the piperidine ring is the NO-donor group -CH 2 -ONO 2 or ONO 2 ; and each one of the R s groups linked to the carbon atoms at positions 4 and 5 of the piperidine ring is H, i.e., 3-nitratomethyl-2,2,6,6- tetramethyipiperidinyloxy (3-nitratomethyl-TEMPO; compound 3a) or 3-nitrato- 2,2,6,6-tetramethyIpiperidinyloxy (3-nitrato-TEMPO; compound 3b), respectively; (ii) the Ri group linked to the carbon atom at position 4 of the piperidine ring is the NO-donor group
  • each one of the R] groups linked to the carbon atoms at positions 3 to 5 of the piperidine ring is the NO-donor group -CH 2 -ONO 2 or ONO 2 , i.e., 3,4,5-trinitratomethyl-2 5 2,6,6- tetramethylpiperidinyloxy (3,4,5-trinitratomethyl-TEMPO; compound 7a) or 3,4,5- trinitrato-2,2,6,6-tetramethylpiperidinyloxy (3,4,5-trinitrato-TEMPO; compound 7b), respectively.
  • the compound used according to the method of the invention is the compound of formula Ic, i.e., a compound of the general formula I wherein n is 3, wherein R 2 each is methyl; and (i) the Ri group linked to the carbon atom at position 3 of the azepane ring is the NO-donor group - CH 2 -ONO 2 or ONO 2 ; and each one of the ] groups linked to the carbon atoms at positions 4 to 6 of the azepane ring is H, i.e., 3-nitratomethyI-2,2,7,7- tetramethylazepanyloxy (compound 8a) or 3-nitrato-2,2,7,7-tetramethylazepanyloxy (compound 8b), respectively; (ii) the R
  • the compound used according to the method of the invention is the compound of formula la, wherein R 2 each is methyl; the Rj group linked to the carbon atom at position 3 of the pyrrolidine ring is the NO-donor group -CH 2 -ONO 2 or -ONO 2 ; and the Rj group linked to the carbon atom at position 4 of the pyrrolidine ring is -CONH 2 , i.e., 3-nitratomethyl-4-carbamoyl- 2,2,5,5-tetramethylpyrrolidinyloxy (compound 16a) or 3-nitrato-4-carbamoyl- 2,2,5, 5-tetramethylpyrrolidinyloxy (compound 16b), respectively.
  • the compound used according to the method- of the invention is the compound of formula lb, wherein R 2 each is methyl; the Rj group linked to the carbon atom at position 3 of the piperidine ring is the NO-donor group -CH 2 -ONO 2 or -ONO 2 ; the R t group linked to the carbon atom at position 4 of the piperidine ring is -COOH; and the R] group linked to the carbon atoms at position 5 of the piperidine ring is H, i.e., 3-nitratomethyI-4-carboxy- 2,2,6,6-tetramethylpiperidinyloxy (3-nitratomethyl-4-carboxy-TEMPO; compound 17a) or 3-nitrato-4-carboxy-2,2,6,6-tetramethylpiperidinyloxy (3-nitrato-4-carboxy- TEMPO; compound 17b), respectively.
  • the compound used according to the method of the invention is the compound of formula lb, wherein R 2 each is methyl; the ] group linked to the carbon atom at position 4 of the piperidine ring is the NO-donor group -0-CH2-CH(ON0 2 )CH2-ON0 2 ; and each one of the R, groups linked to the carbon atom at position 3 and 5 of the piperidine ring is H, i.e., 4-(2,3- dinitratopropyloxy)-2,2,6,6-tetramethylpiperidinyloxy (4-(2,3-dinitratopropyloxy)- TEMPO; compound 18).
  • the compound used according to the method of the present invention is a l-pyrrolidinyloxy derivative of the formula la, 1 -piperidinyloxy derivative of the formula lb, or 1-azepanyloxy derivative of the formula Ic; wherein at least one of the NO-donor groups in said compound is of the formula -0-(Ci-C 6 )alkylene-ONO 2 ; and said alkylene is substituted by a moiety of the general formula D as defined above, and is optionally further substituted by one or more -ON0 2 groups.
  • the general formula D in which oxygen atom is linked to the carbon atom at position 3 or 4 of the ring, represents a 3-hydroxy-pyrrolidinoxy, 3- or 4-hydroxy-piperidinyloxy, or 3- or 4-hydroxy-azepanyloxy derivative.
  • the compound used in this case is thus a dimer- or higher multimer- like compound, in which two or more identical or different entities, each independently being selected from 1-pyrrolidinyloxy, 1-piperidinyloxy or 1- azepanyloxy derivatives, are linked via alkylene bridges substituted by one or more -ONO2 groups, wherein each alkylene bridge links two entities only.
