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CN111187252B - Pyridinoyl azaspiroheptane derivatives and their use - Google Patents

Pyridinoyl azaspiroheptane derivatives and their use Download PDF

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CN111187252B
CN111187252B CN201911154247.8A CN201911154247A CN111187252B CN 111187252 B CN111187252 B CN 111187252B CN 201911154247 A CN201911154247 A CN 201911154247A CN 111187252 B CN111187252 B CN 111187252B
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钟文和
金传飞
张英俊
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Guangdong HEC Pharmaceutical
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Abstract

The invention discloses pyridine acyl azaspiroheptane derivatives and application thereof, in particular to novel pyridine acyl azaspiroheptane derivatives and a pharmaceutical composition containing the same, which can be used for activating 5-HT 1F A receptor. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the preparation of therapeutic and 5-HT 1F Use in medicine of receptor-related diseases, in particular migraine.

Description

Pyridinoyl azaspiroheptane derivatives and their use
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to novel pyridine acyl azaspiro heptane derivatives, a pharmaceutical composition containing the compounds, and a use method and application thereof. In particular, the novel pyridine acyl azaspiro heptane derivatives of the present invention are useful for activating 5-HT 1F Receptors for preventing, treating or alleviating 5-HT 1F Receptor-related diseases, especially migraine.
Background
Migraine is a type of episodic and often unilateral pulsating headache, often accompanied by nausea and vomiting, is a common chronic neurovascular disorder, is frequently observed in children and adolescents, reaches the peak of onset in the middle-aged and young, is commonly observed in women, and has a proportion of about 1: 2-3, the prevalence rate of the crowd is 5-10 percent, and genetic background is common.
Migraine is not a fatal disease but can severely affect the social life of a patient. In the united states, migraine causes a socioeconomic burden of dollars 10 to 17 billion. In China, a large number of patients influence work, study and life due to migraine. With the acceleration of the pace of life, the incidence of migraine tends to increase gradually. Recent surveys have found that about 5.7% of men and 17.6% of women have on average more than 1 migraine attacks per year. In addition, there are many people who have a genetic predisposition to migraine.
Migraine is complicated and diverse in pathogenesis, and mainly comprises vascular theory, neurogenic theory, trigeminal vascular theory, biochemical factors and genetic factors. The current drugs for migraine treatment are mainly 5-HT 1B/D The receptor agonist triptan is forbidden for patients suffering from cardiovascular and cerebrovascular diseases and peripheral vascular diseases because the triptan can shrink blood vessels. In addition, 40 to 70 percent of migraine patients have poorer curative effects on triptans, and 1/3 of patients with initial effective treatment can often suffer from headache recurrence, so that the curative effects of the triptans on moderately severe headache patients are obviously reduced. To overcome these adverse effects of triptans, calcitonin Gene Related Peptide (CGRP) receptor antagonists and selective 5-HT 1F Anti-migraine agents of the receptor agonist class have been developed. However, there are a number of drawbacks to CGRP receptor antagonists, such as the fact that olcagepant is only used by intravenous injection and not orally, and long-term use of telcagepant causes elevated liver enzymes, and BI-44370 ceases clinical development due to interactions with cytochrome P450. Therefore, development of new acute phase therapeutic drugs is urgently required. Development of Selective 5-HT 1F Receptor agonist anti-migraine drugs have been considered as a new promising approach.
Since 1938, graham and Wolff work (Arch. Neurol. Psychiary, 39:737-63,1938) has been dominant in theory regarding migraine pathophysiology. They suggested that the cause of migraine is vasodilation of the extracranial blood vessels. This view is supported by the following evidence: ergot alkaloid and sumatriptan as oneWater absorbing 5-HT incapable of crossing the blood-brain barrier 1 Agonists, which can constrict vascular smooth muscle in the head, are effective in the treatment of migraine (Humphrey, et al, ann.NY Acad.Sci.,600:587-600,1990). However, work by the Moskowitz group showed that migraine occurred independent of changes in vessel diameter (Cephalalgia, 12:5-7,1992).
The Moskowitz group suggests that the currently unknown pain trigger stimulates the trigeminal ganglion (which innervates the vasculature in the head tissue), causing the axons on the vasculature to release vasoactive neuropeptides. These released neuropeptides then activate a series of events, resulting in pain. This neurogenic inflammation is blocked by ergot alkaloids and sumatriptan, the blocking mechanism of which involves the 5-HT receptor and is associated with 5-HT located on the vascular fibres of the trigeminal nerve 1D The subtypes are closely related (Neurology, 43 (suppl 1.3): S16-S20,1993). In fact, sumatriptan vs 5-HT 1B And 5-HT 1D The receptor has a high affinity, ki of 10.3nM and 5.1nM, respectively, and this activity shows vasoconstrictor activity.
The 5-hydroxytryptamine receptor, also known as serotonin receptor or 5-HT receptor, is a group of G protein-coupled receptors which occur centrally in the central nervous system and peripherally in the peripheral nervous system and can be divided into seven subfamilies 5-HT 1 、5-HT 2 、5-HT 3 、5-HT 4 、5-HT 5 、5-HT 6 And 5-HT 7 Respectively mediate different physiological activities. Wherein 5-HT 1 The receptor is the most bulky family of 5-HT receptors, currently 5-HT 1A 、5-HT 1B 、5-HT 1D 、5-HT 1E And 5-HT 1F Five subtypes. Isolation of expression of these 5-HT from Kao group 1 One of the receptor subtypes (called 5-HT 1F ) Is described (Proc. Natl. Acad. Sci. USA,90:408-412, 1993). The 5-HT 1F The receptors exhibit pharmacological activity that is significantly different from any of the serotonin receptors disclosed. They found that sumatriptan was not only against 5-HT 1B And 5-HT ID In addition to the strong affinities described above, the receptor has affinities for this receptor subtype, with a Ki of about 23nM. This indicates 5-HT 1F The receptors are in migraineMay play a role in the process.
5-HT 1F Receptors are mainly expressed in mesentery, uterus and brain, but also in parts of the trigeminal vasculature such as cerebral vessels, trigeminal ganglia and the caudal nucleus of the trigeminal nerve, as well as cerebellum, hippocampus and neocortex. As with other 5-HT receptors, 5-HT 1F Receptors are expressed not only in neurons but also in glial cells. Presynaptic 5-HT 1F Activation of the receptor inhibits the release of Calcitonin Gene Related Peptide (CGRP) and blocks neuronal signaling in the tail nucleus of the trigeminal nerve, thereby producing an anti-migraine effect, and this selective 5-HT 1F The receptor agonism greatly reduces the side effects related to vasoconstriction caused by the triptan drugs.
Subsequent development of the 5-HT 1F Various 5-HT of receptor subtypes with relative selectivity 1F Receptor agonists, and this selectivity typically reduces the vasoconstrictor activity specific for other compounds used as prodrugs for the treatment of migraine and related diseases.
As a result of continued research, the inventors have obtained an unexpected new class of selective 5-HT 1F Agonists, which have different chemical and receptor binding properties, inhibit peptide extravasation while avoiding significant vasoconstrictor activity and are therefore useful in the treatment of migraine and other conditions associated with 5-HT 1F Receptor-related diseases. Moreover, the compounds of the present invention have good solubility and thus high suitability in preferred formulations (e.g. sublingual, buccal and/or intranasal formulations).
