CN114671856B - Polysubstituted uracil derivative and use thereof - Google Patents

Polysubstituted uracil derivative and use thereof Download PDF

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CN114671856B
CN114671856B CN202111587346.2A CN202111587346A CN114671856B CN 114671856 B CN114671856 B CN 114671856B CN 202111587346 A CN202111587346 A CN 202111587346A CN 114671856 B CN114671856 B CN 114671856B
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butyl
chf
atoms
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CN114671856A (en
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张铮
池波
韩伟
马发城
刘楚怡
李明
左应林
王晓军
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Guangdong HEC Pharmaceutical
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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention discloses a polysubstituted uracil derivative and application thereof. In particular, the present invention relates to a novel class of polysubstituted uracil derivatives and pharmaceutical compositions comprising the same, which are useful as chymase inhibitors. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and the application of the compound and the pharmaceutical composition in preparing medicaments for treating heart failure, myocardial infarction and other vascular diseases.

Description

Polysubstituted uracil derivative and use thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to novel polysubstituted uracil derivatives and application thereof, and further relates to a pharmaceutical composition containing the compounds, and a use method and application thereof. In particular, the novel polysubstituted uracil derivatives and/or pharmaceutical compositions thereof of the present invention are useful as chymase inhibitors for the prevention, treatment or alleviation of vascular diseases of interest, such as heart failure or myocardial infarction.
Background
Cardiovascular disease (Cardiovascular diseases, CVD) is one of the leading causes of death worldwide. CVD refers to ischemic or hemorrhagic diseases of heart, brain and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc., such as hypertension, coronary artery disease, cardiomyopathy, vascular disease, congenital heart disease, arrhythmia, pericardial disease, heart attack, stroke, etc. Hypertension, high cholesterol, smoking, obesity and diabetes are major risk factors for developing cardiovascular disease. Health conditions such as lifestyle, age and family history also increase the risk of heart disease. While age, gender, genetic and family history are unalterable risks of susceptibility to cardiovascular disease, the burden of cardiovascular disease can be reduced by performing low fat and low sodium diets, maintaining physical activity and avoiding weight gain, among other methods. Several recent preclinical and several clinical studies point to a relatively unrecognized fact that chymase inhibitors may have significant therapeutic advantages over other treatments in preventing the progression of heart and vascular disease.
Chymase (Chymase) is a chymotrypsin-like serine protease whose macromolecular complex with heparin proteoglycans is stored in secretory vesicles of mast cells. After mast cells are activated, chymase is released into the extracellular matrix to cope with inflammatory signals, tissue damage and cellular stress. There is growing evidence that chymase of mast cells is one of the key factors contributing to tissue remodeling and CVD progression. Activated mast cells play an important role in wound healing and inflammation elimination, such as fibrosis, angiogenesis and myocardial remodeling of the wound (Miyazaki et al, pharmacol. Ther,112 (2006), 668-676; shiota et al, J. Hypertens,21 (2003), 1823-1825). An increase in the number of mast cells was observed in the case of heart failure, myocardial infarction and ischemia, in the case of human atherosclerotic plaques and abdominal aortic aneurysms (Kovanen et al Circulation,92 (1995), 1084-1088; libby and Shi et al Circulation,115 (2007), 2555-2558; bacani and Frishman et al, cardiol. Rev,14 (4) (2006), 187-193). Chymase-positive mast cells play an important role in airway vascular remodeling in asthma and chronic obstructive pulmonary disease. It has been found that an increase in the number of mast cells is found in the intrabronchial biopsy of asthmatic patients (Zanini et al, J. Allergy Clin Immunol 120 (2007), 329-333). In addition, chymase is also suspected to be one of the causes of a variety of kidney diseases such as diabetic nephropathy and polycystic kidney disease (Huang et al, J.am.Soc.Nephrol,14 (7), (2003), 1738-1747; mcPherson et al, J.am.Soc.Nephrol,15 (2), (2004), 493-500).
Chymase is mainly involved in the production of angiotensin II in the heart, arterial wall and lungs. Early studies by the cleveland clinic researchers demonstrated for the first time the role of chymase as an Ang II (angiotensin II) forming enzyme (uarta H et al, j. Biol. Chem,1990,265 (36): 22348-57). Over the past several decades, several studies have demonstrated and expanded the importance of chymase as a synthase for the Ang II production pathway (Chandrasekharan UM et al Science 1996,271 (5248):502-5). Subsequent studies of human and rodent heart Ang- (1-12) treatment showed that either Ang I or Ang- (1-12) directly formed Ang-II enzymes were chymase-based (Ahmad S et al, J.Am.Soc. Hypertens,2013 (2): 128-36). Ang II (angiotensin II) is an effector molecule that effects blood pressure regulation and water and electrolyte balance control mainly by acting on the cell surface nuclear membrane of the vessel wall, the renal tubule, glomerulus, and multiple target receptors of the adrenal gland. When angiotensin II binds to angiotensin receptor, corresponding physiological effects are caused, including systemic arteriole and venous constriction, blood pressure rise and blood return quantity increase; stimulating adrenal synthesis and release of aldosterone. Thus inhibiting chymase activation can reduce angiotensin production, and can control vasoconstriction and blood pressure elevation to a certain extent.
The possibility of treating various cardiovascular diseases with chymase inhibitors has been demonstrated in many animal experimental studies. Chymase inhibitors, for example, are very useful for treating myocardial infarction (Jin et al, pharmacol. Exp. Ther,309 (2004), 409-417), experiments have shown that when a coronary artery ligation in a dog causes ventricular arrhythmias, the production of angiotensin II in the heart is promoted, enhancing chymase activity. In recent years, bayer corporation is developing an oral small molecule chymase inhibitor BAY-1142524 for the treatment of heart failure and diabetic nephropathy, and preclinical results indicate that the compound can improve cardiac function after myocardial infarction in hamsters. Whereas clinical primary results also showed good safety, tolerability and pharmacokinetic properties of BAY-1142524 in healthy subjects. At present, bayer company has developed a second-stage clinical experiment of diabetic nephropathy, and further verifies the curative effect and safety of the novel chymase inhibitor.
Chymase inhibition thus constitutes an effective method of treating cardiovascular disorders, inflammatory, allergic and various fibrotic disorders.
Disclosure of Invention
The invention provides a novel polysubstituted uracil derivative used as chymase inhibitor, which is used for preventing, treating or relieving heart failure or myocardial infarction and other vascular diseases. Experiments show that the polysubstituted uracil derivative has stable property, good safety, good pharmacodynamics and pharmacokinetics, such as good chymase inhibition activity, good bioavailability, good metabolic stability and the like. Therefore, the compound has good clinical application prospect.
The invention also provides a method for preparing the compounds, a pharmaceutical composition containing the compounds and application of the compounds and/or the pharmaceutical composition of the compounds in preparing medicines.
In one aspect, the present invention relates to a compound which is a compound of formula (I), or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),
wherein: each m, A, R 1 、R 2 、R 3 And R is 4 Has the meaning as described in the present invention.
In one embodiment, the compounds of the present invention may be compounds of formula (IIa) or (IIb), or stereoisomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,
wherein: each m, A, R 1 、R 2 、R 3 And R is 4 Has the meaning as described in the present invention.
In one embodiment, A is a saturated or partially unsaturated C 3-10 Carbocycles, heterocyclic groups of 3-8 atoms, C 6-10 Aryl or heteroaryl of 5-12 atoms, wherein said saturated or partially unsaturated C 3-10 Carbocycles, heterocyclic groups of 3-8 atoms, C 6-10 Aryl and heteroaryl consisting of 5-12 atoms are independently unsubstituted or substituted with 1, 2, 3, 4 or 5 members selected from D, F, cl, br, I, NO 2 、CN、OH、NH 2 、C 1-3 Alkyl, C 1-3、 Alkyl, C 1-3 Alkoxy and C 1-3 The substituent of the haloalkoxy group is substituted.
In one embodiment, A is C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclyl of 3-8 atoms or heteroaryl of 5-12 atoms, wherein said C 3-8 Cycloalkyl, C 6-10 Aryl, 3-8 atom heterocyclyl and 5-12 atom heteroaryl are independently unsubstituted orIs selected from D, F, cl, br, I, NO by 1, 2, 3, 4 or 5 2 、CN、OH、NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 The substituent of the haloalkoxy group is substituted.
