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WO2016206097A1 - 新的5型磷酸二酯酶抑制剂及其应用 - Google Patents

新的5型磷酸二酯酶抑制剂及其应用 Download PDF

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Publication number
WO2016206097A1
WO2016206097A1 PCT/CN2015/082507 CN2015082507W WO2016206097A1 WO 2016206097 A1 WO2016206097 A1 WO 2016206097A1 CN 2015082507 W CN2015082507 W CN 2015082507W WO 2016206097 A1 WO2016206097 A1 WO 2016206097A1
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Prior art keywords
alkyl
group
hydrogen atom
compound
atom
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PCT/CN2015/082507
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English (en)
French (fr)
Inventor
陈中祝
徐志刚
唐典勇
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Chongqing University of Arts and Sciences
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Chongqing University of Arts and Sciences
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Application filed by Chongqing University of Arts and Sciences filed Critical Chongqing University of Arts and Sciences
Priority to ES15895995T priority Critical patent/ES2774048T3/es
Priority to AU2015399642A priority patent/AU2015399642B2/en
Priority to JP2017564549A priority patent/JP6595011B2/ja
Priority to EP15895995.7A priority patent/EP3301095B1/en
Priority to PCT/CN2015/082507 priority patent/WO2016206097A1/zh
Priority to CA2987109A priority patent/CA2987109C/en
Priority to KR1020177025360A priority patent/KR102457316B1/ko
Priority to US14/954,375 priority patent/US9920057B2/en
Priority to TW104143514A priority patent/TWI613201B/zh
Publication of WO2016206097A1 publication Critical patent/WO2016206097A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the present application relates to the field of medicine, and in particular to selective 5D phosphodiesterase (PDE5) inhibitors and their use in the treatment and/or prevention of diseases or conditions, wherein such inhibition is considered to be beneficial.
  • PDE5 selective 5D phosphodiesterase
  • Erectile dysfunction has an important impact on men's psychology and physiology.
  • PDE5 inhibitors can effectively treat ED.
  • the chemical structure of Eli Lilly's Cialis is as follows:
  • PDE5 inhibitors can improve ED caused by a variety of reasons, and the difference between the compounds is small in terms of onset time, but the difference between the compounds is large in terms of half-life.
  • the half-life of Xi'ai in the human body is as long as 24 to 36 hours, while the half-life of the two drugs produced by Pfizer and Bayer Pharmaceuticals by Pfizer is only about 4 to 5 hours.
  • the present application relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a disease associated with type 5 phosphodiesterase for use in the treatment and/or prevention of a mammal Or the use of a drug in a disease state, wherein inhibition of phosphodiesterase type 5 is considered to be beneficial,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a method of preventing and/or treating a disease or disease state associated with phosphodiesterase type 5 in a mammal, wherein inhibition of phosphodiesterase type 5 in the disease or disease state is considered to be beneficial
  • the method comprises administering a therapeutically effective amount of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a mammal in need of such prevention and/or treatment,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a medicament thereof, for use in the prevention and/or treatment of a disease or disease state associated with phosphodiesterase type 5 in a mammal a composition wherein inhibition of type 5 phosphodiesterase in the disease or disease state is considered to be beneficial,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a method of inhibiting phosphodiesterase type 5, wherein the method comprises the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof and a phosphodiesterase type 5 Contact in vitro or in vivo.
  • the present application relates to the use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as defined above as a phosphodiesterase inhibitor of type 5.
  • the present application relates to the use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as defined above for use as a medicament for the treatment and/or prevention of erectile dysfunction in a human.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof of the present application has a good inhibitory effect on PDE5, and has a suitable half-life and biological metabolism in vivo, and thus, it is easy to develop into a clinical drug.
  • references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
  • Related articles Reference to a feature, structure, or feature.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • C 1 -C 6 alkyl describes an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • Cyano refers to the -CN group.
  • Amino refers to the -NH 2 group.
  • Haldroxy means an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Carboxyl means a -COOH group.
  • Alkyl means a straight or branched hydrocarbon chain radical consisting of only carbon and hydrogen atoms, free of unsaturation, having from 1 to 6 carbon atoms, and through a single bond to the molecule The remainder is linked, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), etc. Wait.
  • an alkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, cyano, hydroxy, decyl, amino, carboxy, sulfonic acid. Base or sulfinate group, and the like.
  • Alkylene chain means a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, free of unsaturation and having from 1 to 6 carbon atoms, linking the remainder of the molecule to a group, for example Methylene, ethylene, propylene, n-butylene and the like.
  • the alkylene chain can be attached to the remainder of the molecule and to the group through one carbon in the chain or through any two of the carbons in the chain.
  • Optional or “optionally” means that the subsequently described condition may or may not occur, and that the statement includes instances where the event or circumstance occurs and conditions that do not occur.
  • optionally substituted alkyl means that the alkyl group may or may not be substituted, and the description includes substituted alkyl groups and unsubstituted alkyl groups. Base group.
  • carrier is defined as a compound that facilitates the introduction of a compound into a cell or tissue.
  • dimethyl sulfoxide is commonly used as a carrier because it is easy to introduce certain compounds into cells or tissues of an organism.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, antiseptic that has been approved by the National Food and Drug Administration for use in humans or animals. Agents, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, and the like, which have no side effects on the pharmaceutical composition. Carrier.
  • pharmaceutically acceptable salt means those salts which retain the biological effects and properties of the PDE5 inhibitors of the present application and which are not biologically or otherwise unacceptable.
  • a pharmaceutically acceptable salt does not interfere with the beneficial effects of the agents of the present application in inhibiting PDE5, including “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts.”
  • the term "pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are derived from inorganic or organic acids.
  • the inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., such as but not limited to acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid , aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, ring Hexyl sulfamic acid, dodecyl sulphate, ethane-1,2-disulfonic
  • salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like.
  • Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, salts of substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • mammal includes humans and domestic animals such as laboratory animals and domestic pets such as cats, dogs, pigs, cows, sheep, goats, horses and rabbits, as well as non-domestic animals such as wild animals and the like.
  • composition refers to a formulation of a compound of the present invention and a medium which is generally accepted in the art for delivery of a biologically active compound to a mammal such as a human.
  • Such media include all pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical composition facilitates administration of the compound to the organism.
  • methods for administering a compound or pharmaceutical composition in the art including, but not limited to, oral administration, injection administration, inhalation administration, parenteral administration, and topical administration.
  • pharmaceutically acceptable is defined as a carrier, excipient or diluent that does not abrogate the biological activity and properties of the compound.
  • terapéuticaally effective amount means that when administered to a mammal, preferably to a human, the compound of the present application is sufficient to effectively treat a mammalian, preferably human, amount of a disease or condition associated with PDE5.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, and the age of the mammal to be treated, but those skilled in the art can, based on their own knowledge and the present disclosure, The amount of the compound of the present application is determined conventionally.
  • treating encompasses a mammal having a related disease or condition, preferably a treatment-related disease or condition in a human, and includes:
  • the application relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom;
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted by a halogen, a cyano group, a hydroxyl group, an amino group, a decyl group, a carboxyl group, a sulfonic acid group or a sulfinic acid group, -C(O )-C 1 -C 6 alkyl, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted by a halogen, a cyano group, a hydroxyl group, an amino group, a decyl group, a carboxyl group, a sulfonic acid group or a sulfinic acid group, -C(O)-C 1 - C 6 alkyl, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl Or -S(O)-H.
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom;
  • R 3 represents a hydrogen atom, -Q-OR 6 , anthracenyl, -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain represented by (CH 2 ) n and n is an integer from 1 to 6;
  • R 4 and R 5 are independently selected from a hydrogen atom, an unsubstituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2- C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an unsubstituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 - C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H.
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom;
  • R 3 is selected from a hydrogen atom, -Q-OR 6 or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain, wherein the alkylene chain is represented by (CH 2 ) n and n is an integer of 1-6;
  • R 4 and R 5 are independently selected from a hydrogen atom, an unsubstituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2- C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom or an unsubstituted C 1 -C 6 alkyl group.
  • the present application relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, among them
  • R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom, preferably both R 1 and R 2 are ruthenium atoms;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted by a halogen, a cyano group, a hydroxyl group, an amino group, a decyl group, a carboxyl group, a sulfonic acid group or a sulfinic acid group, -C(O )-C 1 -C 6 alkyl, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H.
