WO2021203779A1 - Composé destiné au traitement de l'hypertension artérielle pulmonaire et son application - Google Patents

Composé destiné au traitement de l'hypertension artérielle pulmonaire et son application Download PDF

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WO2021203779A1
WO2021203779A1 PCT/CN2021/000082 CN2021000082W WO2021203779A1 WO 2021203779 A1 WO2021203779 A1 WO 2021203779A1 CN 2021000082 W CN2021000082 W CN 2021000082W WO 2021203779 A1 WO2021203779 A1 WO 2021203779A1
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李洪林
王蕊
焦茜
赵振江
朱丽丽
李诗良
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华东理工大学
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P27/06—Antiglaucoma agents or miotics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Pulmonary arterial hypertension refers to the most common type of pulmonary vascular disease in which the mean pulmonary artery pressure (mPAP) of the right heart catheter (mPAP) ⁇ 25 mmHg measured in a resting state, which is 30 mmHg during exercise.
  • mPAP mean pulmonary artery pressure
  • mPAP right heart catheter
  • hemodynamic characteristics and clinical diagnosis and treatment strategies it can be divided into five categories: 1Arterial pulmonary hypertension; 2Pulmonary hypertension caused by left heart disease; 3Pulmonary hypertension caused by hypoxia and/or lung disease; 4Chronic thromboembolic pulmonary hypertension; 5Pulmonary hypertension caused by multiple mechanisms and/or unknown mechanisms.
  • This disease is a relatively serious disease, with low survival rate, poor prognosis, difficult clinical treatment and other problems, and it has seriously threatened human life and health.
  • CTEPH patients are classified into grades I to IV based on the WHO functional classification that represents the severity of symptoms.
  • Class I No symptoms during daily physical activity
  • Class II Comfortable at rest, but symptoms occur during general physical activity, and daily activities are slightly restricted
  • Class III Can be asymptomatic at rest, but appear after light activity Symptoms, obvious limitation of daily activities
  • Grade IV Pulmonary hypertension makes the patient unable to withstand any physical activity, signs of right heart failure, breathing difficulties and/or fatigue may occur at rest, and any physical activity will aggravate the symptoms.
  • prostacyclin drugs epoprostol, beraprostacyclin
  • endothelin receptor antagonists bosentan, macitentan
  • phosphodiesterase- 5 Inhibitors phosphodiesterase- 5 Inhibitors
  • vascular remodeling is considered to be the main cause of PAH, so anti-vascular remodeling is considered to be a more promising therapeutic method.
  • sGC stimulators and agonists have attracted much attention due to their unique ways of action. Lioxigar is the first new type of sGC stimulant developed by Bayer in Germany.
  • TKI tyrosine kinase inhibitors
  • Imatinib imatinib
  • statins are endogenous cholesterol synthesis inhibitors that act on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Previous studies have shown that multiple statins are used alone [Kao, PN (2005). "Simvastatin treatment of pulmonary hypertension: an observational case series.” Chest 127(4): 1446-1452] or with tadalafil [Girgis , RE, D. Li, et al.
  • Rosiglitazone is a highly selective agonist of Peroxisome proliferator activated receptor (PPARy)! J, clinically used as an insulin sensitizer to treat type 2 diabetes. Because PPAR Y plays an important role in the pathogenesis of PAH, the effect of rosiglitazone in improving PAH is gradually known to everyone [Crossno, JT, Jr.; Garat, CV; Reusch, J.
  • the object of the present invention is to provide a compound with pulmonary hypertension therapeutic activity; specifically, the compound of the present invention can treat, reduce or alleviate pulmonary hypertension, right heart hypertrophy caused by pulmonary hypertension, and pulmonary arterial hypertension. Pulmonary arteriole hypertrophy and abnormal proliferation of pulmonary artery smooth muscle cells.
  • the present invention provides the use of proton pump inhibitor compounds in the preparation of drugs for the treatment of pulmonary hypertension and related diseases.
  • the pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory disorders, inflammatory bowel disease, cardiovascular disease, kidney disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary disorders Systemic diseases and neurological diseases.