Disclosure of Invention
The present invention provides a class of 5-HT 1F Novel pyridine acyl azaspiroheptane derivatives of receptor agonists, which are useful for activating 5-HT 1F Receptors, inhibiting neuronal protein extravasation, and thus, can be used in the treatment of disorders resulting from 5-HT 1F Receptor mediated diseases, particularly for the treatment of migraine. And experiments show that the pyridine acyl azaspiro heptane derivatives have stable property, good safety, good pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio (brain plasma ratio), good stability and good stabilityBioavailability or good metabolic stability, etc. Therefore, the kit 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 the pharmaceutical composition containing 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),
Figure BDA0002284376100000021
wherein:
x is N or CR x ；
Each R is 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I, -CN, -NO independently 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (=o) - (C 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, hydroxy-substituted C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl;
R 2 h, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy or hydroxy-substituted C 1 -C 6 An alkyl group;
R 3 、R 4 and R is 5 Each independently is H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy or hydroxy-substituted C 1 -C 6 An alkyl group; and
R 6 h, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (=o) - (C 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, hydroxy-substituted C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl.
In one embodiment, each R 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I, -CN, -NO independently 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 4 Alkyl), -C (=o) - (C 1 -C 4 Alkoxy group), C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkylthio, C 1 -C 4 AlkanolamineC substituted by radicals, hydroxy radicals 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl;
R 2 h, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy or hydroxy-substituted C 1 -C 4 An alkyl group;
R 3 、R 4 and R is 5 Each independently is H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy or hydroxy-substituted C 1 -C 4 An alkyl group.
In another embodiment, each R 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I, -CN, -NO independently 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-CH 3 、-C(＝O)-OCH 3 Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 、-CF 3 、-CHFCH 2 F、-CF 2 CHF 2 、-CH 2 CF 3 、-CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, i-propyloxy, -OCHF 2 、-OCF 3 、-OCHFCH 2 F、-OCF 2 CHF 2 、-OCH 2 CF 3 、-OCH 2 CF 2 CHF 2 Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazine A group, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl, or quinolinyl;
R 2 h, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy;
R 3 、R 4 and R is 5 Each independently is H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, R 6 H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 4 Alkyl), -C (=o) - (C 1 -C 4 Alkoxy group), C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkylthio, C 1 -C 4 Alkylamino, hydroxy-substituted C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl.
In another embodiment, R 6 H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-CH 3 、-C(＝O)-OCH 3 Methyl groupEthyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 、-CF 3 、-CHFCH 2 F、-CF 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, i-propyloxy, -OCHF 2 、-OCF 3 、-OCHFCH 2 F、-OCF 2 CHF 2 、-OCH 2 CF 3 、-OCH 2 CF 2 CHF 2 Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as disclosed herein.
In one embodiment, the invention relates to a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In a further aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed in the present invention for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT 1F Receptor-related diseases.
In one embodiment, the peptide is a peptide corresponding to 5-HT 1F The receptor-related disorder is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, destructive behavior disorder, impulse control disorder, attentionHyperactivity disorder, alcoholism, tobacco abuse, mutism, hair-plucking and hair-nodule, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.
In a further aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed in the present invention for the preparation of a medicament for activating 5-HT 1F A receptor.
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Biological test results indicate that the compounds of the invention can activate 5-HT 1F Receptors, inhibit neuronal protein extravasation, and act as better 5-HT 1F Receptor agonists.
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.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention 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 invention. The present invention 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 invention, 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 invention, 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 invention, 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.
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, which mixture lacks 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:A Practical 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," i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including, but not limited to D, F, cl, br, I, N 3 、-CN、-NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 -C (=o) -alkyl, -C (=o) -alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.
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.
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 "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "D" represents a single deuterium atom.
The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
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, R is a substituent according to the invention).
The term "alkyl" or "alkyl group" as used herein means a saturated, straight or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. 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 ) And so on.
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 A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group comprises 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch) 2 ) Allyl (-CH) 2 CH＝CH 2 ) 1-propenyl (i.e., propenyl, -ch=ch-CH) 3 ) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 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 (i.e., propynyl, -C.ident.C-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 one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-propyloxy, n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-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 ) And so on.
The term "alkylthio" means that the alkyl group is attached to the remainder of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein.
Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH 3 ) Ethylthio (EtS, -SCH) 2 CH 3 ) 1-propylthio (n-PrS, n-propylthio, -SCH) 2 CH 2 CH 3 ) 2-propylthio (i-PrS, i-propylthio, -SCH (CH) 3 ) 2 ) 1-butylsulfanyl (n-BuS, n-butylsulfanyl, -SCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propylsulfanyl (i-BuS, i-butylsulfanyl, -SCH) 2 CH(CH 3 ) 2 ) 2-butylsulfanyl (s-BuS, s-butylsulfanyl, -SCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propylsulfanyl (t-BuS, t-butylsulfanyl, -SC (CH) 3 ) 3 ) And so on.
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups, where the alkyl groups have the meaning as described herein. Suitable alkylamino groups may be mono-or dialkylamino, such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N, N-dimethylamino (dimethylamino), N, N-diethylamino (diethylamino), and the like. The alkylamino group is optionally substituted with one or more substituents described herein.
The term "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.
The term "halogenSubstituted alkyl "means that the alkyl group is substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CHF 2 、-CF 3 、-CHFCH 2 F、-CF 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CF 3 、-CHFCH 3 、-CH 2 CH 2 F、-CF 2 CH 3 、-CH 2 CF 2 CHF 2 Etc. In one embodiment, C 1 -C 6 Haloalkyl comprises fluorine substituted C 1 -C 6 An alkyl group; in another embodiment, C 1 -C 4 Haloalkyl comprises fluorine substituted C 1 -C 4 An alkyl group; in yet another embodiment, C 1 -C 2 Haloalkyl comprises fluorine substituted C 1 -C 2 An alkyl group.
The term "haloalkoxy" means that the alkoxy group is substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -OCHF 2 、-OCF 3 、-OCHFCH 2 F、-OCF 2 CHF 2 、-OCH 2 CHF 2 、-OCH 2 CF 3 、-OCHFCH 3 、-OCH 2 CH 2 F、-OCF 2 CH 3 、-OCH 2 CF 2 CHF 2 Etc. In one embodiment, C 1 -C 6 Haloalkoxy groups comprising fluorine substituted C 1 -C 6 An alkoxy group; in another embodiment, C 1 -C 4 Haloalkoxy groups comprising fluorine substituted C 1 -C 4 An alkoxy group; in yet another embodiment, C 1 -C 2 Haloalkoxy groups comprising fluorine substituted C 1 -C 2 An alkoxy group.
The terms "n-atom composition" or "n-membered" are used interchangeably herein, where n is an integer, typically describing the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, a 5-10 membered heteroaryl represents a heteroaryl consisting of 5, 6, 7, 8, 9 or 10 ring atoms. For another example, a piperidinyl group is a 6-ring-atom-composed heterocyclyl group or a 6-membered heterocyclyl group, and a pyridinyl group is a 6-ring-atom-composed heteroaryl group or a 6-membered heteroaryl group.