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom, preferably both R 1 and R 2 are ruthenium atoms;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain, wherein the alkylene chain is represented by (CH 2 ) n and n is an integer of 1-6;
  • R 4 and R 5 are independently selected from a hydrogen atom or an unsubstituted C 1 -C 6 alkyl group.
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 and R 2 are each a hydrogen atom
  • R 3 is -Q-NR 4 R 5 ,
  • R 4 and R 5 is hydrogen and the other is selected from -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 Alkyl or -S(O)-H.
  • the compounds of formula (I) of the present application are preferably the following compounds:
  • the compound represented by the general formula (I) is a potent and selective PDE5 inhibitor which has a suitable half-life and biological metabolism in the body and can meet the needs of patients.
  • the present application is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and a therapeutically effective amount of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom.
  • R 1 and R 2 are each a halogen atom;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain;
  • R 4 and R 5 are independently selected from a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted by a halogen, a cyano group, a hydroxyl group, an amino group, a decyl group, a carboxyl group, a sulfonic acid group or a sulfinic acid group, -C(O )-C 1 -C 6 alkyl, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H.
  • R ⁇ 1> and R ⁇ 2> are deuterium atoms
  • R ⁇ 3> is -Q-NR ⁇ 4>
  • R ⁇ 5> is absent
  • R ⁇ 4> and R ⁇ 5> are both hydrogen.
  • R 1 and R 2 are a hydrogen atom
  • R 3 is —Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 One of them is hydrogen and the other is selected from -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S (O)-H.
  • the pharmaceutical composition is formulated into a pharmaceutical dosage form suitable for oral administration, buccal administration, intravenous injection, intraperitoneal injection, subcutaneous injection, intramuscular injection, inhalation, or epidermal administration, Oral administration or buccal administration is preferred.
  • the pharmaceutical compositions are formulated into suitable dosage forms including, but not limited to, tablets, capsules, troches, pills, granules, powders, solutions, emulsions, suspensions, dispersions, A syrup, gel, or aerosol.
  • the pharmaceutical compositions further comprise a pharmaceutically acceptable surfactant, film forming material, coating aid, stabilizer, dye, flavor, fragrance, perfume, excipient, lubricant, Disintegrants, glidants, solubilizers, fillers, solvents, diluents, suspending agents, osmotic pressure regulators, buffers, preservatives, antioxidants, sweeteners, colorants and/or binders.
  • a pharmaceutically acceptable surfactant film forming material, coating aid, stabilizer, dye, flavor, fragrance, perfume, excipient, lubricant, Disintegrants, glidants, solubilizers, fillers, solvents, diluents, suspending agents, osmotic pressure regulators, buffers, preservatives, antioxidants, sweeteners, colorants and/or binders.
  • Pharmaceutically acceptable carriers, excipients or diluents for therapeutic use are well known in the pharmaceutical arts and are for example in Remington's Pharmaceutical Sciences, 18th Ed
  • compositions of the present application can be produced in a known manner, for example, by conventional methods of mixing, dissolving, granulating, making tablets, grinding, emulsifying, encapsulating, entrapping or tableting.
  • the pharmaceutical composition used can be formulated into a pharmaceutically acceptable formulation in a conventional manner using one or more pharmaceutically acceptable excipients, carriers, diluents and/or excipients.
  • suitable formulations will depend on the route of administration chosen. Any suitable formulation technique, carrier, and excipient in the art can be used.
  • the present application relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a medicament for treating and/or preventing a PDE5-related disease or disease state in a mammal Use in which inhibition of PDE5 is considered beneficial,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom.
  • R 1 and R 2 are each a halogen atom;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain;
  • R 4 and R 5 are independently selected from a hydrogen atom a C 1 -C 6 alkyl group optionally substituted by halogen, cyano, hydroxy, amino, thiol, carboxyl, sulfonic acid or sulfinate, -C(O)-C 1 -C 6 alkyl, - C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O) -H.
  • R ⁇ 1> and R ⁇ 2> are deuterium atoms
  • R ⁇ 3> is -Q-NR ⁇ 4>
  • R ⁇ 5> is absent
  • R ⁇ 4> and R ⁇ 5> are both hydrogen.
  • R 1 and R 2 are a hydrogen atom
  • R 3 is —Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 One of them is hydrogen and the other is selected from -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S (O)-H.
  • the mammal is a human.
  • the disease or condition associated with PDE5 is erectile dysfunction.
  • the present application relates to a method of treating and/or preventing a PDE5-related disease or condition in a mammal, wherein inhibition of PDE5 is considered beneficial, the method comprising expressing a therapeutically effective amount of Formula (I) a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for administration to said mammal,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom.
  • R 1 and R 2 are each a halogen atom;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain;
  • R 4 and R 5 are independently selected from a hydrogen atom a C 1 -C 6 alkyl group optionally substituted by halogen, cyano, hydroxy, amino, thiol, carboxyl, sulfonic acid or sulfinate, -C(O)-C 1 -C 6 alkyl, - C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O) -H.
  • R ⁇ 1> and R ⁇ 2> are deuterium atoms
  • R ⁇ 3> is -Q-NR ⁇ 4>
  • R ⁇ 5> is absent
  • R ⁇ 4> and R ⁇ 5> are both hydrogen.
  • R 1 and R 2 are a hydrogen atom
  • R 3 is —Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 One of them is hydrogen and the other is selected from -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S (O)-H.
  • the mammal is a human.
  • the disease or condition associated with PDE5 is erectile dysfunction.
  • the present application relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment and/or prevention of a PDE5-related disease or disease state in a mammal, wherein the inhibition thereof PDE5 is considered to be beneficial,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom.
  • R 1 and R 2 are each a halogen atom;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain;
  • R 4 and R 5 are independently selected from a hydrogen atom a C 1 -C 6 alkyl group optionally substituted by halogen, cyano, hydroxy, amino, thiol, carboxyl, sulfonic acid or sulfinate, -C(O)-C 1 -C 6 alkyl, - C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O) -H.
  • R ⁇ 1> and R ⁇ 2> are deuterium atoms
  • R ⁇ 3> is -Q-NR ⁇ 4>
  • R ⁇ 5> is absent
  • R ⁇ 4> and R ⁇ 5> are both hydrogen.
  • R 1 and R 2 are a hydrogen atom
  • R 3 is —Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 One of them is hydrogen and the other is selected from -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S (O)-H.
  • the mammal is a human.
  • the disease or condition associated with PDE5 is erectile dysfunction.
  • the present application relates to a method of inhibiting PDE5 activity, the method comprising contacting a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof with PDE5 in vitro or in vivo,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom.
  • R 1 and R 2 are each a halogen atom;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain;
  • R 4 and R 5 are independently selected from a hydrogen atom a C 1 -C 6 alkyl group optionally substituted by halogen, cyano, hydroxy, amino, thiol, carboxyl, sulfonic acid or sulfinate, -C(O)-C 1 -C 6 alkyl, - C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O) -H.
  • R ⁇ 1> and R ⁇ 2> are deuterium atoms
  • R ⁇ 3> is -Q-NR ⁇ 4>
  • R ⁇ 5> is absent
  • R ⁇ 4> and R ⁇ 5> are both hydrogen.
  • R 1 and R 2 are a hydrogen atom
  • R 3 is —Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 One of them is hydrogen and the other is selected from -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S (O)-H.
  • the present application relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for use as a PDE5 inhibitor,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom.
  • R 1 and R 2 are each a halogen atom;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain;
  • R 4 and R 5 are independently selected from a hydrogen atom a C 1 -C 6 alkyl group optionally substituted by halogen, cyano, hydroxy, amino, thiol, carboxyl, sulfonic acid or sulfinate, -C(O)-C 1 -C 6 alkyl, - C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O) -H.
  • R ⁇ 1> and R ⁇ 2> are deuterium atoms
  • R ⁇ 3> is -Q-NR ⁇ 4>
  • R ⁇ 5> is absent
  • R ⁇ 4> and R ⁇ 5> are both hydrogen.
  • R 1 and R 2 are a hydrogen atom
  • R 3 is —Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 One of them is hydrogen and the other is selected from -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S (O)-H.