  • Preferred dimer- or higher multimer-like compounds to be used according to the method of the invention are those in which (i) a 1-pyrrolidinyloxy derivative of the general formula la is linked via one or two NO-donor groups thereof to one or two identical or different moieties of a 3-hydroxy-pyrrolidinoxy, i.e., one or two moieties of the general formula D in which m is 1 ; (ii) a 1-piperidinyloxy derivative of the general formula lb is linked via one, two or three NO-donor groups thereof to one, two or three identical or different moieties of a 3-, or 4-hydroxy- piperidinyloxy, i.e., one to three moieties of the general formula D in which m is 2; or (iii) a 1-azepanyloxy derivative of the general formula Ic is linked via one, two, three or four NO-donor groups thereof to one, two, three or four identical or different moieties of a 3-, or 4-hydroxy
  • the compound used according to the method of the invention is the dimer-like compound of formula lb, wherein each one of R
  • the compounds used according to the method of the present invention may be synthesized according to any technology or procedure known in the. art, e.g., as described in detail in US 6,448,267, 6,455,542 and 6,759,430.
  • the compounds of the general formula I may have one or more asymmetric centers, and may accordingly exist both as enantiomers, i.e., optical isomers (R, S, or racemate, wherein a certain enantiomer may have an optical purity of 90%, 95%, 99% or more) and as diastereoisomers.
  • those chiral centers may be, e.g., in each one of the carbon atoms of the 1-pyrrolidinyloxy derivative, 1- piperidinyloxy derivative; and 1-azepanyloxy derivative of the general formulas la, lb and Ic, respectively.
  • treatment of sepsis and conditions associated therewith can be carried out by administration of all such enantiomers, isomers and mixtures thereof, as well as pharmaceutically acceptable salts and solvates thereof.
  • Optically active forms of the compounds of the general formula I may be prepared using any method known in the art, e.g., by resolution of the racemic form by recrystallization techniques; by chiral synthesis; by extraction with chiral solvents; or by chromatographic separation using a chiral stationary phase.
  • a non- limiting example of a method for obtaining optically active materials is transport across chiral membranes, i.e., a technique whereby a racemate is placed in contact with a thin membrane barrier, the concentration or pressure differential causes preferential transport across the membrane barrier, and separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the . racemate to pass through.
  • Chiral chromatography including simulated moving bed chromatography, can also be used.
  • a wide variety of chiral stationary phases are commercially available.
  • an aqueous solution of a compound of the general formula I having a concentration several times greater than that with commonly used co-solvents can be obtained by stirring said compound in water with an hydroxyalkyl-cyclodextrin such as hydroxyalkyl- -cyclodextrin, in particular 2-hydroxyalkyl ⁇ -cyclodextrin (HPCD), in ratios typically between 1 : 10 and 1 ;20 w/w, depending on the degree of substitution of the cyclodextrin with the hydroxypropyl side chain.
  • an hydroxyalkyl-cyclodextrin such as hydroxyalkyl- -cyclodextrin, in particular 2-hydroxyalkyl ⁇ -cyclodextrin (HPCD)
  • an aqueous solution containing substantially higher concentration of said compound with HPCD can be achieved by stirring HPCD in distilled water with said compound; filtering and freeze drying the filtrate; and re-dissolving the resulting freeze dried solid, i.e., the lyophilizate, in a volume of water that is less than that originally used to prepare the solution prior to lyophilization.
  • Sepsis is a serious, life-threatening medical condition characterized by an overwhelming systemic infection resulting in vasolidation leading to hypotension, i.e., to septic shock, which may consequently lead to an inadequate tissue perfusion that is insufficient to meet cellular metabolic needs and is also known as hypoperfusional state.
