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WO2025007935A1 - 一种新型前列环素用于治疗肺高压 - Google Patents

一种新型前列环素用于治疗肺高压 Download PDF

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Publication number
WO2025007935A1
WO2025007935A1 PCT/CN2024/103697 CN2024103697W WO2025007935A1 WO 2025007935 A1 WO2025007935 A1 WO 2025007935A1 CN 2024103697 W CN2024103697 W CN 2024103697W WO 2025007935 A1 WO2025007935 A1 WO 2025007935A1
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group
substituted
alkyl
unsubstituted
pharmaceutically acceptable
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PCT/CN2024/103697
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English (en)
French (fr)
Inventor
任毅
朱林桂
黄金程
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上海众强药业有限公司
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Priority to CN202480003964.3A priority Critical patent/CN119894861A/zh
Priority to EP24835413.6A priority patent/EP4588908A1/en
Priority to AU2024291348A priority patent/AU2024291348A1/en
Priority to KR1020257007650A priority patent/KR20250051691A/ko
Publication of WO2025007935A1 publication Critical patent/WO2025007935A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C07C59/70—Ethers of hydroxy-acetic acid, e.g. substitutes on the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
    • C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/93—Spiro compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/93—Spiro compounds
    • C07C2603/94—Spiro compounds containing "free" spiro atoms