In one embodiment, each R 1 H, D, halogen, NO independently 2 、CN、OH、NH 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms.
In one embodiment, m is 0, 1, 2, 3, or 4.
In one embodiment, R 2 Is thatWherein R is 5 And R is 6 Having the meaning described in the present invention.
In one embodiment, R 5 is-NR n -, -O-, -S-or-CR c R d -; wherein R is n 、R c And R is d Having the meaning described in the present invention.
In one embodiment, R n H, D, C of a shape of H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 3-8 cycloalkyl-C 1-6 Alkylene, heterocyclyl-C of 3-8 atoms 1-6 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-6 Alkylene, heteroaryl-C consisting of 5-12 atoms 1-6 Alkylene or heteroaryl consisting of 5 to 12 atoms.
In one embodiment, R c And R is d Each independently H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl or aryl radicalsHeteroaryl groups of 5 to 12 atoms.
In one embodiment, R 6 H, D, C of a shape of H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkyl-C 1-6 Alkylene, heterocyclyl of 3 to 8 atoms, heterocyclyl-C of 3 to 8 atoms 1-6 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-6 Alkylene, heteroaryl-C consisting of 5-12 atoms 1-6 Alkylene or heteroaryl consisting of 5 to 12 atoms.
In one embodiment, R 3 H, D, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl, heteroaryl consisting of 5-12 atoms, -NR a1 R b OR-OR a Wherein said C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl and heteroaryl consisting of 5-12 atoms are independently unsubstituted or substituted with 1, 2, 3, 4 or 5 members selected from D, F, cl, br, I, NO 2 、CN、OH、NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituted by a substituent of haloalkoxy; wherein R is a1 、R a And R is b Having the meaning described in the present invention.
In one embodiment, R a1 、R a And R is b Each independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclyl consisting of 3 to 8 atoms or heteroaryl consisting of 5 to 12 atoms.
In one embodiment, R 4 H, D, halogen or C 1-6 An alkyl group.
In some embodiments, A is C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic radicals of 3-6 atoms or 5-10 atomsHeteroaryl, wherein said C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclyl of 3-6 atoms or heteroaryl of 5-10 atoms independently unsubstituted or substituted with 1, 2, 3, 4 or 5 members selected from D, F, cl, br, I, NO 2 、CN、OH、NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 The substituent of the haloalkoxy group is substituted.
In some embodiments, each R 1 Independently selected from H, D, halogen, NO 2 、CN、OH、NH 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, R n H, D, C of a shape of H, D, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl-C of 3-6 atoms 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl-C consisting of 5-10 atoms 1-4 Alkylene or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, R c And R is d Each independently H, D, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, R 6 H, D, C of a shape of H, D, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl-C of 3-6 atoms 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl-C consisting of 5-10 atoms 1-4 Alkylene or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, R 3 H, D, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl, heteroaryl consisting of 5-10 atoms, -NR a1 R b OR-OR a The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl and heteroaryl consisting of 5-10 atoms are independently unsubstituted or substituted with 1, 2, 3, 4 or 5 members selected from D, F, cl, br, I, NO 2 、CN、OH、NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituted by a substituent of haloalkoxy; wherein R is a1 、R a And R is b Having the meaning described in the present invention.
In some embodiments, R a1 、R a And R is b Each independently H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, R 4 H, D, halogen or C 1-4 An alkyl group.
In some embodiments, a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, which The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl groups independently being unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, NO 2 、CN、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy.
In one embodiment, each R 1 H, D, F, cl, br, I, NO independently 2 、CN、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In one embodiment, R n H, D is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In one embodiment, R c And R is d Each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl A group, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl group.
In one embodiment, R 6 H, D is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In one embodiment, R 3 H, D, F, cl, br is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopent Group, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -NR a1 R b OR-OR a The method comprises the steps of carrying out a first treatment on the surface of the Wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, NO 2 、CN、OH、NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituted by a substituent of haloalkoxy; wherein R is a1 、R a And R is b Having the meaning described in the present invention.
In one embodiment, R a1 、R a And R is b Each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In one embodiment，R 4 H, D, F, cl, br is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment, it is a compound having one of the following structures or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:
in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention; optionally, it further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In some embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional active ingredients selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vascular peptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloproteinase inhibitors, soluble guanylate cyclase stimulators and activators, and phosphodiesterase inhibitors.
In one aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prevention of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, kidney disease, fibrotic disorders of internal organs or skin fibrosis.
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Biological test results show that the compound has good chymase inhibition activity and can be used as a good chymase inhibitor, thereby having potential effects of preventing occurrence and progress of related diseases.
Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict.
The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification is different from that of the cited document, the disclosure of the present specification controls.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the application, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the application, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present application, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, the articles refer to articles of manufacture that include one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "stereoisomer" refers to a compound having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
The term "chiral molecule" is a molecule that has the property of not overlapping its mirror image; and "achiral molecule" refers to a molecule that may overlap with its mirror image.
The term "enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.
The term "diastereoisomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994.
Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One particular stereoisomer is an enantiomer, and a mixture of such isomers is referred to as an enantiomeric mixture. A50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation.
By "pharmaceutically acceptable" is meant those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
The term "optionally substituted with … …" may be used interchangeably with the term "unsubstituted or substituted with …," i.e., the structure is unsubstituted or substituted with one or more substituents described herein.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a particular substituent. Unless otherwise indicated, a substituent may be substituted at a reasonable position at which each of the groups may be substituted. When more than one position in a given formula can be substituted with one or more specific substituents selected from, then the substituents may be the same or different at each reasonable position in the formula.
The term "unsubstituted" means that the specified group does not carry a substituent.
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1 -C 6 Alkyl "or" C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group.
The term "D" represents a single deuterium atom.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "alkyl" or "alkyl group" as used herein means a saturated, straight or branched, monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 An alkyl group; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms, i.e., C 1-4 An alkyl group; in some embodiments, the alkyl group contains 1 to 3 carbon atoms, i.e., C 1-3 An alkyl group. In some embodiments, C as described in the present invention 1-6 Alkyl includes C 1-4 An alkyl group; in another aspectIn some embodiments, C as described in the present invention 1-6 Alkyl includes C 1-3 An alkyl group.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 2, 2-dimethylbutyl (neopentyl, -CH) 2 CH(CH 3 ) 2 CH 3 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight-chain or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, in which there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 Double bonds, which include the positioning of "cis" and "trans", or the positioning of "E" and "Z". Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl (propenyl, -ch=ch-CH 3 ) 2-propenyl (allyl, -CH) 2 -CH＝CH 2 ) And so on.
The term "alkynyl" denotes a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, in which there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond. In some embodiments, alkynyl groups contain 2 to 8 carbon atoms; in other embodiments, alkynyl groups contain 2 to 6 carbon atoms; in still other embodiments, alkynyl groups contain 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) 1-propargyl (-CH) 2 CH 2 C.ident.CH), 2-alkynylbutyl (-CH) 2 C≡CCH 3 ) 3-propargyl (-C.ident.CCH) 2 CH 3 ) And so on.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, the alkoxy group contains 1 to 3 carbon atoms.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO),n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "haloalkoxy" means an alkoxy group substituted with one or more halogen atoms, wherein alkoxy has the meaning described herein; examples include, but are not limited to, difluoromethoxy (-OCHF) 2 ) Trifluoromethoxy (-OCF) 3 ) Difluoroethoxy (e.g. -OCH) 2 CHF 2 Etc.), trifluoroethoxy groups (e.g. -OCH 2 CF 3 Etc.), and so on.
