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WO2015161510A1 - Composé dérivé de saa permettant le rétablissement de l'enos et inhibant les affections induites par le stress oxydatif dans l'hypoxie - Google Patents

Composé dérivé de saa permettant le rétablissement de l'enos et inhibant les affections induites par le stress oxydatif dans l'hypoxie Download PDF

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WO2015161510A1
WO2015161510A1 PCT/CN2014/076237 CN2014076237W WO2015161510A1 WO 2015161510 A1 WO2015161510 A1 WO 2015161510A1 CN 2014076237 W CN2014076237 W CN 2014076237W WO 2015161510 A1 WO2015161510 A1 WO 2015161510A1
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Prior art keywords
acid
group
dimethylxanthine
saax
spaax
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PCT/CN2014/076237
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English (en)
Inventor
Ing-Jun Chen
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Jansfat Biotechnology Co Ltd
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Jansfat Biotechnology Co Ltd
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Priority to PCT/CN2014/076237 priority Critical patent/WO2015161510A1/fr
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to SAA derivatives or SAA complex compounds capable of inhibiting disorders caused by oxidative stress, and more particularly to the SPAAX derivatives or SPAAX complex compounds of xanthines and SPAAS derivatives or SPAAS complex compounds of Sildenafil capable of inhibiting disorders caused by oxidative stress on human diseases.
  • the present invention provides synthesized by the KMUPs amine complex compounds and a carboxylic acid derivatives of one selected from a group consisting of a Statin, a non-steroid anti-inflammatory (NSAIDs) and an anti-asthmatic drug.
  • a Statin a non-steroid anti-inflammatory
  • NSAIDs non-steroid anti-inflammatory
  • the pharmaceutical compositions for a treatment of an interstitial lung disease were applied as No. 11/857,483 filed on September 19, 2007.
  • the method for inhibiting a disorder caused by oxidative stress in a subject comprises a step of: administering to the subject suffering the disorder an effective amount of a composition comprises an ingredient being one of an Substituted Amine Analogs (SAA) derivatives compound or an acceptable salt thereof, and one or more additional co-active agents, a acceptable carriers, diluents or excipients.
  • SAA Substituted Amine Analogs
  • the method for inhibiting a disorder caused by oxidative stress in a subject comprises a step of: administering to the subject suffering the disorder an effective amount of a composition comprises an ingredient being an SAA complex compounds or an acceptable salt thereof, and one or more acceptable carriers, diluents or excipients.
  • a pharmaceutical composition, cosmetic composition, food composition and bodywash which comprises a compound of formula I, or an acceptable salt thereof, and one or more additional co-active agents, a acceptable carriers, diluents or excipients.
  • a pharmaceutical composition, cosmetic composition, food composition and bodywash which comprises a compound of formula II, and one or more acceptable carriers, diluents or excipients.
  • Fig. 1 A-1D show the chemical structures of the compounds Fig. 1A shows the chemical structure of SPAAX-1 ascorbate complex
  • Fig. IB shows the chemical structure of SPAAS methanesulfonate complex
  • Fig. 1C shows the chemical structure of SPAAX ascorbate complex
  • Fig. ID shows the chemical structure of SPAAS ascorbate complex
  • Fig. 2 shows the animal model under chronic h poxia for 21 days
  • Fig. 3A-3D show the recording of pulmonary artery blood pressure (PABP)
  • Fig. 3A shows the pulmonary artery blood pressure of normoxia (20% 0 2 ) treated with vehicle for 21 days
  • Fig. 3B shows the pulmonary artery blood pressure of hypoxia (10% 0 2 ) treated with vehicle for 21 days
  • Fig. 3C shows the normoxia treated with SPAAX-1 and hypoxia with SPAAX-1 ascorbate complex
  • Fig. 3D shows the normoxia treated with Sildenafil and hypoxia with Sildenafil ascorbate complex
  • Fig. 4A-4D show the morphologic demonstration of a cross-section of pulmonary artery caused by long-term hypoxia and treatments
  • Fig. 4A shows the normoxia (20% 0 2 ) treated with vehicle for 21 days [0022]
  • Fig. 4B shows the hypoxia (10% O 2 ) treated with vehicle for 21 days
  • Fig. 4C shows the effects of the SPAAX-1 [Hypoxia with
  • Fig. 4D shows the effects of the Sildenafil [Hypoxia with
  • FIG. 5 shows the relative wall thickness of pulmonary artery l, Normoxia 2, Hypoxia
  • FIG. 6A-6B show the ventricle/left ventricle+septum
  • Fig. 6A shows the effects of the SPAAX-1 and Sildenafil
  • Fig. 6B shows the effects of the SPAAX-1 ascorbate complex and Sildenafil ascorbate complex for 21 days
  • Fig. 7A-7D show the effects of the pulmonary immunohistochemistry of eNOS, where (+) indicates thick brown immunostaining and (-) indicates abated immunostaining reactivity. [0030] Fig. 7A shows the effect on rats which were exposed to normoxia (20% 0 2 )
  • Fig. 7B shows the effect on rats which were exposed to hypoxia (10% 0 2 )
  • Fig. 7C shows the effect on rats treated with SPAAX-1
  • Fig. 7D shows the effect on rats treated with Sildenafil
  • Fig. 8A-8D show the effects of the pulmonary immunohistochemistry of vascular endothelium growth factor (VEGF), where (+) indicates thick brown immunostaining and (-) indicates abated immunostaining reactivity.
  • VEGF vascular endothelium growth factor
  • Fig. 8A shows the effect on rats which were exposed to normoxia (20% 0 2 )
  • Fig. 8B shows the effect on rats which were exposed to hypoxia (10% O 2 )
  • Fig. 8C shows the effects of the SPAAX-1 [Hypoxia with
  • Fig. 8D shows the effects of the Sildenafil [Hypoxia with
  • FIG. A-9D show the effects of pulmonary immunohistochemistry of eNOS, (+) indicates thick brown immunostaining and (-) indicates abated immunostaining reactivity.
  • Fig. 9A shows the effect on rats which were exposed to normoxia (20% 0 2 )
  • Fig. 9B shows the effect on rats which were exposed to hypoxia (10% 0 2 )
  • Fig. 9C shows the effects of the SPAAX-1 [Hypoxia with
  • Fig. 9D shows the effects of the Sildenafil [Hypoxia with
  • Fig.lOA-lOD show the effects of pulmonary immunohistochemistry of VEGF, (+) indicates thicken brown immunostaining and (-) indicates abated immunostaining reactivity.
  • Fig. 10A shows the effect on rats which were exposed to normoxia (20% 0 2 )
  • Fig. 10B shows the effect on rats which were exposed to hypoxia (10% 0 2 )
  • Fig. IOC shows the effects of the SPAAX-1 [Hypoxia with
  • FIG. 10D shows the effects of the Sildenafil [Hypoxia with Sildenafil ascorbate complex (5 mg/kg/day)] for 21 days
  • Fig. 11A-11F show the effects of long-term hypoxia-induced eNOS, sGCal, PKQ PDE-5A, ROCKII and VEGF expression of lung tissue
  • Fig. 11A shows the effects of long-term hypoxia-induced eNOS expression
  • Fig. 11B shows the effects of long-term hypoxia-induced sGCal expression
  • Fig. llC shows the effects of long-term hypoxia-induced
  • Fig. 11D shows the effects of long-term hypoxia-induced
  • Fig. HE shows the effects of long-term hypoxia-induced
  • Fig. 11F shows the effects of long-term hypoxia-induced
  • Fig. 12A-12D show the effects of pulmonary artery expression of ROCKII, sGCal and VEGF after short-term hypoxia
  • Fig. 12A shows the effects on rats which were exposed to normoxia (20% O 2 ) [0058]
  • Fig. 12B shows the effects of ROCKII expression
  • Fig. 12C shows the effects of sGCal expression
  • Fig. 12D shows the effects of VEGF expression
  • Fig. 13 shows the effects of pulmonary NOx production
  • Fig. 14 shows the effects of pulmonary ROS production
  • Rm is one selected from a group consisting of a first hydrogen, a first C1-C6 alkyl group, a first C1-C6 alkoxyl group and a 3-membered to 8-membered ring, and either one of Rl and Ra is classified into one of a category I and a category II, and wherein:
  • Rl is one selected from a group consisting of a second hydrogen, a first halogen, a second C1-C6 alkyl group, a first C1-C5 alkoxyl group: and
  • a first benzene ring having one or more substitute group selected from a second C1-C5 alkoxyl group, a first nitro group, a second halogen, a halogen substitute C1-C5 alkoxyl group and a halogen substitute C1-C6 alkyl group
  • Ra is a xanthine group having a substitute of a fourth C1-C5 alkyl group, a third C1-C5 alkoxyl group and a third halogen.