Definitions

  • the invention relates to the field of medicines, and in particular to a novel prostacyclin for treating pulmonary hypertension.
  • Treprostinil is a drug for the treatment of pulmonary artery hypertension (PAH). It is a prostacyclin derivative with the activity of inhibiting platelet aggregation and vasodilation. Its approved marketing dosage forms include injection, inhalation and oral tablets. The raw material of the injection and inhalation is treprostinil sodium salt.
  • Ralinepag is a drug currently in Phase III clinical trials for the treatment of pulmonary arterial hypertension. Its structure is as follows:
  • the purpose of the present invention is to provide a compound represented by formula (I), a preparation method thereof and use thereof in treating pulmonary hypertension.
  • R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkane substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; the substitutions are each independently selected from the group consisting of 1, 2 or 3 substituents: deuterium, halogen, hydroxyl, amino, C1-C6 al
  • R 1 , R 2 together with the C to which they are attached form a C3-C8 monocyclic cycloalkyl, a C3-C8 bridged-ring cycloalkyl, a C7-C10 spirocyclic cycloalkyl, or a 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 1 and R 2 are not hydrogen at the same time;
  • R 5 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, inorganic metal ion, ammonium ion.
  • R 1 is hydrogen
  • R2 is selected from the following groups: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, R substituted or unsubstituted C6-C10 aryl substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • R is selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 alkoxy.
  • R 1 is hydrogen
  • R2 is a C1-C6 alkyl group.
  • R 1 is hydrogen
  • R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, and tert-pentyl.
  • R 1 is hydrogen
  • R2 is ethyl
  • R 1 is H, halogen, methyl, ethyl
  • R2 is selected from the following group: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, trifluoromethyl, difluoromethyl, monofluoromethyl, monofluoroethyl, trifluoroethyl, difluoroisopropyl, hydroxy-substituted ethyl, vinyl, propenyl, ethynyl, propynyl, benzyl, diphenylmethyl, methoxybenzyl, monochlorobenzyl, phenyl-substituted ethyl, hydroxy-substituted benzyl.
  • R 1 , R 2 and the C to which they are connected together form a group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 3 and R 4 are hydrogen.
  • R 5 is hydrogen
  • the inorganic metal ions are selected from the following group: Li + , Na + , K + , Rb + , Cs + , Mg 2+ , Ca 2+ , Ba 2+ , Zn 2+ , and Al 3+ .
  • R 5 is Na + .
  • the ammonium ion is the ammonium ion corresponding to a base selected from the group consisting of ammonia, methylamine, ethylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, tromethamine, meglumine, morpholine, piperazine, piperidine, pyridine, ethylenediamine, N,N'-dibenzylethylenediamine, proline, phenylalanine, aspartic acid, glutamic acid, and lysine.
  • a base selected from the group consisting of ammonia, methylamine, ethylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, tromethamine, meglumine, morpholine, piperazine, piperidine, pyridine
  • ammonium ion is a cation
  • the pharmaceutically acceptable salt is an alkali metal salt or an alkaline earth metal salt.
  • the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of lithium salt, sodium salt, potassium salt, cesium salt, magnesium salt, calcium salt, barium salt, zinc salt, and aluminum salt.
  • the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of lithium salt, sodium salt, potassium salt, and cesium salt.
  • the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of magnesium salt, calcium salt, barium salt, zinc salt, and aluminum salt.
  • the pharmaceutically acceptable salt is the sodium salt of the compound.
  • the pharmaceutically acceptable salt is a salt formed by the compound and a nitrogen-containing organic base.
  • the pharmaceutically acceptable salt is a salt formed by the compound and a base selected from the group consisting of ammonia, methylamine, ethylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, tromethamine, meglumine, morpholine, piperazine, piperidine, pyridine, ethylenediamine, N,N'-dibenzylethylenediamine, proline, phenylalanine, aspartic acid, glutamic acid, and lysine.
  • a base selected from the group consisting of ammonia, methylamine, ethylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, tromethamine, meglumine, morpholine, piperazine, piperidine, pyridine, ethylened
  • the solvate is a hydrate.
  • the compound has a structure shown in formula (II) or formula (III):
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first aspect of the present invention, or a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the third aspect of the present invention provides a use of the compound described in the first aspect of the present invention, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating pulmonary arterial hypertension.
  • the drug is an oral preparation.
  • the dosage of the drug is 5-7 mg/kg/day, preferably 6 mg/kg/day.
  • the drug is used for a purpose selected from the following group:
  • FIG1 shows the technical route of the present invention.
  • FIG. 2 is a bar graph corresponding to the body weight data in Table 1 obtained by the present invention.
  • FIG. 3 is a bar graph corresponding to the RVSP data in Table 2 obtained in the present invention.
  • FIG. 4 is a bar graph corresponding to the Fulton index data in Table 3 obtained in the present invention.
  • the inventors After long-term and in-depth research, the inventors have obtained a new prostacyclin drug with better efficacy in treating pulmonary hypertension by optimizing the structure of the existing sodium salt of treprostinil. Specifically, by substituting at the R 1 and R 2 positions of the compound of formula I (preferably C1-C6 alkyl substitution, more preferably mono-C1-C6 alkyl substitution), a compound of formula (I) with better RVSP (right ventricular systolic pressure) and better Fulton index is obtained. On this basis, the inventors have completed the present invention.
  • RVSP right ventricular systolic pressure
  • halogen refers to F, Cl, Br or I.
  • C1-C6 alkyl refers to a straight or branched alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.
  • C2-C6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.
  • C2-C6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.
  • C3-C8 cycloalkyl refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • C1-C6 alkoxy refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.
  • heterocyclic group refers to a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including (but not limited to) the following groups:
  • aromatic ring or "aryl group” has the same meaning, preferably “C6-C10 aryl group”.
  • C6-C10 aryl group refers to an aromatic ring group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.
  • aromatic heterocycle or “heteroaryl” has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms.
  • heteroaromatic group containing one to multiple heteroatoms.
  • 5-10 membered heteroaryl refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms.
  • Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • halo means substituted with halogen
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituent is the substituent described above or the substituent appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.
  • the substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (—COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
  • the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings.
  • the term “plurality” refers to 2-6, such as 2, 3, 4, 5 or 6.
  • ester group has a -C(O)-O-R' or R'-C(O)-O- structure, wherein R' independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, heteroaryl, heterocyclic group, as defined above.
  • COPD chronic obstructive pulmonary disease
  • the Fulton Index reflects the organ remodeling caused by PAH. Changes in this index mean that new drugs may be able to reverse the altered cardiopulmonary structure caused by PAH, which means that they can not only alleviate the symptoms of PAH (treat the symptoms), but also reverse or even cure PAH (treat the root cause). This is a goal that existing drugs in the PAH field cannot achieve, but new PAH drugs hope to achieve.
  • the present invention provides a compound represented by formula I, or a solvate thereof, or a pharmaceutically acceptable salt thereof,