  • Sepsis can particularly be caused by Gram negative bacteria such as, without being limited to, Escherichia coli, Pseudomonas aeruginosa, Serratia species, Salmonella species, Shigella species, Enterobacter species, Citrobacter species, Proteus species, and Klebsiella species; Gram-positive cocci such as, without limiting, Pneumococcal species, Enterococcal species. Staphylococcal species, and Streptococcal species; certain fungi and yeast, Rickettsial species, Plasmodial species, Clostridial species, and viruses; as well as Gram-positive bacterial toxins.
  • treatment refers to administration of a compound of the general formula I as defined above, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, after the onset of symptoms of sepsis, regardless of the cause for that medical condition.
  • administration of said compound for treatment of sepsis and conditions associated therewith is aimed at inhibiting, i.e., limiting or reducing, medical conditions resulting from the systemic infection, most particularly pulmonary hypertension, pulmonary shunt, and loss of pulmonary compliance.
  • administration of said compound is further aimed at inhibiting development of sepsis-related coagulopathy.
  • terapéuticaally effective amount refers to the quantit of the compound of the genera ) formula I as defined above, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, that is useful to treat prevent or treat sepsis and conditions associated therewith.
  • R-100 was dose-dependently protective against injury to the kidney, liver, and pancreas, as indicated by the levels of certain parameters, more particular, creatinine, aspartate transminase (AST), alanine transaminase (ALT), bilirubin, amylase, lipase, and alkaline phosphatase, measured in the serum of the animals about 16 hours after LPS administration.
  • AST aspartate transminase
  • ALT alanine transaminase
  • bilirubin amylase
  • lipase lipase
  • alkaline phosphatase alkaline phosphatase
  • R- 100 formulated as an aqueous solution in HPCD (R- 100:HPCD 1 : 13 w/w) and diluted in 500 ml of 5% Dextrose, in a an ovine Pseudomonas aeruginosa (PSA)- septic shock model, 1 hour post-injury and then continuously for 24 hours, stabilized the pulmonary function of the treated sheep, wherein all the treated sheep showed significant improvement in PaO 2 /Fi0 2 ratio at 24 hours and peak ventilatory pressures; a markedly reduced increase in the pulmonary artery pressure; and a lower total fluid balance 24 hours post-injury compared to the control group.
  • MAP peripheral blood pressure
  • the sepsis treated according to the method of the present invention is caused by microorganisms or products thereof.
  • the sepsis is caused by Gram negative bacteria, e.g., Escherichia coli, Pseudomonas aeruginosa, Serratia species, Salmonella species, Shigella species, Enterobacter species, Citrobacter species, Proteus species, and Klebsiella species; Gram-positive cocci, e.g., Pneumococcal species, Staphylococcal species, Enterococcal species, and Streptococcal species; certain fungi and yeast, Rickettsial species Plasmodial species, Clostridial species or viruses; or Gram-positive bacterial toxins, including toxic shock syndrome toxins.
  • Gram negative bacteria e.g., Escherichia coli, Pseudomonas aeruginosa, Serratia species, Salmonella species, Shigella species, Enterobacter species, Citr
  • the method of the invention is aimed at inhibiting development of sepsis-related coagulopathy.
  • the present invention provides a pharmaceutical composition for treatment of sepsis and conditions associated therewith comprising a compound of the general formula I as defined above, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the invention comprises a compound selected from compounds la, lb, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, lib, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, 16b, 17a, 17b, 18, 19 or 20, preferably compound la, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof.
  • compositions of the present invention can be provided in a variety of formulations, e.g., in a pharmaceutically acceptable form and/or in a salt form, as well as in a variety of dosages.