  • Ri is one of a second benzene ring having a substitute being one of a fourth C1-C5 alkoxyl group, a sulfonyl phenyl group and a heterocyclic ring having a substitute being one of a second C1-C6 alkoxyl group and a third C1-C6 alkyl group
  • Ra is one selected from a group consisting of a third hydrogen, a second halogen, an amino group, a second nitro group, a second C1-C5 alkyl group and a fifth C1-C5 alkoxyl group
  • the heterocyclic ring is one selected from a group consisting of pyrazolo, pyrimidin, imidazo, pyrollidinyl, triazin and a fused ring having at least one selected from the group consisting of pyrazolo, pyrimidin, pyrollidinyl, imidazo and triazin;
  • each of the first and the second halogens is one selected from a group consisting of fluorine, chlorine, bromine and iodine.
  • Rm is one selected from a group consisting of an
  • the Substituted Amine Analogs (SAA) complex compounds is represented by formula II, RX
  • RX is a carboxylic group having a negative charge, and the carboxylic group is donated from one selected from a group consisting of a sodium carboxymethylcellulose (sodium CMC), a plant acid, a substituted-sulfonic acid derivatives, a oxygen-contakiing acid (oxyacid), a non-steroid anti-inflammatory (NSAIDs), an anti-asthmatic drug, abiodegradable polymer and a combination thereof.
  • sodium CMC sodium carboxymethylcellulose
  • NSAIDs non-steroid anti-inflammatory
  • the plant acid is one selected from a group consisting of acetic acid, adipic acid, aketoglutaric acid, allantoic acid, aspartic acid, citramalic acid, ascorbic acid, benzoic acid,citric acid, cresylic acid, formic acid, fumaric acid, galacturonic acid, glutamic acid, gluconic acid, glucuronic acid, glyceric acid, glycolic acid, hydrochloric acid, isocitric acid, lactic acid, lactoisocitric acid, malic acid, maleic acid, nicotinic acid, oxalacetic acid, oxalic acid, oleic acid, phosphoric acid, pyroglutamic acid, pyrrolidinone carboxylic acid, pyruvic acid, quinic acid, salicylic acid, shikimic acid, succinic acid, sulfuric acid, and tartaric acid.
  • the oxygen containing acid (oxoacid) name above comes from the root name of the ox anion name or the central elements of the ox anion, and well-known inorganic acid examples of such acids are sulfuric acid, nitric acid, glycolic acid and phosphoric acid.
  • Substituted-sulfonic acids refer to a sulfonic acid group which is optionally substituted with one or more groups selected from C1-C8 alkoxyl group, halogen, C1-C8 alkyl group, halogen substituted C1-C8 alkoxyl group, halogen substituted C1-C8 alkyl group, benzene group substituted with at least one group selected from the group consisting of a C1-C5 alkyl group and a halogen group.
  • the substituted-sulfonic acid is one selected from a group consisting of sulfonate, methanesulfonate, benzenesulfonate, cyclohexyl methylbenzenesulfonate, para-toluenesulfonic acid, methylbenzenesulfonate.
  • a non-steroid anti-inflammatory contains a carboxyl functional group, usually one selected from a group consisting of aspirin, salicylic acid, indomethacin, meclofenamic acid, Tolmetin, Ketoprofen, methotrexate, Diclofenac acid, Meclofenamic acid, Mefenamic acid, flurbiprofen, fenoprofen, tiaprofen, diflunisal, etodolac, and ibuprofen, as well as the compounds which contain a functional group of carboxylic acid as with native PGD2, PGE2, PGF2a, PGI2, Thromboxane A2 and prostacyclin analogon.
  • NSAIDs contains a carboxyl functional group, usually one selected from a group consisting of aspirin, salicylic acid, indomethacin, meclofenamic acid, Tolmetin, Ketoprofen, methotrexate, Diclofenac
  • a ⁇ -Polyglutamic acid ( ⁇ -PGA) derivatives is one selected from a group consisting of alginate sodium, poly-y-polyglutamic acid sodium (poly ⁇ -PGA sodium), poly-y-polyglutamic acid (poly y-PGA), alginate-poly-lysine-alginate (APA), poly(alginic acid), poly(glutamic acid), poly(lysine), poly(aspartic acid), poly(leucine), alginate, poly(glutamic acid-co-ethyl glutamate), poly(amino acids), poly(leucine-co-hydroxyethyl glutamine), poly(benzyl glutamate) and a combination thereof.
  • a biodegradable polymers capable of hydrogen bonding carboxylic group and vinyl group or acyl group wherein selected from a group consisting of gelatin, collagen, polysaccharide, non-water soluble chitosan, dextrose, dextran, copolymers containing poly(ethylene glycol), poly(D,L-lactic acid), poly (L-lactic acid), poly(glycolic acid), polyglycolic acid sodium (PGCA sodium), hyaluronic acid (HA), polyacrylic acid (PAA), copolymers of poly(lactic) and glycolic acid, polymethacrylates (PMMA), Eudragit, dextran sulfate, heparan sulfate, polylactic acid (polylactide, PLA), polylactic acid sodium (PLA sodium) and a combination thereof.
  • Ra is a group consisting of xanthmes group, the structure of formula III; the relative Substituted Amine Analogs (SAA) compound may also be called the Substituted Amine Xanthines Analogs (SAAX) derivatives compound, wherein n is a positive integer, include numbers from 1 to 16, for example 1, 2, 3, 4, 5 to 16.
  • the SAAX derivatives compound is one selected from a group consisting of haloalkyl-l,3-dimethylxanthine (SAAX-100), aminoalkyl-l,3-dimethylxanthine (SAAX-200), alkylaminoalkyl-1,3- dimethylxanthine (SAAX-300), haloaminoalkyl-l,3-dimethylxanthine (SAAX-400), azirinylalkyl-l,3-dimethylxanthine (SAAX-31), alkylazirinyl- alkyl-l,3-dimethylxanthine (SAAX-32), aminoalkylazirinylalkyl-1,3- dimethylxanthine (S AAX-33 ), haloaminoalkylazirinyl-alkyl- 1 ,3 -dimethyl- xanthine (SAAX-100), aminoalkyl-l
  • a further embodiment is to administer a combination of an effective amount of a Substituted Amine Analogs (SAA) derivatives compound and other type of additional co-active agent to a mammal in need thereof.
  • the combination therapies which employ the SAA derivatives compound are selected from the group consisting of SPAAX derivatives and SPAAS derivatives.
  • additional co-active agents having a carboxylic group being one selected from the RX group, eg. plant acid, a substituted-sulfonic acid derivatives, a oxygen-containing acid (oxyacid), a non-steroidanti-inflammatory (NSAIDs), an anti-asthmatic drug, a ⁇ -polyglutamic acid derivatives, a biodegradable polymer and sodium carboxyl methyl cellulose (sodium CMC).
  • RX group eg. plant acid, a substituted-sulfonic acid derivatives, a oxygen-containing acid (oxyacid), a non-steroidanti-inflammatory (NSAIDs), an anti-asthmatic drug, a ⁇ -polyglutamic acid derivatives, a biodegradable polymer and sodium carboxyl methyl cellulose (sodium CMC).
  • a combination therapy for treating and/or preventing disorders caused by oxidative stress.
  • the compositions are formulated and administered in the same general manner as follows.
  • the SAA derivatives compounds represented by formula I or an acceptable salt may be effectively used alone or in combination with one or more active agents depending on the desired target therapy.
  • Combination therapy includes the administration of a single pharmaceutical dosage composition which contains a compound of formula I or an acceptable salt and one or more additional co-active agents, and each active agent in its own separate pharmaceutical dosage formulation, health functional food composition, bodywash or cosmetic composition.
  • the compound of formula I may be administered as a single dosage composition that contains additional co-active agents. Said the composition, included pharmaceutical dosage formulation, health functional food composition, bodywash and cosmetic composition. In other embodiments, separate dosage compositions are administered; the formula I compound and the other additional agent may be administered at essentially the same time, or at separately staggered times sequentially. In certain examples, the individual components of the combination may be administered separately, at different times during the course of therapy, or concurrently, in divided or single combination forms. Also provided is simultaneous, staggered, or alternating treatment.
  • a compound of formula I can be administered to the patient in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral/drink dosage formulations. Where separate dosage formulations of additional co-active agents are used, they can be administered using another delivery type at essentially the same time.
  • combination treatment may be any suitable administration method including oral (including buccal and sublingual), rectal, nasal, airway inhalation (e.g., dry powder or aerosolized formulation), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous and intradermal), topical administrations include, but are not limited to, sprays, mists, aerosols, solutions, lotions, gels, creams, ointments, pastes, unguents, emulsion and suspensions, with oral or parenteral delivery being preferred.
  • the preferred route may vary with the condition and age of the patient.
  • Rm is a piperazinyl ring and Ra is a group consisting of xanthine group
  • RK, RM, RS and RT may be at any position on the benzene ring and are independently hydrogen, a C1-C5 alkoxyl group, a C1-C5 alkyl group, a nitro group and a halogen atom.
  • N is a positive integer from 1 to 6.
  • the structure of Substituted Piperazinyl Amine Analogs (SPAA) compound and SPAA complex compounds may also change to formula VI and formula VII, respectively.