The term "carbocyclyl" or "carbocycle" means a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclo groups include spirocarbobicyclo groups and fused carbobicyclo groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group is optionally substituted with one or more substituents described herein.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused rings, bridged rings, and spiro rings. In one embodiment, cycloalkyl groups contain 3 to 10 carbon atoms; in another embodiment, cycloalkyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. Wherein one or more atoms in the ring are independently replaced by heteroatoms having the meaning as described herein. In one embodiment, the heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or moreSubstituted by oxygen atoms to give a ring like SO, SO 2 ，PO，PO 2 Is a group of (2); in yet another embodiment, the heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a ring like SO, SO 2 ，PO，PO 2 Is a group of (2); in another embodiment, the heterocyclyl is a bicyclic heterocyclyl consisting of 7 to 12 ring atoms (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a ring like SO, SO 2 ，PO，PO 2 Is a group of (2). The heterocyclyl group is optionally substituted with one or more substituents described herein.
The heterocyclic group may be a carbon group or a heteroatom group. Wherein, is a ring-CH 2 The group is optionally replaced by-C (=o) -the sulphur atom of the ring is optionally oxidized to S-oxide and the nitrogen atom of the ring is optionally oxidized to N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazalkyl, homopiperazinyl, homopiperidinyl, oxacycloheptyl, thietanyl, oxazanyl, and the like
Figure BDA0002284376100000081
Radical, diaza->
Figure BDA0002284376100000082
Radical, thiazal->
Figure BDA0002284376100000083
Radical, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl, and the like. Examples of sulfur atoms in the heterocyclyl group that are oxidized include, but are not limited to, sulfolane, thiomorpholino 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.
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 rings of 3 to 7 atoms. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups may include phenyl, indenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.
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 system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. Heteroaryl groups are typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "aromatic heterocycle" or "heteroaromatic. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5 to 10 atoms comprises 1,2,3 or 4 heteroatoms independently selected from O, S and N.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-dithiotriazinyl, 1, 3-dithio, 3-triazolyl, 1, 3-triazolyl; the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo [1,2-a ] pyridinyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like.
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). 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.
"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 book 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.
"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).
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are intended to be encompassed within the scope of the 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.
Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the invention may be prepared by oxidizing the corresponding nitrogen-containing basic species at elevated temperatures using customary oxidizing agents, such as hydrogen peroxide, in the presence of an acid such as acetic acid, or by reaction with peracetic acid in a suitable solvent, such as dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
The compounds of formula (I) may be present in the form of salts. In one embodiment, 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 another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying the compound of formula (I) and/or for isolating the enantiomer of the compound of formula (I).
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).
Any formula given in the present invention is also intended to represent the isotopically non-enriched forms of these compoundsForm of the invention. 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 present invention relates to intermediates for preparing compounds of formula (I).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
Description of the Compounds of the invention
The pyridine acyl azaspiroheptane derivatives, pharmaceutically acceptable salts, pharmaceutical preparations and compositions thereof, which are useful for activating 5-HT 1F Receptor, inhibition of neuronal protein extravasation, 5-HT 1F The treatment of receptor-related diseases, particularly migraine, is potentially useful. The invention further describes a method for synthesizing the compounds. The compounds of the present invention exhibit good biological activity.
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),
Figure BDA0002284376100000101
Wherein each R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3 、R 4 、R 5 、R 6 And X has the meaning as described in the present invention.
In one embodiment, X is N or CR x The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is x Has the meaning as described in the present invention.
In one embodiment, each R 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I, -CN, -NO independently 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (=o) - (C 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, hydroxy-substituted C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl.
In one embodiment, R 2 H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy or hydroxy-substituted C 1 -C 6 An alkyl group.
In one embodiment, R 3 、R 4 And R is 5 Each independently is H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy or hydroxyC substituted by radicals 1 -C 6 An alkyl group.
In one embodiment, R 6 H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (=o) - (C 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, hydroxy-substituted C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl.
In one embodiment, each R 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I, -CN, -NO independently 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 4 Alkyl), -C (=o) - (C 1 -C 4 Alkoxy group), C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkylthio, C 1 -C 4 Alkylamino, hydroxy-substituted C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl.
In another embodiment, each R 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I, -CN, -NO independently 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-CH 3 、-C(＝O)-OCH 3 Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 、-CF 3 、-CHFCH 2 F、-CF 2 CHF 2 、-CH 2 CF 3 、-CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, i-propyloxy, -OCHF 2 、-OCF 3 、-OCHFCH 2 F、-OCF 2 CHF 2 、-OCH 2 CF 3 、-OCH 2 CF 2 CHF 2 Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.
In one embodiment, R 2 H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy or hydroxy-substituted C 1 -C 4 An alkyl group.
In another embodiment, R 2 H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, R 3 、R 4 And R is 5 Each independently is H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy or hydroxy-substituted C 1 -C 4 An alkyl group.
In another embodiment, R 3 、R 4 And R is 5 Each independently is H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, R 6 H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 4 Alkyl), -C (=o) - (C 1 -C 4 Alkoxy group), C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkylthio, C 1 -C 4 Alkylamino, hydroxy-substituted C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl.
In another embodiment, R 6 H, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-CH 3 、-C(＝O)-OCH 3 Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 、-CF 3 、-CHFCH 2 F、-CF 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropylOxy, -OCHF 2 、-OCF 3 、-OCHFCH 2 F、-OCF 2 CHF 2 、-OCH 2 CF 3 、-OCH 2 CF 2 CHF 2 Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.
In one embodiment, the compound of the invention is a compound having one of the following structures or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, but in no way limited to:
Figure BDA0002284376100000121
in another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as disclosed herein.
In one embodiment, the invention relates to a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In a further aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed in the present invention for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT 1F Receptor-related diseases.
In one embodiment, the peptide is a peptide corresponding to 5-HT 1F The receptor-related disorder is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social anxiety, generalized anxiety disorderSleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual or post-luteal phase syndrome, borderline personality disorder, destructive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, hair-plucking nodules, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, or dementia.
In another embodiment, the peptide is a peptide which is 5-HT 1F The receptor-related disease is migraine.
In a further aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed in the present invention for the preparation of a medicament for activating 5-HT 1F A receptor.
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition, which comprises a compound shown in a formula (I) or an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate 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.
The type of administration of the compounds used in the methods of the invention may be determined by the particular compound selected, the type of pharmacokinetic profile desired for the route of administration, and the state of the patient.
Formulations suitable for oral, sublingual, intranasal or injection administration are prepared according to methods well known in the pharmaceutical arts and contain at least one active compound. See, e.g., REMINGTON' S PHARMACEUTICAL SCIENCES (16 th ed.1980).
In general, the formulations of the present invention comprise the active ingredient (a compound of formula (I)) and are typically admixed with, diluted with or enclosed in a carrier which may be in the form of a capsule, sachet, paper or other container. When an excipient is used as a diluent, it may be a solid, semi-solid, or liquid material, acting as an excipient, carrier, or medium for the active ingredient. Thus, the formulations may be tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard capsules, gels, suppositories, sterile injectable solutions and sterile packaged powders.
In the preparation of the formulation, it may be necessary to grind the active compound to provide a suitable particle size prior to mixing with the other components. If the active compound is substantially insoluble, it is generally milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, its particle size is adjusted by milling to give a uniform particle size distribution in the formulation, for example, about 40 mesh. In one embodiment of the invention, the particle size is about 0.1 to 100 μm.
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.
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 admixed to avoid interactions that would greatly reduce the efficacy of the disclosed compounds when administered to a patient and/or would result in interactions that are not pharmaceutically acceptable pharmaceutical compositions. 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.