  • the proton pump inhibitor compound is a compound represented by formula I or a compound represented by formula II Where Ring A is a 5-membered or 6-membered aromatic ring or heteroaromatic ring; n is an integer of 0-3;
  • Ri is selected from: H, substituted or unsubstituted ( ⁇ _ 6 alkyl group, a substituted or unsubstituted Cw alkoxy, substituted or unsubstituted 5- or 6-membered aryl or heteroaryl group, halogen, amino, nitro Group, hydroxyl group;
  • Ring B is a 5-membered or 6-membered aromatic ring or a 5-membered or 6-membered heteroaromatic ring containing 1-2 heteroatoms selected from N, 0 or S;
  • R 2 is selected from: H, substituted or unsubstituted Q- 6 alkyl, substituted or unsubstituted Q- 6 alkoxy, substituted or unsubstituted Q- 6 alkylthio, morpholinyl, NR 4 R 5 , wherein R 4 and R 5 are each independently selected from H or substituted or unsubstituted Q- 6 alkyl; m is an integer of 0-4;
  • R 3 is selected from: H, substituted or unsubstituted Cl-6 alkyl; In the formula II,
  • C ring is selected from 6-10 membered aromatic ring or heteroaromatic ring;
  • R 9 is selected from: H, halogen, substituted or unsubstituted Cu 6 alkyl, RuR ⁇ NCw acyl, wherein R u and R 12 are each independently selected from H or substituted or unsubstituted Cp 3 alkyl; o is 0- An integer of 3;
  • Y is selected from: S0 2 , NR 13 , 0, wherein R 13 is selected from H or substituted or unsubstituted Q_ 3 alkyl; q is an integer of 0-2;
  • Ring D is a 5-membered or 6-membered aromatic ring or a 5-membered or 6-membered heteroaromatic ring or heterocyclic ring containing 1-2 heteroatoms selected from N, 0 or S; Rio is selected from: halogen, substituted or unsubstituted Q_ 6 alkyl, substituted or unsubstituted Q_ 6 alkoxy, substituted or unsubstituted 6-10 membered aryl or heteroaryl or heterocyclic group, NR 14 R 15 , wherein R 14 and R 15 are each independently selected from H, substituted or unsubstituted alkyl group or a substituted or unsubstituted CM Q_ 6 the ester group; p is an integer of 1-4.
  • Formula I in Formula I,
  • Ring A is a benzene ring, a pyridine ring or a thiophene ring; n is 0, 1 or 2;
  • Ri is selected from: H, substituted or unsubstituted Alkoxy, substituted or unsubstituted pyrrolyl, or two form a 4-6 membered heterocyclic ring containing heteroatoms selected from N, 0 or S;
  • Ring B is a benzene ring or a pyridine ring
  • R 2 is selected from: substituted or unsubstituted Q_ 3 alkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted Q_ 3 alkylthio, morpholinyl, NR 4 R 5 -wherein R 4 and R 5 are each independently a substituted or unsubstituted CM alkyl group, or two R 2 form a group containing optional A 4-6 membered heterocyclic ring of two heteroatoms from N, 0 or S; m is 1, 2 or 3;
  • 11 3 is 11, or R 3 and R 2 form a substituted or unsubstituted 6-8 carbocyclic ring.
  • the compound is selected from the following group:
  • the compound is represented by the following formula 1-1: 1-1 where
  • Ri is selected from: H, substituted or unsubstituted Alkoxy group, a substituted or unsubstituted alkyl Q_ 3;, 117 and 118 are independently selected from: H, substituted or unsubstituted Q_ 3 alkoxy group, a substituted or unsubstituted CM alkyl.
  • the compound is selected from the following group: In a specific embodiment, in Formula II,
  • Ring C is selected from the group consisting of phenyl, pyridoxyl, pyridoxyl or benzimidazolyl;
  • R 9 is selected from: H, F, substituted or unsubstituted Cu 3 alkyl, RnR ⁇ NCw acyl, wherein R u and R 12 are each independently selected from substituted or unsubstituted Q 3 alkyl;
  • Y is selected from: S0 2 , NH or 0; q is 0 or 1;
  • Ring D is selected from: pyrrolyl, pyrimidinyl, phenyl, chromanyl;
  • R 10 is selected from: F, substituted or unsubstituted Cu 3 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted tetrahydroisoquinolinyl, NR 14 R 15 , wherein R 14 and R 15 are each independently selected from H, substituted or unsubstituted ester group Q_ 3; p is 1, 2 or 3.
  • the compound is selected from the following group:
  • the present invention provides a compound represented by formula 1-2, Where
  • Ring B is phenyl or pyrazinyl
  • R 2 is selected from: H, substituted or unsubstituted C M alkyl, substituted or unsubstituted Q 3 alkoxy, morpholinyl, or two R 2s to form a 4-6 membered heterocyclic ring containing two 0s; m is 1, 2 or 3.
  • the compound is selected from the following group:
  • the present invention also provides the compound described in the first aspect for the treatment of pulmonary hypertension and related diseases.