  • formula VII [0089]
  • Rm is a piperazinyl ring and Ra is a group consisting of xanthine group
  • N is a positive integer from 1 to 6.
  • the structure of Substituted Piperazinyl Amine Analogs (SPAA) compound and SPAA complex compounds may also change to formula IV and formula V, respectively.
  • the SPAAX compound when RK is a chlorine atom at a meta position, and each of RM, RS and RT are hydrogen on the benzene ring of formula VI, the SPAAX compound has the general chemical name 7-[2-[4-(2-chloro-phenyl)piperazinyl]ethyl]-l,3-dimethylxanthine (SPAAX- 1).
  • the compound of formula VI has the chemical name 7-[2-[4-(2-methoxyphenyl)piperazinyl]ethyl]-l,3- dimethylxanthine (SPAAX-2).
  • SPAAX-4 7- [2-[4-(2-flurorophenyl)piperazinyl]ethyl] -1,3 -dimethylxanthine (SPAAX-5), respectively.
  • the SPAAX complex compound is also known as SPAAX-RX complex compounds.
  • SPAAS compound is a Sildenafil derivative compound
  • SPAAS complex compound in this form is also called SPAAS -RX complex compound or Sildenafil-RX complex compound.
  • the structure of formula I Substituted Piperazinyl Amine Analogs (SPAA) compound in which Rm is a piperazinyl ring (formula IV),when Rl is selected from a sulfonyl phenyl group and a pyrazolo[4,3d]pyrimidin group of heterocyclic ring, and Ra is a methyl group, the compound is 5-[2-etthoxy-5-(4-methylpiperazin-l-yl- sulphonyl)phenyl]- 1 -methyl-3 -n-propyl- 1 , 6-dihydro-7H-pyrazolo [4, 3 d] pyrimidin-7-one, or 1 - [[3 -(4,7-dihydro- 1 -methyl-7-oxo-3 -propyl- 1 H- pyrazolo[4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl
  • the compound is l-[[3-(6,7-dihydro-l-methyl-7-oxo-3-propyl-lH- pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy-phenyl]sulfonyl]-4-hydroxyethyl- piperazine (HydroxyhomoSildenafil).
  • the compound is 5-[2-ethoxy-5-(l-piperazinylsulfonyl)- phenyl] - 1 ,6-dihydro- 1 -methyl-3 -propyl-7H-pyrazolo[4,3 -d]pyrimidin-7-one (Desmethylsildenafil).
  • Rl is the pyrazolo[4,3-d]pyrimidin group and sulfonyl phenyl group
  • the ( ) is pyrollidinyl
  • n is the integer 3
  • Ra is selected from the methyl group
  • the compound is 5-[2-propyloxy-5-(l-methyl-2-pyrollidinylethyl- amidosulfonyl)phenyl]- 1 -methyl-3 -propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d] pyrimidine-7-one (Udenafil).
  • Rl is selected from the imidazo[5,l ⁇ f][l,2,4]triazin group in place of pyrazolo[4,3-d]pyrimidine, it is 2-[2-ethoxy- 5-(4-ethyl-piperazin- 1 -yl-sulfonyl)phenyl]-5 -methyl-7-propyl- 1 H-imidazo [5, l-f][l,2,4]triazin-4(3H)-one (Vardenafil).
  • the compound is 5-[2-ethoxy-5-[(4-ethyl-l- piperazinyl)sulfonylphenyl]- 1 ,6-dihydro- 1 -methyl-3 -propyl-7H-pyrazolo [4, 3-d]pyrimidin-7-one (Homo- Sildenafil).
  • methanesulfonic acid (methyl sulfonic), benzene sulfonic acid, methyl benzene sulfonic acid, toluenesulfonic acid, bond to one of SAA, SPAAX and Sildenafil analogs as sulfonate.
  • ascorbic acid bonds to one of SAA, SPAAX and Sildenafil analogs as olate moiety. (Fig.l)
  • SAA Substituted Amine Analogs
  • SAA may represent SAA derivatives compound or SAA complex compounds, unless it is explained specifically.
  • the procedures 1 and 2 include the steps of mixting j?-toluenesulphonic acid (PTSA), dimethylxanthines, and bromohaloalkane in xylene, heating to reflux, wherein the progress of the reaction is monitored by TLC using a Chloroform: Methanol (8:2) solvent system. On completion, the reaction mass is cooled and further chilled, and the first product that crystallizes is the SPAAS compound.
  • PTSA j?-toluenesulphonic acid
  • dimethylxanthines dimethylxanthines
  • bromohaloalkane in xylene
  • the procedures 1 and 2 include steps of dissolving haloxanthine and H-Rm-Rl substituted compound in a hydrous ethanol solution, and the amount of reagent should be conjugated depending on the molecular weight percentage.
  • a heating procedure is performed under reflux for three hours.
  • the Bromo-haloalkane compounds that are associated with alkyl number of formula VI may be selected from the group comprising 1 -bromo-2-chloroethane, 1 -bromo-5-chloro-pentane, 1 -bromo-3-fluoro- propane, 1-bromo-lO-fluorodecane etc.
  • Rm is attached to another nitrogen atom to form a 3- to 8-membered ring, the number of atoms in the ring including the nitrogen atom.
  • Rm is one selected from a group consisting an Azirine ring ⁇ J - ⁇ ⁇ , an Azetidine R 1 _
  • the SPAAX derivatives is dissolved in a mixture of ethanol and ⁇ -Polyglutamic acid.
  • the solution is reacted at a warmer temperature, the methanol is added under room temperature, and the solution is incubated overnight for crystallization and filtrated to obtain the SPAAX derivatives-y-Polyglutamic acid.
  • SPAAX complex compounds represented by the formula VII can be prepared selectively with one of a SPAAX derivatives and one of an RX group.
  • An example of the RX group contains a carboxylic group donated from a group consisting of plant acid, substituted-sulfonic acid derivatives, oxygen-containing acid (oxyacid), non-steroid anti-inflammatory (NSAIDs), anti- asthmatic drag, ⁇ -polyglutamic acid derivatives, biodegradable polymer and sodium CMC.
  • SPAAS complex compounds can be synthetically produced directly, from the haloalkanexanthine compound, piperazine substituted compound and carboxylic acid selected from the group of RX.
  • SPAAS complex compounds can be synthetically produced directly, from the haloalkanexanthine compound, piperazine substituted compound and carboxylic acid selected from the group of RX.
  • Sildenafil analogs complex compounds are also included in the formula IV, were prepared according to the abovementioned general procedure.
  • crude Sildenafil citrate is blended and suspended in a sodium hydroxide solution to dissolve the component.
  • the precipitated Sildenafil base is added to an equal molecular-weight ascorbic acid which are dissolved in methanol to react at 50°C.
  • a white precipitate is obtained by filtration and then re-crystallized as Sildenafil ascorbate from ethanol.
  • Sildenafil citrate is dissolved in diluted water, adjusted with HC1 solution to pH 7.0 and separated into ethyl acetate fraction to remove the citric acid, a hydrochloride and a sodium chloride into water fraction.
  • the obtained Sildenafil base in ethyl acetate is dried under a de-pressurized condition.
  • one carboxylic group of the RX and Sildenafil base is dissolved in methanol to react at 50°C. After sitting over night, a white precipitate is obtained by filtration and then recrystallized as Sildenafil complex compounds from ethanol.
  • Sildenafil HC1 and sodium carboxylate of the RX are dissolved in methanol at an equal molecular- weight to react at 50°C. After overnight cooling, a white precipitate is obtained by filtration and then recrystallized as Sildenafil complex compounds from ethanol.
  • Sildenafil analogs derivatives complex compounds can be prepared selectively with one of the hydrochloride salts of Sildenafil analogs derivatives and one of the RX sodium salts.
  • Sildenafil analogs derivatives include Sildenafil, Hydroxyhomosildenafil, Desmethylsildenafil, Acetidenafil, Udenafil, Vardenafil and Homosildenafil.
  • RX group which contains a carboxyl functional group is one selected from a group consisting of plant acid, a substituted-sulfonic acid derivatives, a oxygen-containing acid (oxyacid), non-steroid anti-inflammatory (NSAIDs), anti-asthmatic drug, ⁇ -polyglutamic acid derivatives, biodegradable polymer and sodium CMC.
  • health functional food is intended to refer to a food prepared or processed from raw materials or components which have functionality beneficial to the body.
  • functionality means the ability to regulate nutrients according to the structure or function of the body or to provide such effects beneficial for health as physiological activities upon the uptake of food.
  • excipients or "composition acceptable carrier or excipients” and “bio-available carriers or excipients” mentioned above include any appropriate compounds known to be used for preparing the dosage form, such as a solvent, a dispersing agent, a coating, anti-bacterial or anti-fungal agent and preserving agent or delayed absorbent. Typically, carriers or excipient do not have any therapeutic activity.
  • Each formulation is prepared by combining the derivatives disclosed in the present invention and pharmaceutically acceptable carriers or excipients that will not cause undesired effect, allergy or other inappropriate effects when administered administered to an animal or human. Accordingly, the derivatives disclosed in the present invention in combination with pharmaceutically acceptable carrier or excipients are adaptable in clinical usage and in humans patients.