Examples of some suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), 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, viscosity increasers, antioxidants, preservatives (such as methyl and propyl hydroxybenzoates), 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 compounds of the present invention may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.
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 using laser diffraction methods) are defined.
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 administered parenterally, by injection, infusion or implantation, for topical or systemic administration. Parenteral administration as used in the present invention includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
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.
Although the compounds of the present invention may be administered directly without any formulation, the compounds of the present invention are generally administered in the form of a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one active ingredient. These formulations may be administered by a variety of routes including oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular and intranasal administration. Many of the compounds used in the methods of the present invention are effective as injectable and oral compositions.
For transdermal administration, a transdermal delivery device ("patch") is required. Such transdermal patches may be used to continuously or intermittently inject controlled amounts of the compounds of the present invention. The construction and use of transdermal patches for the delivery of drugs is well known in the art. See, for example, US5,023,252. The patch can be made to release drug continuously, pulsatively or on demand.
It is often desirable or necessary to introduce the pharmaceutical composition directly or indirectly into the brain. The direct technique generally involves placing a drug delivery catheter in the ventricular system of the host to bypass the blood-brain barrier. Such an implantable delivery system is described in US5,011,472 for delivering biological factors to specific anatomical regions of the body. The delivery of hydrophilic drugs can be enhanced by intra-arterial infusion of hypertonic solutions that are capable of instantaneously opening the blood-brain barrier.
In a preferred embodiment of the present invention, pharmaceutical preparations are provided which contain at least one of the abovementioned active compounds and are suitable for buccal and/or sublingual or nasal administration. This embodiment provides for administration of the active compound in a manner that avoids gastric complications (e.g., first bypassing gastric system metabolism and/or first passing liver metabolism). This route of administration may also reduce the adsorption time, thereby bringing about a therapeutic effect more quickly. The compounds of the present invention may also provide particularly advantageous solubility profiles, facilitating sublingual/buccal formulations. Such formulations generally require relatively high concentrations of active ingredient in order to deliver a sufficient amount of active ingredient to the limited surface of the sublingual/buccal mucosa for a short duration of contact of the formulation with the sublingual/buccal mucosal surface, such that the active ingredient is absorbed. Thus, the extremely high activity of the compounds of the present invention and their high solubility make them suitable for use in the preparation of sublingual/buccal formulations.
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 on a variety of factors including the disease being treated, the severity of the disease, the activity of the particular drug being used, the mode of administration, the clearance of the particular drug, the treatmentDuration, age, 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 compounds of formula (I) are preferably formulated in unit dosage form containing from about 0.001 to 100mg of active ingredient per dose, more often from about 1.0 to 30mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable excipient as described above.
The active compounds are generally effective over a wide dosage range. For example, the daily dose is typically about 0.0001-30mg/kg body weight. For adult treatment, a particularly preferred dose (single or divided) is about 0.1-15 mg/kg/day. However, it will be understood that the actual amount of compound administered will be determined by the attending physician according to the circumstances, including the condition being treated, the route of administration selected, the compound or compounds actually to be administered, the age, weight and response of the particular patient, and the severity of the patient's symptoms, and therefore, the above dosage ranges should not be limiting in any way. In some cases, dosage levels below the lower limit of the above dosage range may be more suitable, while in other cases higher doses may be employed which do not produce any side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
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 a combination 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 additional therapeutic agents.
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 compounds and pharmaceutical compositions provided by the invention are useful in the preparation of compounds and pharmaceutical compositions useful for activating 5-HT 1F The receptor drugs can also be used for preparing drugs for preventing, treating or alleviating 5-HT 1F A medicament for treating a subject-related disorder, particularly migraine.
In particular, the compounds of the present invention or the amount of compounds in the pharmaceutical compositions are effective to detectably selectively activate 5-HT 1F A receptor.
In particular, the amount of a compound in a compound or pharmaceutical composition of the invention is effective to detectably selectively inhibit neuronal protein extravasation.
The compounds of the invention canApplication to, but in no way limited to, the administration of an effective amount of a compound or pharmaceutical composition of the invention to a patient to prevent, treat or ameliorate 5-HT 1F Receptor-related diseases. Said and 5-HT 1F Receptor-related disorders further include, but are not limited to, migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive compulsive disorder, panic disorder, depression, social anxiety disorder, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, destructive behavior disorders, impulse control disorders, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, hair-plucking nodules, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss and dementia.
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 in formula (I), 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 such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin good Chemies, tianjin Fuchen Chemies, wuhan Xinhua Yuan technology development Co., ltd., qingdao Teng Chemies Co., and Qingdao sea chemical Co.
Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.
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, triplet), q (quateset, quartet), quint (quintet ), m (multiplet, multiplet)Br (broad), brs (broadened singlet, broad singlet), dd (doublet of doublets, doublet), ddd (doublet of doublet ofdoublets, 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 pure compounds were detected by UV at 210nm/254nm using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC).
The following abbreviations are used throughout the present invention:
CH 2 Cl 2 DCM dichloromethane mg
CDC1 3 Deuterated chloroform g
DMSO dimethyl sulfoxide mL, mL milliliter
DMSO-d 6 Mu L, mu L microliters of deuterated dimethyl sulfoxide
EtOAc, EA ethyl acetate nL, nL nanoliter
CH 3 OH, meOH min
CD 3 OD deuterated methanol for h hours
nM nanomole per liter PE Petroleum ether (60-90 ℃ C.)
Mu M micromolar RT, RT, r.t. room temperature per liter
mM millimoles per liter of EDTA-K 2 Ethylene diamine tetraacetic acid dipotassium salt
M mol per liter PEG400 polyethylene glycol 400
ng Nag Boc, BOC t-Butoxycarbonyl
Mu g micrograms cAMP Cyclic adenosine monophosphat
e. Adenosine cyclophosphate
HATU 2- (7-oxybenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate
The following synthetic schemes describe the steps for preparing the disclosed compounds of the present invention, wherein each R, unless otherwise indicated 1a 、R 1b 、R 1c 、R 1d And X has the definition of the invention.
Synthesis scheme 1
Figure BDA0002284376100000201
Wherein R is u H, C of a shape of H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 3 -C 8 Cycloalkyl groups.
The [ (x) ray ]8) The compounds shown can be prepared by the following procedure: the [ (x) ray ]1) The compound shown reacts with methoxymethylamine hydrochloride to obtain the compound shown in the formula2) A compound shown; then [ ]2) The compound shown in the formula3) The compounds shown react to obtain the compound with the formula4) The compounds shown. The [ (x) ray ]4) The compound shown in the formula5) The compounds shown react to obtain the compound with the formula6) The compounds shown. The [ (x) ray ]6) The compound shown in the specification removes Boc protecting group to obtain the formula7) A compound shown; in the presence of a reducing agent (e.g., sodium cyanoborohydride), a compound of formula [ ]7) Azaspiro [3.3] of the illustrated compound]NH of heptane with corresponding aldehyde
Figure BDA0002284376100000202
The Borch reductive amination reaction is carried out to obtain the product8) The target product is shown.
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.