The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein alkyl has the meaning described herein. Some of these embodiments are those wherein the haloalkyl group contains from 1 to 12 carbon atoms; still other embodiments are haloalkyl groups containing 1 to 10 carbon atoms; still other embodiments are haloalkyl groups containing 1 to 8 carbon atoms; still other embodiments are haloalkyl groups containing 1 to 6 carbon atoms; still other embodiments are haloalkyl groups containing 1 to 4 carbon atoms, and still other embodiments are haloalkyl groups containing 1 to 3 carbon atoms. Examples include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoroethyl (e.g. -CH 2 CF 3 Etc.), etc.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, cycloalkyl groups comprise 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups comprise 3 to 8 carbon atoms; in other embodiments, cycloalkyl groups comprise 4 to 7 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 6 carbon atoms. In some embodiments, cycloalkyl is C containing 7-12 carbon atoms 7-12 Cycloalkyl group further comprising C 7-12 Spirobicycloalkyl, C 7-12 Condensed bicycloalkyl and C 7-12 Bridged bicycloalkyl; in other embodiments, cycloalkyl is C containing 8 to 11 carbon atoms 8-11 Cycloalkyl group further comprising C 8-11 Spirobicycloalkyl, C 8-11 Condensed bicycloalkyl and C 8-11 Bridged bicycloalkyl radicals. In some embodiments, C 3-6 Cycloalkyl specifically refers to a ring containing 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, a heterocyclic group may be a carbon or nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Heterocyclic groups include saturated heterocyclic groups (i.e., heterocycloalkyl groups) and partially unsaturated heterocyclic groups. In some embodiments, the heterocyclyl is a heterocyclyl consisting of 3 to 8 atoms; in other embodiments, the heterocyclyl is a 3-6 atom constituent heterocyclyl. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, or morpholinyl, and the like. The heterocyclic groups may be composed of 3 to 8, as described in the present inventionAn atom or 3-6 atoms, optionally selected from C, N, O or S and at least one atom is N, O or S; wherein the heterocyclic group consisting of 3 to 8 atoms comprises a heterocyclic group consisting of 3 to 6 atoms; the heterocyclic group consisting of 3 to 6 atoms includes heterocyclic groups consisting of 3 to 5 atoms.
The term "consisting of s atoms", where s is an integer, typically describes the number of ring-forming atoms in a molecule where the number of ring-forming atoms is s. For example, piperidinyl is a heterocycloalkyl of 6 atoms, while 1,2,3, 4-tetrahydronaphthyl is a carbocyclyl of 10 atoms.
The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state forms of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom of the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl where R is any suitable substituent).
The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a ring of 3 to 7 atoms, and one or more points of attachment are attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracenyl.
The term "heteroaryl" means monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one ring contains 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen, sulfur, and wherein said heteroaryl has one or more attachment points attached to the remainder of the molecule. When the-CH is present in the heteroaryl group 2 -said-CH, when a group is 2 The group may optionally be replaced by-C (=o) -. Unless otherwise statedIt is clear that the heteroaryl group may be attached to the remainder of the molecule (e.g., the host structure in the formula) at any reasonable point (which may be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and the like. The heteroaryl group may be optionally substituted with one or more substituents described herein. In some embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 atoms, meaning that the heteroaryl contains 1 to 9 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from O, S and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5-6 atoms, meaning that the heteroaryl contains 1-5 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from O, S and N.
The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: greene et al Protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I) or (IIa) or (IIb). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14of the A.C.S. symposium Series, edward B.Roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al, prodrug: design and Clinical Applications, nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al, prodrugs of Phosphates and Phosphonates, journal of Medicinal Chemistry,2008,51,2328-2345.
"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: s.m. berge et al,describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences,1977, 66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionic aldehyde salts, lactate salts, laurate salts, lauryl sulfate, malate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, propionate salts, stearate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl group 4 Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1 -C 8 Sulfonate and aromatic sulfonate.
"nitroxide" in the present invention means that when a compound contains several amine functions, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as methylene chloride.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that are water.
When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the invention may be associated with a water molecule, such as a monohydrate; in another embodiment, one molecule of the compounds of the present invention may be combined with more than one water molecule, such as dihydrate; in yet another embodiment, one molecule of the compounds of the present invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.
The term "treating" any disease or disorder, in some embodiments refers to ameliorating the disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "preventing" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., stopping the progression of at least one clinical symptom of a disease in a subject who may or may not have been predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).
The term "cardiovascular disease" refers to a collective term for cardiovascular and cerebrovascular diseases, describing ischemic or hemorrhagic diseases of the heart, brain and systemic tissues of a patient due to hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc. Such as acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina, myocardial ischemia, myocardial infarction, shock, atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, preeclampsia, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral perfusion disorders, pulmonary hypertension, coronary and peripheral arterial spasms, thrombosis, thromboembolic diseases, edema development (e.g. pulmonary edema, cerebral edema, renal edema or heart failure-related edema), and restenosis (e.g. restenosis after thrombolytic therapy, percutaneous Transluminal Angioplasty (PTA), percutaneous Transluminal Coronary Angioplasty (PTCA), cardiac grafting and bypass surgery), and microvascular and macrovascular injuries (vasculitis), reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, peripheral and cardiovascular diseases, peripheral perfusion disorders, heart failure-related edema, elevated levels of fibrinogen and low density LDL, and elevated levels of activator of fibrinolytic agent (I-1) inhibitors.
Compounds of the invention
In one aspect, the present invention relates to compounds having the structure of formula (I), wherein the variables are as defined above.
In some embodiments, the compounds of the present invention may be of formula (IIa) or (IIb), wherein the variables are as defined above.
Unless otherwise indicated, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the compounds of formula (I) or formula (IIa) or formula (IIb) are included within the scope of the invention.
The disclosed compounds may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention is intended to encompass all stereoisomeric forms of the compounds of formula (I) or (IIa) or (IIb), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, as part of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.
The compounds of formula (I) or (IIa) or (IIb) may exist in different tautomeric forms and all such tautomers, such as those described herein, are included within the scope of the invention.
The compounds of the formula (I) or (IIa) or (IIb) may be present in salt form. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In other embodiments, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying a compound of formula (I) or formula (IIa) or formula (IIb) and/or for isolating an enantiomer of a compound of formula (I) or formula (IIa) or formula (IIb).
Pharmaceutically acceptable acid addition salts can be formed by reacting a compound of formula (I) or (IIa) or (IIb) with an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, clenchamine salt, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodite, isethionate, lactate, lactobionic aldehyde, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, stearate, oleate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactoate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts may be derived include, for example, ammonium salts and metals of groups I to XII of the periodic Table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts may be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (choline), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine and tromethamine.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.
Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H、 3 H、 11 C、 13 C、 14 C、 15 N、 17 O、 18 O、 18 F、 31 P、 32 P、 35 S、 36 Cl and Cl 125 I。
In another aspect, the compounds of the invention include isotopically enriched compounds of the inventionCompounds defined explicitly, e.g. in which a radioisotope, e.g. 3 H、 14 C and C 18 F, or in which non-radioactive isotopes are present, e.g 2 H and 13 C. such isotopically enriched compounds are useful in metabolic studies (using 14 C) Reaction kinetics studies (using, for example 2 H or 3 H) Detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays, or may be used in radiation therapy of a patient. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or (IIa) or (IIb) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation of the present invention using a suitable isotopically labelled reagent in place of the originally used unlabelled reagent.
In addition, heavier isotopes are in particular deuterium (i.e., 2 substitution of H or D) may provide certain therapeutic advantages, which are brought about by a higher metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the context of the present invention is to be regarded as a substituent of a compound of formula (I) or (IIa) or (IIb). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those wherein the crystallization solvent may be isotopically substituted, e.g. D 2 O, acetone-d 6 、DMSO-d 6 Those solvates of (a).
In another aspect, the present invention relates to intermediates for preparing compounds of formula (I) or (IIa) or (IIb).
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or (IIa) or (IIb).
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition comprising a compound of formula (I) or (IIa) or (IIb) or individual stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or prophylactic ingredients.
Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, ansel h.c. et al, ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, williams & Wilkins, philiadelphia; gennaro a.r.et al, remington: the Science and Practice of Pharmacy (2000) Lippincott, williams & Wilkins, philadelphia; and Rowe R.C., handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, chicago.
A method of treatment comprising administration of a compound or pharmaceutical composition of the invention, further comprising an additional therapeutic agent, wherein the additional active ingredient: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vascular peptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloproteinase inhibitors, soluble guanylate cyclase stimulators and activators, and phosphodiesterase inhibitors.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle associated with consistency of administration dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the disclosed compounds and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.
Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected according to their particular function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients that can aid in the production of stable dosage forms can be selected. Certain pharmaceutically acceptable excipients may be selected that facilitate carrying or transporting the compounds of the present invention from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.