  • therapeutically effective amount refers to an amount sufficient to ameliorate or prevent the medical symptom.
  • the therapeutically effective amount also explains the dosage of the compound that is suitable for use.
  • active compound and “pharmaceutically active compound” mentioned herein are essentially the same, which refer to a substance that has a pharmaceutic, pharmacological, therapeutic or other effect.
  • the carrier may vary with each formulation, and the sterile injection composition can be dissolved or suspended in non-toxic intravenous injection diluents or solvents such as 1,3-butanediol.
  • an acceptable carrier may be mannitol or water.
  • fixing oil, synthetic glycerol ester, and di-glycerol ester are commonly used solvents.
  • Fatty acids such as oleic acid, olive oil, castor oil and glycerol ester derivatives thereof, especially the oxy-acetylated types, may serve as the oil for preparing the injection and as natural pharmaceutically acceptable oil.
  • This oil solution or suspension may include long chain alcohol diluents or dispersing agents, carboxylate methyl cellulose (CMC) or an analogous dispersing agent.
  • CMC carboxylate methyl cellulose
  • Other acceptable carriers are common surfactants such as Tween and Spans, another analogous emulsion, or a pharmaceutically acceptable solid, liquid or other bio-avaliable enhancing agent used to develop a formulation that is used in the pharmaceutical industry.
  • the composition for oral administration may use any acceptable oral formulation, which includes capsules, tablets, pills, emulsions, aqueous suspensions, dispersing agents and solvents.
  • the carrier is generally used in oral formulations. Taking a tablet as an example, the carrier may be lactose, corn starch and lubricant, and magnesium stearate is the basic additive.
  • the diluents used in the capsule include lactose and dried corn starch.
  • an aqueous suspension or an emulsion formulation the active ingredient is suspended or dissolved in an oil interface in combination with the emulsion or the suspending agent, and an appropriate amount of sweetening agent, flavors or colorant is added as needed.
  • the nasal aerosol or inhalation composition may be prepared according to well-known preparation techniques. For example, the bioavailability can be increased by dissolving the composition in the phosphate buffer saline and adding benzyl alcohol or other appropriate preservative, or an absorption enhancing agent.
  • the compounds of the present invention may also formulated as suppositories for rectal or vaginal administration.
  • the compound of the present invention can also be administered intravenously, as well as subcutaneously, parentally, in muscules, or with intra-articular, intracranial, intra-articular fluid or intra-spinal injections, aortic injections, sterna injections, intra-lesion injections or other appropriate methods.
  • Combination therapy for preventing the oxidative stress induced disorders comprises a step of treating the subject suffering the disorder with an effective amount of a composition comprises an ingredient being one of an SAA derivatives compound and an SAA complex compounds and one or more additional co-active agents.
  • additional co-active agents include an eNOS activator, a Rho kinase inhibitor, cosmetic carrier, bodywash carrier, a carboxylic group being one selected from the RX group, and a combination thereof.
  • Food compositions mean products and ingredients, taken by the mouth, the constituents of which are active in and/or absorbed by the G.I. tract with the purposes of nourishment of the body and its tissues, refreshment and indulgence.
  • Examples of food and beverage products are tea, ice cream, frozen fruits and vegetables, snacks including diet foods and beverages; meal substitute and meal replacement.
  • Food compositions may bring any of the following benefits: healthy metabolism; life span extension; optimal growth and development of G.I. tract function; avoidance of metabolic syndrome and insulin resistance; avoidance of dyslipidemias and weight gain ; healthy mineral metabolism; immune health; optimal eye health; avoidance of cognitive impairment and memory loss; hair and skin health; beauty; and taste and smell.
  • Cosmetic compositions comprise a cosmetically- acceptable carrier or vehicle for bonding agent and any optional components.
  • Suitable carriers are well known in the art and are selected based on the end use application.
  • carriers of the present invention include, but are not limited to, those suitable for application to skin.
  • the carriers of the present invention are suitable for application to skin (e.g., sunscreens, creams, milks, lotions, masks, serums, etc.) and hair (paraffin wax, fatty alcohols, cationic surfactant).
  • skin e.g., sunscreens, creams, milks, lotions, masks, serums, etc.
  • hair paraffin wax, fatty alcohols, cationic surfactant
  • Such carriers are well-known to one of ordinary skill in the art, and can include one or more compatible liquid or solid filler diluents, suitable surfactant or vehicles which are suitable for application to skin and hairs.
  • composition according to this disclosure may also comprise at least one carrier chosen from the ingredients commonly used in cosmetics, such as thickeners in moisturizers, trace elements, softeners, sequestering agents, fragrances, acidifying and basifying agents, preserving agents, sunscreens, surfactants, antioxidants, antidandruff agents and propellants, lightening color agents, darkening color agents, anti-acne agents, shine control agents, anti-microbial agents, anti-inflammatory agents, anti-mycotic agents, anti-parasite agents, external analgesic, sunscreens, photo-protectors, keratolytic agents, detergents or surfactants, moisturisers or humectants, nutrients, energy-enhancers, growth factors, anti-perspiration agents, astringents, deodorants, hair-removers, firming agents, anti-callous agents and agents for hair and/or skin conditioning and mixtures thereof.
  • a carrier chosen from the ingredients commonly used in cosmetics, such as thickeners in moisturizers, trace elements,
  • one or more cosmetic agents are selected from the plant group comprises: curcumin, caffeine, saw palmetto extract, taurine, plant sterols, pine bark extract, red tea, white tea, horsetail extract, marine cartilage, kieslerde, melatonin and mimetics, copper peptides, growth factors and growth factor mimetics, minoxidil, spironolactone, ⁇ -glucan, vitamin C, vitamin A, vitamin E, vitamin B, vitamin F, vitamin H, vitamin K (and the vitamin derivatives), bacterial filtrates, glucosamine sulphate, and any combination thereof.
  • VEGF vascular endothelium growth factor
  • Oxidative stress is suspected to be important in neurodegenerative diseases including Motor Neuron Disease (aka. Lou Gehrigs/ MND or ALS), Parkinson's disease, Alzheimer's disease, and Huntington's disease and skin disorders.
  • Indirect evidence via monitoring biomarkers such as reactive oxygen species (ROS), reactive nitrogen species production (RNP) and antioxidant defense indicates that oxidative damage may be involved in the pathogenesis of these diseases, while cumulative oxidative stress with disrupted mitochondrial respiration and mitochondrial damage are related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases.
  • ROS reactive oxygen species
  • RNP reactive nitrogen species production
  • antioxidant defense indicates that oxidative damage may be involved in the pathogenesis of these diseases, while cumulative oxidative stress with disrupted mitochondrial respiration and mitochondrial damage are related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases.
  • Oxidative stress reflects an imbalance between the manifestation of reactive oxygen species (ROS) and a biological system or anti-oxidant environment to detoxify the resulting damage.
  • ROS reactive oxygen species
  • hypoxia is a common cause of persistent pulmonary artery hypertension (PAH) in a newborn and a condition associated with endothelial dysfunction and abnormal pulmonary vascular remodeling.
  • the GTPase RhoA and Rho-associated coiled-coil protein kinase II (ROCK II) have been implicated in the pathogenesis of persistent PAH, but their contribution to endothelial remodeling and function is not well known.
  • ROCK II mediated hypoxia-induced capillary angiogenesis, a previously unrecognized but potentially important adaptive response.
  • Sustained inhibition of the RhoA/ROCK II pathway throughout the period of hypoxic exposure attenuated the PAH and prevented remodeling in blood vessels without enlarging the lumen diameter.
  • this inhibition of RhoA ROCK II has also been confirmed in a monocrotaline-treated model of PAH not in hypoxia.
  • hypoxia-induced PAH is a complication of chronic lung diseases, which increases morbidity and mortality.
  • Hypoxic PAH has previously been attributed to structural changes in the pulmonary vasculature, including narrowing of the vascular lumen and loss of vessels, which cause a fixed increase in resistance.
  • PAH can be characterized by reduced eNOS/sGC, increased ROCK II expression and decreased pulmonary vascular density.
  • the downstream of nitric oxide synthase (eNOS) signaling in the cGMP-pathway for inhibiting PAH includes the expression of soluble guanylyl cyclase (sGC) and protein kinase G (PKG), which have been reported to be down regulated by hypoxia.
  • sGC soluble guanylyl cyclase
  • PKG protein kinase G
  • nitric oxide (NO) releasing can be caused by the down-regulation of eNOS/sGC and up-regulation of ROCK II.
  • Vascular contractility and resistance has been regulated by eNOS, sGC, phosphodiesterase 5A (PDE-5A) and RhoA/ROCK II expression in the cGMP -pathway.
  • PDE-5A phosphodiesterase 5A
  • RhoA/ROCK II expression in the cGMP -pathway co-localized eNOS/sGC/ PDE-5A expression in pulmonary artery has been involved in Sildenafil's inhibition activity of PAH.