  • the present application relates to a method of treating erectile dysfunction in a human, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a human,
  • R 1 and R 2 are independently selected from a hydrogen atom or a halogen atom
  • R 3 is selected from a hydrogen atom, -Q-OR 6 , fluorenyl or -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 are independently selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 6 is selected from a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, -C(O)-C 1 -C 6 alkyl group, -C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H;
  • R 1 and R 2 are a hydrogen atom
  • R 3 is -Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • one of R 4 and R 5 is hydrogen.
  • the other one is selected from the group consisting of -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O)-H .
  • the present application relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both a ruthenium atom or one is a hydrogen atom and the other is a ruthenium atom.
  • R 1 and R 2 are each a halogen atom;
  • R 3 is selected from -Q-NR 4 R 5 ;
  • Q is absent or is a C 1 -C 6 alkylene chain;
  • R 4 and R 5 are independently selected from a hydrogen atom a C 1 -C 6 alkyl group optionally substituted by halogen, cyano, hydroxy, amino, thiol, carboxyl, sulfonic acid or sulfinate, -C(O)-C 1 -C 6 alkyl, - C(O)-H, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S(O) -H.
  • R ⁇ 1> and R ⁇ 2> are deuterium atoms
  • R ⁇ 3> is -Q-NR ⁇ 4>
  • R ⁇ 5> is absent
  • R ⁇ 4> and R ⁇ 5> are both hydrogen.
  • R 1 and R 2 are a hydrogen atom
  • R 3 is —Q-NR 4 R 5
  • Q is absent or is a C 1 -C 6 alkylene chain
  • R 4 and R 5 One of them is hydrogen and the other is selected from -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -H, -S(O)-C 1 -C 6 alkyl or -S (O)-H.
  • Another aspect of the present application relates to a process comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof Agent, route of administration and effective dose.
  • Such formulations are useful for treating a disease or condition associated with PDE5 as described above.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof of the present application can be administered in the form of a pharmaceutical preparation, and is suitable for oral administration (including buccal administration and sublingual administration), topical administration or Those pharmaceutical preparations for parenteral administration (including intramuscular administration, intradermal administration, intraperitoneal administration, subcutaneous administration, and intravenous administration), or the compound may be adapted to be aerosolized, inhaled Alternatively, it can be administered by inhalation.
  • General information regarding drug delivery systems can be found in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)).
  • pharmaceutical formulations include: carriers and excipients including, but not limited to, buffers, carbohydrates, antioxidants, bacteriostats, chelating agents, suspending agents, thickening agents, and/or preservatives; Water; oil; physiological saline solution; flavoring agent; coloring agent; anti-adherent; and other pharmaceutically acceptable additives, adjuvants or binders; other pharmaceutically acceptable auxiliary substances required for physiological conditions, such as pH buffering Agent, tension regulator, emulsifier, wetting agent, preservative, etc.
  • suitable carrier known to those skilled in the art, the type of carrier will vary depending on the route of administration.
  • the concentration of the drug can be adjusted, the pH of the solution buffered, and the isotonicity adjusted to be compatible with intravenous injection.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof of the present application can be formulated into a sterile solution or suspension in a suitable vehicle known in the art.
  • the pharmaceutical compositions can be sterilized by conventional, well known sterilization techniques or can be sterile filtered.
  • the resulting aqueous solution may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration.
  • the compound represented by the formula (I) of the present application or a pharmaceutically acceptable salt thereof can be easily formulated by combining the compound represented by the formula (I) of the present application or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier well known in the art.
  • a pharmaceutically acceptable carrier well known in the art.
  • Such a carrier enables the compound of the present application to be formulated into tablets, pills, dragees, capsules, troches, liquids, gels, syrups, powders, suspensions, elixirs, etc. for treatment. The patient took it orally.
  • compositions suitable for use in the present application include compositions wherein the active ingredient is present in an effective amount (i.e., an amount effective to achieve a therapeutic and/or prophylactic benefit in an individual).
  • an effective amount i.e., an amount effective to achieve a therapeutic and/or prophylactic benefit in an individual.
  • the actual amount effective for a particular application will depend on the condition or conditions being treated, the condition of the individual, the formulation and route of administration, and other factors known to those skilled in the art. Determination of the effective amount of a PDE5 inhibitor is within the abilities of those skilled in the art in light of the disclosure herein and can be determined using conventional optimization techniques.
  • An effective amount for use in humans can be determined from animal models. For example, dosages for use in humans can be formulated to achieve circulating, liver, surface, and/or gastrointestinal concentrations that have been found to be effective in animals.
  • dosages for use in humans can be formulated to achieve circulating, liver, surface, and/or gastrointestinal concentrations that have been found to be effective in animals.
  • One skilled in the art can determine an effective amount for human use, particularly in accordance with animal model experimental data described herein. Based on animal data and other types of similar data, one skilled in the art can determine that the compositions of the present application are suitable for an effective amount in humans.
  • An effective amount when referring to a PDE5 inhibitor of the present application, generally means a variety of medical or pharmaceutical technologies. Any of a management or consulting agency (eg, FDA, SDA) or a dosage range, route of administration, formulation, etc., recommended or approved by the manufacturer or supplier.
  • a management or consulting agency eg, FDA, SDA
  • an appropriate dose of the PDE5 inhibitor can be determined based on the results of in vitro experiments.
  • the in vitro potency of an agent to inhibit PDE5 provides information that can be used to develop effective in vivo doses that achieve similar biological effects.
  • step 1
  • reaction reagent and solvent shown in Table A were added to a 500 mL reaction flask equipped with a reflux condenser. The reaction was refluxed at 120 ° C for 6 h in a N 2 atmosphere. The reaction was monitored by thin layer chromatography (TLC). After cooling the reaction mixture to room temperature, the Cs 2 CO 3 solid was removed by filtration and washed with CH 2 Cl 2 . The filtrate was concentrated to dryness under reduced pressure, and the obtained residue was dissolved with CH 2 Cl 2 , and then washed with water and saturated NaCl solution each time. The organic phase was dried with anhydrous MgSO 4 The obtained crude product was purified by silica gel column chromatography toield.
  • reaction reagent and solvent shown in Table B were added to a 500 mL reaction flask equipped with a reflux condenser. After the reaction was stirred at 100 ° C for 6 h, the reaction was completed by TLC. The reaction was cooled to room temperature then cooled to 0 ° C and left at 0 ° C overnight. The precipitated solid was filtered, the filter cake washed with a small amount of CH 3 NO 2, CH 2 Cl 2 and then washed with white. After drying, 60 g of a product (white powder) was obtained in a yield of 96%.
  • step 3 The total yield of the two steps of step 3 and step 4 was 82%.
  • Compound 1 was prepared in a similar manner to Example 1, except that step 1 was omitted, in which the product obtained from Step 1 was replaced with piperonal (i.e., 3,4-methylenedioxybenzaldehyde).
  • piperonal i.e., 3,4-methylenedioxybenzaldehyde
  • the compound 2 was prepared in a similar manner to Example 1 except that the step 1 was omitted, and the product obtained in Step 1 was replaced with piperonal (i.e., 3,4-methylenedioxybenzaldehyde) in Step 2.
  • piperonal i.e., 3,4-methylenedioxybenzaldehyde
  • HTF Homogenous Time Resolve Fluoresce
  • PDE5A E904, SIGMA-ALDRICH
  • the dose-effect relationship of the inhibitory ability measures the half-inhibitory concentration IC 50 of the sample.
  • Stock solution preparation 1.13 mg of Cialis, 1.15 mg of DDCI02 and 1.23 mg of DDCI01 were weighed and dissolved in 1.13, 1.15, 1.23 ml of dimethyl sulfoxide to prepare a stock solution having a concentration of 1.00 mg/ml.
  • Sample preparation method one-step protein precipitation method
  • Precipitant acetonitrile (containing 5.00 ng / ml of verapamil)
  • Standard curve and quality control sample preparation Transfer 5.00 ⁇ l of standard curve or QC working solution and 45.0 ⁇ l of blank plasma to a 1.5 mL centrifuge tube.
  • the final concentrations of the standard curve samples were 1.00, 2.50, 5.00, 10.0, 50.0, 100, 500, and 1000 ng/ml, respectively.
  • the concentration of the quality control samples were 2.50, 5.00, 50.0 and 800 ng/ml, respectively.
  • the diluted QC sample concentration was 5000 ng/ml.