The skilled artisan will know and be familiar with the art to which they will be able to select the appropriate amount of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there are a number of resources available to the skilled person, who describe pharmaceutically acceptable excipients and are used to select the appropriate pharmaceutically acceptable excipient. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), the Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
For preparing pharmaceutical compositions from the compounds described herein, the pharmaceutically acceptable carrier may be a solid or liquid carrier. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5 to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing the various compositions can be found in the following: gennaro (ed.), remington's Pharmaceutical Sciences,18 th ed.,1990,Mack Publishing Company Co.,Easton,Pennsylvania。
Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, the contents of each of which are incorporated herein by reference. It is within the scope of the present invention to contemplate its use in addition to any common carrier that is incompatible with the compounds of the present invention, such as by producing any undesirable biological effect, or by interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof, which process comprises mixing the various ingredients. Pharmaceutical compositions comprising the compounds of the present disclosure may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) Parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patch tablets; (4) rectal administration, such as suppositories; (5) inhalations, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adducts or derivatives that provide, directly or indirectly, the compounds of the present invention, or metabolites or residues thereof, when administered to a patient in need thereof.
In one embodiment, the presently disclosed compounds may be formulated into oral dosage forms. In another embodiment, the presently disclosed compounds may be formulated into an inhalation dosage form. In another embodiment, the presently disclosed compounds may be formulated for nasal administration. In yet another embodiment, the presently disclosed compounds may be formulated into transdermal dosage forms. In yet another embodiment, the presently disclosed compounds may be formulated into topical dosage forms.
The pharmaceutical compositions provided by the present invention may be provided in the form of compressed tablets, developed tablets, chewable lozenges, instant tablets, reconstituted tablets, enteric tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, aminated shellac, and cellulose acetate phthalate. Dragees are dragee-enclosed compressed tablets that can facilitate masking of unpleasant tastes or odors and prevent oxidation of the tablet. The film coated tablet is a compressed tablet covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general characteristics as the sugar coating. The composite tablet is a compressed tablet prepared through more than one compression cycle, and comprises a multi-layer tablet, a compression coating or a dry coating tablet.
Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or particulate form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.
The pharmaceutical composition provided by the invention can be provided in a soft capsule or a hard capsule, and can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as a Dry Filled Capsule (DFC), consists of two segments, one segment being filled into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. patent nos.4,328,245;4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.
The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in the form of pellets in another liquid, which may be oil-in-water or water-in-oil. The emulsion may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, for example, acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for accurate and convenient administration.
The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for administration by inhalation to a patient, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions can be formulated into dosage forms suitable for administration by inhalation to a patient using dry powders. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for administration by inhalation to a patient via a nebulizer. Dry powder compositions for delivery to the lungs by inhalation typically comprise a finely powdered compound of the presently disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. The fine powder can be prepared by, for example, micronization and grinding. In general, the size-reduced (e.g., micronized) compound may be produced by a D of about 1 to 10 microns 50 Values (e.g. measured by laser diffraction)Meaning.
Pharmaceutical compositions suitable for transdermal administration may be formulated as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch by ion permeation, as generally described in Pharmaceutical Research,3 (6), 318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with water or oil bases, with appropriate thickening and/or gelling agents and/or solvents. Such a base may include water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickening and gelling agents used according to the nature of the matrix include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or nonionic emulsifiers.
The compounds of the present invention may also be conjugated to soluble polymers as carriers for targeted drugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparaginol or palmitoyl residue substituted polyoxyethylene polylysine. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.
The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for making solutions or suspensions in liquids prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical sciences (see Remington: the Science and Practice of Pharmacy, supra).
Pharmaceutical compositions contemplated for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, freezing point depressants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.
The pharmaceutical compositions provided by the present invention may be administered via rectal suppositories by mixing the drug with suitable non-irritating excipients such as cocoa butter, polyethylene glycol synthetic glycerides, which are solid at ordinary temperatures, and then liquefying or dissolving the drug in the rectal cavity. Because of individual differences, the severity of symptoms can vary considerably and each drug has its unique therapeutic properties, the dosage form and treatment regimen should be determined by the practitioner for each individual precise mode of administration.
The pharmaceutical compositions provided herein may be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.
The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure, or alleviate symptoms of the disease is administered or equilibrated in vivo. The effective amount required for a particular therapeutic regimen will depend upon a variety of factors including the disease being treated, the severity of the disease, the activity of the particular agent being used, the mode of administration, the rate of clearance of the particular agent, the duration of the treatment, the combination, the age, body weight, sex, diet and health of the patient, etc. Other factors considered in the art for "therapeutically effective amounts" are described in Gilman et al, eds., goodman And Gilman's: the Pharmacological Bases of Therapeutics,8 th ed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17 th ed.,Mack Publishing Company,Easton,Pa.,1990。
The appropriate dosage of the compounds of the invention to be administered to a patient can be readily determined by one skilled in the art (e.g., an attending physician, pharmacist or other skilled person) and can vary depending on the health of the patient, age, weight, frequency of administration, use of other active ingredients, and/or the indication for which the compounds are being administered. The dosage of the compounds of the present invention may range from about 0.001 to 500mg/kg body weight/day. In some embodiments, the amount of active compound in a unit dose of the formulation may be varied or adjusted depending on the particular application. In other embodiments, for oral administration, a typical daily dosing regimen suggested may be in the range of about 1 mg/day to about 500 mg/day, given two to four separate doses.
The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration form includes paste, lotion, tablet, capsule, pill, powder, granule, suppository, pellet, lozenge, injection, sterile solution or nonaqueous solution, suspension, emulsion, patch, etc. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (e.g., dextrose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).
The preferred route of administration will vary with clinical characteristics, and the dosage will vary depending on the condition of the patient being treated, and the physician will determine the appropriate dosage for the individual patient. The therapeutically effective amount per unit dose depends on the body weight, physiology and the chosen vaccination regimen. The weight of the compound per unit dose is the weight of the compound per administration and does not include the weight of the carrier (the carrier is contained in the drug).
The pharmaceutical compositions provided by the invention can be formulated for single or multiple dose administration. The single dose formulation is packaged in ampules, vials or syringes. The multi-dose parenteral formulation must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.
The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
In one embodiment, the methods of treatment of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Embodiments of the present invention include treating the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.
In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion and includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin, intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered orally. In another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered by inhalation. In yet another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered intranasally.
In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered at once, or at several times at different time intervals over a specified period of time, depending on the dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be performed until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for a compound of the invention or a pharmaceutical composition comprising a compound of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled artisan. Furthermore, suitable dosing regimens for a compound of the invention or a pharmaceutical composition comprising a compound of the invention, including the duration of time for which the regimen is performed, will depend on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustments to the appropriate dosing regimen may be required for the individual patient's response to the dosing regimen, or as the individual patient needs to change over time.
The compounds of the invention may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately from other therapeutic agents by the same or different routes of administration, or in the same pharmaceutical compositions as they are. This is chosen by the person skilled in the art according to the physical conditions of the patient's health, age, weight, etc. If formulated as a fixed dose, such combination products employ the compounds of the invention (within the dosage ranges described herein) and other pharmaceutically active agents (within the dosage ranges thereof).
Accordingly, in one aspect, the invention includes combinations comprising an amount of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more of the additional therapeutic agents described above.
Furthermore, the compounds of the present invention may be administered in the form of prodrugs. In the present invention, a "prodrug" of a compound of the invention is a functional derivative that, when administered to a patient, ultimately releases the compound of the invention in vivo. When the compounds of the invention are administered in prodrug form, one skilled in the art can practice one or more of the following modes: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; (c) altering in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for the preparation of prodrugs include variants of compounds that cleave chemically or enzymatically in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.
Use of the compounds and pharmaceutical compositions of the invention
The compound and the pharmaceutical composition provided by the invention can be used for preparing medicines for inhibiting chymase and also can be used for preparing medicines for treating or preventing heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, nephropathy, fibrosis diseases of internal organs or skin fibrosis diseases.
In the context of the present invention, a disease of the cardiovascular system or cardiovascular disease is understood to mean, for example, the following diseases: acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina, myocardial ischemia, myocardial infarction, shock, atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, preeclampsia, inflammatory cardiovascular disease, peripheral and cardiovascular disease, peripheral perfusion disorders, pulmonary hypertension, coronary and peripheral arterial spasms, thrombosis, thromboembolic disease, edema development (e.g., pulmonary edema, cerebral edema, renal edema, or heart failure-related edema), and restenosis (e.g., restenosis following thrombolytic therapy, percutaneous Transluminal Angioplasty (PTA), percutaneous Transluminal Coronary Angioplasty (PTCA), cardiac transplantation, and bypass surgery), and microvascular and macrovascular injuries (vasculitis), reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, peripheral and heart vascular disease, peripheral perfusion disorders, heart failure-related edema, elevated levels of fibrinogen and low density LDL, and elevated concentrations of activator of fibrinolytic activator/1 (PAI-1) inhibitors.