  • Sildenafil and ROCK inhibitors Y27632 and Fasudil have been beneficial to PAH through, the inactivation of RhoA/ROCK II, the role of VEGF involved is unclear.
  • VEGF is required for the growth of pulmonary endothelial cells and needed to repair the damage from hypoxia.
  • pulmonary VEGF expression is markedly decreased in an experimental model of persistent PAH, mimicking the structural and functional abnormalities of pulmonary artery, and that study found that exogenous treatment with VEGF improved PAH by up-regulating the production of NO.
  • the controversy between increasing and decreasing VEGF for the treatment of PAH in hypoxia has yet to be resolved. Indeed, VEGF exerts its biological effects primarily on endothelial cells in hypoxia. However, a number of VEGF-mediated effects have been reported for non-endothelial cell types. ROCK II and VEGF signaling has been described to co-determine their contribution to angiogenesis.
  • VEGF hypoxia regulation of VEGF has been described through the induction of PI3K/Rho/ROCK and c-Myc, which is a target of the PI3K/ROCK II-signaling pathway and which can regulate the VEGF promoter through the binding elements.
  • RhoA ROCK II is surprisingly close to the signaling of VEGF.
  • RhoA or ROCK II inhibition diminishes the VEGF-induced polymerization of actin.
  • VEGF can induce RhoA activation in endothelial cells, mediate regenerative angiogenesis and tube formation, and the pharmacological inhibition of ROCK II disrupts vasculogenesis caused by VEGF.
  • HMG-Co A 3-hydroxy-3- methyl-glutaryl coenzyme A reductase inhibitor statin can increase eNOS, reduce cell proliferation and interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA.
  • ROCK inhibitor Fasudil inhibits VEGF-induced angiogenesis in vitro and in vivo. This evidence implicates the close relationship between RhoA/ROCK II and VEGF.
  • ROCK inhibitor benefits are partly due to the restoration of PKG-mediated vasodilatation in hypoxia.
  • cGMP has been involved in the regulation of upstream eNOS/sGC/cGMP PKG/ PDE5A and downstream ROCK II VEGF in hypoxia. It is thus suggested that cGMP-dependent inhibition of Rho ROCK II by SPAAX-1 ascorbate complex is a suitable strategy of treatment to ROCK inhibitor Fasudil, cGMP-enhancer Sildenafil ascorbate complex and an ET-1 receptor antagonist, which is effective by inactivating ROCK II for the treatment of hypoxic PAH.
  • ROS is an endogenous initiator and promoter of DNA damage and mutations that contribute to disease. It is essential to determine the production of ROS during hypoxia to evaluate the protective effects of Substituted Amine Analogs (SAA) derivative compound and SAA complex compound against hypoxia-induced oxidative damage.
  • SAA Substituted Amine Analogs
  • Cigarette smoking-induced Rho/ROCKII activation of rat lung tissue Table 1 effects of SAA on VEGF, eNOS and ROCK II expression of rat pulmonary artery ring and carvanosus strip via acute hypoxia
  • Normoxia 100 /100 100 100/100 Hypoxia 65.3 ⁇ 7.8/175 ⁇ 14 560 ⁇ 21 62.4 ⁇ 5.5/170 ⁇ 15
  • SPAAX-1 ascorbate complex or Sildenafil ascorbate complex 5 mg kg/day, p.o.
  • PAH Mean pulmonary arterial pressure
  • MABP mean artery blood pressure
  • heart rate were not significantly changed by either SPAAX-1 ascorbate complex or Sildenafil ascorbate complex.
  • the heart weight/body weight ratio (HW/BW) of rats treated with SPAAX-1 ascorbate complex or Sildenafil ascorbate complex was significantly different from non-treated rats at after 21 days (Table 4).
  • vascular muscularization or remodeling was represented by increases in the pulmonary arterial wall thickness (WT %) of hypoxic rats, examined on day 0 and day 21, following right lung resection.
  • Small pulmonary arterial morphology ( ⁇ 150 ⁇ ) was highly improved in the 5 mg/kg/day SPAAX-1 ascorbate complex treated rats.
  • FIG. 4 sections stained with hematoxylin and eosin (HE staining), indicating muscularizations of distal pulmonary artery (Fig. 4), were significantly lower in hypoxic rats treated with SPAAX-1 ascorbate complex (Fig. 4C) and Sildenafil ascorbate complex (Fig. 4D) than vehicle only (Fig. 4B).
  • Fig. 5 shows that SPAAX-1 ascorbate complex and Sildenafil ascorbate complex reduced the thickness of Right ventricular, compared to under the hypoxia state.
  • hypoxia increased the relative right ventricle (RV)/[left ventricle (LV)+ intraventricular septum (S)] weight ratio, i.e. right heart index, to 184.6 ⁇ 0.7%, compared to the normoxia rats.
  • SPAAX-1 ascorbate complex reduced the right heart index to 117.4 ⁇ 2.6% (PO.01) and the Sildenafil ascorbate complex decreased the right heart index to 145.3 ⁇ 0.4% ( O.01), compared to hypoxic rats (Fig. 6 B).
  • IHC Immunohistochemistry
  • Morphometric immunostaining of lung sections of animal with long-term hypoxia following treatment demonstrated a marked decrease of eNOS located mainly in endothelium of pulmonary artery, and this decrease was correlated with media thickening (Fig. 7A); VEGF-immunostaining was also mainly located in the endothelium and more significantly in the smooth muscle, compared to arterial section without immunostaining reactivity as a control (Fig. 8 A).
  • Treatments with SPAAX-1 ascorbate complex or Sildenafil ascorbate complex after long-term hypoxia restored the decay of eNOS and reduced the VEGF immunostaining reactivity (Fig. 7 B, 8B).
  • Fig. 9 and 10 show that ascorbic/ascorbate buffer (40, 80 ⁇ ) reduced the IHC of eNOS (Fig. 9A-9D) and VEGF (Fig. 10A-10D) in isolated pulmonary artery, indicating an oxidative stress defence against short-term acute hypoxia.
  • Pulmonary artery eNOS, ROCKII and VEGF expression after short-term hypoxia As shown in Fig. 12A, in isolated pulmonary artery ring in normoxia for 24 hrs, the expression of eNOS was increased to 117.9 ⁇ 9.1% (PO.05) by SPAAX-1 ascorbate complex (10 ⁇ ) and increased to 114.1 ⁇ 12.3% (PO.05) by a ROCK inhibitor Y27632 (10 ⁇ ), respectively. Expression of ROCK II decreased to 48.2 ⁇ 5.5% (PO.05) by SPAAX-1 ascorbate complex and to 67.5 ⁇ 14.8% by Y27632 (PO.01), in comparison with non-treated controls.
  • Fig. 13 shows that hypoxia increased the reactive oxygen species (ROS) of lung tissues detected by 2'-7'-dichlorofluorescein (H2DCF-DA) assay using fluorescence analysis.
  • ROS reactive oxygen species
  • SPAAX-1 ascorbate complex and Sildenafil ascorbate complex reduced hypoxia-induced increase of dichlorofluorescein.
  • a normoxia group 10-week old male Wistar rats were equally divided into four groups: a normoxia group, a hypoxia group, a hypoxia+ SPAAX-1 or SPAAX-1 RX complex group, and a hypoxia+Sildenafil or Sildenafil RX complex group. All the rats were maintained on a 12-h light/12-hr dark cycle at 25 ⁇ l°Cand were provided with food and water ad libitum.
  • the normoxia group was housed in standard normoxic conditions and the other three treated groups were continuously housed in a hypoxic chamber (10% 0 2 ) for 21 days, except for a 30-min interval each day when the chamber was cleaned (Fig. 2). During which, a normoxic gas mixture was prepared from compressed air.
  • Normoxic rats were housed in room temperature air at normal atmospheric pressure (760 mm Hg).
  • the hypoxic rats were housed in a hypobaric chamber for 21 days at 10% 0 2 .
  • tissues were prepared as indicated for contraction measurements, Western blot analysis, RNA extraction, or morphological analysis.
  • a femoral vein was then cannulated and heparinized for intravenous administration of normal saline, SPAAX-1 ascorbate complex, or Sildenafil ascorbate complex. The animals were then sacrificed by the administration of an overdose of urethane.
  • the protein extract was boiled to a ratio of 4: 1 with a sample buffer (Tris 100 mM, pH 6.8, glycerol 20%, SDS 4% and bromophenol blue 0.2%). Electrophoresis was performed using 10% SDS-polyacrylamide gel (2 hr, 100 V, 40 mA, 50 mg protein per lane). Separated proteins were transferred to PVDF membranes treated with 5% fat-free milk powder to block the nonspecific IgGs (90 min, 100 V) and incubated for one hour with a specific protein antibody. The blot was then incubated with anti-mouse or anti-goat IgG linked to alkaline phosphatase (1 : 1000) for 1 hr.