  • any one of R 1 , R 2 , R 3 , R 4 and R 5 is independently a corresponding group in the specific compound of the present invention.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention with an acid or base that is suitable for use as a drug.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts is a salt formed by a compound of the present invention with an acid.
  • Suitable acids for forming salts include, but are not limited to, amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and lysine.
  • Another preferred salt type is a salt of a compound of the invention with a base, such as an alkali metal salt (e.g., sodium or potassium Salts), alkaline earth metal salts (e.g., magnesium salts or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), for example, methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • a base such as an alkali metal salt (e.g., sodium or potassium Salts), alkaline earth metal salts (e.
  • solvate refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio.
  • “Hydrate” refers to a complex formed by the coordination of the compound of the present invention with water.
  • the present invention also includes co-crystals formed between the compounds of the present invention and compatible compounds.
  • the compounds of the present invention also include prodrugs of the compounds shown in formula (I).
  • prodrug includes a compound that can be biologically active or inactive, and when taken by an appropriate method, it undergoes metabolism or chemical reactions in the human body and is converted into a class of compounds of formula (I), or a salt or solution composed of a compound of formula (I).
  • the prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compound.
  • the raw materials and reagents used in the process for preparing the compounds of the present invention can be purchased through commercial channels unless otherwise specified.
  • compositions and methods of administration are provided.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound, or a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, and more preferably, contains 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet, and can also be an injection, an inhalant, and an oral preparation.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.
  • compositions of the present invention include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), oral and nasal inhalation, anal, vaginal and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient such as a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof.
  • a lubricant for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof.
  • the dosage form may also contain a buffer.
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.
  • the present invention has the following main advantages:
  • the compounds of the present invention have better therapeutic effects on pulmonary hypertension
  • the compounds of the present invention have better RVSP (right ventricular systolic pressure) and better Fulton index;
  • II-N or III-N and its corresponding sodium salt II-N-Na or III-N-Na are prepared according to the following procedure:
  • II-N represents compounds such as II-1, II-2, etc.
  • III-N represents compounds such as III-1, III-2, etc.
  • electrophilic reagent is selected from the following group:
  • II-N-7 or III-N-7 is dissolved in anhydrous ethanol, then transferred to a hydrogenation reactor, palladium carbon is added and hydrogenated overnight. The palladium carbon is removed by filtration, and the obtained filtrate is concentrated under reduced pressure. The crude product is purified by column chromatography to obtain product II-N-6 or III-N-6. The products are characterized by LC-MS and 1 H NMR, respectively.
  • III-N-5 is dissolved in anhydrous ethanol, then 1M dilute hydrochloric acid is added and stirred at room temperature for 2-6 hours, and product II-N-4 or III-N-4 is obtained after extraction, washing, drying, concentration and column chromatography purification.
  • the products are characterized by LC-MS and 1 H NMR, respectively.
  • III-20-6 was prepared according to the following operation, and the remaining intermediates, III-20 and III-20-Na were prepared according to the aforementioned steps 3-8.
  • step 5 products III-21-3 and III-21’-3 are obtained respectively, and the two are further processed according to steps 6-8 to obtain III-21 and III-21’ as well as their respective sodium salts III-21-Na and III-21’-Na.
  • Twenty-eight rats were randomly divided into the following six groups, including a drug treatment group, a positive control group, a negative control group and a healthy control group, and were marked with ear tags.
  • Group 1 and Group 2 are experimental drugs of the treprostinil type (Compound 1 is Compound III-2-Na), Group 3 and Group 4 are positive controls of treprostinil (Compound C1 is treprostinil sodium 5.5 hydrate); Group 5 is the negative control group, and Group 6 is the healthy control group.
  • the suffix H represents the high-dose group (6 mg/kg); M represents the medium-dose group.
  • MCT Monocrotaline
  • MCT solution injection The skin on the back of the rat's neck was gently lifted, and the MCT solution was subcutaneously injected at a dose of 60 mg/kg using a 1 ml syringe and recorded as day 0.
  • Compound 1 and Compound C1 can be directly dissolved in water. Appropriate amounts of the drugs were weighed according to the concentrations of 0.6 mg/ml and 1.2 mg/ml (3 mg/kg/day and 6 mg/kg/day dose groups), and the solutions were shaken with the corresponding volume of pure water to form a transparent solution.
  • the rats were weighed daily and given corresponding solutions (drugs or saline) by gavage according to the grouping scheme until the 27th day, for a total of 14 days; the gavage dose was 0.5 ml/100 g, and the body weight and survival data of the rats were recorded.
  • rats were anesthetized with 2% isoflurane at a flow rate of 2 L/min, and their limbs and incisors were fixed on the operating table with the head facing the operator;
  • the catheter reaches the right atrium and right ventricle in turn; the right atrial pressure and right ventricular pressure are recorded; at least 5 stable waveforms are recorded at each site; 5 continuous waveforms are taken as segments, and more than 2 segments are intercepted to calculate the right ventricular systolic pressure (RVSP);
  • RVSP right ventricular systolic pressure
  • the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate at a dose of 0.5 ml/100 g, and the samples were collected after weighing;
  • the rat heart, lung, liver, spleen and kidney tissues were cryopreserved and fixed with formaldehyde solution.
  • RV right ventricle
  • LV left ventricle
  • LV+S ventricular septum
  • Body weight on day 0 The average body weights of groups 1-6 on day 0 were 347 ⁇ 12.77, 315 ⁇ 3.63, 316 ⁇ 4.35, 330 ⁇ 25.11, 315 ⁇ 13.50, and 314 ⁇ 5.35 g, respectively.
  • the average body weight of group 1 was significantly greater than that of groups 2, 3, 5, and 6 (P ⁇ 0.01), and there was no significant difference between the groups.
  • Body weight on the 14th day The average body weights of groups 1-6 on the 14th day were 440 ⁇ 32.61, 428 ⁇ 29.90, 413 ⁇ 15.81, 430 ⁇ 34.15, 406 ⁇ 33.50, and 425 ⁇ 20.48 g, respectively, with no significant differences among the groups.
  • Body weight The body weights of groups 1-6 were 436 ⁇ 44.27, 440 ⁇ 55.00, 436 ⁇ 9.65, 431 ⁇ 58.03, 406 ⁇ 42.45, and 445 ⁇ 25.06 g, respectively, with no significant differences among the groups.
  • group 1 was actually administered for 13 days, group 2 was actually administered for 12 days, and both were measured and sampled on the 27th day; groups 3-6 were actually administered for 14 days, and both were measured and sampled on the 27th day.
  • group 1 was actually administered for 13 days, group 2 was actually administered for 12 days, and both were measured and sampled on the 27th day; groups 3-6 were actually administered for 14 days, and both were measured and sampled on the 27th day.
  • the RVSP of rats in groups 1-6 were 22 ⁇ 4.36, 41 ⁇ 16.27, 38 ⁇ 8.86, 46 ⁇ 13.45, 63 ⁇ 7.34, and 22 ⁇ 2.41 mmHg, respectively.
  • the RVSP of rats in modeling groups 2-4 were significantly higher than that in the healthy control group.
  • the Fulton index of groups 1-6 were 0.25 ⁇ 0.27, 0.37 ⁇ 0.12, 0.37 ⁇ 0.07, 0.38 ⁇ 0.10, 0.61 ⁇ 0.080, and 0.29 ⁇ 0.023, respectively.
  • the Fulton index of the negative control group was significantly higher than that of the healthy control group, and the Fulton index of the drug treatment group was significantly lower than that of the negative control group, but there was no significant difference between the two groups.