  • the pharmaceutical composition of the present invention comprises a non-toxic pharmaceutically acceptable salt of a compound of the general formula I.
  • Suitable pharmaceutically acceptable salts include acid addition salts such as, without being limited to, those formed with hydrochloric acid, fumaric acid, -toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
  • suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g., sodium or potassium salts, and alkaline earth metal salts, e.g., calcium or magnesium salts.
  • the pharmaceutically acceptable salts of the present invention may be formed by conventional means, e.g., by reacting the free base form of the product, i.e., the compound of the general formula I, with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying, or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the present invention encompasses solvates of the compounds of the general formula I as well as salts thereof, e.g., hydrates.
  • compositions provided by the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 19 Ed., 1995.
  • the compositions can be prepared, e.g., by uniformly and intimately bringing the active ingredient, i.e., the compound of the general formula I, into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.
  • the compositions may be in liquid, solid or semisolid form and may further include pharmaceutically acceptable fillers, carriers, diluents or adjuvants, and other inert ingredients and excipients.
  • the pharmaceutical composition of the present invention is formulated as nanoparticles.
  • compositions can be formulated for any suitable route of administration, but they are preferably formulated for parenteral administration, e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, subcutaneous, intratracheal or administration, as well as for inhalation.
  • parenteral administration e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, subcutaneous, intratracheal or administration, as well as for inhalation.
  • the dosage will depend on the state of the patient, and will be determined as deemed appropriate by the practitioner.
  • the pharmaceutical composition of the invention may be in the form of a sterile injectable aqueous or oleagenous suspension, which may be formulated according to the known art using suitable dispersing, wetting or suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Acceptable vehicles and solvents include, without limiting, water, Ringer's solution and isotonic sodium chloride solution.
  • compositions according to the present invention when formulated for inhalation, may be administered utilizing any suitable device known in the art, such as metered dose inhalers, liquid nebulizers, dry powder inhalers, sprayers, thermal vaporizers, electrohydrodynamic aerosolizers, and the like.
  • compositions according to the present invention when formulated for administration route other than parenteral administration, may be in a form suitable for oral use, e.g., as tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and may further comprise one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients may be, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, e.g., corn starch or alginic acid; binding agents, e.g., starch, gelatin or acacia; and lubricating agents, e.g., magnesium stearate, stearic acid, or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate
  • granulating and disintegrating agents e.g., corn starch or alginic acid
  • binding agents e.g., starch, gelatin or acacia
  • lubricating agents e.g., magnesium ste
  • the tablets may be either uncoated or coated utilizing 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 may be employed. They may also be coated using the techniques described in the US Patent Nos. 4,256, 108, 4, 166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
  • the pharmaceutical composition of the invention may also be in the form of oil-in-water emulsion.
  • compositions of the invention may be formulated for controlled release of the active agent.