  • the pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory disorders, inflammatory bowel disease, cardiovascular disease, kidney disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary disorders Systemic diseases and neurological diseases.
  • the present invention provides a method for treating pulmonary hypertension and related diseases, the method comprising administering a therapeutically effective amount of the compound described in the first aspect to a patient in need of treatment of pulmonary hypertension and related diseases.
  • the pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory disorders, inflammatory bowel disease, cardiovascular disease, kidney disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary disorders Systemic diseases and neurological diseases.
  • the present invention provides a medicament containing the compound described in the first aspect for the treatment of pulmonary hypertension and related diseases.
  • the pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory disorders, inflammatory bowel disease, cardiovascular disease, kidney disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary disorders Systemic diseases and neurological diseases.
  • Figure 1 shows the effect of dexlansoprazole on RVSP, mPAP and RVHI in rats with monocrotaline-induced pulmonary hypertension
  • Figure 1A is RVSP: pulmonary artery systolic pressure
  • Figure 1B is mPAP: mean pulmonary artery pressure
  • Figure 1C is RVHI: right ventricular hypertrophy index
  • Figure 2 shows the lungs of a rat with dextrolansolaw versus monocrotaline-induced pulmonary hypertension
  • arteriole remodeling Figure 2A is the H&E staining image of the lung
  • Figure 2B is the WT% : the thickness of the middle pulmonary arterioles as a percentage of the outer diameter of the blood vessel
  • Figure 2C is the WA%: the area of the middle pulmonary arterioles accounts for the wall area Percentage of total blood vessel area
  • Figure 3 shows the effect of esomeravamagnesium, voronolazan fumarate, pumaravail and lan
  • the aromatic ring may be optionally substituted with 1-4 (for example, 1, 2, 3, or 4) substituents selected from the group consisting of halogen, C M aldehyde, Cw alkyl, cyano, nitro , Amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (such as trifluoromethyl), carboxy, C M alkoxy, ethoxyformyl, N (CH 3 ) and C M acyl, etc., heterocyclic group or Heteroaryl, etc.
  • the term "5-membered or 6-membered heteroaromatic ring" means that at least one of the atoms forming the aromatic ring skeleton is not carbon, but nitrogen, oxygen, or sulfur, etc.
  • a heterocyclic ring contains no more than 4 nitrogens , No more than 2 oxygens and/or no more than 2 sulfurs.
  • heterocycles can be saturated, partially unsaturated or fully unsaturated rings.
  • Cp 6 alkyl refers to having 1-6 A straight or branched chain alkyl group with three carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
  • Central oxy refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy Group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group or similar groups.
  • alkylthio refers to a group obtained by replacing the oxygen atom in an alkoxy group with a sulfur atom.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • halogenated refers to a group substituted with one or more of the same or different halogen atoms, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or similar groups.
  • Q_ 3 acyl refers to the group represented by RC(O)-, where R is H, Q_ 2 alkyl; similarly, the term “C M Ester group "refers to a QC (0) -0 - group, in which Q is H or alkyl Q_ 5 proton pump inhibitor compounds described herein and their use in the prevention and treatment of pulmonary hypertension.”
  • Proton “Pump inhibitor” has the meaning conventionally understood by those skilled in the art; that is, it exists on the biofilm and actively transports H + membrane proteins against the electrochemical potential difference of H on both sides of the membrane ( ⁇ #[ + ). Stomach.
  • H + -K + ATPase proton pump
  • H + protons
  • K + K + into the gastric parietal cells.
  • protons proton pump inhibitors
  • common clinical proton pump inhibitors include omeprazole, Lansolaw, pantoprazole, rabeprazole and esmelawa, etc.
  • the proton pump inhibitor compound of the present invention is a compound represented by formula I or a compound represented by formula II: In the formula, C ring, R 9 , o, Y, q, D ring, R 1() and p are as defined above. In a specific embodiment, the proton pump inhibitor compound of the present invention is a compound selected from the following group:
  • the present invention provides lansoprazole or dexlansoprazole as the prevention and/or treatment of pulmonary hypertension.
  • the structural formulas of the lansoprazole and dexlansolaw are shown below
  • the present invention also provides various derivatives of lansoprazole as drugs for preventing and/or treating pulmonary hypertension.
  • the present invention provides the compound represented by the following formula 1-2 as a medicine for preventing and/or treating pulmonary hypertension, 1-2 where
  • Ring B, R 2 and m are as described above.