Examples
Example 1 4 Synthesis of fluoro-N- (6- (2-methyl-2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) benzamide
Figure BDA0002284376100000203
Step 1) tert-butyl 6- (methoxy (methyl) carbamoyl) -2-azaspiro [3.3]Synthesis of heptane-2-carboxylic acid esters
Figure BDA0002284376100000204
2- (tert-Butoxycarbonyl) -2-azaspiro [3.3] heptane-6-carboxylic acid (1.5 g,6.2 mmol) and dichloromethane (15 mL) were added to a 100mL one-neck flask at 0deg.C, N-diisopropylethylamine (3 mL,18.2 mmol) and HATU (4.7 g,11.7 mmol) were added and the reaction continued for half-hour under nitrogen; methoxy methylamine hydrochloride (1.2 g,12.3 mmol) was then added and transferred to 25℃for 3 hours; the reaction was stopped, water (20 mL) was added, extracted with dichloromethane (30 ml×2), the organic phase was collected, dried over anhydrous sodium sulfate (1 g) was added, filtered, the filtrate was dried under reduced pressure, and the purification by column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) gave the title compound as a pale yellow oil (1.67 g, 94.0%).
MS(ESI,pos.ion)m/z:285.1[M+H] + ；
Step 2) tert-butyl 6- (6-bromopyridine-2-carbonyl) -2-azaspiro [3.3]Synthesis of heptane-2-carboxylic acid esters
Figure BDA0002284376100000211
2, 6-dibromopyridine (2.8 g,11.8 mmol) and methylene chloride (20 mL) were added to a 100mL single-necked flask at-78℃under nitrogen protection, n-butyllithium (2.5M, 4.2 mL) was added dropwise, and after stirring for 1 hour, tert-butyl 6- (methoxy (methyl) carbamoyl) -2-azaspiro [3.3] heptane-2-carboxylate (1.67 g,5.87 mmol) was added, stirring continued for 2 hours, then water (20 mL) was added to quench the reaction, the organic phase was collected, and after drying under reduced pressure the column chromatography was performed to purify (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a red oil (1.2 g,%).
MS(ESI,pos.ion)m/z:325.3[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.00(dd,J＝7.3,0.9Hz,1H),7.68(dt,J＝7.8,7.4Hz,2H),4.31(quint,J＝8.4Hz,1H),4.04(s,2H),3.86(s,2H),2.50(dd,J＝8.3,4.8Hz,4H),1.44(s,9H).
Step 3) tert-butyl 6- (6- ((4-fluorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3]Heptane- Synthesis of 2-carboxylic acid esters
Figure BDA0002284376100000212
Tert-butyl 6- (6-bromopyridine-2-carbonyl) -2-azaspiro [3.3]]Heptane-2-carboxylic acid ester (600 mg,1.57 mmol), 4-fluorobenzamide (350 mg,2.51 mmol), potassium carbonate (1.5 g,10.9 mmol), cuprous iodide (100 mg,0.52 mmol), (1R, 2R) -N 1 ,N 2 Dimethylcyclohexane-1, 2-diamine (135 mg,0.95 mmol), water (1.5 mL) and toluene (10 mL) were added to a 100mL single-neck flask, and the reaction was continued at 90℃for 12 hours under nitrogen; the reaction was stopped, water (20 mL) was added, extracted with dichloromethane (30 ml×2), the organic phase was collected, dried over anhydrous sodium sulfate (1.5 g) was added, filtered, the filtrate was dried under reduced pressure, and the purification by column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) afforded the title compound as a white solid (0.3 g, 43.4%).
MS(ESI,pos.ion)m/z:440.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.00(dd,J＝7.3,0.9Hz,1H),7.68(dt,J＝7.8,7.4Hz,2H),4.31(quint,J＝8.4Hz,1H),4.04(s,2H),3.86(s,2H),2.50(dd,J＝8.3,4.8Hz,4H),1.44(s,9H).
Step 4) N- (6- (2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) -4-fluorobenzamideSynthesis
Figure BDA0002284376100000213
Tert-butyl 6- (6- ((4-fluorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] heptane-2-carboxylate (430 mg,0.98 mmol) and dichloromethane (10 mL) were added to a 100mL single neck round bottom flask at 25 ℃, methanesulfonic acid (0.3 mL,4.8 mmol) was added and the reaction stirred for a further 10 hours; stopping the reaction, spin-drying under reduced pressure, adding saturated sodium bicarbonate solution (40 mL), and then adding dichloromethane for extraction (40 mL); separating, and drying the organic phase by using anhydrous sodium sulfate (1 g); the mixture was filtered and the filtrate was dried under reduced pressure to give the title compound as a pale yellow solid (320 mg, 86%).
MS(ESI,pos.ion)m/z:340.2[M+H] + ；
Step 5) 4-fluoro-N- (6- (2-methyl-2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) benzamide Synthesis
Figure BDA0002284376100000214
N- (6- (2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) -4-fluorobenzamide (320 mg,0.94 mmol) and methanol (5 mL) were added to a 50mL single neck round bottom flask at 25℃and acetic acid (0.18 mL,3.0 mmol) was added; formaldehyde (40%, 0.2ml,3.5 mmol) was added, and then sodium cyanoborohydride (188 mg,3.0 mmol) was added in portions to the reaction solution. After the reaction was continued for 3 hours, it was quenched by addition of saturated sodium bicarbonate solution (20 mL) and then extracted with dichloromethane (20 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate (2 g); filtration, spin-drying of the filtrate under reduced pressure, and column chromatography separation and purification (dichloromethane/methanol (v/v) =20/1) gave the title compound as a white solid (210 mg, 63.2%).
MS(ESI,pos.ion)m/z:354.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.56(d,J＝12.7Hz,1H),8.52(d,J＝7.8Hz,1H),7.98(s,2H),7.92–7.86(m,1H),7.80(d,J＝6.8Hz,1H),7.23(d,J＝7.4Hz,2H),4.28–4.15(m,1H),3.32(br,5H),2.53–2.29(m,6H).
Example 2 4 Synthesis of chloro-N- (6- (2-methyl-2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) benzamide
Figure BDA0002284376100000221
Step 1) tert-butyl 6- (6- ((4-chlorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3]Heptane- Synthesis of 2-carboxylic acid esters
Figure BDA0002284376100000222
The title compound was prepared by the method described in example 1, step 3 by tert-butyl 6- (6-bromopyridine-2-carbonyl) -2-azaspiro [3.3]Heptane-2-carboxylic acid ester (600 mg,1.57 mmol), 4-chlorobenzamide (370 mg,2.38 mmol), potassium carbonate (1.5 g,10.9 mmol), cuprous iodide (180 mg,0.95 mmol), (1R, 2R) -N 1 ,N 2 Dimethyl cyclohexane-1, 2-diamine (130 mg,0.91 mmol), water (1.5 mL) were prepared by reaction in toluene (10 mL), and the crude product was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (470 mg, 65.5%).
MS(ESI,pos.ion)m/z:456.4[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.56(d,J＝8.2Hz,1H),8.48(s,1H),7.97–7.88(m,3H),7.84(d,J＝7.5Hz,1H),7.52(d,J＝8.6Hz,2H),4.28(p,J＝8.2Hz,1H),4.05(s,2H),3.88(s,2H),2.58–2.43(m,4H),1.45(s,9H).
Step 2) N- (6- (2-azaspiro [ 3.3)]Synthesis of heptane-6-carbonyl) pyridin-2-yl) -4-chlorobenzamide
Figure BDA0002284376100000223
The title compound was prepared as described in example 1, step 4 by reacting tert-butyl 6- (6- ((4-chlorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] heptane-2-carboxylate (470 mg,1.03 mmol) and methanesulfonic acid (0.6 mL,9.6 mmol) in dichloromethane (5 mL) to give the title compound as a pale yellow solid (360 mg, 98.1%).