  • Plasma sample preparation Transfer 100 ⁇ l of precipitant to 10.0 ⁇ l of sample to be tested, standard curve sample and quality control sample, respectively. After 3.00 minutes of vortexing and 5.00 minutes of centrifugation (12,000 rpm), 10 microliters of supernatant was aspirated for LC-MS/MS analysis.
  • Blood collection time 0 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours
  • DDCI01 was significantly superior to Cialis and DDCI02 in terms of Cmax and AUC, and the half-life (t 1/2 ) study in SD rats showed that DDCI01 was slightly shorter than cialis and longer than DDCI02.
  • the right carotid artery was isolated and connected to a pressure sensor on a Powerlab recorder via a PE-50 silicone catheter to record continuous changes in arterial blood pressure (at the beginning of electrical stimulation)
  • the blood pressure of the rats began to drop rapidly, and the blood pressure quickly returned to normal after the stimulation.
  • remove the midline incision extend to the scrotum mediastinum, expose the penis feet on both sides, insert a 23 gauge trocar in the left penis foot, connect with the pressure sensor of the Powerlab recorder through the PE-50 silica gel catheter, and the catheter contains heparin physiology.
  • Erectile function test Rats were given a single oral administration. The erectile function of the pelvic nerve was detected by electrodes after 2, 6 and 24 hours after administration. The changes of arterial blood pressure before and after stimulation, the change of intracavernous pressure/value of blood pressure, and stimulation were recorded. Before and after the change of the intracavernous pressure, the rat penile regression time after stimulation. The main evaluation index of erectile function is the change of intracavernous pressure and the time of corpus cavernosum regression.
  • the blood pressure before stimulation is the detection value two hours after administration.
  • results shown in the table indicate that low, medium and high doses can significantly increase the intracavernous pressure difference and prolong the penile regression time after administration of the compound DDCI-01 in normal rats, that is, the compound can significantly enhance the erectile function of normal rats.
  • the dosage of the tadalafil group was close to the normal dose of the human body, which was similar to the low- and medium-dose group of DDCI-01.
  • Table 10 shows the inhibition of various phosphodiesterase activities by the compounds.

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Abstract

公开了作为5型磷酸二酯酶抑制剂的通式(I)表示的化合物或其药物可接受的盐及其在治疗和/或预防哺乳动物的与5型磷酸二酯酶相关的疾病或疾病状态中的用途

Description

新的5型磷酸二酯酶抑制剂及其应用 技术领域
本申请涉及医药领域，尤其是涉及选择性的5型磷酸二酯酶(PDE5)抑制剂及其在治疗和/或预防疾病或疾病状态中的应用，其中这种抑制被认为是有益的。
背景技术
勃起功能障碍(ED)对男性心理和生理有着重要的影响。研究发现PDE5抑制剂能有效治疗ED。例如，礼来公司的希爱力(Cialis)，其化学结构如下所示:
Figure PCTCN2015082507-appb-000001
研究发现PDE5抑制剂均可以改善由多种原因造成的ED，而且对于起效时间而言，各化合物之间的区别不大，但是就半衰期而言，各化合物之间的差异较大。例如，希爱力在人体内的半衰期长达24～36小时，而辉瑞制药公司生产的万艾可和拜耳制药公司生产的艾力达这两种药物的半衰期则仅为约4～5小时。
由于药物的半衰期不同，不同年龄和不同体质的人会选择具有不同半衰期的产品以满足不同的需要。但是上述这三种药物的半衰期之间存在着巨大的差异。因此，仍然亟需新的5型磷酸二酯酶抑制剂。
发明概述
一方面，本申请涉及由通式(I)表示的化合物或其药物可接受的盐，
Figure PCTCN2015082507-appb-000002
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、 -S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
另一方面，本申请涉及药物组合物，其包含由通式(I)表示的化合物或其药物可接受的盐和药物可接受的载体、赋形剂或稀释剂，
Figure PCTCN2015082507-appb-000003
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
另一方面，本申请涉及由通式(I)表示的化合物或其药物可接受的盐或其药物组合物在制备用于治疗和/或预防哺乳动物的与5型磷酸二酯酶相关的疾病或疾病状态的药物中的用途，其中抑制5型磷酸二酯酶被认为是有益的，
Figure PCTCN2015082507-appb-000004
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
另一方面，本申请涉及预防和/或治疗哺乳动物的与5型磷酸二酯酶相关的疾病或疾病状态的方法，其中在该疾病或疾病状态中抑制5型磷酸二酯酶被认为是有益的，该方法包括将治疗有效量的由通式(I)表示的化合物或其药物可接受的盐或其药物组合物对需要该预防和/或治疗的哺乳动物给药，
Figure PCTCN2015082507-appb-000005
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
另一方面，本申请涉及用于预防和/或治疗哺乳动物的与5型磷酸二酯酶相关的疾病或疾病状态的由通式(I)表示的化合物或其药物可接受的盐或其药物组合物，其中在该疾病或疾病状态中抑制5型磷酸二酯酶被认为是有益的，
Figure PCTCN2015082507-appb-000006
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
再一方面，本申请涉及抑制5型磷酸二酯酶活性的方法，其中该方法包括将上文定义的由通式(I)表示的化合物或其药物可接受的盐与5型磷酸二酯酶在体外或体内接触。
再一方面，本申请涉及上文定义的由通式(I)表示的化合物或其药物可接受的盐用作5型磷酸二酯酶抑制剂的用途。
再一方面，本申请涉及上文定义的由通式(I)表示的化合物或其药物可接受的盐用作治疗和/或预防人的勃起功能障碍的药物的用途。
本申请的由通式(I)表示的化合物或其药物可接受的盐对PDE5具有良好的抑制作用，其在体内具有适宜的半衰期和生物代谢，因此，易于开发为临床药物。
发明的详细说明
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括”和“包含”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具 体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
定义
由表明在指定化学基团中发现的碳原子总数的简化符号在前面标示本文中命名的某些化学基团。例如，C1-C6烷基描述具有总数为1至6个碳原子的如下定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
因此，除非另有相反的说明，否则说明书和所附权利要求中所用的如下术语具有如下的含义：
“巯基”指-SH基。
“氰基”指-CN基。
“氨基”指-NH2基。
“羟基”指-OH基。
“卤素”指氟、氯、溴或碘。
“羧基”指-COOH基。
“磺酸基”指-SO3H。
“亚磺酸基”指-SO2H。
“烷基”指直链或支链的烃链基团，所述烃链基团仅由碳和氢原子组成、不含不饱和，具有1至6个碳原子，且通过单键与分子的其余部分连接，例如甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)等等。除非本说明书中另外明确述及，烷基可任选地被一个或多个独立地选自下列基团的取代基取代：烷基、卤素、氰基、羟基、巯基、氨基、羧基、磺酸基或亚磺酸基等。