  • the compound represented by formula II is the following compound: Based on the compounds of the present invention, those skilled in the art can make them into pharmaceutically acceptable salts. For example, the compound of the present invention can be reacted with an inorganic acid or an organic acid to form a conventional pharmaceutically acceptable salt.
  • the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc.
  • the organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, Methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, hexanoic acid , Hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and ise
  • the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, containing asymmetric centers The R and S configuration of the double bond, the (Z) and (E) isomers of the double bond, etc. Therefore, the individual stereochemical isomers of the compounds of the present invention or their enantiomers, diastereomers or geometric Mixtures of isomers (or conformational isomers) are within the scope of the present invention.
  • the proton pump inhibitor compound of the present invention can prevent and/or treat pulmonary hypertension and related diseases
  • the pulmonary hypertension is manifested by the phenomenon of increased pulmonary artery pressure, thickening of small pulmonary arteries, etc.
  • pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory diseases, inflammatory bowel disease, and cardiovascular disease , Nephropathy, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary system disorders and neurological disorders, etc.
  • the proton pump inhibitor compounds of the present invention and their pharmaceutically acceptable salts
  • the present invention also provides a pharmaceutical composition containing the proton pump inhibitor compound, and the pharmaceutical composition optionally contains pharmaceutically acceptable excipients.
  • the drug of the present invention includes a safe and effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition, Without causing serious side effects.
  • “Pharmaceutically acceptable excipients or carriers” refer 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 each component of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include, but are not limited to, oral and inhalation preparations.
  • 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 (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (1) accelerated absorption Agents, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • the dosage form may also contain buffering agents.
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other It is a well-known material in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule 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 inert diluents 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-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • 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 at the time of administration is the effective dosage considered pharmaceutically.
  • the compounds and pharmaceutical compositions of the present invention can be administered via oral or gastrointestinal routes. It is most preferably taken orally, taken in one time or taken in divided doses. Regardless of the method of administration, the individual's optimal dosage should be determined based on the specific treatment. Usually, start with a small dose and gradually increase the dose until the most suitable dose is found. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • dexlansoprazole has the following effects in the prevention and/or treatment of pulmonary hypertension drugs:
  • Each dose of dexlansolawine significantly reduces the pulmonary artery pressure in rats with pulmonary hypertension caused by monocrotaline, and inhibits the hypertrophy of small pulmonary arteries;
  • the present invention proves for the first time that a proton pump inhibitor compound, such as dexlansolaw, has the effect of treating monocrotaline-induced pulmonary hypertension in rats, and can be used to prepare a therapeutic drug for pulmonary hypertension;
  • a proton pump inhibitor compound such as dexlansolaw
  • the structure of the drug of the present invention is significantly different from that of known pulmonary hypertension drugs, which can lay a new material foundation for the view of pulmonary hypertension drugs.
  • the present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.
  • the experimental methods that do not indicate specific conditions in the following examples are usually based on conventional conditions. Or in accordance with the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight.
  • the experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified. Example 1.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time administer the proton pump inhibitor dexlansolaw for treatment, to detect rat pulmonary artery hemodynamics and right heart hypertrophy index RVHI, to judge dexlansolar The efficacy of azole.
  • mice Male SD rats weighing 200-230 g (purchased from Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.), feeding conditions: constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light The light and dark are 12 h/day, and the food and water are free for 24 h.
  • SD rats were randomly divided into 6 groups: blank control group, pulmonary hypertension model group, selexipag treatment group, dexlansolaw (Annaiji Chemical Co., Ltd.) low-dose and medium-dose And high-dose treatment group, each group has 6 animals.
  • the Powerlab biological information collection and processing system After the administration, start the Powerlab biological information collection and processing system, connect the prefabricated right heart catheter, fill with 0.2% heparin sodium (Beijing Solebold Technology Co., Ltd.) solution, and then the pressure is zeroed for standby. After injecting 20% urethane (Shanghai Yuanye Biotechnology Co., Ltd.) solution into the abdominal cavity of the rat for anesthesia, the right neck hair was shaved and the right jugular vein was isolated and exposed. The right heart catheter enters the right jugular vein of the rat, enters the right atrium through the superior vena cava, and reaches the right ventricle through the atrioventricular valve.
  • heparin sodium Beijing Solebold Technology Co., Ltd.
  • 20% urethane Shanghai Yuanye Biotechnology Co., Ltd.