MS(ESI,pos.ion)m/z:356.1[M+H] + ；
Step 3) 4-chloro-N- (6- (2-methyl-2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) benzamide Synthesis
Figure BDA0002284376100000224
The title compound was prepared as described in example 1, step 5 by reacting N- (6- (2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) -4-chlorobenzamide (360 mg,1.01 mmol), acetic acid (100 mg,1.67 mmol), sodium cyanoborohydride (160 mg,2.53 mmol) and formaldehyde (40%, 0.65mL,9 mmol) in methanol (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a white solid (210 mg, 56.1%).
MS(ESI,pos.ion)m/z:370.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.66–8.38(m,2H),7.93–7.89(m,3H),7.81(d,J＝7.5Hz,1H),7.53(d,J＝8.4Hz,2H),4.24(quint,J＝8.4Hz,1H),3.47–3.13(m,4H),2.49–2.44(m,4H),2.31(s,3H).
Example 3 Synthesis of 2, 4-difluoro-N- (6- (2-methyl-2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) benzamide
Figure BDA0002284376100000231
Step 1) tert-butyl 6- (6- ((2, 4-difluorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3]Heptyl (P) Synthesis of alkyl-2-carboxylates
Figure BDA0002284376100000232
The title compound was prepared by the method described in example 1, step 3 by tert-butyl 6- (6-bromopyridine-2-carbonyl) -2-azaspiro [3.3]Heptane-2-carboxylic acid ester (700 mg,1.84 mmol), 2, 4-difluorobenzamide (600 mg,3.82 mmol), potassium carbonate (1.7 g,12.3 mmol), cuprous iodide (200 mg,1.05 mmol), (1R, 2R) -N 1 ,N 2 Dimethyl cyclohexane-1, 2-diamine (160 mg,1.12 mmol), water (1.5 mL) were prepared by reaction in toluene (10 mL), and the crude product was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (0.5 g, 59.5%).
MS(ESI,pos.ion)m/z:458.1[M+H] + ；
Step 2) N- (6- (2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) -2, 4-difluorobenzamide Finished products
Figure BDA0002284376100000233
The title compound was prepared as described in example 1, step 4 by reacting tert-butyl 6- (6- ((2, 4-difluorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] heptane-2-carboxylate (500 mg,1.09 mmol) and methanesulfonic acid (0.32 mL,5.2 mmol) in dichloromethane (5 mL) to give the title compound as a light yellow solid (390 mg, 99%).
MS(ESI,pos.ion)m/z:358.1[M+H] + ；
Step 3) 2, 4-difluoro-N- (6- (2-methyl-2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) benzoyl Synthesis of amines
Figure BDA0002284376100000234
The title compound was prepared as described in example 1, step 5 by reacting N- (6- (2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) -2, 4-difluorobenzamide (390 mg,1.09 mmol), acetic acid (100 mg,1.67 mmol), sodium cyanoborohydride (82 mg,1.31 mmol) and formaldehyde (40%, 0.65mL,9 mmol) in methanol (5 mL) and separating and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a white solid (170 mg, 41.9%).
MS(ESI,pos.ion)m/z:372.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.98(d,J＝12.9Hz,1H),8.54(d,J＝8.1Hz,1H),8.18(dd,J＝15.4,8.6Hz,1H),7.90(t,J＝7.8Hz,1H),7.84–7.74(m,1H),7.08(t,J＝7.3Hz,1H),7.04–6.93(m,1H),4.55–3.86(m,5H),2.80(s,3H),2.64(d,J＝6.5Hz,4H).
Example 4 4-chloro-2-fluoro-N- (6- (2-methyl-2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) benzenes Synthesis of formamide
Figure BDA0002284376100000241
Step 1) tert-butyl 6- (6- ((4-chloro-2-fluorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] Synthesis of heptane-2-carboxylic acid esters
Figure BDA0002284376100000242
The title compound was prepared by the method described in example 1, step 3 by tert-butyl 6- (6-bromopyridine-2-carbonyl) -2-azaspiro [3.3]Heptane-2-carboxylic acid ester (500 mg,1.31 mmol), 4-chloro-2-fluorobenzamide (350 mg,2.02 mmol), potassium carbonate (1.5 g,10.9 mmol), cuprous iodide (100 mg,0.53 mmol), (1R, 2R) -N 1 ,N 2 Dimethylcyclohexane-1, 2-diamine (135 mg,0.95 mmol), water (1.5 mL)) Prepared by reaction in toluene (10 mL), the crude product was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (418 mg, 66.8%).
MS(ESI,pos.ion)m/z:474.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.00(d,J＝13.8Hz,1H),8.56(d,J＝8.2Hz,1H),8.16(t,J＝8.5Hz,1H),7.93(t,J＝7.9Hz,1H),7.89–7.81(m,1H),7.38(dd,J＝8.5,1.7Hz,1H),7.31(dd,J＝11.7,1.8Hz,1H),4.28(quint,J＝8.4Hz,1H),4.06(s,2H),3.88(s,2H),2.58–2.44(m,4H),1.46(s,9H).
Step 2) N- (6- (2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) -4-chloro-2-fluorobenzamide Finished products
Figure BDA0002284376100000243
The title compound was prepared as described in example 1, step 4 by reacting tert-butyl 6- (6- ((4-chloro-2-fluorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] heptane-2-carboxylate (510 mg,1.07 mmol) and methanesulfonic acid (0.35 mL,5.7 mmol) in dichloromethane (5 mL) to give the title compound as a light yellow solid (400 mg, 99%).
MS(ESI,pos.ion)m/z:374.1[M+H] + ；
Step 3) 4-chloro-2-fluoro-N- (6- (2-methyl-2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) benzals Synthesis of amides
Figure BDA0002284376100000244
The title compound was prepared as described in example 1, step 5 by reacting N- (6- (2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) -4-chloro-2-fluorobenzamide (400 mg,1.07 mmol), acetic acid (100 mg,1.67 mmol), sodium cyanoborohydride (80 mg,1.27 mmol) and formaldehyde (40%, 0.65mL,9 mmol) in methanol (5 mL) and separating and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a white solid (0.21 mg, 50.6%).
MS(ESI,pos.ion)m/z:388.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.00(d,J＝13.4Hz,1H),8.54(d,J＝8.1Hz,1H),8.14(t,J＝8.5Hz,1H),7.91(t,J＝7.8Hz,1H),7.84(d,J＝7.4Hz,1H),7.36(d,J＝8.4Hz,1H),4.33–4.17(m,1H),3.49–3.16(m,4H),2.48(d,J＝8.4Hz,4H),2.35(s,3H).
Example 5 Synthesis of 2,4, 6-trifluoro-N- (6- (2-methyl-2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) benzamide
Figure BDA0002284376100000251
Step 1) tert-butyl 6- (6- ((2, 4, 6-trifluorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] Synthesis of heptane-2-carboxylic acid esters
Figure BDA0002284376100000252
The title compound was prepared by the method described in example 1, step 3 by tert-butyl 6- (6-bromopyridine-2-carbonyl) -2-azaspiro [3.3]Heptane-2-carboxylic acid ester (600 mg,1.57 mmol), 2,4, 6-trifluorobenzamide (350 mg,2.0 mmol), potassium carbonate (1.5 g,10.9 mmol), cuprous iodide (100 mg,0.53 mmol), (1R, 2R) -N 1 ,N 2 Dimethyl cyclohexane-1, 2-diamine (135 mg,0.95 mmol), water (1.5 mL) were prepared by reaction in toluene (10 mL), and the crude product was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (0.51 g, 68.2%).