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Abstract

本发明涉及一种新型前列环素用于治疗肺高压。具体地，本发明化合物具有式(I)所示结构，其中各基团和取代基的定义如说明书中所述。相比于曲前列尼尔及其盐，本发明化合物具有更优的RVSP(右心室收缩压)和更优Fulton指数。

Description

一种新型前列环素用于治疗肺高压 技术领域
本发明涉及药物领域，具体地涉及一种新型前列环素用于治疗肺高压。
背景技术
曲前列尼尔为治疗肺动脉高压(pulmonary artery hypertension,PAH)药物，为前列环素衍生物，具有抑制血小板聚集和舒张血管的活性，其批准上市剂型有注射剂、吸入剂和口服片剂，其中注射剂和吸入剂的原料药为曲前列尼尔钠盐。
但是，在治疗肺动脉高压时，现有的曲前列尼尔钠盐仍存在疗效欠佳的问题，因此，本领域急需开发疗效更佳的治疗肺动脉高压的药物。
Ralinepag为目前处于临床三期的治疗肺动脉高压的药物，其结构如下：
发明内容
本发明的目的在于提供一种式(I)所示化合物及其制备方法和其在治疗肺动脉高压方面的用途。
本发明的第一方面，提供了一种式(I)所示化合物、或其溶剂合物、或其药学上可接受的盐，
其中，
R1和R2各自独立地选自下组：氢、氘、卤素、羟基、氨基、取代或未取代的C1-C6烷 基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的含1、2或3个选自N、O或S的杂原子的4-8元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的含1、2或3个选自N、O或S的杂原子的5-10元杂芳基；所述取代各自独立地是指被选自下组的1、2或3个取代基取代：氘、卤素、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环烷基、R取代或未取代的C6-C10芳基、R取代或未取代的含1、2或3个选自N、O或S的杂原子的5-10元杂芳基；R选自下组：卤素、羟基、C1-C6烷基、C1-C6烷氧基；
或者R1、R2与其所连接的C一起形成C3-C8单环环烷基、C3-C8桥环环烷基、C7-C10螺环环烷基、或含1、2或3个选自N、O或S的杂原子的4-8元杂环烷基；
并且，R1和R2不同时为氢；
R3和R4各自独立地选自下组：氢、-(C＝O)-C1-C6烷基、C1-C6烷基、卤代C1-C6烷基、C3-C8环烷基、卤代C3-C8环烷基；
R5选自下组：氢、C1-C6烷基、卤代C1-C6烷基、C3-C8环烷基、卤代C3-C8环烷基、无机金属离子、铵根离子。
在另一优选例中，R1为氢；
R2选自下组：卤素、C1-C6烷基、卤代C1-C6烷基、R取代或未取代的C6-C10芳基取代的C1-C6烷基、羟基取代的C1-C6烷基、C2-C6烯基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环烷基、C6-C10芳基、含1、2或3个选自N、O或S的杂原子的5-10元杂芳基；
R选自下组：卤素、C1-C6烷基、C1-C6烷氧基。
在另一优选例中，R1为氢；
R2为C1-C6烷基。
在另一优选例中，R1为氢；
R2选自下组：甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基。
在另一优选例中，R1为氢；
R2为乙基。
在另一优选例中，R1为H、卤素、甲基、乙基；
R2选自下组：卤素、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、三氟甲基、二氟甲基、一氟甲基、一氟乙基、三氟乙基、二氟异丙基、羟基取代的乙基、乙烯基、丙烯基、乙炔基、丙炔基、苄基、二苯基甲基、甲氧基苄基、一氯苄基、苯基取代的乙基、羟基取代的苄基。
在另一优选例中，R1、R2与其所连接的C一起形成选自下组的基团：环丙基、环丁基、环戊基、环己基。
在另一优选例中，R3和R4为氢。
在另一优选例中，R5为氢。
在另一优选例中，所述无机金属离子选自下组：Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Ba2+、Zn2+、Al3+。
在另一优选例中，R5为Na+。
在另一优选例中，所述铵根离子为选自下组的碱对应的铵根离子：氨、甲胺、乙胺、二甲胺、三甲胺、二乙胺、三乙胺、乙醇胺、二乙醇胺、三乙醇胺、叔丁胺、氨丁三醇、葡甲胺、吗啉、哌嗪、哌啶、吡啶、乙二胺、N,N’-二苄基乙二胺、脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸、赖氨酸。
在另一优选例中，所述铵根离子为阳离子。
在另一优选例中，所述药学上可接受的盐为碱金属盐或碱土金属盐。
在另一优选例中，所述药学上可接受的盐为所述化合物的选自下组的盐：锂盐、钠盐、钾盐、铯盐、镁盐、钙盐、钡盐、锌盐、铝盐。
在另一优选例中，所述药学上可接受的盐为所述化合物的选自下组的盐：锂盐、钠盐、钾盐、铯盐。
在另一优选例中，所述药学上可接受的盐为所述化合物的选自下组的盐：镁盐、钙盐、钡盐、锌盐、铝盐。
在另一优选例中，所述药学上可接受的盐为所述化合物的钠盐。
在另一优选例中，所述药学上可接受的盐为所述化合物与含氮有机碱形成的盐。
在另一优选例中，所述药学上可接受的盐为所述化合物与选自下组的碱形成的盐：氨、甲胺、乙胺、二甲胺、三甲胺、二乙胺、三乙胺、乙醇胺、二乙醇胺、三乙醇胺、叔丁胺、氨丁三醇、葡甲胺、吗啉、哌嗪、哌啶、吡啶、乙二胺、N,N’-二苄基乙二胺、脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸、赖氨酸。
在另一优选例中，所述溶剂合物为水合物。
在另一优选例中，所述化合物具有式(II)或式(III)所示结构：
其中，R1、R2、R3、R4、R5如上文所定义。
在另一优选例中，所述化合物选自下组：