  • RV right ventricle
  • LV+S left ventricle and interventricular septum
  • RVSP right ventricular systolic pressure
  • mPAP right ventricular mean pressure
  • the right heart hypertrophy index of the blank control group and model group rats were 0.196 ⁇ 0.022 and 0.430 ⁇ 0.044, respectively.
  • the right heart hypertrophy index of the model group was significantly increased (p ⁇ 0.001).
  • the right ventricular hypertrophy index of each dose of dexlansolaw in the treatment group was higher than that of the blank control group, but was significantly lower than that of the untreated model group.
  • Ratio;? ⁇ 0.01) meanwhile, the right heart hypertrophy index of the selexipag treatment group was 0.296 ⁇ 0.027, which was significantly lower than that of the model group (p ⁇ 0.01). It is suggested that dexlansoprazole can relieve the right heart hypertrophy caused by pulmonary hypertension.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time give the proton pump inhibitor esomerazole magnesium for treatment, to detect the pulmonary artery hemodynamics and right heart hypertrophy indexes in rats, and to judge Esomera Wow the medicinal effect of magnesium.
  • mice Male SD rats weighing 200-230 g are kept under constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light and dark for 12 h/day, and 24 h free intake of food and water.
  • SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag-positive drug (1 mg/kg, bid) treatment group, esomerazole magnesium (10 mg/kg, qd) Treatment group, 6 animals in each group.
  • normal saline was injected subcutaneously into the back of the neck of the control group of rats, and monocrotaline solution was injected into the other groups at a dose of 60 mg/kg.
  • the positive drug and esomerazole magnesium were administered continuously for 21 days from the day of modeling (the dosage is 0.5 ml/100 g body weight, intragastric administration), the blank control group and model group were given corresponding volumes of solvent according to body weight.
  • start the Powerlab biological information acquisition and processing system connect the prefabricated right heart catheter, fill the heparin sodium solution, and zero the pressure for use. After injecting 20% urethane solution into the abdominal cavity of the rat for anesthesia, the right neck hair was shaved and the right jugular vein was separated and exposed.
  • RVSP right ventricular systolic pressure
  • mPAP mean right ventricular pressure
  • the experiment set up a selexipag positive drug control group (RVSP: p ⁇ 0.001 compared with the model group, mPAP: 0.001), suggesting that esomeprazole magnesium can improve the increase of pulmonary artery pressure in rats with monocrotaline-induced pulmonary hypertension.
  • the right heart hypertrophy index of the blank control group and model group rats were 0.190 ⁇ 0.045 and 0.382 ⁇ 0.085, respectively.
  • the right heart hypertrophy index of the model group was significantly increased (p ⁇ 0.001).
  • the right heart hypertrophy index of the esomeprazole magnesium treatment group was higher than that of the blank control group, but was significantly lower than the untreated model group (p ⁇ 0.01).
  • the right heart hypertrophy index of the selexipag treatment group was 0.271 ⁇ 0.068. Significantly lower than the model group (p ⁇ 0.01). It is suggested that Esomerazole magnesium can relieve the right heart hypertrophy caused by pulmonary hypertension.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time give proton pump inhibitor voronolazan fumarate for treatment, to detect rat pulmonary artery hemodynamics and right heart hypertrophy indexes, and to determine fumaric acid The medicinal effect of Vonuolazan.
  • mice Male SD rats weighing 200-230 g are kept under constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light and dark for 12 h/day, and 24 h free intake of food and water.
  • SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag positive drug (1 mg/kg, bid) treatment group, vornorazan fumarate (10 mg/kg, qd) ) Treatment group, 6 rats in each group.
  • normal saline was injected subcutaneously into the back of the neck of the blank control group of rats, and monocrotaline solution was injected into the other groups at a dose of 60 mg/kg.
  • the positive drug and voronolazan fumarate were administered continuously for 21 days from the day of modeling (dosage 0.5 ml/100 g body weight, intragastric administration), the blank control group and model group were given corresponding volumes of solvent according to body weight.
  • start the Powerlab biological information acquisition and processing system connect the prefabricated right heart catheter, fill the heparin sodium solution, and zero the pressure for use. After injecting 20% urethane solution into the abdominal cavity of the rat for anesthesia, the right neck hair was shaved and the right jugular vein was separated and exposed.
  • RVSP right ventricular systolic pressure
  • mPAP mean right ventricular pressure
  • the experiment set up a selexipag positive drug control group (compared with the model group RVSP: ⁇ ⁇ 0.001, mPAP: 0.001), suggesting that voronolazan fumarate can improve the increase of monocrotaline-induced pulmonary artery pressure in rats with pulmonary hypertension.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time give the proton pump inhibitor pramalazole for treatment, to detect the pulmonary artery hemodynamics and right heart hypertrophy indexes in rats, and to determine the drug of pulmonary valine effect.