MS(ESI,pos.ion)m/z:476.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.53(d,J＝8.1Hz,1H),8.37(s,1H),7.94(t,J＝7.9Hz,1H),7.86(d,J＝7.5Hz,1H),6.83(dd,J＝14.5,6.2Hz,2H),4.23(quint,J＝8.3Hz,1H),4.03(s,2H),3.86(s,2H),2.53–2.43(m,4H),1.44(s,9H).
Step 2) N- (6- (2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) -2,4, 6-trifluorobenzamide Synthesis
Figure BDA0002284376100000253
The title compound was prepared as described in example 1, step 4 by reacting tert-butyl 6- (6- ((2, 4, 6-trifluorobenzoyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] heptane-2-carboxylate (510 mg,1.07 mmol) and methanesulfonic acid (0.32 mL,5.2 mmol) in dichloromethane (5 mL) to give the title compound as a pale yellow solid (0.39 g, 97%).
MS(ESI,pos.ion)m/z:376.1[M+H] + ；
Step 3) 2,4, 6-trifluoro-N- (6- (2-methyl-2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) benzals Synthesis of amides
Figure BDA0002284376100000254
The title compound was prepared as described in example 1, step 5 by reacting N- (6- (2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) -2,4, 6-trifluorobenzamide (390 mg,1.04 mmol), acetic acid (100 mg,1.67 mmol), sodium cyanoborohydride (80 mg,1.27 mmol) and formaldehyde (40%, 0.65mL,9 mmol) in methanol (5 mL) and separating and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a white solid (0.22 g, 54.4%).
MS(ESI,pos.ion)m/z:390.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.98(d,J＝12.9Hz,1H),8.54(d,J＝8.1Hz,1H),8.18(dd,J＝15.4,8.6Hz,1H),7.90(t,J＝7.8Hz,1H),7.84–7.74(m,1H),7.08(t,J＝7.3Hz,1H),7.04–6.93(m,1H),4.55–3.86(m,5H),2.80(s,3H),2.64(d,J＝6.5Hz,4H).
Example 65 Synthesis of fluoro-N- (6- (2-methyl-2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) picolinamide
Figure BDA0002284376100000261
Step 1) tert-butyl 6- (6- ((5-fluoropyridine-2-carbonyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] Synthesis of heptane-2-carboxylic acid esters
Figure BDA0002284376100000262
The title compound was prepared by the method described in example 1, step 3 by tert-butyl 6- (6-bromopyridine-2-carbonyl) -2-azaspiro [3.3]Heptane-2-carboxylic acid ester (600 mg,1.57 mmol), 5-fluoropyridine-2-carboxamide (330 mg,2.36 mmol), potassium carbonate (1.5 g,10.9 mmol), cuprous iodide (180 mg,0.95 mmol), (1R, 2R) -N 1 ,N 2 Dimethyl cyclohexane-1, 2-diamine (135 mg,0.95 mmol), water (1.5 mL) were prepared by reaction in toluene (10 mL), and the crude product was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (0.43 g, 62.0%).
MS(ESI,pos.ion)m/z:441.4[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.30(s,1H),8.59(dd,J＝12.3,5.4Hz,2H),8.38(dd,J＝8.7,4.5Hz,1H),7.92(t,J＝7.9Hz,1H),7.87–7.80(m,1H),7.65(td,J＝8.3,2.7Hz,1H),4.36(quint,J＝8.4Hz,1H),4.08(s,2H),3.87(s,2H),2.53(d,J＝8.4Hz,4H),1.46(s,9H).
Step 2) N- (6- (2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) -5-fluoropyridine-2-carboxamide Finished products
Figure BDA0002284376100000263
The title compound was prepared as described in example 1, step 4 by reacting tert-butyl 6- (6- ((5-fluoropyridine-2-carbonyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] heptane-2-carboxylate (430 mg,0.98 mmol) and methanesulfonic acid (0.3 mL,4.88 mmol) in dichloromethane (5 mL) to give the title compound as a light yellow solid (0.33 g, 99%).
MS(ESI,pos.ion)m/z:341.1[M+H] + ；
Step 3) 5-fluoro-N- (6- (2-methyl-2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) picolinamides Synthesis
Figure BDA0002284376100000264
The title compound was prepared as described in example 1 step 5 by reacting N- (6- (2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) -5-fluoropyridine-2-carboxamide (330 mg,0.97 mmol), acetic acid (100 mg,1.67 mmol), sodium cyanoborohydride (70 mg,1.11 mmol) and formaldehyde (40%, 0.65mL,9 mmol) in methanol (5 mL) and separating and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a white solid (207 mg, 60.3%).
MS(ESI,pos.ion)m/z:355.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.98(d,J＝12.9Hz,1H),8.54(d,J＝8.1Hz,1H),8.18(dd,J＝15.4,8.6Hz,1H),7.90(t,J＝7.8Hz,1H),7.84–7.74(m,1H),7.08(t,J＝7.3Hz,1H),7.04–6.93(m,1H),4.55–3.86(m,5H),2.80(s,3H),2.64(d,J＝6.5Hz,4H).
Example 7 5 Synthesis of chloro-N- (6- (2-methyl-2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) picolinamide
Figure BDA0002284376100000271
Step 1) tert-butyl 6- (6- ((5-chloropyridine-2-formyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] Synthesis of heptane-2-carboxylic acid esters
Figure BDA0002284376100000272
The title compound was prepared by the method described in example 1, step 3 by tert-butyl 6- (6-bromopyridine-2-carbonyl) -2-azaspiro [3.3]Heptane-2-carboxylic acid ester (600 mg,1.57 mmol), 5-chloropyridine-2-carboxamide (350 mg,2.23 mmol), potassium carbonate (1.5 g,10.9 mmol), cuprous iodide (100 mg,0.53 mmol), (1R, 2R) -N 1 ,N 2 Dimethyl cyclohexane-1, 2-diamine (135 mg,0.95 mmol), water (1.5 mL) were prepared by reaction in toluene (10 mL), and the crude product was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (0.44 g, 61.2%).
MS(ESI,pos.ion)m/z:457.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.32(s,1H),8.69(d,J＝1.9Hz,1H),8.61(d,J＝8.1Hz,1H),8.29(t,J＝7.2Hz,1H),7.99–7.88(m,2H),7.85(d,J＝7.5Hz,1H),4.37(quint,J＝8.4Hz,1H),4.09(s,2H),3.89(s,2H),2.54(d,J＝8.4Hz,4H),1.46(s,9H).
Step 2) N- (6- (2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) -5-chloropyridine-2-carboxamide Finished products
Figure BDA0002284376100000273
The title compound was prepared as described in example 1, step 4 by reacting tert-butyl 6- (6- ((5-chloropyridine-2-carbonyl) amino) pyridine-2-carbonyl) -2-azaspiro [3.3] heptane-2-carboxylate (440 mg,0.96 mmol) and methanesulfonic acid (0.6 g,6.2 mmol) in dichloromethane (5 mL) to give the title compound as a light yellow solid (0.34 g, 98.9%).