本发明的第二方面，提供了一种药物组合物，包含药学上可接受的载体和一种或多种安全有效量的本发明第一方面所述的化合物、或其溶剂合物、或其药学上可接受的盐。
本发明的第三方面，提供了一种本发明第一方面所述的化合物、或其溶剂合物、或其药学上可接受的盐的用途，用于制备药物，所述药物用于治疗肺动脉高压。
在另一优选例中，所述药物为口服制剂。
在另一优选例中，所述药物的给药剂量为5-7mg/kg/天，较佳的为6mg/kg/天。
在另一优选例中，所述药物用于选自下组的用途：
1)降低右心室收缩压；
2)降低Fulton指数；
3)降低PVR(肺血管阻力)；
4)治疗间质性肺病导致的肺高压；
5)治疗COPD导致的肺高压；
6)治疗特发性肺纤维化。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了本发明的技术路线。
图2是本发明所得表1体重数据所对应的柱状图。
图3是本发明所得表2RVSP数据所对应的柱状图。
图4是本发明所得表3Fulton指数数据所对应的柱状图。
具体实施方式
本发明人经过长期而深入的研究，通过对现有曲前列尼尔钠盐进行结构优化获得了一种治疗肺动脉高压疗效更佳的新型前列环素类药物。具体地，通过在式I化合物的R1、R2位置进行取代(优选C1-C6烷基取代，更优选单C1-C6烷基取代)获得了一种具有更优RVSP(右心室收缩压)和更优Fulton指数的式(I)化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。
在本发明中，术语“C2-C6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-C6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C3-C8环烷基”是指在环上具有3-8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中，术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中，术语“杂环基”为含1、2或3个选自N、O、S的杂原子的4-8元杂环基，包括(但并不限于)如下基团：
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。例如“5-10元杂芳基”是指含有1～4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括：呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“卤代”是指被卤素取代。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(—COOH)、C1-C6烷基、C2-C6烯基、 C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中，术语1-6指1、2、3、4、5或6。其他类似术语各自独立地具有类似含义。术语“多个”指2-6个，如2、3、4、5或6个。
术语“酯基”具有-C(O)-O-R'或R'-C(O)-O-结构，其中，R'独立地代表氢、C1-C6烷基、C3-C6环烷基、C6-C10芳基、杂芳基、杂环基，如上文所定义。
应理解，当某一基团同时存在于化合物的多个不同位置时，其在各位置的定义是相互独立的，可以相同也可以不同。亦即，术语“选自下组：”与术语“各独立地选自下组：”具有相同含义。
术语“COPD”指慢性阻塞性肺疾病。
Fulton指数反映的是由于PAH导致的器官改构(remodeling)。这个指数的变化意味着新药有可能逆转阴PAH已经改变的心肺结构，即不仅减轻PAH的症状(治标)，还可以逆转甚至治愈PAH(治本)。这是PAH领域目前现有药物不能达到，而PAH新药希望达到的一个目标。
化合物
本发明提供了一种式I所示化合物、或其溶剂合物、或其药学上可接受的盐，
其中，各基团如上文所定义。
在另一优选例中，所述的化合物中，R1、R2、R3、R4、R5中任一个分别独立地为本发明所述具体化合物中所对应的基团。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸、赖氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾 盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
本发明还包括本发明化合物与适配的化合物形成的共晶。
此外，本发明化合物还包括式(I)所示的化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
应理解，本发明实施例更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程中所用原料和试剂如无特殊说明，均可通过商业途径购买。
药物组合物和施用方法
本发明还提供了一种药物组合物，包含药学上可接受的载体和一种或多种安全有效量的所述的化合物、或其溶剂合物、或其药学上可接受的盐。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片，也可以是注射液、吸入剂和口服制剂。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、口鼻腔吸入、肛门、阴道和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂如润滑剂混合，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明具有以下主要优点：
(1)本发明所述化合物具有更优的治疗肺动脉高压的疗效；
(2)本发明所述化合物具有更优RVSP(右心室收缩压)和更优Fulton指数；
(3)与处于临床三期的Ralinepag(United Therapeutics Corporation)相比，本发明中的化合物相应的动物实验数据也优于Ralinepag；
(4)基于体重数据和临床观察，给药组大鼠进食、排便、活动、爪力均与健康组大鼠无异。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
制备实施例
II-N或III-N及其相应的钠盐II-N-Na或III-N-Na按以下操作程序进行制备：
说明：II-N代表II-1、II-2等化合物；III-N代表III-1、III-2等化合物。
步骤1：
在反应瓶中加入起始原料(SM1)和四氢呋喃并冷却至-65℃，在此温度下慢慢滴加LDA或LiHMDS(1.0～5.0当量)，滴加结束后在此温度下继续搅拌3小时，然后将亲电试剂(1.0～5.0当量)加至反应体系中，滴加完成后缓慢升温并搅拌过夜。向反应体系中加入饱和氯化铵水溶液淬灭反应，经常规萃取、洗涤、干燥、浓缩、柱层析得到产物II-N-7或III-N-7。产物分别用LC-MS和1H NMR进行表征。
其中，所述亲电试剂选自下组：