  • mice Male SD rats weighing 200-230 g are kept under constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light and dark for 12 h/day, 24 h free intake of food and water.
  • SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag positive drug (1 mg/kg, bid) treatment group, and pramalava (10 mg/kg, qd) treatment group , 6 in each group.
  • normal saline was injected subcutaneously into the back of the neck of the blank control group of rats, and monocrotaline solution was injected into the other groups at a dose of 60 mg/kg.
  • the positive drug and pramalazole were administered for 21 consecutive days from the day of modeling (the dosage is 0.5 ml/100 g Body weight, intragastric administration), blank control group and model group were given corresponding volumes of solvent according to body weight.
  • start the Powerlab biological information acquisition and processing system connect the prefabricated right heart catheter, fill the heparin sodium solution, and zero the pressure for use.
  • the right heart catheter enters the right jugular vein of the rat, enters the right atrium through the superior vena cava, and reaches the right ventricle through the atrioventricular valve.
  • RV right ventricle
  • LV + S left ventricle and interventricular septum
  • RVSP right ventricular systolic pressure
  • mPAP mean right ventricular pressure
  • the experiment also set up a selexipag positive drug control group (compared with the model group, RVSP: p ⁇ 0.001, mPAP: ⁇ ⁇ 0.001), suggesting that pramalazole can improve the increase of monocrotaline-induced pulmonary artery pressure in rats with pulmonary hypertension.
  • the right heart hypertrophy index of the blank control group and model group rats were 0.190 ⁇ 0.045 and 0.382 ⁇ 0.085, respectively.
  • the right heart hypertrophy index of the model group was significantly increased (p ⁇ 0.001).
  • the right ventricular hypertrophy index of the pramalawa treatment group was higher than that of the blank control group, but was significantly lower than that of the untreated model group (p ⁇ 0.001).
  • the right ventricular hypertrophy index of the selexipag treatment group was 0.271 ⁇ 0.068, which is similar to that of the model group. Significantly lower than the group (p ⁇ 0.01).
  • pramalazole has the effect of relieving right heart hypertrophy caused by pulmonary hypertension.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time administer dexlansoprazole derivative 119 for treatment, detect the pulmonary artery hemodynamics and right heart hypertrophy indexes in rats, and determine the dexlansoprazole-derived The efficacy of ⁇ 119.
  • mice Male SD rats weighing 200-230 g are kept under constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light and dark for 12 h/day, 24 h free food and water. During the experiment, SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag positive drug (1 mg/kg, bid) treatment group, 119 (10 mg/kg, qd) treatment group, each group 6 only. On the first day of the experiment, normal saline was injected subcutaneously into the back of the neck of the blank control group of rats, and monocrotaline solution was injected into the other groups at a dose of 60 mg/kg.
  • the positive drug and 119 were administered for 21 consecutive days from the day of modeling (the dosage is 0.5 mL/100 g body weight, Stomach administration), the blank control group and the model group were given corresponding volumes of solvent according to body weight.
  • start the Powerlab biological information acquisition and processing system connect the prefabricated right heart catheter, fill the heparin sodium solution, and zero the pressure for use.
  • the right heart catheter enters the right jugular vein of the rat, enters the right atrium through the superior vena cava, and reaches the right ventricle through the atrioventricular valve.
  • the waveform is recorded, and then it passes through the Powerlab biological information acquisition and processing system Read the pressure value.
  • the catheter was taken out, the rat was dissected immediately, and the heart and lung tissues were taken out.
  • RV right ventricle
  • LV + S left ventricle and interventricular septum
  • Separate the right heart hypertrophy index, right heart hypertrophy index ⁇ /; ⁇ + 3).
  • Separate the right lower lung lobe tissue immerse it in 4% paraformaldehyde and fix it for about 1 week, make a 3 pm paraffin section, and then perform hematoxylin-eosin staining.
  • the right ventricular systolic pressure (RVSP) and mean right ventricular pressure (mPAP) of the blank control group were 31.44 ⁇ 2.30 mmHg and 10.88 ⁇ 2.09 mmHg, respectively.
  • RVSP and mPAP were 31.44 ⁇ 2.30 mmHg and 10.88 ⁇ 2.09 mmHg, respectively.
  • the pressure in the dexlansoprazole derivative 119 treatment group was higher than that of the blank control group, but the RVSP was significantly lower than that of the untreated model group (p ⁇ 0.01), and mPAP was also present.