  • Such compositions may be formulated as controlled-re lease matrix, e.g., as controlled-release matrix tablets in which the release of a soluble active agent is controlled by having the active diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid (in vitro) or gastro-intestinal fluid (in vivo).
  • compositions comprise the active agent formulated for controlled release in microencapsulated dosage form, in which small droplets of the active agent are surrounded by a coating or a membrane to form particles in the range of a few micrometers to a few millimeters.
  • Another contemplated formulation is depot systems, based on biodegradable polymers, wherein as the polymer degrades, the active ingredient is slowly released.
  • biodegradable polymers is the hydrolytically labile polyesters prepared from lactic acid, glycolic acid, or combinations of these two molecules.
  • Polymers prepared from these individual monomers include poly (D,L-lactide) (PLA), poly (glycolide) (PGA), and the copolymer poly (D,L-lactide-co-glycolide) (PLG).
  • the present invention provides a compound of the general formula I as defined above, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, for use in treatment of sepsis and conditions associated therewith.
  • the present invention relates to use of a compound of the general formula I as defined above, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, for the preparation of a pharmaceutical composition for treatment of sepsis and conditions associated therewith.
  • Example 1 R-100 is effective in a murine model of sepsis
  • R-100 protects the kidney, pancreas and liver from LPS-mediated injury
  • mice were exposed to a lethal dose of E. coli lipopolysaccharide (LPS; 10 mg/kg IP).
  • LPS E. coli lipopolysaccharide
  • mice were anaesthetized with an intraperitoneal injection of ketamine:xylazine (100:2.5 mg/kg) and placed on a heating pad.
  • a tracheotomy was performed to facilitate respiration.
  • the animal's temperature was monitored using a rectal probe, and the body temperature was kept constant at 37 ⁇ 2°C throughout the study with the heating pad.
  • the right carotid artery was cannulated with polyethylene tubing connected to a pressure transducer for continuously monitoring arterial blood pressure using the MacLab data acquisition and analysis software. Changes in blood pressure were expressed as percentages of control values.
  • mice treated with LPS showed a marked reduction in mean arterial pressure when compared to the control untreated group.
  • compound la (R-100) at the dose of 10 mg/kg (IP) was administered 1 and 6 hrs after LPS treatment, there was a significant increase in blood pressure when compared with the LPS-treated controls.
  • Example 3 R-100 improves pulmonary function in sheep suffering from
  • the animal in the treatment group were intravenously (IV) administered with a total of 80 mg/kg of R-100, formulated as an aqueous solution in hydroxypropyl- -cyclodextrin (HPCD) (R-100:HPCD 1 :13 w/w) and diluted in 500 ml of 5% dextrose, wherein a bolus (30 min) of 10 mg/kg was started 1 hr post-injury and followed by the continuous infusion of the remaining 70 mg/kg for 24 hrs. Ringer's lactate solution was titrated IV to maintain hematocrit (hct) at baseline ⁇ 3%.
  • the control group received the same amount of HPCD diluted in the same amount of dextrose. Measurements were taken at baseline and every 3 hrs during the 24 hrs study period. Data are expressed as mean ⁇ SEM. Statistical analysis; two-way ANOVA and Bonferroni post hoc comparison. A p-value p ⁇ 0.05 was considered as statistically significant.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur des compositions et des procédés pour le traitement de la sepsie et d'affections associées à celle-ci comprenant des dérivés de pipéridine, de pyrrolidine, ou d'azépane comprenant un à quatre groupes donneurs d'oxyde nitrique (NO) et un catalyseur de dégradation d'espèces réactives de l'oxygène (ROS).
PCT/IL2011/000879 2011-01-04 2011-11-15 Compositions et procédés pour le traitement de la sepsie et d'affections apparentées WO2012093383A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161429588P 2011-01-04 2011-01-04
US61/429,588 2011-01-04