In the context of the present invention, the term "heart failure" also includes more specific or related types of diseases, such as acute decompensated heart failure, right heart failure, left heart failure, overall failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart storage disorders, and diastolic and systolic heart failure.
The compounds of the invention may be used, but are in no way limited to, the administration to a patient of an effective amount of a compound or pharmaceutical composition of the invention to prevent, treat or ameliorate chymase-related diseases. The chymase-associated diseases further include, but are not limited to, heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, kidney disease, fibrotic disorders of internal organs, or skin fibrosis.
The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
General synthetic procedure
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined for formula (I) or formula (IIa) or formula (IIb), unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers and used without further purification unless otherwise indicated.
1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. 1 H NMR Spectroscopy with CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, quartet), q (quartet), m (multiplet ), br (broadened, broad), brs (broadened singlet, broad singlet), dd (doublet of doublets, doublet), ddd (doublet of doublet of doublets, doublet), dt (doublet of triplets, doublet), td (triplet of doublets, triplet), tt (triplet of triplets, triplet). Coupling constant J, expressed in hertz (Hz).
The measurement conditions for low resolution Mass Spectrometry (MS) data are: agilent 6120 four-stage HPLC-M (column type: zorbax SB-C18,2.1x30mm,3.5 μm, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O) was detected by UV at 210nm/254nm using electrospray ionization (ESI).
The following abbreviations are used throughout the present invention:
CDC1 3 mu g micrograms of deuterated chloroform
DMSO dimethyl sulfoxide mg
DMSO-d 6 Deuterated dimethyl sulfoxide g gram
mL, mL mu L, mu L micro L
mol mmol
The following synthetic schemes describe the steps for preparing the disclosed compounds of the present invention, wherein R, unless otherwise indicated 2 Having the definition according to the invention.
Synthesis scheme 1
The compound represented by the formula (M9) can be produced by this synthesis scheme 1: the compound represented by the formula (M1) is reacted under the action of NBS to obtain a compound represented by the formula (M2). The compound shown in the formula (M2) reacts under the action of triethylamine to obtain the compound shown in the formula (M3). The compound shown in the formula (M3) reacts under the action of trimethyl silanized diazomethane to obtain the compound shown in the formula (M4). The trimethylsilyl group of the compound represented by the formula (M4) is removed to obtain a compound represented by the formula (M5). The compound shown in the formula (M5) is subjected to chiral catalytic reduction by triethylamine and formic acid to obtain the compound shown in the formula (M6). The compound represented by the formula (M6) and the compound represented by the formula (M7) are coupled to obtain the compound represented by the formula (M8). The compound represented by the formula (M8) is hydrolyzed under strong acid conditions to obtain the compound represented by the formula (M9).
Synthesis scheme 2
The compound of formula (M12) can be prepared by this synthesis scheme 2: the compound shown in the formula (M5) is reduced by sodium borohydride to obtain the compound shown in the formula (M10). The compound represented by the formula (M10) and the compound represented by the formula (M7) are coupled to obtain the compound represented by the formula (M11). The compound represented by the formula (M11) is hydrolyzed under strong acid conditions to obtain a compound represented by the formula (M12).
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.
Examples
Example 1:
compound 1a:
compound 1b:
step one: synthesis of 3-bromo-4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-one
4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-one (10.00 g,49.96 mmol) was dissolved in chlorobenzene (100 mL), N-bromosuccinimide (10.67 g,59.95 mmol) and azobisisobutyronitrile (255 mg,1.49 mmol) were added, and the mixture was heated to 70℃for 1 hour. The reaction mixture was filtered to remove insoluble material and the filter cake was washed with chlorobenzene (20 ml×2), the filtrate was collected and concentrated under reduced pressure to give the title compound as a reddish brown oil (15.10 g, 100%).
Step two: synthesis of 4- (trifluoromethyl) -1H-inden-1-one
3-bromo-4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-one (13.90 g,49.8 mmol) was dissolved in tetrahydrofuran (100 mL), and triethylamine (20.8 mL,150 mmol) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 0.5H. The reaction mixture was removed by suction filtration under reduced pressure, and the filter cake was washed with tetrahydrofuran (20 ml×2), the filtrate was collected, and the resulting residue was purified by silica gel column chromatography (petroleum ether) to give the title compound as a yellow oil (7.80 g, 79%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.95(d,J＝5.9Hz,1H),7.70(d,J＝8.0Hz,1H),7.63(d,J＝7.1Hz,1H),7.51(t,J＝7.6Hz,1H),6.25(d,J＝6.1Hz,1H).
Step three: synthesis of 2- (trifluoromethyl) -1- (trimethylsilyl) -1a,6 a-dihydro-cyclopropa [ a ] inden-6 (1H) -one
Palladium acetate (900 mg,3.93 mmol) was added to a toluene solution (80 mL) of 4- (trifluoromethyl) -1H-inden-1-one (7.80 g,39.00 mmol), the system was cooled to 0℃under nitrogen, and trimethylsilylated diazomethane (39 mL,78mmol,2.0mol/L in n-hexane) was added dropwise, and the mixture was allowed to react at room temperature for 12 hours after the completion of the dropwise addition. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.2), the organic phases were collected, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether) to give the title compound as a yellow semisolid (2.48 g, 22%).
MS(ESI,pos.ion)m/z:285.1[M+H] + 。
Step four: synthesis of 2- (trifluoromethyl) -1a,6 a-dihydro-cyclopropa [ a ] inden-6 (1H) -one
To a solution of 2- (trifluoromethyl) -1- (trimethylsilyl) -1a,6 a-dihydrocyclopropano [ a ] inden-6 (1H) -one (2.48 g,8.73 mmol) in tetrahydrofuran (25 mL) was slowly added tetrabutylammonium fluoride in tetrahydrofuran (26.2 mL,26.2mmol,1 mol/L) under ice bath, and the mixture was allowed to react at 60℃for 2 hours after the completion of the dropwise addition. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (15 ml×2), the organic phases were collected, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =96/4) to give the title compound as a yellow oil (1.03 g, 55.6%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.81(d,J＝7.6Hz,1H),7.73(d,J＝7.7Hz,1H),7.42(t,J＝7.7Hz,1H),3.22(s,1H),2.66–2.53(m,1H),1.75–1.68(m,1H),1.44–1.33(m,1H).
Step five: synthesis of (6S) -2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropa [ a ] inden-6-ol
To a solution of 2- (trifluoromethyl) -1a,6 a-dihydro-cyclopropaneo [ a ] inden-6 (1H) -one (507 mg,2.39 mmol) in methylene chloride (3 mL) under nitrogen was added triethylamine (1.67 mL,11.9 mmol) and ruthenium (II) chloride (16 mg,0.0244 mmol) of (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene), and formic acid (0.51 mL,12 mmol) was added dropwise after heating to 35℃and the reaction was continued for 2H. Ruthenium (II) chloride (16 mg,0.0244 mmol), triethylamine (1.67 mL,11.9 mmol) and formic acid (0.51 mL,12 mmol) were added in addition to the reaction mixture, and the reaction was continued for 2h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (431 mg, 84.21%).
Step six: n (N) 1 Synthesis of methyl-4-nitrobenzene-1, 2-diamine
To a solution of 2-fluoro-5-nitroaniline (20.00 g,128.1 mmol) in N, N-dimethylformamide (150 mL) was added aqueous methylamine (35.00 g,450.8 mmol), and the mixture was reacted at 90℃for 8 hours. The reaction mixture was added with water (500 mL), extracted with ethyl acetate (300 ml×2), the organic phases were combined, washed with water (400 ml×2), the organic phases were collected, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3/7) to give the title compound as a red solid (10.20 g, 47.63%).
MS(ESI,pos.ion)m/z:168.1[M+H] + .