  • the experiment set up a selexipag positive drug control group (compared with the model group RVSP: ⁇ 0.001, mPAP: /? ⁇ 0.001), suggesting that dexlansoprazole derivative 119 can improve monocrotaline-induced pulmonary hypertension in rats with increased pulmonary artery pressure Phenomenon.
  • the right heart hypertrophy index of the blank control group and model group rats were 0.190 ⁇ 0.045 and 0.382 ⁇ 0.085, respectively, and the right heart hypertrophy index of the model group increased significantly (p ⁇ 0.001).
  • the right ventricular hypertrophy index of compound 119 is still higher than that of the blank control group, but is significantly lower than that of the untreated model group ( ⁇ ⁇ 0.05).
  • the right ventricular hypertrophy index of the selexipag treatment group is 0.271 ⁇ 0.068, which is significant compared with the model group Decrease in sex (p ⁇ 0.01). It is suggested that the dexlansolava derivative 119 has the effect of relieving the right heart hypertrophy caused by pulmonary hypertension.
  • Table 5 Comparison of hemodynamic indexes, right heart hypertrophy indexes and pulmonary arteriolar hypertrophy indexes in each experimental group Example 6. The effect of proton pump inhibitors on cell proliferation
  • MTT method to detect PDGF-BB-induced PASMC proliferation After digestion and resuspension, PASMCs that have grown to a confluent state are evenly spread in a transparent 96-well plate, with 5000 cells per well, and placed in a cell incubator overnight. On the second day, the old medium was discarded and all replaced with serum-free DMEM medium to normalize the growth rate of the cells. After 24 h, groups were given dexlansoprazole stimulation. The grouping settings are: normal group (model group), PDGF-BB group, PDGF-BB+rightlansolava 10 pM group, PDGF-BB+rightlansolava 50 pM group and PDGF-BB+rightlansolava 100 nM Group.
  • mice Male SD rats (Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.), 8 weeks old, were randomly divided into 6 groups, namely normoxia group, hypoxia model group, hypoxia +5 mg/ kg dexlansoprazole group, hypoxia + 10 mg/kg dexlansoprazole group, hypoxia + 20 mg/kg dexlansoprazole group and hypoxia + 10 mg/kg sildenafil group, each Group of 8 each.
  • normoxia group hypoxia model group
  • hypoxia +5 mg/ kg dexlansoprazole group hypoxia + 10 mg/kg dexlansoprazole group
  • hypoxia + 20 mg/kg dexlansoprazole group hypoxia + 10 mg/kg sildenafil group
  • Rats in the normoxia group were kept in a normoxia (21% 02) environment for 4 weeks, and the animals in the other 3 groups were kept in a low-pressure and hypoxic chamber (an environment with a simulated altitude of 5500 m, 02 concentration was 10%), daily Hypoxia was 8 hours and continued hypoxia for 4 weeks. Drug intervention was performed while hypoxia was induced.
  • the normoxia group and hypoxia model group were given a mixed solution of (1% DMSO+19% PEG 400+80% normal saline) by intragastric administration, hypoxia+10 mg/kg sidium
  • the nafil group was given sildenafil solution at a concentration of 2 mg/mL by gavage, and the other 3 groups were given dexlansolar at a concentration of 1 mg/mL, 2 mg/mL, and 4 mg/mL by gavage.
  • Wow solution continued administration for 4 weeks.
  • the Powerlab biological information acquisition and processing system (AD Instruments, Australia) was started, and a PE 50 catheter filled with 0.2% heparin sodium normal saline was connected to the pressure transducer for use.
  • the rats were injected intraperitoneally 20% urethane anesthesia, shave the right neck hair and separate and expose the right jugular vein.
  • the PE50 catheter enters the right jugular vein of the rat, enters the right atrium through the superior vena cava, and reaches the right ventricle through the atrioventricular valve. After a typical right ventricular waveform appears and stabilizes for a period of time, the RVSP and mRVP are recorded and analyzed.
  • the left lung of the rat was taken out and fixed in 4% poly formic acid for 1 week, and lung tissue of appropriate size was cut out to make paraffin sections. Place the H&E stained sections under a microscope for observation.
  • Each section is randomly selected with a diameter of 50-300
  • the small arteries of the lung were photographed and saved.
  • Fig. 5A and Fig. 5B show that the RVSP of rats reared under normoxia is 40.27 ⁇ 2.34 mmHg, while the average RVSP of rats in the model group after exposure to hypoxia for 28 days is 71.09 ⁇ 3.29 mmHg, which is higher than normal. Compared with the group, it was significantly higher (P ⁇ 0.001).