MS(ESI,pos.ion)m/z:357.1[M+H] + ；
Step 3) 5-chloro-N- (6- (2-methyl-2-azaspiro [ 3.3)]Heptane-6-carbonyl) pyridin-2-yl) picolinamides Synthesis
Figure BDA0002284376100000274
The title compound was prepared as described in example 1 step 5 by reacting N- (6- (2-azaspiro [3.3] heptane-6-carbonyl) pyridin-2-yl) -5-chloropyridine-2-carboxamide (340 mg,0.95 mmol), acetic acid (100 mg,1.67 mmol), sodium cyanoborohydride (50 mg,0.79 mmol) and formaldehyde (40%, 0.65mL,9 mmol) in methanol (5 mL) and separating and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a white solid (195 mg, 55.2%).
MS(ESI,pos.ion)m/z:371.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.28(s,1H),8.65(s,1H),8.57(d,J＝8.2Hz,1H),8.26(d,J＝8.4Hz,1H),7.90(dt,J＝16.0,5.4Hz,2H),7.80(d,J＝7.5Hz,1H),4.33(quint,J＝8.4Hz,1H),3.60(s,2H),3.42(s,2H),2.54–2.51(m,4H),2.45(s,3H).
Biological assay
Example a: evaluation of the Compounds of the invention for human 5-HT transfected into CHO-K1 cells 1F Agonism of receptors
The purpose of the experiment is as follows: evaluation of human 5-HT transfected with the inventive Compounds against CHO-K1 cells Using HitHunter cAMP detection kit 1F Agonism of the receptor.
Experimental brief flow: CHO-K1 cells were cultured in 384 microwell plates, cell culture medium (assay complete TM Cell Plating Reagent, DISCOVERX) volume of 20. Mu.L, cell density of 10,000 per well, and 5% CO at 37 ℃ 2 Culturing overnight. The medium was then removed and 15. Mu. L cAMP Assay Buffer (DISCOVERX) was added to each well followed by 5. Mu.L of the test containing 4X total Samples (test compound or 5-HT) and 4X Mao Housu (Mao Housu final concentration 15. Mu.M) were tested and the microplates were incubated at 37℃for 30 minutes. Then 5 μ L cAMP Antibody Reagent (discover x) and 20 μ L cAMP Working Detection Solution (discover x) were added and incubated for 1 hour in the dark, then 20 μ L cAMP Solution A was added and incubated for 3 hours in the dark. The microplate was placed in an microplate reader (PerkinElmer EnvisionTM) to read the luminescence signal intensity. By testing compounds with different concentrations, corresponding luminescence signal intensities are obtained, so that the excitation rate ((1- (Y/Z)). Times.100% = excitation rate) is calculated, wherein Y represents the luminescence signal intensity added to the test sample, Z represents the luminescence signal intensity added only to Mao Housu), then the compound dose-effect curve is calculated by Prism software, and the half-maximum response of the concentration of the agonist is generated to EC 50 The value represents. The results are shown in Table A. The experiment adopts 5-HT as a positive control drug to ensure the normal experimental system.
Table a: human 5-HT transfected by the inventive compound on CHO-K1 cells 1F Results of receptor agonism assay
Example number EC 50 (μM)
Example 3 +++
Example 4 +++
Example 5 +++
Note that: ++ represents 1 mu M<EC 50 <10μM
Experimental results show that the compound of the invention has stronger 5-HT 1F Receptor agonistic activity.
Example B: pharmacokinetic evaluation of Compound of the invention by intravenous injection or gastric lavage in rats, dogs
The inventors performed pharmacokinetic evaluations of the compounds of the invention in rats, dogs. Wherein, the animal information is shown in Table 1.
Table 1: subject animal information table of the invention
Germ line Grade Sex (sex) Weight of body Age of Source
SD rat SPF Male male 180-350g For 6-11 weeks HUNAN SLAC JINGDA EXPERIMENTAL ANIMAL Co.,Ltd.
Beagle dog Common grade Male male 8～12kg For 6-12 months BEIJING MARSHALL BIOTECHNOLOGY Co.,Ltd.
Experimental method
The compound of the invention was administered to the test animals as 5% dmso+60% peg400+35% saline solution or 10%DMSO+10%Kolliphor HS15+30%PEG400+50%Saline solution, and the animals were fasted for 12 hours before administration and were free to drink water. For the intravenous administration group, the administration dose was 0.5mg/kg or 1mg/kg, and intravenous blood was taken (blood taking amount was about 0.15 mL) at the following time points after administration: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours (canine) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours (rat), EDTA-K is added in advance into the blood collection tube 2 As an anticoagulant, the blood samples were centrifuged at 12,000rpm for 2 minutes, and the plasma was collected and stored at-20℃or-70 ℃. For the gavage administration group, the administration dose was 2.5mg/kg or 5mg/kg, and intravenous blood sampling (blood sampling amount about 0.15 mL) was performed at the following time points after administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours (canine) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours (rat), EDTA-K was previously added to the blood collection tube 2 As an anticoagulant, the blood samples were centrifuged at 12,000rpm for 2 minutes, and the plasma was collected and stored at-20℃or-70 ℃.
The collected plasma samples were treated (frozen plasma was thawed at room temperature, vortexed for 15s, 10-20. Mu.L of plasma was taken, 120-150. Mu.L of acetonitrile solution containing an internal standard was added, vortexed for 5min, centrifuged at 4,000rpm for 5min, 100. Mu.L of supernatant was taken, 120-150. Mu.L of methanol-water (v/v=1/1) was added, and the concentration of the compound in the plasma was analyzed by LC-MS/MS. The analysis result shows that the compound has better pharmacokinetic properties in rats and dogs. The compound of the invention has better pharmaceutical property and better clinical application prospect.
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 (10)

1. A compound represented by the formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by the formula (I),
Figure FDA0004046637980000011
wherein:
x is N or CR x ；
Each R is 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I or C independently 1 -C 6 An alkyl group;
R 2 is H;
R 3 、R 4 and R is 5 Each independently is H, F, cl, br, I or C 1 -C 6 An alkyl group; and
R 6 is H or C 1 -C 6 An alkyl group.
2. The compound of claim 1, wherein each R 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I or C independently 1 -C 4 An alkyl group;
R 2 is H;
R 3 、R 4 and R is 5 Each independently is H, F, cl, br, I or C 1 -C 4 An alkyl group.
3. The compound according to claim 1 or 2, wherein each R 1a 、R 1b 、R 1c 、R 1d And R is x H, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl;
R 2 is H;
R 3 、R 4 and R is 5 Each independently H, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl.
4. The compound of claim 1, wherein R 6 Is H or C 1 -C 4 An alkyl group.
5. The compound of claim 1 or 4, wherein R 6 Is H, methyl, ethyl, n-propyl or isopropyl.
6. The compound of claim 1, which is a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound having one of the following structures:
Figure FDA0004046637980000012
Figure FDA0004046637980000021
7. a pharmaceutical composition comprising a compound according to any one of claims 1-6; and
the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT 1F Receptor-related diseases.
9. The use according to claim 8, wherein said peptide is associated with 5-HT 1F The receptor-related disorder is migraine, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive compulsive disorder, panic disorder, depression, social phobia, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual or post-luteal phase syndrome, borderline personality disorder, destructive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, hair-plucking nodules, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.
10. Use of a compound according to any one of claims 1-6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for activating 5-HT 1F A receptor.
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