Step seven: synthesis of 1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one
To N 1 To a solution of methyl-4-nitrobenzene-1, 2-diamine (1.67 g,9.99 mmol) in anhydrous tetrahydrofuran (30 mL) was added N, N' -carbonyldiimidazole (1.94 g,12.0 mmol), and the mixture was heated to 65℃and stirred overnight. The reaction mixture was filtered under reduced pressure and the filter cake was collected and dried under vacuum to give the title compound as a yellow solid (1.79 g, 92.8%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)11.41(s,1H),7.99(dd,J＝8.7,2.1Hz,1H),7.74(d,J＝2.1Hz,1H),7.26(d,J＝8.7Hz,1H),3.34(s,3H).
Step eight: synthesis of 3-ethyl-1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one
To a solution of 1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (500 mg,2.58 mmol) in N, N-dimethylformamide (6 mL) was added potassium carbonate (723 mg,5.18 mmol) under an ice bath, followed by iodoethane (0.25 mL,3.1 mmol) dropwise, and the mixture was allowed to react at room temperature for 9 hours. The reaction mixture was slowly poured into ice water (100 mL) and slurried with stirring for 0.5h. Suction filtration under reduced pressure, washing the filter cake with water (20 mL. Times.2), collecting the filter cake, and drying in vacuo gave the title compound as a yellow solid (515 mg, 89.94%).
MS(ESI,pos.ion)m/z:222.1[M+H] + .
Step nine: synthesis of 5-amino-3-ethyl-1-methyl-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one
To a solution of 3-ethyl-1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (515 mg,2.32 mmol) in ethanol (30 mL) was added palladium on carbon (52 mg), hydrogen was replaced 2 times, and the reaction was carried out under a hydrogen gas bag at room temperature for 12 hours. The reaction mixture was removed palladium on carbon by suction filtration under reduced pressure, and the filtrate was collected and concentrated under reduced pressure to give the title compound as a pale pink solid (433 mg, 97.48%).
MS(ESI,pos.ion)m/z:192.1[M+H] + .
Step ten: synthesis of ethyl 1- (3-ethyl-1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate
To a solution of 5-amino-3-ethyl-1-methyl-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (433 mg,2.27 mmol) in ethanol (20 mL) was added ethyl (Z) -3-ethoxy-2- ((ethoxycarbonyl) carbamoyl) acrylate (647 mg,2.49 mmol) and warmed to reflux for 4H. The reaction mixture was then cooled to 60℃and potassium tert-butoxide (280 mg,2.49 mmol) was added and the temperature was raised to reflux for 2h. The reaction mixture was cooled to 60℃and slowly poured into ice 1N hydrochloric acid (100 mL) and stirring continued for 1h. Suction filtration under reduced pressure, washing of the filter cake with ice water (10 mL. Times.2), collecting the filter cake, and concentration under reduced pressure gave the title compound as a white solid (320 mg, 39.34%).
MS(ESI,pos.ion)m/z:359.2[M+H] + .
Step eleven: synthesis of ethyl 1- (3-ethyl-1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxo-3- ((6R) -2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropaneo [ a ] inden-6-yl) -1,2,3, 4-tetrahydropyrimidine-5-carboxylate
Triphenylphosphine (441 mg,1.67 mmol) was added to a mixed solution of ethyl 1- (3-ethyl-1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate (300 mg,0.83 mmol) and (6S) -2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropa [ a ] inden-6-ol (180 mg,0.84 mmol) in tetrahydrofuran (4 mL) and N, N-dimethylformamide (8 mL), and the mixture was cooled to 0℃under nitrogen protection, diisopropyl azodicarboxylate (0.35 mL,1.7 mmol) was slowly added dropwise, and the reaction was continued at 0℃overnight after the completion of the dropwise addition. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the organic phases were collected, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =56/44) to give the title compound as a yellow oil (460 mg, 99.97%).
MS(ESI,pos.ion)m/z:555.2[M+H] + .
Step twelve: synthesis of Compounds 1a and 1b
1- (3-Ethyl-1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxo-3- ((6R) -2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropa [ a ] inden-6-yl) -1,2,3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (460 mg,0.83 mmol) was dissolved in a mixed solvent of glacial acetic acid (6 mL) and concentrated hydrochloric acid (3 mL,12 mol/L), and the mixture was heated to 70℃to react for 1H. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to give a crude product, and chiral produced and purified to give Compound 1a (50 mg) and Compound 1b (60 mg), both as white solids.
Compound 1a: HPLC:99.87%; MS (ESI, pos.ion) m/z 527.0[ M+H ]] + .
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.60(s,1H),7.52(d,J＝7.2Hz,1H),7.37(d,J＝7.5Hz,1H),7.26(d,J＝7.7Hz,1H),7.08(d,J＝39.8Hz,3H),6.43(s,1H),3.96(s,2H),3.47(s,3H),2.99(s,1H),2.20(s,1H),1.35(s,2H),1.29(d,J＝10.4Hz,3H).
Compound 1b: HPLC:99.10%; MS (ESI, pos.ion) m/z 527.0[ M+H ]] + .
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.60(s,1H),7.52(d,J＝7.2Hz,1H),7.37(d,J＝7.5Hz,1H),7.26(d,J＝7.7Hz,1H),7.08(d,J＝39.8Hz,3H),6.43(s,1H),3.96(s,2H),3.47(s,3H),2.99(s,1H),2.20(s,1H),1.35(s,2H),1.29(d,J＝10.4Hz,3H).
Example 2:
compound 2a:
compound 2b:
step one: synthesis of 3-cyclopropyl-1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one
To a solution of 1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (1.00 g,5.18 mmol) and cyclopropylboronic acid (889 mg,10.35 mmol) in dry dichloromethane (15 mL) were added copper acetate (2.82 g,15.5 mmol), triethylamine (3.63 mL,25.9 mmol) and 4A molecular sieve (1.00 g), respectively, and the reaction was stirred at room temperature under oxygen for 8H. The molecular sieve was removed by filtration, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1/1) to give the title compound as a yellow solid (521 mg, 43.2%).
MS(ESI,pos.ion)m/z:234.1[M+H] + .
Step two: synthesis of 5-amino-3-cyclopropyl-1-methyl-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one
Pd/C (52 mg) was added to a solution of 3-cyclopropyl-1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (521 mg,2.23 mmol) in ethanol (30 mL), the mixture was replaced with hydrogen gas 2 times, and the mixture was reacted under a hydrogen gas bag at room temperature for 14 hours. The reaction mixture was removed palladium on carbon by suction filtration under reduced pressure, and the filtrate was collected and concentrated under reduced pressure to give the title compound as a pale pink solid (433 mg, 95.58%).
Step three: synthesis of ethyl 1- (3-cyclopropyl-1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate
To a solution of 5-amino-3-cyclopropyl-1-methyl-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (433 mg,2.13 mmol) in ethanol (30 mL) was added ethyl (Z) -3-ethoxy-2- ((ethoxycarbonyl) carbamoyl) acrylate (608 mg,2.34 mmol) and heated to reflux for 1H. Then cooled to 60 ℃, potassium tert-butoxide (263 mg,2.34 mmol) was added, then warmed to reflux and stirring continued for 2h. The reaction mixture was cooled to 60 ℃, slowly poured into ice 1N hydrochloric acid (200 mL), stirred for 30 min, suction filtered under reduced pressure, the filter cake washed with ice water (20 ml×2), the filter cake collected and dried in vacuo to give the title compound as a white solid (544 mg, 68.78%).
MS(ESI,pos.ion)m/z:371.1[M+H] + .
Step four: synthesis of ethyl 1- (3-cyclopropyl-1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxo-3- ((6R) -2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropan [ a ] inden-6-yl) -1,2,3, 4-tetrahydropyrimidine-5-carboxylate
To a mixed solution of ethyl 1- (3-cyclopropyl-1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate (300 mg,0.81 mmol) in tetrahydrofuran (4 mL) and N, N-dimethylformamide (8 mL) were added (6S) -2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropaneo [ a ] inden-6-ol (173 mg,0.81 mmol) and triphenylphosphine (427 mg,1.62 mmol), and the mixture was cooled to-10 ℃ under nitrogen protection, diisopropyl azodicarboxylate (0.35 mL,1.7 mmol) was slowly added dropwise, and the reaction was continued at-10 ℃ for 1H after the dropwise addition. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the organic phases were collected, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =52/48) to give the title compound as a yellow oil (459 mg, 100.0%).