步骤2：
将II-N-7或III-N-7溶解在无水乙醇中，然后转移至氢化反应釜中，加入钯碳并氢化过夜。过滤除去钯碳，所得滤液减压浓缩，粗品经柱层析柱纯化后得到产物II-N-6或III-N-6。产物分别用LC-MS和1H NMR进行表征。
步骤3：
将II-N-6或III-N-6溶解在无水乙醇中，冷却至-25～-15℃然后加入适量的2M氢氧化钠水溶液并在此温度下搅拌2-4小时，然后在此温度下加入硼氢化钠(1.0～2.0当量)并继续搅拌4～6小时。经常规萃取、洗涤、干燥、浓缩、柱层析得到产物II-N-5或III-N-5。产物分别用LC-MS和1H NMR进行表征。
步骤4：
将II-N-5或III-N-5溶解在无水乙醇中，然后加入1M稀盐酸室温搅拌2-6小时，经萃取、洗涤、干燥、浓缩、柱层析纯化后得到产物II-N-4或III-N-4。产物分别用LC-MS和1H NMR进行表征。
步骤5：
将二苯基膦氢(5.0-10.0当量)溶解在无水四氢呋喃中并冷却至-25～-15℃，缓慢滴加正丁基锂(5.0-10.0当量)，滴加结束后继续在此温度搅拌2-4小时得到二苯基膦锂的四氢呋喃溶液。
另取一反应瓶，加入II-N-4或III-N-4并用四氢呋喃溶解，室温下将现制的二苯基膦锂的四氢呋喃溶液缓慢加入。滴加结束后反应体系回流过夜。撤去加热冷却并进一步用冰水浴冷却，加入饱和氯化铵淬灭反应。经过常规萃取、洗涤、干燥、过滤、减压浓缩，粗品经柱层析纯化后得到产物II-N-3或III-N-3。产物分别用LC-MS和1H NMR进行表征。
步骤6：
将II-N-3或III-N-3溶解在丙酮中，然后依次加入碳酸钾和溴乙腈(各1.5～3.0当量)，室温搅拌过夜。过滤除去固体不溶物，滤液直接减压浓缩。粗品经柱层析纯化 后得到产物II-N-2或III-N-2。产物分别用LC-MS和1H NMR进行表征。
步骤7：
将II-N-2或III-N-2溶解在四氢呋喃中，依次加入20％氢氧化钾水溶液，搅拌至水解结束。用2M盐酸调节pH值至3～4，经常规萃取、洗涤、干燥、过滤、减压浓缩得粗品、再经柱层析纯化后得到产物II-N或III-N。产物分别用LC-MS和1H NMR进行表征。
步骤8：
将II-N或III-N溶解在四氢呋喃中，然后加入等当量的氢氧化钠固体，搅拌过夜。减压浓缩，加入乙腈打浆得到白色固体沉淀，过滤洗涤干燥后即得到钠盐II-N-Na或III-N-Na。产物分别用LC-MS和1H NMR进行表征。
本发明如上制法所得各化合物的表征数据如表A、表B和表C所示。
表A














III-20-6按以下操作制备，其余的中间体、III-20及III-20-Na按前面提到的步骤3-8进行制备。
在反应瓶中加入起始原料(SM2)、PhBr(1.5当量)、叔丁醇钠(1.5当量)、催化量的Pd(OAc)2和XPhos以及溶剂甲苯，升温至80℃搅拌。原料消失后，经饱和NaCl水溶液猝灭、萃取、干燥、过滤、浓缩、柱层析纯化得到产物III-20-6。产物分别用LC-MS和1H NMR进行表征。
表B


在步骤5分别得到产物III-21-3和III-21’-3，二者继续按步骤6-8得到III-21和III-21’以及各自的钠盐III-21-Na和III-21’-Na。
表C