Publications (1)

Publication Number Publication Date
WO2012093383A1 true WO2012093383A1 (fr) 2012-07-12

Family

ID=45464028

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2011/000879 WO2012093383A1 (fr) 2011-01-04 2011-11-15 Compositions et procédés pour le traitement de la sepsie et d'affections apparentées

Country Status (1)

Country Link
WO (1) WO2012093383A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013190497A2 (fr) 2012-06-21 2013-12-27 Radikal Therapeutics Inc. Compositions et procédés pour le traitement de maladies inflammatoires du poumon
WO2014136059A2 (fr) 2013-03-05 2014-09-12 Radikal Therapeutics Inc. Promédicaments de dérivés d'oxydes d'azote multifonctionnels et leurs utilisations

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4166452A (en) 1976-05-03 1979-09-04 Generales Constantine D J Jr Apparatus for testing human responses to stimuli
US4256108A (en) 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
US4265874A (en) 1980-04-25 1981-05-05 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
US6448267B1 (en) 1998-01-22 2002-09-10 Oxon Medica, Inc. Piperidine and pyrrolidine derivatives comprising a nitric oxide donor for treating stress
WO2003088961A1 (fr) * 2002-04-19 2003-10-30 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composes beta-agonistes contenant des groupes donneurs d'oxyde nitrique et des groupes piegeurs d'especes d'oxygene reactifs et leur utilisation dans le traitement de troubles respiratoires
WO2004087212A2 (fr) * 2003-04-03 2004-10-14 Aga Ab Utilisation d'oxyde nitrique dans le traitement de l'inflammation
WO2005105065A2 (fr) * 2004-05-05 2005-11-10 Renopharm Ltd. Donneurs d'oxyde nitrique destines au traitement de maladies intestinales inflammatoires
US20100197702A1 (en) * 2009-02-04 2010-08-05 Hellberg Mark R Ophthalmic composition with nitric oxide donor compound and method of forming and using same
WO2011092690A1 (fr) * 2010-01-26 2011-08-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Compositions et procédés pour la prévention et le traitement de l'hypertension pulmonaire

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4166452A (en) 1976-05-03 1979-09-04 Generales Constantine D J Jr Apparatus for testing human responses to stimuli
US4256108A (en) 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
US4265874A (en) 1980-04-25 1981-05-05 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
US6448267B1 (en) 1998-01-22 2002-09-10 Oxon Medica, Inc. Piperidine and pyrrolidine derivatives comprising a nitric oxide donor for treating stress
US6455542B1 (en) 1998-01-22 2002-09-24 Oxon Medica Inc. Piperidine and pyrrolidine derivatives comprising a nitric oxide donor for treating stress
US20030069429A1 (en) * 1998-01-22 2003-04-10 Anggard Erik Emil Piperidine and pyrrolidine derivatives comprising a nitric oxide donor for treating stress
US6759430B2 (en) 1998-01-22 2004-07-06 Oxon Medica Inc. Piperidine and pyrrolidine derivatives comprising a nitric oxide donor for treating stress
WO2003088961A1 (fr) * 2002-04-19 2003-10-30 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composes beta-agonistes contenant des groupes donneurs d'oxyde nitrique et des groupes piegeurs d'especes d'oxygene reactifs et leur utilisation dans le traitement de troubles respiratoires
WO2004087212A2 (fr) * 2003-04-03 2004-10-14 Aga Ab Utilisation d'oxyde nitrique dans le traitement de l'inflammation
WO2005105065A2 (fr) * 2004-05-05 2005-11-10 Renopharm Ltd. Donneurs d'oxyde nitrique destines au traitement de maladies intestinales inflammatoires
US20100197702A1 (en) * 2009-02-04 2010-08-05 Hellberg Mark R Ophthalmic composition with nitric oxide donor compound and method of forming and using same
WO2011092690A1 (fr) * 2010-01-26 2011-08-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Compositions et procédés pour la prévention et le traitement de l'hypertension pulmonaire