MS(ESI,pos.ion)m/z:567.2[M+H] + .
Step five: synthesis of Compounds 2a and 2b
1- (3-cyclopropyl-1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxo-3- ((6R) -2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropan [ a ] inden-6-yl) -1,2,3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (350 mg,0.62 mmol) was dissolved in a mixed solvent of glacial acetic acid (6 mL) and concentrated hydrochloric acid (3 mL,12 mol/L), and the mixture was heated to 70℃to react for 1H. The reaction solution was cooled to room temperature, the solvent was then removed under reduced pressure, and the crude product was purified by preparative separation to give compound 2a (50 mg) and compound 2b (42 mg) as white solids.
Compound 2a: HPLC:99.94%; MS (ESI, pos.ion) m/z 539.0[ M+H ]] + .
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.60(s,1H),7.53(d,J＝7.1Hz,1H),7.38(d,J＝7.6Hz,1H),7.27(d,J＝7.7Hz,1H),7.06(d,J＝56.5Hz,3H),6.43(s,1H),3.43(s,3H),3.00(s,1H),2.91(s,1H),2.21(s,1H),1.53(dd,J＝13.3,7.9Hz,1H),1.32(d,J＝7.3Hz,1H),1.14(s,2H),1.03(s,2H).
Compound 2b: HPLC:98.76%; MS (ESI, pos.ion) m/z 539.0[ M+H ]] + .
1 H NMR(600MHz,CDCl 3 )δ8.65(s,1H),7.50(d,J＝7.8Hz,1H),7.25(t,J＝7.6Hz,1H),7.21–7.15(m,2H),7.09(d,J＝8.0Hz,1H),7.05(d,J＝8.2Hz,1H),6.63(d,J＝6.4Hz,1H),3.44(s,3H),2.96–2.89(m,1H),2.83(s,1H),2.28(d,J＝5.6Hz,1H),1.40(dd,J＝8.2,4.2Hz,1H),1.32(dd,J＝14.1,6.9Hz,1H),1.16(d,J＝5.9Hz,2H),1.04(s,2H).
Example 3
Each of the compounds 3a, 3b, 3c and 3d is independently of one of the following structures:
step one: synthesis of 2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropa [ a ] inden-6-ol
To a solution of 2- (trifluoromethyl) -1a,6 a-dihydro-cyclopropaneo [ a ] inden-6 (1H) -one (961 mg,4.53 mmol) in methanol (10 mL) at 0deg.C was slowly added sodium borohydride (196 mg,4.97 mmol), and the reaction was continued at 0deg.C for 1H. The reaction mixture was quenched with 1M diluted hydrochloric acid (10 mL), concentrated under reduced pressure to remove most of the methanol, extracted with water (10 mL), combined with ethyl acetate (10 ml×3), washed with saturated brine (10 ml×2), the organic phases were collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =6/1) to give the title compound as a white solid (745 mg, 76.80%).
MS(ESI,pos.ion)m/z:197.1[M-H 2 O+H] + 。
Step two: synthesis of ethyl 1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2, 4-dioxo-3- (2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropaneo [ a ] inden-6-yl) -1,2,3, 4-tetrahydropyrimidine-5-carboxylate
To a mixed solution of ethyl 1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate (400 mg,1.21 mmol) in anhydrous tetrahydrofuran (4 mL) and anhydrous N, N-dimethylformamide (8 mL) were added 2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropa [ a ] inden-6-ol (258 mg,1.20 mmol) and triphenylphosphine (637 mg,2.42 mmol), and after the dropwise addition was completed, diisopropyl azodicarboxylate (0.49 mL,2.4 mmol) was slowly added dropwise under nitrogen atmosphere to react at-10℃for 1h. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the organic phases were collected, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3/2) to give the title compound as a yellow oil (636 mg, 99.86%).
MS(ESI,pos.ion)m/z:528.2[M+H] + .
Step three: synthesis of Compounds 3a and 3b
1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2, 4-dioxo-3- (2- (trifluoromethyl) -1,1a,6 a-tetrahydrocyclopropa [ a ] inden-6-yl) -1,2,3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (600 mg,1.14 mmol) was dissolved in a mixed solvent of glacial acetic acid (6 mL) and concentrated hydrochloric acid (3 mL,12 mol/L), and the mixture was heated to 80℃to react for 1h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by preparative separation to give a mixture of compounds 3a and 3b (42 mg) and a mixture of compounds 3c and 3d (13 mg) as white solids, which were the same molecular weight and non-corresponding isomers.
Mixture of Compounds 3c and 3d MS (ESI, pos.ion) m/z 500.0[ M+H ]] + ；HPLC:97.89％；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)13.27–12.12(m,1H),8.42(s,1H),7.43(dd,J＝72.4,41.9Hz,6H),6.45(s,1H),2.64(s,1H),2.11(d,J＝30.8Hz,1H),1.23–1.12(m,1H),1.04(s,1H).
Mixture of Compounds 3a and 3b MS (ESI, pos.ion) m/z 500.0[ M+H ]] + ；HPLC:97.88％；
The mixture of compounds 3a and 3b was isolated by chiral preparation to give compound 3a and compound 3b.
Compound 3a: 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.38(s,1H),7.39(d,J＝75.1Hz,6H),6.14(d,J＝89.1Hz,1H),2.70(s,1H),2.30(s,1H),1.46(s,1H),1.22(s,1H).
compound 3b: 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.38(s,1H),7.39(d,J＝75.1Hz,6H),6.14(d,J＝89.1Hz,1H),2.70(s,1H),2.30(s,1H),1.46(s,1H),1.22(s,1H).
biological assay
Example a: enzymatic assay of chymotrypsin-like enzymes
The experimental method comprises the following steps:
1) The enzyme source used was recombinant human chymotrypsin (sigma). The chymotrypsin-like substrate used was N-succinyl-Ala-Ala-Pro-Phe-7-amido-4-methyloumarin.
2) For this assay, the test article was diluted with DMSO, 20nL of test article (1000X) and 10 μl of enzyme solution (2X) were mixed in 384 well plates and incubated at room temperature for 15 minutes, followed by addition of substrate solution (2X), and dynamic reading of the fluorescent signal emitted at 460nm after excitation at 370nm wavelength was performed with Synergy 2.
3) One test compound was assayed twice on the same microtiter plate at 10 different concentrations ranging from 300nM to 0.0152 nM. The data were normalized (enzyme reaction without inhibitor = 0% inhibition, all assay components without enzyme = 100% inhibition) and IC50 values were calculated using GraphPad Prism 5 software.
Compounds in the context of the present invention tested in this assay inhibited chymase activity, the results are shown in table a.
Table A results of in vitro inhibition test of chymase by the inventive Compounds
Test compounds IC 50 (nM) Test compounds IC 50 (nM)
Compound 1a 2.9 Compound 1b 9.3
Compound 2a 3.5 Compound 2b 11.0
Compound 3b 2.7
Experimental results show that the compound has good inhibition effect on chymase.
Example B: pharmacokinetic experiments
The experimental method comprises the following steps:
1) Preparation of compound solution: the test compounds were formulated as solutions in 10% dimethylsulfoxide, 10% RH40 and 80% physiological saline for oral or intravenous administration.
2) Taking 180-220g of male SD rats, randomly dividing into 2 groups, wherein one group is used for intravenous injection of a compound to be tested, the dosage is 1.0mg/kg, and the other group is used for oral administration of the compound to be tested, and the dosage is 5mg/kg; blood was collected at time point 0.083,0.25,0.5,1,2,5,7 and 24 hours after administration.
3) A standard curve of the appropriate range was established based on the sample concentration, and the concentration of the test compound in the plasma sample was determined in MRM mode using the AB SCIEX API4000 type LC-MS/MS. According to the drug concentration-time curve, the pharmacokinetic parameters were calculated using the WinNonLin 6.3 software non-compartmental model method. The results are shown in Table B.
TABLE B pharmacokinetic data of the inventive compounds in SD rats
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The experimental results show that: the compounds of the invention exhibit good pharmacokinetic properties in SD rats.
EXAMPLE C liver microsome stability experiment
The experimental method comprises the following steps:
1) Preparation of compound solution: preparing stock solution of test compound and positive control with dimethyl sulfoxide, and diluting (ACN: H) 2 O=1:1) into working fluid, followed by dilution with potassium phosphate buffer solution to the appropriate concentration of dosing solution.
