A prodrug of treprostinil

Abstract

The present invention provides a prodrug of treprostinil as shown in formula I and a pharmaceutical composition thereof. The prodrug improves the in vivo metabolism of treprostinil, reduces the dosage and frequency of administration, improves the effectiveness and safety of the drug, and can be used to prepare drugs for treating pulmonary hypertension, chronic arterial occlusive disease, and idiopathic pulmonary fibrosis.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to a prodrug of treprostinil, a pharmaceutical composition thereof and uses thereof. Background Art

[0002] Pulmonary arterial hypertension (PAH) refers to a hemodynamic and pathophysiological state in which the pulmonary artery pressure rises above a certain threshold, which can cause right heart failure and serious complications, and eventually lead to death. In recent years, based on the research on the molecular pathology of PAH treatment, there are three targeted treatment pathways, namely the nitric oxide pathway, the prostacyclin pathway, and the endothelin pathway. Prostacyclin and its analogs are targeted drugs developed in the early stage for the clinical treatment of PAH. Four types of drugs are used clinically, namely epoprostenol, treprostinil, iloprost, and beraprost sodium. Among them, treprostinil has a long half-life, a stable drug structure, and is easy to use. It is widely used as a first-line treatment and rescue drug.

[0003] Treprostinil is a stable exogenous tricyclic prostacyclin analogue with a molecular formula of C 23 H 34 O5, with a relative molecular mass of 390.52. Treprostinil acts on the treatment of PAH mainly based on the following mechanisms: (1) It can effectively mimic endogenous prostacyclin, bind to its receptor, increase the concentration of cAMP in the cytoplasm, and resist the vasoconstriction effect caused by increased TAX2; (2) By binding to IP receptors, it acts on peroxisome proliferator-activated receptors to inhibit cell proliferation; (3) By reducing the level of tumor necrosis factor (TNF)-related apoptosis-inducing ligand in plasma, it improves right ventricular systolic pressure and right ventricular hypertrophy; (4) Through the secretion of vascular endothelial growth factor-A by mesenchymal stem cells, it effectively increases the proliferation number of endothelial colony-forming cells and protects endothelial function; (5) It can downregulate the inflammatory factors and chemokines secreted by macrophages, monocytes and T lymphocytes in various lung tissues to achieve the purpose of anti-inflammatory.

[0004] Treprostinil is the only prostacyclin drug currently used in the clinic to treat PAH that can be administered by multiple routes, subcutaneously / intravenously, orally, and by inhalation. It has a stable structure and a longer duration of action than prostacyclin. It takes effect quickly when administered by subcutaneous / intravenous routes and can exert biological effects within minutes. In clinical studies of PAH, subcutaneous, intravenous, and inhaled administration have shown good efficacy and safety. Among them, subcutaneous and intravenous preparations (treprostinil for injection, trade name: Remodulin) and inhalation solution (trade name: Tyvaso) sustained-release tablets (trade name: Orenitram) and injection (trade name: Remodulin) were approved for marketing by the FDA in 2002, 2009, 2013, and 2018, respectively.

[0005] Since long-term administration is required, injection and inhalation administration are very inconvenient. Oral administration is the best route of administration. However, the oral form has poor efficacy, systemic toxic side effects, and requires multiple administrations a day. Therefore, sustained-release tablets have been developed and marketed for clinical use. However, due to the defects of the compound itself, the current clinical use of oral preparations has not been good, and inhalation preparations are mainly used. For example, the latest summary report of the international multicenter clinical trial of inhaled treprostinil for the treatment of pulmonary hypertension was published in the New England Journal of Medicine in 2021. In order to improve patient compliance and reduce the toxic side effects of systemic administration, INSMED modified treprostinil to palmitic acid (treprostinil palmitil) as a long-acting release prodrug inhaler (patents US09255064 and US09469600) for the treatment of pulmonary arterial hypertension, interstitial lung disease-associated pulmonary hypertension, and idiopathic fibrosis. The project has now entered the Phase II clinical trial stage.

[0006] In view of this, it is of great significance to explore suitable prodrugs or dosage forms to further improve the in vivo metabolism of treprostinil and reduce the dosage and frequency of administration. Summary of the invention

[0007] The present invention aims at the problems existing in the prior art and provides a prodrug of treprostinil, which improves the in vivo metabolism of treprostinil, reduces the dosage and frequency of administration, and improves the effectiveness and safety of the drug.

[0008] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0009] In one aspect, the present invention provides a prodrug of treprostinil as shown in the following formula I:

[0010]

[0011] or a pharmaceutically acceptable salt or stereoisomer thereof;

[0012] Wherein, R1 is hydrogen, alkyl, cycloalkyl, alkenyl, alkoxy, aryl or aryloxy;

[0013] R2 is alkyl, cycloalkyl or alkenyl;

[0014] n is an integer from 0 to 6.

[0015] On the other hand, the present invention provides a pharmaceutical composition comprising the above-mentioned prodrug of treprostinil or a pharmaceutically acceptable salt or stereoisomer thereof.