  • a sample buffer Tris 100 mM, pH 6.8, glycerol 20%, SDS 4% and bromophenol blue 0.25%. Electrophoresis was performed using 10% SDS-polyacrylamide gel (2 hr, 100 V, 40 mA, 50 mg protein per
  • Immunoreactive bands were visualized using horseradish peroxidase-conjugated secondary antibodies and subsequent electrochemiluminescence (ECL) detection (GE Healthcare Bio-Sciences Corp., Piscataway, NJ, U.S.A.).
  • ECL electrochemiluminescence
  • Mouse or rabbit monoclonal antibody of eNOS Upstate, NY, U.S.A.
  • sGCa/Sigma-Adrich CA, U.S.A.., sGCp .
  • the 4 ⁇ m-thick paraffin sections were cut from paraffin-embedded tissue blocks and de-paraffmized by immersion in xylene and rehydrated as previously described (Bivalacqua TJ, et al., PLoSONE 8: e68028. doi:10.1371/journal. pone.0068028). The slices were then dyed with H&E. After gently rinsing with water, each slide was dehydrated through graded alcohols and finally soaked in xylene twice. The relative cardiac weight of right ventricle (RV)/[left ventricle (LV)+intraventricular septum (S)] ratio ( i.e. right heart index) was calculated using right ventricle/left ventricle+septum (RV/LV+S). Measurements were obtained with Histolab software (Micro vision Instruments, Evry, France).
  • rat pulmonary right lung sections or pulmonary artery were fixed in 4% formaldehyde for 1 hour at 4°C. After washing with phosphate buffer saline (PBS), they were sent for paraffin-embedded serial-sections. Serial cross-sections 7 ⁇ thick were obtained from the cross-section of each pulmonary artery. Tissue sections were deparaffinized and rehydrated in an ethanol series. After tissue rehydration, endogenous peroxidase activity was quenched with 3% hydrogen peroxide for 30 minutes, and the sections were gently washed in PBS. Non-specific binding was blocked by incubation with 1% nonimmune bovine serum albumin (BSA) in PBS for 30 minutes at room temperature.
  • BSA nonimmune bovine serum albumin
  • tissue sections were incubated for 1 hour at room temperature with antibody against VEGF (abl442, Millipore) or against eNOS (ab5589, Abeam) diluted 1 :200 in PBS with 1% BSA. After being washed with PBS, the sections were incubated for 1 hour at room temperature with biotinylated goat antibody against rabbit (Dako, E-0432) and diluted 1 :200 in PBS for 30 minutes at room temperature. The reaction was visualized by the addition of 3-3-diaminobenzidine (DAB) in a working solution of DAB substrate kit for peroxidase (vector lab, SK-4100) at room temperature for 5 minutes. The sections were washed in PBS for 10 minutes between each step, and counterstained with haematoxylin. Lastly, the sections were dehydrated, and after drying were mounted with DAKO aqueous mount (Dako, 003181).
  • DAB 3-3-diaminobenzidine
  • NOx NO metabolites
  • the lung tissue extracts (100 ⁇ ,) were incubated (37°C) for 30 min with 50 mM (pH 7.4) N-2-hydroxyethylpiperazine-N'-ethane sulphonic acid buffer (HEPES), flavin adenine dinucleotide (5 ⁇ ), nicotinamide adenine dinucleotide phosphate (0.1 mM), distilled water (290 ⁇ ), and nitrate reductase (0.2 U/ml) for the conversion of nitrate into nitrite.
  • HEPES N-2-hydroxyethylpiperazine-N'-ethane sulphonic acid buffer
  • flavin adenine dinucleotide 5 ⁇
  • nicotinamide adenine dinucleotide phosphate 0.1 mM
  • distilled water 290 ⁇
  • nitrate reductase 0.2 U/ml
  • Pulmonary ROS was measured using 2'-7'-dichloro- fluorescein (H2DCF-DA, Molecular Probe, USA). Briefly, 10 ⁇ of lung tissue extract was diluted 100-fold with cold PBS and labelled with 5 ⁇ /L 2'-7'-dichlorofluorescein, and the mixture was incubated at 37°C for 30 minutes and put in a centrifuge (1000 rpm) for 5 min. Fluorescence was measured at 485 nm excitation and 530 nm emission to determine the concentration of H 2 O 2 (FLUOstar Galaxy, Germany).
  • the anti-eNOS antibody was obtained from BD Biotechnology (New York, USA); anti-PKG antibodies from Santa Cruz (CA, USA); anti-sGCal and ?-actin antibodies and Y27632 from Sigma Chemical Co..
  • SPAAX-1 was synthesized in our laboratory and whose salt form SPAAX-1 ascorbate complex (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]- 1,3-dimethylxanthine ⁇ ascorbic acid) was used in the all of experiments in this study.
  • SPAAX-1 ascorbate complex or Sildenafil ascorbate complex was dissolved in a vehicle (distilled water containing 0.5 % methyl cellulose).
  • SPAAX-1 ascorbate complex, Sildenafil ascorbate complex and L-ascorbic acid dilutions were made with distilled water. All the other reagents we used were of analytical grade or higher and were obtained from commercial sources.
  • L-sodium ascorbate+L-ascorbic acid buffer Aldrich-Sigma, St. Louis, MO, USA was used as an anti-oxidant system.
  • results were expressed as mean ⁇ SE.
  • Statistical differences were determined by independent and paired Student's f-test in unpaired and paired samples, respectively. Whenever a control group was compared with more than one treated group, one way ANOVA or two way repeated measure ANOVA was used. When the ANOVA showed a statistical difference, the Dunnett's or Student-Newman-Keuls test was applied. A P value less than 0.05 was considered significant in all experiments. Analysis of the data and plotting of the figures were done with the aid of SigmaPlot software (Version 8.0, Chicago, IL, U.S.A.) and SigmaStat (Version 2.03, Chicago, IL, U.S.A.) run on an IBM compatible computer.
  • Example 2 Preparation of 7-[2-[4-(2-chlorophenyl) piperazinyl] ethyl] - 1 , 3 -dimethylxanthine HCl complex (SPAAX-1 HCl complex)
  • the toluene solution was further washed twice with 20% sodium hydroxide solution (2x50 mL) followed by 2% brine solution (2x 50 mL) at 50°C.
  • the precipitated hydrochloride salt of the target molecule was isolated by filtration and re-crystallized from methanol to achieve the white crystalline SPAAX-1 HCl compound (7.4 g).
  • Example 3 Preparation of SPAAX-1 ascorbate complex from SPAAX-1 base
  • SPAAX-1 base (13.2 g) was dissolved in a mixture of ethanol (100 mL) and an ethanol solution of equal mole ascorbic acid was added then to react at 50°C for 20 mins. After cooling, a white precipitate was obtained and the sodium chloride was removed by filtration. The solvent methanol (100 mL) was added to resolve the precipitate under room temperature and incubated overnight for re-crystallization. The SPAAX-1 ascorbate complex compound (16.8 g) was obtained after filtering the crystals.
  • Method 1 20 g of sodium carboxyl methylcellulose was suspended in distilled water and added to 16 g of SPAAX-1 HC1 and 100 ml of methanol to reflux in a three-neck reactor, equipped with a condenser, for 1 hour. After cooling, the obtained precipitate was dissolved in 100 ml methanol and the resulting solution was incubated for crystallization and filtrated to obtain the SPAAX-1CMC complex (35.4 g).
  • Method 2 SPAAX-1 HC1 (16 g) was dissolved in 100 ml of methanol and added to 20g of sodium CMC and refluxed in a three-neck reactor, equipped with a condenser, for 1 hour. After cooling, the obtained precipitate was filtrated and re-crystallized with 100 ml of methanol to obtain the SPAAX-1 CMC complex (35.2 g).
  • Method 1 20 g of sodium ⁇ -polyglutamic acid was suspended in distilled water and added to 16 g of SPAAX-1 HC1 dissolved in 100 ml of methanol to reflux in a three-neck reactor, equipped with a condenser, for 1 hour. After cooling, the obtained precipitate was dissolved in 100 ml of methanol and the resulting solution was incubated for crystallization and filtrated to obtain SPAAX-1 ⁇ -Polyglutamate complex (35.6 g).
  • Method 2 16 g of SPAAX- 1 HCl was dissolved in 100 ml of methanol and added to 20 g of sodium ⁇ -poly glutamic acid dissolved in 100 ml methanol to reflux in a three-neck reactor, equipped with a condenser, for 1 hour. After cooling, the obtained precipitate was filtrated and re-crystallized with 100ml methanol to obtain SPAAX- 1 ⁇ -polyglutamate complex (35. 8 g).
  • Methodl 20 g of sodium alginic acid was suspended in distilled water and added to 16 g of SPAAX- 1 HCl was dissolved in 100 ml methanol to reflux in a three-neck reactor, equipped with a condenser, for 1 hour. After cooling, the obtained precipitate was dissolved in 100 ml methanol and the resulted solution was incubated for crystallization and filtrated to obtain SPAAX- 1 alginate complex (35.4 g).