性能测试及结果
1.购买及预适应
从维通利华购买7周龄雄性Sprague-Dawley大鼠(平均体重为200-250g)28只，购买后在实验地点适应性饲养1周(温度20-26℃，湿度30-70％，昼夜比1：1)，达8周龄。
2.分组
将28只大鼠随机分为下列6组，包括药物治疗组、阳性对照组、阴性对照组和健康对照组，并打上耳标序号。
注1：组1、组2为曲前列尼尔类实验药物(化合物1即化合物III-2-Na)，组3和组4为曲前列尼尔阳性对照组(化合物C1为曲前列尼尔钠5.5水合物)；组5为阴性对照组，组6为健康对照组。
注2：后缀H代表高剂量组(6mg/kg)；M代表中剂量组。
3.造模
(1)野百合碱(Monocrotaline,MCT)溶液配制：称取足量MCT倒入50ml 20％乙醇-生理盐水溶液中，轻微缓慢摇晃后转移至50ml离心管中倾斜放入37℃，220rpm恒温摇床中震荡12-14小时，使MCT充分溶解，以肉眼不可见结晶颗粒为准。
(2)MCT溶液注射：轻轻提起大鼠颈背部皮肤，使用1ml注射器按照60mg/kg剂量皮下注射MCT溶液并记为第0天。
(3)健康对照：同样方法注射同剂量生理盐水。
4.实验药物配制
(1)化合物1和化合物C1可直接溶于水，按照0.6mg/ml、1.2mg/ml浓度(3mg/kg/day、6mg/kg/day剂量组)分别称取适量药物，用相应体积纯水振摇溶解，即得，以形成透明溶液为准；
(2)置于4℃冰箱中冷藏，使用前取出，放置室温后使用；
5.给药
第14天开始，每日称重后依据分组方案给予相应溶液(药物或生理盐水)灌胃给药，至第27天为止，共14天；灌胃剂量为0.5ml/100g，并记录大鼠体重和生存数据。
6.血流动力学测量
第28天，使用右心导管对大鼠评估血流动力学状态：
(1)准备PE-50导管、压力换能器及测压工作站；使用肝素盐水冲洗管路，保证管路中没有气泡；导管调零；
(2)使用2％异氟烷以2L/min流量持续气体麻醉大鼠，将四肢与门齿固定在手术台上，头端朝向操作者；
(3)颈部手术区域备皮；
(4)沿正中线剪开颈部皮肤，使用止血钳牵拉固定颈部皮肤，用剪刀逐层分离组织，暴露右侧颈内静脉；
(5)使用止血钳钝性分离，游离颈内静脉；
(6)使用4-0缝线结扎颈内静脉远心端，并在颈内静脉近心端穿过缝线备用；
(7)使用眼科剪在颈内静脉上剪一个v字型切口，从该处置入PE-50导管。导管置入后，结扎颈内静脉近心端预置的缝线，固定导管；
(8)导管依次到达右心房、右心室；记录右心房压、右心室压；每个部位至少记录5个稳定的波形；以5个连续波形为片段，截取2个以上片段，计算右心室收缩压(Right Ventricular Systolic Pressure，RVSP)；
(9)撤除PE-50导管，完成检查。
7.取材
(1)血流动力学评估完毕后，按照0.5ml/100g剂量腹腔注射10％水合氯醛麻醉大鼠，称重后开始取材；
(2)打开腹腔后用5ml注射器于下腔腔静脉抽取尽量多的血液于EDTA抗凝管中，颠倒摇匀6-8次；
(3)继续打开胸腔，暴露肺和心脏；
(4)将左心耳剪开，使用5ml注射器抽取一管肝素生理盐水于右心耳处进针，缓慢注射以冲洗肺血管；
(5)留取大鼠心脏、肺、肝脏、脾脏和肾脏组织分别冻存和甲醛溶液固定。
8.Fulton指数测量
分离心脏后剪掉心室以外部分，如心房、血管和瓣环等，使用镊子尽量清除心室内血栓，后用直剪沿紧绷的右心室(Right Ventricle,RV)和室间隔(Interventricular Septum,S)交界剪开右心室(RV)和左心室(Left Ventricle,LV)+室间隔(LV+S)，用纱布吸干水分，分别称重。计算RV/(LV+S)即Fulton指数。
化合物C1结构如下：
实验结果如下：
体重
1.第0天体重：1-6组第0天平均体重分别为347±12.77，315±3.63，316±4.35，330±25.11，315±13.50，314±5.35g，1组平均体重显著大于2、3、5、6组(P＜0.01)，无明显组间差异。
2.第14天体重：1-6组第14天平均体重分别为440±32.61，428±29.90，413±15.81，430±34.15，406±33.50，425±20.48g，无明显组间差异。
3.取材体重：1-6组取材体重分别为436±44.27，440±55.00，436±9.65，431±58.03，406±42.45，445±25.06g，无明显组间差异。
注：因化合物1总重量限制，组1实际给药13天，组2实际给药12天，均于第27天进行测量和取材；组3-6实际给药14天，均于第27天进行测量和取材。
表1各组大鼠体重变化情况对比

存活情况
因化合物1总重量限制，组1实际给药13天，组2实际给药12天，均于第27天进行测量和取材；组3-6实际给药14天，均于第27天进行测量和取材。
血流动力学结果
1-6组RVSP分别为22±4.36，41±16.27，38±8.86，46±13.45，63±7.34，22±2.41mmHg，2-4造模组大鼠RVSP均显著高于健康对照组，化合物1 6mg/kg治疗组大鼠RVSP已下降至健康对照组水平(22±4.36vs 22±2.41mmHg，P＝0.939)。
表2各组大鼠RVSP值对比
从表2可知：
1)实验药物治疗组：化合物1 6mg/kg治疗组RVSP显著低于3mg/kg治疗组(22±4.36vs 41±16.27mmHg，P＝0.01)，存在剂量组间差异；
2)阳性对照组：化合物C1即曲前列尼尔钠5.5水合物3、6mg/kg剂量均可显著降低大鼠RVSP，但仍高于健康对照且两剂量组间效果无明显差异(38±8.86vs 46±13.45mmHg，P＝0.201)；
3)化合物1 6mg/kg治疗组大鼠RVSP低于同等剂量曲前列尼尔钠5.5水合物治疗组(22±4.36vs 38±8.86mmHg，P＝0.013)，扩张肺血管作用优于同等剂量曲前列尼尔钠5.5水合物。
Fulton指数结果
1-6组Fulton指数分别为0.25±0.27，0.37±0.12，0.37±0.07，0.38±0.10，0.61±0.080，0.29±0.023，阴性对照组Fulton指数显著高于健康对照组，药物治疗组Fulton指数显著低于阴性对照组而与健康对照组均无明显差异。
表3各组大鼠Fulton指数对比