2) The compound administration solution was added to the above-mentioned liver microsome buffer, mixed well, and approximately equally split-packed into 3 wells. Immediately taking out a proper amount of the mixed solution into a 96 shallow hole plate, adding a proper amount of internal standard working solution (100 ng/ml of propranolol acetonitrile solution) for precipitation, adding a proper amount of NADPH solution for uniform mixing, and putting the mixture into a refrigerator at the temperature of 2-8 ℃ to serve as an initial 0-point sample.
3) Adding a proper amount of solution of the compound and liver microsome at the designed time point, and pre-incubating the system at 37 ℃ for 5-10min. An appropriate amount of potassium phosphate buffer was added at the NCF time point, and an appropriate amount of NADPH was added at the remaining time point to initiate the reaction. The final concentration of microsomes in the experimental system is 0.5mg/mL, the compound is 1 mu M, and the proportion of the organic solvent is less than 1%. After the incubation time is over, a proper amount of internal standard working solution is added to stop the reaction. After centrifugation of the samples, the supernatant was taken and tested in MRM mode using the AB SCIEX API4000 model LC-MS/MS. The results are shown in Table C, which is the experimental results of the stability of the compounds provided in the examples of the present invention in liver microparticles of humans, rats and dogs.
Table C experimental results of stability of the compounds provided in the examples of the present invention in liver microparticles
From table C, it can be seen that the compounds of the present invention exhibit suitable stability in liver microsomes of humans, rats and dogs.
Example D oxidative Metabolic phenotype characterization experiments
The experimental method comprises the following steps:
1) Preparing a compound solution to be tested: preparing stock solution of test compound and probe substrate with dimethyl sulfoxide, and diluting (ACN: H) 2 O=1:1) into working fluid, followed by dilution with potassium phosphate buffer solution to the appropriate concentration of dosing solution.
2) A certain amount of dosing solution and a certain amount of human recombinase are added into potassium phosphate buffer solution, and a mixed solution of a compound/substrate to be tested and the human recombinase is added into a well plate at a set position, and at least two parallel double wells are operated in parallel at each time point. The compound in the experimental system is 1 mu M, and the proportion of the organic solvent is less than 1%. After pre-incubation for 5min at 37 ℃, NADPH/phosphate buffer solution is added into the corresponding hole of each CYP subunit to start the reaction, and after incubation for a certain time, a certain amount of working solution containing an internal standard is used for stopping the reaction. Centrifugation, supernatant was taken and tested in MRM mode using the AB SCIEX API4000 type LC-MS/MS. The experimental results are shown in table D, which is oxidative metabolism phenotype identification data for the compounds provided in the examples of the present invention.
Table D data for identifying oxidative metabolic phenotypes of Compounds provided by examples of the invention
As can be seen from Table D, the compounds of the present invention were not significantly metabolized in the 7 major CYP subtype recombinase system, indicating that they may not be metabolized.
Example E enzyme inhibition assay
The experimental method comprises the following steps:
1) Preparing a compound solution to be tested: preparing stock solution of test compound, positive control and probe substrate with dimethyl sulfoxide, and diluting (ACN: H) 2 O=1:1) into working fluid, followed by dilution with 0.1M potassium phosphate buffer solution to the appropriate concentration of dosing solution.
2) And adding a compound and human liver microsome mixed solution at a set position of a 96-well plate, and operating at least three multiple wells in parallel at each concentration point. The corresponding substrate solution is added into the corresponding hole of each sub-enzyme, the compound in the system is 10 mu M, and the proportion of the organic solvent is less than 1%. After preheating at 37℃NADPH solution was added to start the reaction and after incubation for a certain period of time (recommended incubation time 3A4 is 5min,1A2, 2B6, 2C9, 2D6 is 10min,2C8, 2C19 is 20 min) the reaction was stopped with an internal standard working solution. After centrifugation, the supernatant was collected and subjected to detection in MRM mode using AB SCIEX API4000 type LC-MS/MS. The experimental results are shown in Table E, which is the data for inhibition of the enzyme by the compounds provided in the examples of the present invention.
Table E enzyme inhibition data for compounds provided in the examples of the present invention.
From table E, the compounds of the invention have no risk of inhibition for all 7 major CYP subtypes other than CYP2C 8.
EXAMPLE F hepatocyte enzyme Induction assay
The experimental method comprises the following steps:
1) Preparing a compound solution to be tested: preparing stock solution of the compound to be tested, positive control and negative control with dimethyl sulfoxide, and preparing corresponding inducing incubation solution with culture medium
2) Cryopreserved human primary hepatocytes were thawed at 37℃and seeded at a density of about 5 to 7X 105/mL in 48 wells (200. Mu.L per well). Two plates are typically laid in parallel for enzyme induction testing and cytotoxicity testing, respectively. Incubation of inducer: a plate sample position map was designed prior to the experiment, three wells per compound. According to the sample position diagram of the culture plate, a freshly prepared and preheated dosing solution containing the positive/negative control or the compound to be tested is added to the corresponding well and is continuously dosed for three days, and the dosing solution is changed every day. The enzyme-induced test plate and the cytotoxic test plate were operated in parallel.
3) Cytotoxicity test: after the last administration for about 24 hours, the prepared and preheated substrate solution is added into an enzyme-induced test plate and placed into an incubator for incubation for about 2 hours. The cytotoxic assay plate was incubated with 100-200. Mu.L of 10% CCK-8 solution for about 1.5h. After the incubation time is over, the cell chamber is transferred out, and the absorbance of each cell well at 450nm is measured immediately by using an enzyme-labeled instrument or a spectrophotometer. Enzyme induction detection: the enzyme-induced test plate was removed from the incubator and 0.5mL of cell lysate (typically with RNAiso plus) was added to each well of the plate. cDNA is obtained through RNA extraction and reverse transcription. The expression level of CYP mRNA in the sample was detected by a fluorescent quantitative PCR reaction (set: pre-denaturation, 20s at 95 ℃, PCR reaction, 3s at 95 ℃, 30s at 60 ℃,40 cycles). The experimental results are shown in Table F, which is the hepatocyte enzyme induction data provided by the examples of the present invention.
Table F Compound liver cell enzyme induction data provided by the examples of the invention
Wherein N/A represents undetected.
As can be seen from Table F, the compounds of the present invention have no significant risk of induction for all of the 3 major CYP subtypes at risk of enzyme induction
In the description of the present specification, reference to the terms "one embodiment," "an embodiment," "some embodiments," "examples," "a particular example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, implementation, or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily for the same examples, implementations or illustrations. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the features of the different embodiments, implementations or examples and the different embodiments, implementations or examples described in this specification may be combined and combined by persons skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (8)

1. A compound represented by the formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by the formula (I),
wherein: a is cyclopropyl;
each R is 1 Is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups;
m is 0, 1, 2, 3 or 4;
R 2 is that
R 5 is-NR n -, -O-or-S-;
R n h, D, C of a shape of H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or heterocyclyl consisting of 3 to 8 atoms;
R 6 is C 1-6 Alkyl, or C 1-6 A haloalkyl group;
R 3 is-OR a ，R a Is H or D;
R 4 h or D.
2. The compound of claim 1, wherein each R 1 Is independently H, D, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy groups;
R n h, D, C of a shape of H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or a heterocyclic group consisting of 3 to 6 atoms;
R 6 is C 1-4 Alkyl or C 1-4 A haloalkyl group;
R 3 is-OR a ；R a Is H or D;
R 4 H or D.
3. The compound of claim 1 or 2, wherein each R 1 Is independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;
R n h, D is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl;
R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 or-CH 2 CH 2 CF 3 。
4. The compound of claim 1, which is a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound having one of the following structures:
5. a pharmaceutical composition comprising a compound of any one of claims 1-4, and a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
6. The pharmaceutical composition of claim 5, further comprising one or more additional active ingredients selected from the group consisting of: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vascular peptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, diuretics, kinase inhibitors, matrix metalloproteinase inhibitors, soluble guanylate cyclase stimulators and activators, and phosphodiesterase inhibitors.
7. The pharmaceutical composition of claim 6, wherein the kinase inhibitor is a p-kinase inhibitor.
8. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 7 for the manufacture of a medicament for the treatment or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, renal disease, fibrotic disorders of the internal organs or skin fibrosis.
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