  • Method 1 8.5 g of sodium oleic acid was suspended in distilled water and added to 12.1 g of SPAAX-2 HCl dissolved in 100 ml of methanol to reflux in a three-neck reactor, equipped with a condenser, for 1 hour. After cooling, the obtained precipitate was dissolved in 100 ml of methanol and the resulting solution was incubated for crystallization and filtrated to obtain SPAAX-2 oleate complex (16.3g).
  • Method 2 12.1 g of SPAAX-2 HC1 was dissolved in 100 ml of methanol and added to 8.5 g of sodium oleic acid dissolved in 100 ml methanol to reflux in a three-neck reactor, equipped with a condenser, for 1 hour. After cooling, the obtained precipitate was filtrated and re-crystallized with 100ml methanol to obtain SPAAX-1 oleate complex (16.5g).
  • SPAAX-3 HC1 (8.5 g) was dissolved in 100 ml of ethanol and added to 3.9g of sodium ascorbic acid and refluxed in a three-neck reactor, equipped with a condenser, for 1 hour. After cooling, the obtained precipitate was filtrated and re-crystallized with 100 ml of methanol to obtain the SPAAX-3 ascorbate complex (9.7 g).
  • Example 11 Preparation of the composition in tablets
  • Tablets were prepared using standard mixing and formation techniques as described in U.S. Pat. No. 5,358,941, to Bechard et al., issued Oct. 25, 1994, which is incorporated by reference herein in its entirety.
  • Example 12 Preparation of the composition in tablets
  • Embodiment 1 A method for inhibiting a disorder caused by oxidative stress in a subject, comprises a step of:
  • an effective amount of a pharmaceutical composition comprises an ingredient being one of an SAA derivatives compound and an SAA complex compounds, wherein:
  • Rm is one selected from a group consisting of a first hydrogen, a first C1-C6 alkyl group, a first C1-C6 alkoxyl group and a 3-membered to 8-membered ring, and either one of Rl and Ra is classified into one of a category I and a category II, and wherein:
  • Rl is one selected from a group consisting of a second hydrogen, a first halogen, a second C1-C6 alkyl group, a first C1-C5 alkoxyl group: and
  • a first benzene ring having one or more substitute group selected from a second C1-C5 alkoxyl group, a first nitro group, a second halogen, a halogen substitute C1-C5 alkoxyl group and a halogen substitute C1-C6 all y 1 group
  • Ra is a xanthine group having a substitute of a fourth C1-C5 alkyl group, a third C1-C5 alkoxyl group and a third halogen.
  • R] is one of a second benzene ring having a substitute being one of a fourth C1-C5 alkoxyl group and a sulfonyl phenyl group and a heterocyclic ring having a substitute being one of a second C1-C6 alkoxyl group and a third C1-C6 alkyl group
  • Ra is one selected from a group consisting of a third hydrogen, a second halogen, an amino group, a second nitro group, a second C1-C5 alkyl group and a fifth C1-C5 alkoxyl group
  • the heterocyclic ring is one selected from a group consisting of pyrazolo, pyrimidin, imidazo, pyrollidinyl, triazin and a fused ring having at least one selected from the group consisting of pyrazolo, pyrimidin, pyrollidinyl, imidazo and triazin, " RX is a carboxylic group having a negative charge, and the carboxylic group is donated from one selected from a group consisting of a plant acid, a substituted-sulfonic acids, a oxygen-containing acid (oxyacid), and a combination thereof.
  • Embodiment 2 The method as example 1, wherein the SAA derivatives compound is one of an SPAAX derivatives compound and an SPAAS derivatives compound, the SPAAX derivatives compound is represented by formula VI
  • each of RK, RM, RS and RT is one selected from a group consisting of a sixth hydrogen, a sixth C1-C5 alkoxyl group, a third nitro group and a third halogen, and n is a positive integer ranging from 1 to 6.
  • Embodiment 3 The method as example 2, wherein the SPAAS derivatives compound is one selected from a group consisting of Sildenafil, Hydroxyhomosildenafil, Desmethyl sildenafil, Acetidenafil, Udenafil, Vardenafil, Homosildenafil and a combination thereof.
  • Embodiment 4 The method as in example 2, wherein the SPAAX derivatives compound is one selected from a group consisting of 7-[2-[4-(2-chloro-phenyl)piperazinyl]ethyl]- 1 ,3-dimethylxanthine (SPAAX- 1 ), 7-[2-[4-(2-methoxyphenyl)-piperazinyl]ethyl]- 1 ,3- dimethylxanthine (SPAAX-2), 7-[2-[4-(4-nitrophenyl)piperazinyl] ethyl]-l,3-dimethylxanthine (SPAAX-3), 7-[2-[4-(2-nitrophenyl)- piperaz.inyl]ethyl]-l,3-dimethylxanthme (SPAAX-4), 7-[2-[4-(2- flurorophenyl)piperazinyl]ethyl]-l,3-dimethylxanthin
  • Embodiment 5 The method as in example 1, wherein each of the first and the second halogens is one selected from a group consisting of fluorine, chlorine, bromine and iodine.
  • Embodiment 6 The method as example 1, wherein the SAA complex compounds is one of an SPAAX complex compounds and an SPAAS complex compounds.
  • Embodiment 7 The method as example 1, wherein when both Rl and Ra are classified into the category I and Rl is one selected from the group consisting of the first halogen, the second C1-C6 alkyl group, the first C1-C5 alkoxyl group, the benzene ring and the first nitro group, there is a first bridge formed between Ra and Rl, and when Rl and Ra are both classified into the category II, there is a second bridge formed between Ra and Rl
  • Embodiment 8 The method as example 1 , wherein the plant acid is one selected from a group consisting of acetic acid, adipic acid, aketoglutaric acid, allantoic acid, aspartic acid, citramalic acid, ascorbic acid, benzoic acid, citric acid, cresylic acid, formic acid, fumaric acid, galacturonic acid, glutamic acid, gluconic acid, glucuronic acid, glyceric acid, glycolic acid, hydrochloric acid, isocitric acid, lactic acid, lactoisocitric acid, malic acid, maleic acid, nicotinic acid, oxalacetic acid, oxalic acid, oleic acid, phosphoric acid, pyroglutamic acid, pyrrolidinone carboxylic acid, pyruvic acid, quinic acid, salicylic acid, shikimic acid, succinic acid, sulfuric acid, tartaric acid, and a combination thereof.
  • Embodiment 9 The method as example 1, wherein the NSAIDs is one selected from a group consisting of aspirin, salicylic acid, indomethacin, meclofenamic acid, Tolmetin, Ketoprofen, methotrexate, Diclofenac acid, Meclofenamic acid, Mefenamic acid, flurbiprofen, fenoprofen, tiaprofen, diflunisal, etodolac, ibuprofen, prostacyclin analogon and a combination thereof.
  • the NSAIDs is one selected from a group consisting of aspirin, salicylic acid, indomethacin, meclofenamic acid, Tolmetin, Ketoprofen, methotrexate, Diclofenac acid, Meclofenamic acid, Mefenamic acid, flurbiprofen, fenoprofen, tiaprofen, diflunis
  • Embodiment 10 The method as example 1, wherein the anti-asthmatic drug is one selected from a group consisting of montelukast, cromolyn sodium, nedocromil and a combination thereof.
  • Embodiment 11 The method as example I, wherein the ⁇ -polyglutamic acid derivatives is one selected from a group consisting of alginate sodium, poly-y-polyglutamic acid ( ⁇ -PGA), alginate-poly- lysine-alginate (APA) oly(alginic acid), poly(glutamic acid), alginate, poly(glutamic acid-co-ethyl glutamate), poly(amino acids), poly(leucine-co-hydroxyethyl glutamine), poly(benzyl glutamate) and a combination thereof.
  • ⁇ -PGA poly-y-polyglutamic acid
  • APA alginate-poly- lysine-alginate
  • oly(alginic acid) poly(glutamic acid), alginate, poly(glutamic acid-co-ethyl glutamate), poly(amino acids), poly(leucine-co-hydroxyethyl glutamine), poly(benzyl gluta
  • Embodiment 12 The method as example 1, wherein the substituted-sulfonic acids optionally substituted with one or more groups selected from C1-C8 alkoxyl group, halogen, C1-C8 alkyl group, halogen substituted C1-C8 alkoxyl group and halogen substituted C1-C8 alkyl group.
  • Embodiment 13 The method as example 1, wherein the biodegradable polymer is one selected from a group consisting of gelatin, collagen, polysaccharide, non-water soluble chitosan, dextrose, dextran, copolymers containing poly(ethylene glycol), poly(D,L-lactic acid), poly (L-lactic acid), poly(glycolic acid), polyglycolic acid sodium (PGCA sodium), hyaluronic acid (HA), polyacrylic acid (PAA), copolymers of poly(lactic) and glycolic acid, polymethacrylates (PMMA), Eudragit, dextran sulfate, heparan sulfate, polylactic acid (polylactide, PLA), polylactic acid sodium (PLA sodium) and a combination thereof.