  • High-dose dexlansoprazole (20 mg/kg) can reduce rat RVSP to 57.57 ⁇ 3.96 mmHg (p ⁇ 0.05).
  • high-dose dexlansolaw (20 mg/kg) can also reduce mRVP to 21.20 ⁇ 1.53 mmHg (p ⁇ 0.05).
  • Sildenafil is a PDE-5 inhibitor, used as a positive control drug in this experiment to inhibit the increase in right ventricular pressure caused by hypoxia.
  • FIG. 5D and Figure 5E statistically analyze the WT% and WA% of each group of pulmonary arteries.
  • the analysis shows that the WT% and WA% of the model group are (50.17 ⁇ 4.15)% and (72.38 ⁇ 4.54)%, respectively, which are significantly higher than the normal group (p ⁇ 0.05).
  • the average WT% and WA% values of rats at a dose of 20 mg/kg of dexlansolaw were reduced to (36.57 ⁇ 1.97)% and (57.08 ⁇ 12.16)% respectively after 28 days, which significantly inhibited pulmonary vascular remodeling. (p ⁇ 0.05).
  • Example 8 The effect of dexlansolaw on treatment of pulmonary hypertension in mice induced by SU5416 combined with chronic hypoxia
  • mice Male C57BL/6 mice, 6-8 weeks old, were randomly divided into 4 groups, namely, normoxia group, normoxia + dexlansolaw (10 mg/kg) group, SU5416/low Oxygen (SuHy) group and SuHy+dexlansoprazole (10 mg/kg) group, with 10 rats in each group.
  • the three groups of mice were treated as follows: (1) The normoxic group: The mice were kept in a normoxic (21% 02) environment for 4 weeks, and the blank solvent was injected weekly, and the blank solution was given daily by gavage after 2 weeks.
  • mice were kept in a low-pressure and hypoxic chamber (10% 02) for 4 weeks, and SU5416 solution (20 mg/kg, sc) was subcutaneously injected every week, and a blank was given by gavage after 2 weeks of hypoxia. Solution;
  • SuHy + dexlansolaw (10 mg/kg) group mice are kept in a low-pressure hypoxic chamber for 4 weeks, and SU5416 solution (20 mg/kg, sc) is injected subcutaneously every week, hypoxia 2 A week later, the dexlansoprazole solution was given by gavage.
  • mice After the mice were exposed to SU5416 and hypoxic environment for 4 weeks, they were anesthetized by intraperitoneal injection of pentobarbital (30 mg/kg) and passed through the trachea The catheter is mechanically ventilated. After the mouse has opened the chest, a 1.2 F pressure sensor ((Millar Instruments, USA) is carefully inserted from the apex of the right ventricle, a stable right ventricular pressure is recorded through the Powerlab biological information acquisition and processing system, and RVSP is calculated. After the right ventricular pressure measurement is completed , Take out the catheter, immediately dissect the rat or mouse and take out the heart, absorb the blood in it with filter paper.
  • a 1.2 F pressure sensor (Millar Instruments, USA) is carefully inserted from the apex of the right ventricle, a stable right ventricular pressure is recorded through the Powerlab biological information acquisition and processing system, and RVSP is calculated. After the right ventricular pressure measurement is completed , Take out the catheter, immediately dissect the rat or
  • RV right ventricular wall
  • LV+S left ventricle and ventricular septum

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Abstract

Dans la présente invention, une nouvelle utilisation d'un inhibiteur de la pompe à protons et d'un dérivé de ce dernier dans le traitement de l'hypertension artérielle pulmonaire est découverte pour la première fois. Dans la présente invention, un modèle d'hypertension artérielle pulmonaire chez le rat induite par la monocrotaline est utilisé, et le facteur de croissance dérivé des plaquettes-BB (PDGF-BB) induit une prolifération anormale des cellules du muscle lisse artériel pulmonaire (PASMC); il est découvert qu'un inhibiteur de la pompe à protons, tel que le dexlansoprazole et un dérivé de ce dernier, peut réduire la pression artérielle pulmonaire, réduire l'épaississement des petites et moyennes artères pulmonaires, et inhiber la prolifération anormale des PASMC, ce qui permet d'obtenir un traitement de l'hypertension artérielle pulmonaire.
PCT/CN2021/000082 2020-04-09 2021-04-09 Composé destiné au traitement de l'hypertension artérielle pulmonaire et son application WO2021203779A1 (fr)

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