[0016] In another aspect, the present invention provides a use of the above-mentioned prodrug of treprostinil or its pharmaceutically acceptable salt, stereoisomer or the above-mentioned pharmaceutical composition as a procyclidine analog.

[0017] In another aspect, the present invention provides a use of the above-mentioned prodrug of treprostinil or its pharmaceutically acceptable salt, stereoisomer or the above-mentioned pharmaceutical composition in the preparation of a drug for treating pulmonary arterial hypertension.

[0018] Compared with the prior art, the present invention has the following beneficial effects: the treprostinil prodrug provided by the present invention has excellent oral administration potential and better peak time and half-life, improves the disadvantages of treprostinil's in vivo metabolism, reduces the dosage and frequency of administration, and improves the effectiveness and safety of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 These are the in vivo test results of Experimental Example 2 on rats with hypoxic pulmonary hypertension. DETAILED DESCRIPTION

[0020] The present invention is described in detail below.

[0021] In one aspect, the present invention provides a prodrug of treprostinil as shown in the following formula I:

[0022]

[0023] or a pharmaceutically acceptable salt or stereoisomer thereof;

[0024] Wherein, R1 is hydrogen, alkyl, cycloalkyl, alkenyl, alkoxy, aryl or aryloxy;

[0025] R2 is alkyl, cycloalkyl or alkenyl;

[0026] n is an integer of 0-6, for example, n is 0, 1, 2, 3, 4, 5 or 6.

[0027] In some embodiments of the present invention, R1 is hydrogen, C1-20 alkyl, C3-20 cycloalkyl, C2-20 alkenyl, C1-20 alkoxy, C6-20 aryl or C6-20 aryloxy;

[0028] R2 is a linear or branched C2-20 alkyl group, a C3-20 cycloalkyl group or a linear or branched C2-20 alkenyl group.

[0029] In some embodiments of the present invention, R1 is hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C2-10 alkenyl; R2 is a linear or branched C3-20 alkyl or C3-20 alkenyl.

[0030] In some embodiments of the present invention, R1 is hydrogen or C1-4 alkyl; R2 is a linear or branched C11-18 alkyl.

[0031] In some embodiments of the present invention, R1 is hydrogen, methyl or isopropyl; R2 is undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl; and n is 0, 1, 2 or 3.

[0032] In some embodiments of the present invention, compound I is any of the following structures:

[0033]

[0034]

[0035] On the other hand, the present invention provides a pharmaceutical composition comprising the above-mentioned prodrug of treprostinil or a pharmaceutically acceptable salt or stereoisomer thereof.

[0036] In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0037] The pharmaceutical excipients can be those widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0038] In some embodiments of the present invention, the pharmaceutical composition is generally formulated into a dosage form suitable for oral administration, injection or inhalation administration to a patient.

[0039] In some embodiments of the invention, the dosage form is an oral dosage form, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, granules, cachets, and the like.

[0040] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0041] In another aspect, the present invention provides a use of the above-mentioned prodrug of treprostinil or its pharmaceutically acceptable salt, stereoisomer or the above-mentioned pharmaceutical composition as a procyclidine analog.

[0042] On the other hand, the present invention provides a use of the above-mentioned prodrug of treprostinil or its pharmaceutically acceptable salt, stereoisomer or the above-mentioned pharmaceutical composition in the preparation of drugs for treating cardiovascular diseases, cerebrovascular diseases, respiratory diseases, etc., especially in the preparation of drugs for treating pulmonary hypertension, chronic arterial occlusive disease, idiopathic pulmonary fibrosis, etc.

[0043] Definitions and general terms

[0044] The term "alkyl" or "alkyl group" used in the present invention refers to a saturated straight or branched monovalent hydrocarbon radical containing 1 to 20 carbon atoms. The alkyl group may be independently and optionally substituted with one or more substituents. Examples of alkyl or alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, etc.

[0045] The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical in which at least one position is unsaturated, i.e., one CC is sp 2 Double bond. Specific examples of alkenyl include but are not limited to vinyl, allyl, etc. The alkenyl group can be independently optionally substituted with one or more substituents described in the present invention, including groups with "cis", "trans", "E" or "Z" configurations.

[0046] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has a meaning as described herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy, 2-methyl-1-butoxy, and the like.

[0047] The term "aryl" refers to a monocyclic, bicyclic or tricyclic carbon ring system containing 6-20 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and the like.

[0048] The term "cycloalkyl" refers to a C3-C20 cycloaliphatic ring structure; examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0049] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1977, 66, 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, etc.; and organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, etc., or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. The salt obtained by appropriate base includes alkali metal, alkaline earth metal, ammonium salt. Alkali metal or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium and amine cations that counter-form counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates.

[0050] The term "stereoisomer" refers to compounds with the same chemical structure, but with different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers, (cis / trans) isomers, atropisomers, and the like. "Enantiomers" refer to two isomers of a compound that are not superimposable but are mirror images of each other. "Diastereomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.