  • the biodegradable polymer is one selected from a group consisting of gelatin, collagen, polysaccharide, non-water soluble chitosan, dextrose, dextran, copolymers
  • Embodiment 14 The method as example 1, wherein the disorder is one selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, dementia, Huntington's disease, asthma, emphysema, pneumonia, chronic bronchitis, acute bronchitis, cystic fibrosis, pulmonary fibrosis, pulmonary artery hypertension (PAH), chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), oxidative stress-induced heart disease and cavernous dysfunction.
  • the disorder is one selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, dementia, Huntington's disease, asthma, emphysema, pneumonia, chronic bronchitis, acute bronchitis, cystic fibrosis, pulmonary fibrosis, pulmonary artery hypertension (PAH), chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), oxidative stress-induced heart disease and ca
  • the SAA derivatives compound is one selected from a group consisting of haloalkyl- 1,3 -dimethylxanthine (SAAX-100), aminoalkyl-1,3- dimethylxanthine (SAAX-200), alkylaminoalkyl- 1 ,3 -dimethylxanthine (SAAX-300), haloaminoalkyl-l,3-dimethylxanthine (SAAX-400), azirinylalkyl- 1 ,3 -dimethylxanthine (SAAX-31 ), alkylazirinylalkyl- 1,3- dimethylxanthine (SAAX-32), aminoalkylazirinylalkyl- 1 ,3 -dimethylxanthine (SAAX-33), haloaminoalkylazirinylalkyl- 1,3 -dimethylxanthine (SAAX-34), a group consisting of hal
  • Embodiment 16 The method as example 1, wherein Rxn is one selected from a group consisting of an azirine ring
  • Embodiment 17 A method for inhibiting a disorder caused by oxidative stress in a subject, comprises steps of:
  • an effective amount of a pharmaceutical composition comprises an ingredient being one selected from a group consisting of an SAA derivatives, an SAAX derivatives, an SPAAX derivatives, an SPAAS derivatives compound and a combination thereof;
  • Embodiment 18 The method as example 17, wherein the additional co-active compound is one selected from a group consisting of a plant acid, a substituted-sulfonic acid derivatives, a oxygen-containing acid (oxyacid), a non-steroid anti-inflammatory (NSAIDs), an anti-asthmatic drug, a ⁇ -polyglutamic acid derivatives, a biodegradable polymers, a sodium CMC and a combination thereof.
  • the additional co-active compound is one selected from a group consisting of a plant acid, a substituted-sulfonic acid derivatives, a oxygen-containing acid (oxyacid), a non-steroid anti-inflammatory (NSAIDs), an anti-asthmatic drug, a ⁇ -polyglutamic acid derivatives, a biodegradable polymers, a sodium CMC and a combination thereof.
  • Embodiment 19 The method as example 17, wherein the SPAAS derivatives compound is one selected from a group consisting of Sildenafil, Hydroxyhomosildenafil, Desmethylsildenafil, Acetidenafil, Udenafil, Vardenafil, Homosildenafil and a combination thereof.
  • Embodiment 20 The method as example 17, wherein the plant acid is one selected from, a group consisting of acetic acid, adipic acid, aketoglutaric acid, allantoic acid, aspartic acid, citramalic acid, ascorbic acid, benzoic acid,citric acid, cresylic acid, formic acid, fumaric acid, galacturonic acid, glutamic acid, gluconic acid, glucuronic acid, glyceric acid, glycolic acid, hydrochloric acid, isocitric acid, lactic acid, lactoisocitric acid, malic acid, maleic acid, nicotinic acid, oxalacetic acid, oxalic acid, oleic acid, phosphoric acid, pyroglutamic acid, pyrrolidinone carboxylic acid, pyruvic acid, quinic acid, salicylic acid, shikimic acid, succinic acid, sulfuric acid, tartaric acid, and a combination thereof
  • Embodiment 21 The method as example 17, wherein the additional co-active compound is one selected from a group consisting of a L-sodium ascorbate:L-ascorbic acid (1 :1) buffer in hypoxia.
  • Embodiment 22 The method as example 17, wherein the substituted-sulfonic acids optionally substituted with one or more groups selected from C1-C5 alkoxyl group, halogen, C1-C5 alkyl group, benzene group and substituted benzene group; wherein the substituted benzene group can be substituted in turn by one or more substituents selected from C1-C8 alkyl group, halogen group and halogen substituted C1-C8 alkyl group.
  • a combination therapy method for inhibiting a disorder caused by oxidative stress in a subject comprises steps of:
  • an effective amount of a first composition comprises an ingredient being one selected from a group consisting of an SAA derivatives, an SAAX derivatives, an SPAAX derivatives, an SPAAS derivatives compound and a combination thereof;
  • a second composition comprises an additional co-active compound having a carboxylic group.
  • Embodiment 24 The method as example 23, wherein the first composition and the second composition are selected independently from pharmaceutical composition, cosmetic composition, food composition and bodywash.
  • Embodiment 25 The method as example 23, wherein additional co-active agents include an eNOS activator, a Rho kinase inhibitor, cosmetic carrier, bodywash carrier, a carboxylic group being one selected from the RX group, and a combination thereof.
  • additional co-active agents include an eNOS activator, a Rho kinase inhibitor, cosmetic carrier, bodywash carrier, a carboxylic group being one selected from the RX group, and a combination thereof.
  • Embodiment 26 A method of preparing an SAA derivatives compound, comprises steps of:

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Abstract

L'invention concerne des composés dérivés d'analogues d'amines substituées (SAA) et des composés correspondant à un complexe de SAA qui sont caractérisés comme étant des compositions ayant pour effet d'inhiber les affections provoquées par le stress oxydatif et, plus particulièrement, des composés dérivés de SAA capables d'inhiber des affections provoquées par le stress oxydatif de type maladies neurodégénératives, maladies pulmonaires, maladie cardiaque induite par le stress oxydatif et dysfonctionnement du sinus caverneux.
PCT/CN2014/076237 2014-04-25 2014-04-25 Composé dérivé de saa permettant le rétablissement de l'enos et inhibant les affections induites par le stress oxydatif dans l'hypoxie Ceased WO2015161510A1 (fr)

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CN108379246A (zh) * 2018-05-16 2018-08-10 中国人民解放军第二军医大学 莽草酸在制备预防或治疗脱髓鞘疾病药物中的应用
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CN113461694A (zh) * 2021-08-05 2021-10-01 广东西捷药业有限公司 一种伐地那非类似物及其合成方法和应用
CN113583003A (zh) * 2021-08-05 2021-11-02 广东西捷药业有限公司 一种伐地那非类似物及其合成方法和应用

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US9707206B2 (en) 2014-02-10 2017-07-18 Patara Pharma, LLC Mast cell stabilizers treatment for systemic disorders
US9962363B2 (en) 2014-02-10 2018-05-08 Patara Pharma, LLC Mast cell stabilizers treatment for systemic disorders
US9968586B2 (en) 2014-02-10 2018-05-15 Patara Pharma, LLC Mast cell stabilizers treatment for systemic disorders
US10835512B2 (en) 2014-02-10 2020-11-17 Respivant Sciences Gmbh Methods of treating respiratory syncytial virus infections
US10238628B2 (en) 2014-02-10 2019-03-26 Respivant Sciences Gmbh Mast cell stabilizers treatment for systemic disorders
US10398673B2 (en) 2014-02-10 2019-09-03 Respivant Services GmbH Mast cell stabilizers treatment for systemic disorders
US10391078B2 (en) 2015-08-07 2019-08-27 Respivant Sciences Gmbh Methods for the treatment of mast cell related disorders with mast cell stabilizers
US10265296B2 (en) 2015-08-07 2019-04-23 Respivant Sciences Gmbh Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders
US10238625B2 (en) 2015-08-07 2019-03-26 Respivant Sciences Gmbh Methods for the treatment of mast cell related disorders with mast cell stabilizers
US10596146B2 (en) 2015-08-07 2020-03-24 Respivant Sciences Gmbh Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders
US10265267B2 (en) 2016-08-31 2019-04-23 Respivant Sciences Gmbh Cromolyn compositions for treatment of chronic cough due to idiopathic pulmonary fibrosis
US10463613B2 (en) 2016-08-31 2019-11-05 Respivant Sciences Gmbh Cromolyn compositions for treatment of chronic cough due to idiopathic pulmonary fibrosis
US10561635B2 (en) 2016-10-07 2020-02-18 Respivant Sciences Gmbh Cromolyn compositions for treatment of pulmonary fibrosis
US10583113B2 (en) 2016-10-07 2020-03-10 Respivant Sciences Gmbh Cromolyn compositions for treatment of pulmonary fibrosis
CN108379246A (zh) * 2018-05-16 2018-08-10 中国人民解放军第二军医大学 莽草酸在制备预防或治疗脱髓鞘疾病药物中的应用
CN113461694A (zh) * 2021-08-05 2021-10-01 广东西捷药业有限公司 一种伐地那非类似物及其合成方法和应用
CN113583003A (zh) * 2021-08-05 2021-11-02 广东西捷药业有限公司 一种伐地那非类似物及其合成方法和应用

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