“亚烷基链”指仅由碳和氢组成、不含不饱和且具有1-6个碳原子、将分子的其余部分与基团相连接的直链或支链的二价烃链，例如亚甲基、亚乙基、亚丙基、正亚丁基等等。亚烷基链可以通过该链中的一个碳或通过该链中的任意两个碳与分子的其余部分和基团连接。
“任选的”或“任选地”指随后叙述的状况可能出现或可能不出现，且该叙述包括所述事件或情形出现的情况及不会出现的情况。例如，“任选取代的烷基”指所述烷基可能被取代或可能不被取代，且该叙述包括取代的烷基基团和未取代的烷 基基团。
术语“载体”定义为有利于将化合物引入细胞或组织的化合物。例如，二甲基亚砜通常用作载体，这是因为它易于将某些化合物引入生物体的细胞或组织中。
术语“药物可接受的载体”包括但不限于已经被国家药品食品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对药物组合物无副作用的各种形式的载体。
术语“药物可接受的盐”意指保留本申请的PDE5抑制剂的生物效应及性质且并非生物学上或其他方面不可接受的那些盐。举例而言，药物可接受的盐并不干扰本申请的作用剂抑制PDE5的有益作用，其包括“药物可接受的酸加合盐”和“药物可接受的碱加合盐”。
术语“药物可接受的酸加合盐”指保持游离碱的生物学有效性和性质的那些盐，所述酸加合盐是在生物学或其它方面合适的并且是使用无机酸或有机酸来形成的，所述无机酸例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等，所述有机酸例如但不限于乙酸、2,2-二氯乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯羧酸、4-乙酰胺基苯羧酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
术语“药物可接受的碱加合盐”指保持游离酸的生物学有效性和性质的那些盐，所述碱加合盐在生物学或其它方面是合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。优选的无机盐为铵、钠、钾、钙和镁盐。由有机碱衍生的盐包括但不限于伯胺、仲胺和叔胺的盐、包括天然存在的取代的胺在内的取代的胺的盐、环胺和碱性离子交换树脂的盐，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲氨基乙醇、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、苄胺、苯乙二胺、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等等的盐。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
术语“哺乳动物”包括人和家畜，如实验室动物与家庭宠物，如猫、狗、猪、牛、绵羊、山羊、马和家兔，以及非驯养动物，如野生动物等。
术语“药物组合物”指本申请化合物与通常被本领域所接受的将生物活性化合物输送至诸如人类等哺乳动物的介质所形成的制剂。这样的介质包括所有药物可接受的载体、稀释剂或赋形剂。药物组合物有利于化合物向生物体的给药。在本领域中存在多种方法对化合物或药物组合物进行给药，包括但不限于口服给药、注射给药、吸入给药、肠胃外给药以及局部给药。
术语“药物可接受的”定义为不消除化合物的生物活性和性质的载体、赋形剂或稀释剂。
术语“治疗有效量”指当对哺乳动物，优选对人类给药时，本申请的化合物足以有效治疗哺乳动物的，优选人类的与PDE5相关的疾病或疾病状态的量。根据化合物、疾病状态及其严重性、以及待治疗的哺乳动物的年龄，构成“治疗有效量”的本申请化合物的量将会不同，但是本领域的技术人员根据其自身的知识以及本公开可以依惯例确定本申请化合物的量。
本文所用的“进行治疗”或“治疗”涵盖患有相关疾病或病症的哺乳动物，优选人类中治疗相关的疾病或疾病状态，并且包括：
(I)预防疾病或疾病状态在哺乳动物中发生，尤其是当该哺乳动物易感于所述疾病状态，但尚未被诊断出患有这种疾病状态时；
(II)抑制疾病或疾病状态，即阻止其发生；或者
(III)缓解疾病或疾病状态，即使疾病或疾病状态消退。
具体实施方案
一方面，本申请涉及由通式(I)表示的化合物或其药物可接受的盐：
Figure PCTCN2015082507-appb-000007
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中
R1和R2均为氘原子或一个为氢原子且另一个为氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中
R1和R2均为氘原子或一个为氢原子且另一个为氘原子；
R3表示氢原子、-Q-OR6、巯基、-Q-NR4R5；
Q不存在或为C1-C6亚烷基链，所述亚烷基链由(CH2)n表示，n为1-6的整数；
R4和R5独立地选自氢原子、未取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、未取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中
R1和R2均为氘原子或一个为氢原子且另一个为氘原子；
R3选自氢原子、-Q-OR6或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链，其中所述亚烷基链由(CH2)n表示，n为1-6的整数；
R4和R5独立地选自氢原子、未取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子或未取代的C1-C6烷基。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐， 其中
R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；
R3选自-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中
R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；
R3选自-Q-NR4R5；
Q不存在或为C1-C6亚烷基链，其中所述亚烷基链由(CH2)n表示，n为1-6的整数；
R4和R5独立地选自氢原子或未取代的C1-C6烷基。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中
R1和R2均为氢原子，
R3为-Q-NR4R5，
Q不存在或为C1-C6亚烷基链，
R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请的通式(I)化合物优选为如下化合物：
Figure PCTCN2015082507-appb-000008
Figure PCTCN2015082507-appb-000009
由通式(I)表示的化合物是强效的选择性PDE5抑制剂，其在体内具有适宜的半衰期和生物代谢，能够满足患者的需要。
药物组合物
另一方面，本申请涉及药物组合物，其包含药物可接受的载体、赋形剂或稀释剂以及治疗有效量的由通式(I)表示的化合物或其药物可接受的盐：
Figure PCTCN2015082507-appb-000010
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；R3选自-Q-NR4R5；Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，当R1和R2均为氘原子时，R3为-Q-NR4R5，Q不存在，且R4 和R5均为氢。
在某些实施方案中，当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，药物组合物被制成适于口服给药、口含给药、静脉内注射、腹腔内注射、皮下注射、肌内注射、吸入、或表皮给药等的药物剂型，优选口服给药或口含给药。
在某些实施方案中，药物组合物被制成合适的剂型，包括但不限于片剂、胶囊剂、锭剂、丸剂、颗粒剂、粉末剂、溶液剂、乳剂、混悬剂、分散体、糖浆剂、凝胶剂、或气溶胶剂。
在某些实施方案中，药物组合物还含有药物可接受的表面活性剂、成膜物质、包衣助剂、稳定剂、染料、矫味剂、芳香剂、香料、赋形剂、润滑剂、崩解剂、助流剂、增溶剂、填充剂、溶剂、稀释剂、助悬剂、渗透压调节剂、缓冲剂、防腐剂、抗氧化剂、甜味剂、着色剂和/或粘合剂。用于治疗用途的药物可接受的载体、赋形剂或稀释剂在医药领域中是公知的，并且例如在Remington’s Pharmaceutical Sciences(雷明顿制药学)，18th Ed.,Mack Publishing Co.,Easton,PA(1990)中由描述，本文将其全部内容引入作为参考。
本申请的药物组合物可按已知的方法进行生产，例如，通过常规的混合、溶解、粒化、制造锭剂、研磨、乳化、包囊、截留或压片等常规操作方法进行生产。
因此，根据本申请，所使用的药物组合物可使用一种或多种药物可接受的赋形剂、载体、稀释剂和/或辅料以常规方法进行配制成药学可用的制剂。合适的制剂取决于所选的给药途径。可以使用本领域中任何合适的制剂技术、载体和赋形剂。
治疗用途和治疗方法
又一方面，本申请涉及由通式(I)表示的化合物或其药物可接受的盐或其药物组合物在制备用于治疗和/或预防哺乳动物的与PDE5相关的疾病或疾病状态的药物中的用途，其中抑制PDE5被认为是有益的，
Figure PCTCN2015082507-appb-000011
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；R3选自-Q-NR4R5；Q不存在或为C1-C6亚烷基链；R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，当R1和R2均为氘原子时，R3为-Q-NR4R5，Q不存在，且R4和R5均为氢。
在某些实施方案中，当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，所述哺乳动物为人。
在某些实施方案中，所述与PDE5相关的疾病或疾病状态为勃起功能障碍。
又一方面，本申请涉及治疗和/或预防哺乳动物的与PDE5相关的疾病或疾病状态的方法，其中抑制PDE5被认为是有益的，所述方法包括将治疗有效量的通式(I)表示的化合物或其药物可接受的盐或其药物组合物对所述哺乳动物给药，
Figure PCTCN2015082507-appb-000012
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、 -S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；R3选自-Q-NR4R5；Q不存在或为C1-C6亚烷基链；R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，当R1和R2均为氘原子时，R3为-Q-NR4R5，Q不存在，且R4和R5均为氢。