[0051] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are only a part of embodiments of the present invention, rather than all embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work, all belong to the scope of protection of the present invention. In addition, it is worth noting that the raw materials involved in the present invention are all common commercial products unless otherwise specified.

[0052] Synthesis method

[0053]

[0054] Treprostinil (10 mg / mL) and the corresponding alkoxy hydrocarbon (50 mg / mL) were dissolved in 1,4-dioxane, and the reaction was catalyzed by NKC-9 strong acid resin. The reaction was stirred at 40° C. overnight. The reaction was complete after monitoring by TLC, and the product was obtained by HPLC purification.

[0055] The following are the structures and NMR data of the specific examples:

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] Test Example 1 Pharmacokinetics of Compounds

[0063] 1. Experimental instruments and materials

[0064] High-speed refrigerated centrifuge, vortex oscillator (Vortex Genius3), high-speed centrifuge (Eppendorf5415D), disposable syringes, pipettes (Eppendorf), SD male rats used in the experiment were purchased from Yangzhou University, EDTA-K2 vacuum blood collection tubes, and normal saline. All rats in the oral group fasted for 12 hours before administration, had free access to water, and had free access to water and food during administration.

[0065] (II) Experimental steps

[0066] The example compounds of the present invention were dissolved in DMSO / solutol / water (10 / 10 / 80) to prepare a clear solution. The compound dose for oral administration was 25 mg / kg, and the compound dose for tail vein administration was 5 mg / kg. At 2min, 10min, 30min, 1h, 2h, 3h, 5h, 8h, 12h, 16h, and 24h after tail vein administration, 0.5mL of blood was continuously taken from the venous plexus of the fundus into a heparin tube. At 5min, 15min, 30min, 1h, 2h, 3h, 5h, 8h, 12h, 16h, and 24h after oral administration, 0.5mL of blood was continuously taken from the venous plexus of the fundus into a heparin tube. After the sample was centrifuged at 8000r and 4°C for 10min, 0.15mL of upper plasma was taken and stored at -20°C, and then analyzed by LC-MS / MS. The data was analyzed by WinNolin non-compartmental model to obtain key pharmacokinetic parameters.

[0067] (III) Experimental results

[0068] Table 1 Pharmacokinetic parameters of compounds

[0069]

[0070] From the above test results, it can be found that compared with the peak time (0.5h) and half-life (1h) of treprostinil, the compound of the present invention significantly prolongs the peak time and half-life, and has excellent long-term drug delivery potential and good oral administration potential.

[0071] Test Example 2 In vivo test on rats with hypoxic pulmonary hypertension

[0072] 1. Experimental instruments and materials

[0073] HX-200 animal ventilator, SD male rats used in the experiment were purchased from Yangzhou University, and physiological saline was used. All control groups were raised in normal environment, and intervention groups and model groups were raised in a low-pressure hypoxic chamber (air pressure 50 kPa, oxygen concentration 10%).

[0074] (II) Experimental steps

[0075] Compound 8 was dissolved in DMSO / solutol / water (10 / 10 / 80) to make a clear solution. The intervention group was gavaged with compound 8 at a dose of 5 mg / kg starting from the second day of hypoxia. All rats were weighed weekly, and survival was recorded. Pulmonary artery pressure was measured four weeks later. Rats were anesthetized with chloral hydrate (100 g / L) (3 mL / kg), fixed in the supine position, tracheotomy, and assisted breathing with a small animal ventilator (frequency 60 times / min, tidal volume 5 mL, respiratory ratio 4:5). The third rib on the left was freed, and a catheter with a tension transducer at one end was sent to the pulmonary artery, and the mean pulmonary artery pressure (mPAP) was recorded by the BL-420E biofunctional experimental system. Pleural effusion and ascites were examined and collected, and finally blood was drawn from the abdominal aorta to kill the rats.

[0076] (III) Experimental results

[0077] See attached Figure 1 Compared with the control group, the mPAP of the model group rats was significantly increased, and the mPAP of the intervention group treated with compound 8 was lower than that of the model group.

[0078] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. The prodrug of treprostinil as shown below or its pharmaceutically acceptable salt, stereoisomer, characterized in that Select from any of the following structures:

2. A pharmaceutical composition comprising the prodrug of treprostinil according to claim 1 or a pharmaceutically acceptable salt, stereoisomer thereof and a pharmaceutically acceptable excipient.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition is in the form of oral administration, injection administration or inhalation administration.

4. The pharmaceutical composition according to claim 3, characterized in that: The pharmaceutical composition is in the form of an oral administration, and the dosage form includes tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, granules or cachets.

5. Use of the prodrug of treprostinil or its pharmaceutically acceptable salt or stereoisomer as claimed in claim 1 as a procyclidine analog.

6. Use of the prodrug of treprostinil or its pharmaceutically acceptable salt or stereoisomer according to claim 1 in the preparation of a drug for treating pulmonary hypertension, chronic arterial occlusive disease and idiopathic pulmonary fibrosis.

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