从表3可知：
1)实验药物治疗组：化合物1 6mg/kg治疗组Fulton指数小于3mg/kg治疗组，但两剂量组间无明显差异(0.25±0.27vs 0.37±0.12，P＝0.06)；
2)阳性对照组：化合物C1即曲前列尼尔钠5.5水合物3、6mg/kg剂量均可显著降低大鼠心脏Fulton指数，但仍高于健康对照且两剂量组间效果无明显差异(0.37±0.07vs 0.38±0.10，P＝0.921)；
3)化合物1 6mg/kg治疗组大鼠心脏Fulton指数低于同等剂量曲前列尼尔钠5.5水合物治疗组(0.25±0.27vs 0.37±0.07，P＝0.029)；3mg/kg治疗组大鼠心脏Fulton指数则与同等剂量曲前列尼尔钠5.5水合物治疗组无明显差异。
此外，按照如上相同实验方法，对于Ralinepag，其相应实验结果如表4和表5所示。
表4各组大鼠RVSP值对比
表5各组大鼠Fulton指数对比
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式(I)所示化合物、或其溶剂合物、或其药学上可接受的盐，
    其中，
    R1和R2各自独立地选自下组：氢、氘、卤素、羟基、氨基、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的含1、2或3个选自N、O或S的杂原子的4-8元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的含1、2或3个选自N、O或S的杂原子的5-10元杂芳基；所述取代各自独立地是指被选自下组的1、2或3个取代基取代：氘、卤素、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环烷基、R取代或未取代的C6-C10芳基、R取代或未取代的含1、2或3个选自N、O或S的杂原子的5-10元杂芳基；R选自下组：卤素、羟基、C1-C6烷基、C1-C6烷氧基；
    或者R1、R2与其所连接的C一起形成C3-C8单环环烷基、C3-C8桥环环烷基、C7-C10螺环环烷基、或含1、2或3个选自N、O或S的杂原子的4-8元杂环烷基；
    并且，R1和R2不同时为氢；
    R3和R4各自独立地选自下组：氢、-(C＝O)-C1-C6烷基、C1-C6烷基、卤代C1-C6烷基、C3-C8环烷基、卤代C3-C8环烷基；
    R5选自下组：氢、C1-C6烷基、卤代C1-C6烷基、C3-C8环烷基、卤代C3-C8环烷基、无机金属离子、铵根离子。
  2. 如权利要求1所述的化合物、或其溶剂合物、或其药学上可接受的盐，其特征在于，R1为氢；
    R2选自下组：卤素、C1-C6烷基、卤代C1-C6烷基、R取代或未取代的C6-C10芳基取代的C1-C6烷基、羟基取代的C1-C6烷基、C2-C6烯基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环烷基、C6-C10芳基、含1、2或3个选自N、O或S的杂原子的5-10 元杂芳基；
    R选自下组：卤素、C1-C6烷基、C1-C6烷氧基。
  3. 如权利要求1所述的化合物、或其溶剂合物、或其药学上可接受的盐，其特征在于，R1为H、卤素、甲基、乙基；
    R2选自下组：卤素、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、三氟甲基、二氟甲基、一氟甲基、一氟乙基、三氟乙基、二氟异丙基、羟基取代的乙基、乙烯基、丙烯基、乙炔基、丙炔基、苄基、二苯基甲基、甲氧基苄基、一氯苄基、苯基取代的乙基、羟基取代的苄基。
  4. 如权利要求1所述的化合物、或其溶剂合物、或其药学上可接受的盐，其特征在于，R3和R4为氢。
  5. 如权利要求1所述的化合物、或其溶剂合物、或其药学上可接受的盐，其特征在于，所述无机金属离子选自下组：Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Ba2+、Zn2+、Al3+；和/或
    所述铵根离子为选自下组的碱对应的铵根离子：氨、甲胺、乙胺、二甲胺、三甲胺、二乙胺、三乙胺、乙醇胺、二乙醇胺、三乙醇胺、叔丁胺、氨丁三醇、葡甲胺、吗啉、哌嗪、哌啶、吡啶、乙二胺、N,N’-二苄基乙二胺、脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸、赖氨酸。
  6. 如权利要求1所述的化合物、或其溶剂合物、或其药学上可接受的盐，其特征在于，所述化合物具有式(II)或式(III)所示结构：
    其中，R1、R2、R3、R4、R5如权利要求1所定义。
  7. 如权利要求1所述的化合物、或其溶剂合物、或其药学上可接受的盐，其特征在于，所述化合物选自下组：


  8. 一种药物组合物，其特征在于，包含药学上可接受的载体和一种或多种安全有效量的权利要求1所述的化合物、或其溶剂合物、或其药学上可接受的盐。
  9. 一种权利要求1所述的化合物、或其溶剂合物、或其药学上可接受的盐的用途，其特征在于，用于制备药物，所述药物用于治疗肺动脉高压。
  10. 如权利要求9所述用途，其特征在于，所述药物用于选自下组的用途：
    1)降低右心室收缩压；
    2)降低Fulton指数；
    3)降低PVR；
    4)治疗间质性肺病导致的肺高压；
    5)治疗COPD导致的肺高压；
    6)治疗特发性肺纤维化。
PCT/CN2024/103697 2023-07-05 2024-07-04 一种新型前列环素用于治疗肺高压 WO2025007935A1 (zh)

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