在某些实施方案中，当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，所述哺乳动物为人。
在某些实施方案中，所述与PDE5相关的疾病或疾病状态为勃起功能障碍。
又一方面，本申请涉及用于治疗和/或预防哺乳动物的与PDE5相关的疾病或疾病状态的由通式(I)表示的化合物或其药物可接受的盐或其药物组合物，其中抑制PDE5被认为是有益的，
Figure PCTCN2015082507-appb-000013
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；R3选自-Q-NR4R5；Q不存在或为C1-C6亚烷基链；R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，当R1和R2均为氘原子时，R3为-Q-NR4R5，Q不存在，且R4和R5均为氢。
在某些实施方案中，当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，所述哺乳动物为人。
在某些实施方案中，所述与PDE5相关的疾病或疾病状态为勃起功能障碍。
又一方面，本申请涉及抑制PDE5活性的方法，所述方法包括将通式(I)表示的化合物或其药物可接受的盐与PDE5在体外或在体内接触，
Figure PCTCN2015082507-appb-000014
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐， 其中R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；R3选自-Q-NR4R5；Q不存在或为C1-C6亚烷基链；R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，当R1和R2均为氘原子时，R3为-Q-NR4R5，Q不存在，且R4和R5均为氢。
在某些实施方案中，当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
又一方面，本申请涉及用作PDE5抑制剂的由通式(I)表示的化合物或其药物可接受的盐，
Figure PCTCN2015082507-appb-000015
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；R3选自-Q-NR4R5；Q不存在或为C1-C6亚烷基链；R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，当R1和R2均为氘原子时，R3为-Q-NR4R5，Q不存在，且R4和R5均为氢。
在某些实施方案中，当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
又一方面，本申请涉及治疗人的勃起功能障碍的方法，所述方法包括将通式(I)表示的化合物或其药物可接受的盐或其药物组合物对人给药，
Figure PCTCN2015082507-appb-000016
其中
R1和R2独立地选自氢原子或氘原子；
R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
Q不存在或为C1-C6亚烷基链；
R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，本申请涉及由所述通式(I)表示的化合物或其药物可接受的盐，其中R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；R3选自-Q-NR4R5；Q不存在或为C1-C6亚烷基链；R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
在某些实施方案中，当R1和R2均为氘原子时，R3为-Q-NR4R5，Q不存在，且R4和R5均为氢。
在某些实施方案中，当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
制剂、给药途径和有效剂量
本申请的另一方面涉及包含由通式(I)表示的化合物或其药物可接受的盐的制 剂、给药途径及有效剂量。这样的制剂可用于治疗如上文所述的与PDE5相关的疾病或疾病状态。
本申请的由通式(I)表示的化合物或其药物可接受的盐可以以药物制剂的形式给予，包括适于口服给药(包括经颊给药及舌下给药)、局部给药或非经肠给药(包括肌内给药、皮内给药、腹膜内给药、皮下给药及静脉内给药)的那些药物制剂，或者所述化合物可以以适于通过气雾化、吸入或吹入给药的形式来给药。关于药物递送系统的一般信息可见于Ansel等人，Pharmaceutical Dosage Forms and Drug Delivery Systems(Lippencott Williams&Wilkins,Baltimore Md.(1999))中。
在多个方面，药物制剂包括：载体及赋形剂(包括但不限于，缓冲剂、碳水化合物、抗氧化剂、抑菌剂、螯合剂、助悬剂、增稠剂和/或防腐剂)；水；油；生理盐水溶液；调味剂；着色剂；防粘剂；及其他药物可接受的添加剂、佐剂或粘合剂；接近生理条件所需的其他药物可接受的辅助物质，诸如pH缓冲剂、张力调节剂、乳化剂、湿润剂、防腐剂等。应认识到，尽管可使用本领域技术人员已知的任何适合载体来给予本申请的组合物，但载体的类型将视给药途径而变。
如本领域内所公知的，药物的浓度可进行调节，溶液的pH值进行缓冲，以及等渗性进行调节，从而与静脉内注射相容。
本申请的由通式(I)表示的化合物或其药物可接受的盐可在本领域内公知的适合媒介物中配制成无菌溶液或混悬液。药物组合物可通过常用的公知灭菌技术灭菌，或可经无菌过滤。所得水溶液可经包装以供原样使用，或经冻干，冻干的制剂在给药前与无菌溶液进行组合。
对于口服给药，可容易地通过将本申请的由通式(I)表示的化合物或其药物可接受的盐与本领域内公知的药物可接受的载体组合来配制。这样的载体能够使本申请的化合物配制成片剂、丸剂、糖衣药丸、胶囊剂、糖锭、液体剂、凝胶剂、糖浆剂、散剂、混悬剂、酏剂等，以供待治疗的患者口服摄取。
适用于本申请的药物组合物包括其中活性成分以有效量(即，可在个体中有效实现治疗和/或预防益处的量)存在的组合物。对特定应用有效的实际量应取决于所治疗的一种或多种病况、个体的状况、制剂及给药途径，以及本领域技术人员所知的其他因素。根据本文的公开内容，PDE5抑制剂的有效量的确定在本领域技术人员的能力范围内，且可使用常规优化技术来确定。
可根据动物模型确定用于人类中的有效量。举例而言，用于人类的剂量可配制为实现在动物中已发现为有效的循环、肝脏、表面和/或胃肠浓度。本领域技术人员可确定供人类使用的有效量，特别是根据本文所述的动物模型实验数据。基于动物数据及其他类型的类似数据，本领域技术人员可确定本申请的组合物适于人类的有效量。
有效量在涉及本申请的PDE5抑制剂时一般意指由医学或制药技术中的各种 管理或咨询机构(例如FDA、SDA)中的任一个或由制造商或供货商推荐或批准的剂量范围、给药途径、制剂等。
此外，可基于体外实验结果确定PDE5抑制剂的适当剂量。举例而言，作用剂抑制PDE5的体外效能提供了可用于开发实现类似生物学作用的有效体内剂量的信息。
现已一般地描述多种方面，这些方面通过参考以下实施例可更容易地理解，除非说明，否则实施例是以例示方式提供且不旨在进行限制。
实施例
实施例1化合物3的制备(编号：DDCI01)
步骤1：
Figure PCTCN2015082507-appb-000017
表A
Figure PCTCN2015082507-appb-000018
向配备有回流冷凝器的500mL反应瓶中加入表A中所示的反应试剂和溶剂。在N2气氛中，于120℃下回流反应6h。经薄层色谱法(TLC)监测反应完全。将反应液冷却至室温后，过滤除去Cs2CO3固体，用CH2Cl2洗涤滤饼。在减压下将滤液浓缩至干，将所得剩余物用CH2Cl2溶解，随后分别用水和饱和NaCl溶液各洗涤一次。有机相用无水MgSO4干燥，过滤，减压浓缩至干，得到粗产品。将所得粗产品经硅胶柱色谱法纯化，得到24.4g纯产物，产率80％。
步骤2：
Figure PCTCN2015082507-appb-000019
表B
Figure PCTCN2015082507-appb-000020
向配备有回流冷凝器的500mL反应瓶中加入表B中所示的反应试剂和溶剂。在100℃下回流搅拌反应6h后，经TLC监测反应完全。将反应液冷却至室温，随后冷却至0℃并于0℃下放置过夜。有固体沉淀出，过滤，滤饼先用少量CH3NO2洗涤，再用CH2Cl2洗涤成白色。经干燥后，得到产品60g(白色粉末)，产率96％。
步骤3：
Figure PCTCN2015082507-appb-000021
表C
Figure PCTCN2015082507-appb-000022
向1L反应瓶中加入得自步骤2的产品、Et3N、CH2Cl2后，在室温下搅拌成澄清液，再冰浴冷却到0℃，缓慢滴加氯乙酰氯的CH2Cl2溶液，同时保持反应温度在0℃-5℃。滴加完毕后，继续在冰浴下(0℃-5℃)反应，并经TLC监测直至反应完全。将反应液过滤，滤饼用少量CH2Cl2洗涤，干燥，得到白色固体32.4g(含有Et3N.HCl，但可以直接用于下一步反应中)。将滤液用10％K2CO3溶液洗涤一次，再用饱和NaCl溶液洗涤一次，分层，有机相用无水MgSO4干燥，过滤，浓缩至干。残余物再用CH3OH:H2O＝4:1重结晶，得到棕黄色固体31g。
步骤4：
Figure PCTCN2015082507-appb-000023
表D
Figure PCTCN2015082507-appb-000024
在室温下，向1L反应瓶中加入得自步骤3的产品、Et3N和DMF后，搅拌均匀，再缓慢滴加水合肼的DMF溶液，并室温下将反应搅拌过夜。经TLC监测反应完全后，于冰水浴下向反应混合物中缓慢加入约3倍体积的纯净水，并剧烈搅拌2h后，静置，过滤。滤饼用水洗涤，再用异丙醇洗涤，干燥，得到粗产物。最后将粗产物用少量CHCl3回流20min，过滤，干燥，得到纯的产品35.5g。
步骤3和步骤4两步的总产率为82％。
1HNMR(d-DMSO，400M):11.01(s,1H),7.55(d,J＝7.6Hz,1H),7.29(d,J＝8.0Hz,1H),7.07(t,J＝7.2Hz,1H),7.02(t,J＝7.2Hz,1H),6.87(d,J＝1.2Hz,1H),6.80(dd,J＝8.4,1.6Hz,1H),6.77(d,J＝8.0Hz,1H),6.09(s,1H),5.12(s,2H),4.44(dd,J＝11.6,3.6Hz,1H),4.26(dd,J＝16.8,1.6Hz,1H),3.96(d,J＝17.2Hz,1H),3.56(dd,J＝16.0,4.4Hz,1H),2.98(dd,J＝15.6,12.0Hz,1H).13CNMR(d-DMSO，100M):166.76,165.09,147.53,146.54,137.56,136.7,134.50,126.23,121.73,119.77,119.35,118.59,111.79,108.43,107.40,105.27,56.05,55.89,53.81,23.94.