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 1995
LUIKING Y.C.; DEUTZ N.E.: "Exogenous arginine in sepsis", CRIT CARE MED, vol. 35, no. 9, 2007, pages 5557 - 63
LUIKING Y.C.; POEZE M.; DEJONG C.H.; RAMSAY G.; DEUTZ N.E.: "Sepsis: an arginine deficiency state?", CRIT CARE MED, vol. 32, no. 10, 2004, pages 2135 - 2145
MAYBAUER M.O.; REHBERG S.; TRABER D.L.; HERNDON D.N.; MAYBAUER D.M.: "Pathophysiology of acute lung injury in severe bum and smoke inhalation injury", ANAESTHESIST, vol. 58, no. 8, 2009, pages 805 - 812
TRABER D.L.; HAWKINS H.K.; ENKHBAATAR P.; COX R.A.; SCHMALSTIEG F.C.; ZWISCHENBERGER J.B.; TRABER L.D.: "The role of the bronchial circulation in the acute lung injury resulting from burn and smoke inhalation", PULM PHARMACOL THER, vol. 20, no. 2, 2007, pages 163 - 166, XP005727336, DOI: doi:10.1016/j.pupt.2005.12.006
TRZECIAK S.; CINEL I.; PHILLIP DELLINGER R.; SHAPIRO N.I.; ARNOLD R.C.; PARRILLO J.E.; HOLLENBERG S.M.: "Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials", A CAD EMERG MED, vol. 15, no. 5, 2008, pages 399 - 413
XIZHONG CUI ET AL: "Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis", INTENSIVE CARE MEDICINE, SPRINGER, BERLIN, DE, vol. 33, no. 11, 8 August 2007 (2007-08-08), pages 1993 - 2003, XP019558954, ISSN: 1432-1238, DOI: 10.1007/S00134-007-0814-9 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013190497A2 (fr) 2012-06-21 2013-12-27 Radikal Therapeutics Inc. Compositions et procédés pour le traitement de maladies inflammatoires du poumon
WO2014136059A2 (fr) 2013-03-05 2014-09-12 Radikal Therapeutics Inc. Promédicaments de dérivés d'oxydes d'azote multifonctionnels et leurs utilisations
RU2659220C2 (ru) * 2013-03-05 2018-06-29 Зальцман Груп, Инк. Пролекарства многофункциональных производных нитроксида и их применение

Similar Documents

Publication Publication Date Title
US10000455B2 (en) Method for treating diseases associated with oxidative stress or endothelial dysfunction using substituted 1-pyrrolidinyloxy, 1-piperidinyloxy and 1-azepanyloxy compounds
US20210009549A1 (en) Cannabinoid derivatives and conjugates and uses thereof
US9522903B2 (en) Multifunctional nitroxide derivatives and uses thereof
US8623856B2 (en) Phenoxy-azetidine derivatives as sphingosine 1-phosphate (S1P) receptor modulators
US20130217651A1 (en) Phenoxy derivatives as sphingosine 1-phosphate (s1p) receptor modulators
WO2012093383A1 (fr) Compositions et procédés pour le traitement de la sepsie et d'affections apparentées
TW200942237A (en) MMP-2 and/or MMP-9 inhibitor
US20130338108A1 (en) Phenyl bicyclic methyl amine derivatives as sphingosine-1 phosphate receptors modulators
EP1963270A1 (fr) Sels quaternaires de 3-amido, n-methylpyridinium en tant qu'agents anti-inflammatoires
US20150057253A1 (en) Alkyl derivatives as sphingosine-1 phosphate receptors modulators
US20150051176A1 (en) Aryl derivatives as sphingosine-1 phosphate receptors modulators
US20230118459A1 (en) Antiviral treatment
CN112239447A (zh) 二羟基二甲基异色满-3-甲酰极性氨基酸,其制备,抗栓活性和应用
US20150051186A1 (en) Aryl azetidine derivatives as sphingosine-1 phosphate receptors modulators
US20150045328A1 (en) Disubstituted aryl oxy derivatives as sphingosine-1 phosphate receptors modulators
JPH06506483A (ja) メタロプロテイナーゼ阻害剤としてのアミノ酸のホスホノ誘導体
US20150057261A1 (en) Azetidine derivatives as sphingosine-1 phosphate receptors modulators
US20150045341A1 (en) Disubstituted aryl azetidine derivatives as sphingosine-1 phosphate receptors modulators
WO2014124234A1 (fr) Dérivés de phenoxy-azétidine utilisés comme modulateurs des récepteurs de la sphingosine 1-phosphate (s1p)
US20140221498A1 (en) Amino diol derivatives as sphingosine 1-phosphate (s1p) receptor modulators
US20140135293A1 (en) Allene derivatives as sphingosine 1-phosphate (s1p) receptor modulators

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11805613

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11805613

Country of ref document: EP

Kind code of ref document: A1