实施例2化合物1的制备
除了省略步骤1，在步骤2中使用胡椒醛(即，3,4-亚甲基二氧苯甲醛)代替得自步骤1的产品，采用与实施例1类似的方法制备化合物1。
1HNMR(500M,d-DMSO):δ11.06(s,1H),9.50(s,1H),8.65(s,1H),7.50(d,J＝7.7Hz,1H),7.24(d,J＝7.9Hz,1H),7.01(t,J＝7.3Hz,1H),6.95(t,J＝7.3Hz,1H),6.84(s,1H),6.80-6.70(m,2H),6.10(s,1H),5.84(s,2H),4.33(dd,J＝11.5,3.8Hz,1H),4.10(d,J＝17.1Hz,1H),3.87(d,J＝17.2Hz,1H),3.46-3.40(m,1H),3.00-2.90(m,1 H).
实施例3化合物2的制备
除了省略步骤1，在步骤2中使用胡椒醛(即，3,4-亚甲基二氧苯甲醛)代替得自步骤1的产品，采用与实施例1类似的方法制备化合物2.
1HNMR(500M,d-DMSO):δ11.16(s,1H),7.52(d,J＝7.7Hz,1H),7.31(d,J＝7.9Hz,1H),7.07(t,J＝7.3Hz,1H),7.01(t,J＝7.3Hz,1H),6.90(s,1H),6.80-6.70(m,2H),6.11(s,1H),5.91(s,2H),4.41(dd,J＝11.5,3.8Hz,1H),4.10(d,J＝17.1Hz,1H),3.91(d,J＝17.2Hz,1H),3.51-3.40(m,1H),3.21(s,3H),3.02-2.95(m,1H),3.00-2.95(m,4H).
实施例4：对PED5的抑制
方法：以Sildenafil(S1431，selleck)为正对照标定，以均相时间能量共振转移(Homogenous Time Resolve Fluoresce,HTF)方法(Cat.No.62GM2PEB,Cisbio)，依样品对PDE5A(E904，SIGMA-ALDRICH)抑制能力的量效关系测得样品半数抑制浓度IC50。
样品 IC50值
Cialis 111.6nM
DDCI01 33.6nM
DDCI02注 566.2nM
注：化合物DDCI02的结构如下所示：
Figure PCTCN2015082507-appb-000025
实施例5：药物代谢动力学研究
实验方法：
储备溶液配制：称量1.13毫克Cialis,1.15毫克DDCI02和1.23毫克DDCI01，并分别将它们溶解在1.13、1.15、1.23毫升的二甲基亚砜制成浓度为1.00毫克/毫升的储备液。
样品制备方法：一步蛋白沉淀法
沉淀剂：乙腈(含5.00纳克/毫升的维拉帕米)
标准曲线和质控样品制备：转移5.00微升的标准曲线或质控工作液和45.0微升的空白血浆至一个1.5毫升的离心管。标准曲线样品的终浓度分别为1.00、2.50、5.00、10.0、50.0、100、500和1000纳克/毫升。质控样品的浓度分别为2.50、5.00、50.0和800纳克/毫升。稀释质控样品浓度为5000纳克/毫升。
血浆样品制备：分别转移100微升的沉淀剂至10.0微升的待测样品、标准曲线样品和质控样品。经3.00分钟的涡旋震荡和5.00分钟的离心(12000转/分钟)后，吸取10微升上清液用于LC-MS/MS分析。
大鼠数：每组3只大鼠，
给药方式：口服给药，
采血时间点：0分钟，15分钟，30分钟，1h，2h，4h，6h，8h，24h
实验结果：
DDCI01：
Figure PCTCN2015082507-appb-000026
DDCI02
Figure PCTCN2015082507-appb-000027
Figure PCTCN2015082507-appb-000028
Cialis
Figure PCTCN2015082507-appb-000029
药物代谢动力学结果表明DDCI01在Cmax和AUC方面明显优于Cialis和DDCI02，并且在SD大鼠体内半衰期(t1/2)研究表明DDCI01比cialis稍短，比DDCI02长。
实施例6：正常大鼠勃起功能药效学研究
大鼠血压及海绵体内压变化检测：
大鼠经2％戊巴比妥麻醉(3毫克/千克)后，分离右侧颈动脉，通过PE-50硅胶导管与Powerlab记录仪的一个压力传感器相连，记录动脉血压持续变化(电刺激开始时大鼠血压开始迅速下降，刺激结束血压很快恢复正常)。之后取下腹正中切口，延长至阴囊纵膈，暴露两侧阴茎脚，在左侧阴茎脚插入23号套管针头，通过PE-50硅胶导管与Powerlab记录仪的压力传感器相连，导管内含有肝素生理盐水(250单位/毫升)，双侧电极刺激实验组左侧盆神经节海绵体神经发出段，调整Powerlab系统使电刺激盆神经节的参数为波宽2.56ms，频率7.98HZ，电流3mA，持续时间40s，记录海绵体内压变化。
勃起功能检测：大鼠单次口服给药，给药后2、6、24小时通过电极刺激盆神经检测动物勃起功能，记录刺激前后动脉血压变化值，海绵体内压变化值/血压变化值，刺激前后海绵体内压变化值，刺激后大鼠阴茎消退时间。勃起功能主要评价指标为海绵体内压变化值，阴茎海绵体消退时间。
表1：各实验组大鼠给药后2小时血压变化数据(均值±标准差)
Figure PCTCN2015082507-appb-000030
注：与对照组比较*P<0.05，**P<0.01。
#动物刺激前血压为给药后两小时检测值
表2：各实验组大鼠给药后2小时海绵体内压变化数据(均值±标准差)
Figure PCTCN2015082507-appb-000031
注：与对照组比较*P<0.05，**P<0.01。
表3：各实验组大鼠给药后2小时阴茎消退时间数据(均值±标准差)
组别 刺激前后血压差值/海绵体内压差值 消退时间(S)
阴性对照组 38.14±13.17 9.75±4.92
他达那非组 89.75±33.30 40.50±21.14*
DDCI-01低剂量组 105.52±41.17* 38.00±10.42*
DDCI-01中剂量组 128.64±35.20* 40.75±4.79*
DDCI-01高剂量组 136.85±41.98** 101.00±21.56**
注：与对照组比较*P<0.05，**P<0.01。
表4：各实验组大鼠给药后6小时血压变化数据(均值±标准差)
Figure PCTCN2015082507-appb-000032
注：与对照组比较，均无显著性差异
表5：各实验组大鼠给药后6小时海绵体内压变化数据(均值±标准差)
Figure PCTCN2015082507-appb-000033
注：与对照组比较*P<0.05，**P<0.01。
表6：各实验组大鼠给药后6小时阴茎消退时间数据(均值±标准差)
组别 刺激前后血压差值/海绵体内压差值 消退时间(S)
阴性对照组 39.30±15.86 9.50±2.52
他达那非组 117.16±42.07* 44.25±13.35**
DDCI-01低剂量组 94.70±33.16* 47.75±11.79*
DDCI-01中剂量组 106.19±16.03* 48.00±23.85*
DDCI-01高剂量组 159.65±33.86** 64.00±19.37**
注：与对照组比较*P<0.05，**P<0.01。
表7：各实验组大鼠给药后24小时血压变化数据(均值±标准差)
Figure PCTCN2015082507-appb-000034
注：与对照组比较，均无显著性差异
表8：各实验组大鼠给药后24小时海绵体内压变化数据(均值±标准差)
Figure PCTCN2015082507-appb-000035
注：与对照组比较**P<0.01。
表9：各实验组大鼠给药后24小时阴茎消退时间数据(均值±标准差)
组别 刺激前后血压差值/海绵体内压差值 消退时间(S)
阴性对照组 49.67±5.59 8.75±1.71
他达那非组 107.99±32.42 41.25±10.34*
DDCI-01低剂量组 92.05±31.72 23.75±12.84
DDCI-01中剂量组 106.03±44.12 41.25±14.50*
DDCI-01高剂量组 113.00±38.23 60.75±24.14**
注：与对照组比较*P<0.05，**P<0.01。
表中所示的结果表明，在给予正常大鼠化合物DDCI-01后，低、中、高剂量可以显著增加海绵体内压差，延长阴茎消退时间，即该化合物能够明显增强正常大鼠勃起功能。实验中他达那非组给药剂量接近人体正常给药剂量，与DDCI-01低、中剂量组评价结果相近。
实施例7DDCI-01生物有效性研究
化合物的配制及添加:用DMSO梯度稀释化合物；从10mM母液开始，用DMSO三倍稀释化合物Cialis和DDCI-01。化合物稀释板(V96MicroWell Plates)每孔加入99μl反应缓冲液，再分别加入1μl的化合物DMSO稀释液，充分混匀。反应板(96-well microplate)每孔加入5μl上述稀释好的化合物；化合物的终浓度为：10000,3333,1111,370.4,123.5,41.2,13.7,4.6,1.5,0.51,0.17[nM]；
采用相关试剂盒评价化合物对多种磷酸二酯酶(PDE)活性的抑制作用。具体筛选结果如表1所示。
表10化合物对多种磷酸二酯酶活性的抑制作用。
Figure PCTCN2015082507-appb-000036
结果显示，DDCI-01其它7个PDE亚型的测定结果显示，DDCI-01对PDE6C(IC50>10μM)和PDE11A(IC50＝2.6μM)具有微弱的抑制作用，对PDE1A、2A、3A、4A1A和7A则无明显的抑制作用(在10μM时其对酶活性的抑制率为0％)。

Claims (17)

  1. 通式(I)表示的化合物或其药物可接受的盐，
    Figure PCTCN2015082507-appb-100001
    其中
    R1和R2独立地选自氢原子或氘原子；
    R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
    Q不存在或为C1-C6亚烷基链；
    R4和R5独立地选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
    R6选自氢原子、任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；
    前提是当R1和R2均为氢原子时，R3为-Q-NR4R5，Q不存在或为C1-C6亚烷基链，R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
  2. 如权利要求1所述的化合物，其中
    R1和R2均为氘原子或一个为氢原子且另一个为氘原子；
    R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
    Q不存在或为C1-C6亚烷基链；
    R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
    R6选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
  3. 如权利要求1所述的化合物，其中
    R1和R2均为氘原子或一个为氢原子且另一个为氘原子；
    R3选自氢原子、-Q-OR6、巯基或-Q-NR4R5；
    Q不存在或为C1-C6亚烷基链，所述亚烷基链由(CH2)n表示，n为1-6的整数；
    R4和R5独立地选自氢原子、未取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
    R6选自氢原子、未取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
  4. 如权利要求1所述的化合物，其中
    R1和R2均为氘原子或一个为氢原子且另一个为氘原子；
    R3选自氢原子、-Q-OR6或-Q-NR4R5；
    Q不存在或为C1-C6亚烷基链，其中所述亚烷基链由(CH2)n表示，n为1-6的整数；
    R4和R5独立地选自氢原子、未取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H；以及
    R6选自氢原子或未取代的C1-C6烷基。
  5. 如权利要求1所述的化合物，其中
    R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；
    R3选自-Q-NR4R5；
    Q不存在或为C1-C6亚烷基链；
    R4和R5独立地选自氢原子、被卤素、氰基、羟基、氨基、巯基、羧基、磺酸基或亚磺酸基任选取代的C1-C6烷基、-C(O)-C1-C6烷基、-C(O)-H、-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
  6. 如权利要求1所述的化合物，其中
    R1和R2均为氘原子或一个为氢原子且另一个为氘原子，优选R1和R2均为氘原子；
    R3选自-Q-NR4R5；
    Q不存在或为C1-C6亚烷基链，其中所述亚烷基链由(CH2)n表示，n为1-6的整数；
    R4和R5独立地选自氢原子或未取代的C1-C6烷基。
  7. 如权利要求1所述的化合物，其中
    R1和R2均为氘原子；
    R3为-Q-NR4R5；
    Q不存在；且
    R4和R5均为氢。
  8. 如权利要求1所述的化合物，其中
    R1和R2均为氢原子；
    R3为-Q-NR4R5；Q不存在或为C1-C6亚烷基链；
    R4和R5中的一个为氢且另一个选自-S(O)2-C1-C6烷基、-S(O)2-H、-S(O)-C1-C6烷基或-S(O)-H。
  9. 如权利要求1所述的化合物，其中所述通式I化合物选自：
    Figure PCTCN2015082507-appb-100002
  10. 药物组合物，其包含权利要求1-9中任一项所述的化合物或其药物可接受的盐以及药物可接受的载体、赋形剂或稀释剂。
  11. 权利要求1-9中任一项所述的化合物或其药物可接受的盐或权利要求10所述的药物组合物在制备用于治疗和/或预防哺乳动物的与5型磷酸二酯酶相关的疾病或疾病状态的药物中的用途，其中抑制5型磷酸二酯酶被认为是有益的。
  12. 治疗和/或预防哺乳动物的与5型磷酸二酯酶相关的疾病或疾病状态的方法，其中在所述疾病或疾病状态中抑制5型磷酸二酯酶被认为是有益的，所述方法包括将权利要求1-9中任一项所述的化合物或其药物可接受的盐或权利要求10所述的药物组合物对所述哺乳动物给药。
  13. 用于治疗和/或预防哺乳动物的与5型磷酸二酯酶相关的疾病或疾病状态的权利要求1-9中任一项所述的化合物或其药物可接受的盐或权利要求10所述的药物组合物，其中在所述疾病或疾病状态中抑制5型磷酸二酯酶被认为是有益的。
  14. 如权利要求11-13项中任一项所述的用途、方法或化合物或药物组合物，其中所述哺乳动物为人。
  15. 如权利要求11-14项中任一项所述的用途、方法或化合物或药物组合物，其中所述与5型磷酸二酯酶相关的疾病或疾病状态为勃起功能障碍。
  16. 如权利要求11-15项中任一项所述的用途、方法或化合物或药物组合物，其中所述化合物或药物组合物用于口服给药、局部给药、肌内给药、皮内给药、腹膜内给药、皮下给药、静脉内给药或吸入给药，优选口服给药。
  17. 如权利要求11-16项中任一项所述的用途、方法或化合物或药物组合物，其中所述化合物或药物组合物被配制为片剂、胶囊剂、锭剂、糖衣丸剂、丸剂、颗粒剂、粉末剂、溶液剂、乳剂、混悬剂、分散体、糖浆剂、凝胶剂、或气溶胶剂。
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See also references of EP3301095A4 *
ULLOA, JERONIMO ET AL.: "Detection of a Tadalafil Analogue as an Adulterant in a Dietary Supplement for Erectile Dysfunction", JOURNAL OF SEXUAL MEDICINE, vol. 12, no. 1, 17 November 2014 (2014-11-17), pages 152 - 157, XP055337994 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119390694A (zh) * 2024-12-31 2025-02-07 威胜生物医药(苏州)股份有限公司 一种氨基他达那非丁二酸衍生物的制备方法
CN119390694B (zh) * 2024-12-31 2025-11-18 威胜生物医药(苏州)股份有限公司 一种氨基他达那非丁二酸衍生物的制备方法

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US9920057B2 (en) 2018-03-20
CA2987109C (en) 2020-07-07
AU2015399642A1 (en) 2017-10-05
KR102457316B1 (ko) 2022-10-20
KR20180020119A (ko) 2018-02-27
JP6595011B2 (ja) 2019-10-23
EP3301095B1 (en) 2019-12-04
US20160376273A1 (en) 2016-12-29
EP3301095A4 (en) 2018-08-01
EP3301095A1 (en) 2018-04-04
AU2015399642B2 (en) 2020-04-09
TWI613201B (zh) 2018-02-01
CA2987109A1 (en) 2016-12-29
TW201700474A (zh) 2017-01-01
ES2774048T3 (es) 2020-07-16

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