WO2022161423A1 - 环胺衍生物及其制备方法和应用 - Google Patents

环胺衍生物及其制备方法和应用 Download PDF

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WO2022161423A1
WO2022161423A1 PCT/CN2022/074190 CN2022074190W WO2022161423A1 WO 2022161423 A1 WO2022161423 A1 WO 2022161423A1 CN 2022074190 W CN2022074190 W CN 2022074190W WO 2022161423 A1 WO2022161423 A1 WO 2022161423A1
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compound
pharmaceutically acceptable
group
hydrogen
present
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PCT/CN2022/074190
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English (en)
French (fr)
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程辉敏
温晓明
张佩宇
刘志强
罗岚
赖力鹏
马健
温书豪
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深圳晶泰科技有限公司
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Publication of WO2022161423A1 publication Critical patent/WO2022161423A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a cyclic amine derivative and a preparation method and application thereof.
  • Prostaglandin E2 is a member of the prostaglandin family and has a variety of physiological effects, including mucosal protection, induction of gastric acid secretion in the stomach, generation of fever, hyperalgesia, inflammation, and immunity.
  • the four receptors for PGE 2 EP 1 , EP 2 , EP 3 and EP 4 are widely distributed in various tissues.
  • the EP 4 receptor is characterized by the longest intracellular C-terminal loop when compared to other prostanoid receptors. EP 4 receptors are coupled to G proteins and mediate increased cyclic adenosine monophosphate concentrations. The expression of the EP 4 receptor is controlled by various physiological and pathophysiological processes, as the receptor is involved in ovulation and fertilization, induction of bone formation, T cell factor signaling, prevention of inflammatory bowel disease, promotion of Langerhans cell migration and maturation, and mediates joint inflammation as well as other processes in a collagen-induced arthritis model.
  • the object of the present invention is to provide a new class of novel compounds with EP 4 receptor inhibitory activity and/or good pharmacodynamic/pharmacokinetic properties that can be used as EP 4 receptor antagonists and pharmaceutically acceptable salts thereof, and pharmaceutical compositions using them as active ingredients, and their use in the treatment or alleviation of EP 4 receptor related diseases such as prostaglandin EP 4 receptor mediated diseases.
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, or, R 1 and R 2 and the carbon atom to which they are attached together form a C 3-5 cycloalkyl (eg, cyclopropyl) ;
  • R3 and R4 are each independently selected from the group consisting of hydrogen, halogen (eg, fluorine), C1-3 alkyl; alternatively, R3 and R4 and the carbon atom to which they are attached together form a C3-5 cycloalkyl group (such as cyclopropyl);
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl; alternatively, R 5 and R 6 and the carbon atom to which they are attached together form a C 3-5 cycloalkyl group (eg, cyclopropyl) ;
  • R 7 is none or a substituent selected from the group consisting of halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl (such as trifluoromethyl);
  • R 8 is selected from the group consisting of hydrogen, C 1-3 alkyl
  • n 0, 1 or 2;
  • alkyl and cycloalkyl can also be optionally substituted by one or more (such as 1, 2 or 3) substituents selected from the group consisting of halogen, C 1-3 alkyl, C 1- 3 haloalkyl.
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, or, R 1 and R 2 and the carbon atom to which they are attached together form a cyclopropyl;
  • R3 and R4 are each independently selected from the group consisting of hydrogen, fluorine, C1-3 alkyl, or R3 and R4 and the carbon atom to which they are attached together form a cyclopropyl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen or C 1-3 alkyl
  • R 7 is none or a substituent selected from the group consisting of halogen, cyano, trifluoromethyl;
  • R 8 is selected from the group consisting of hydrogen, C 1-3 alkyl
  • n 0, 1 or 2.
  • R 1 is hydrogen and R 2 is methyl, or, R 1 and R 2 and the carbon atoms to which they are attached together form a cyclopropyl group.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, fluorine, methyl; or R 3 and R 4 and the carbon atoms to which they are attached together form a cyclopropyl group.
  • R 5 and R 6 are each independently hydrogen or methyl.
  • R 7 when R 7 is not null, R 7 is located at the ortho or meta position of -SF 5 .
  • n is 2.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and n are each independently an example compound (as listed in Table 1) the corresponding group in .
  • the compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof is selected from the group consisting of:
  • a pharmaceutical composition comprising a compound as described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrugs, and pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition described in the second aspect is used in the preparation of (i) a drug for inhibiting EP 4 receptor activity and/or (ii) a drug for treating or preventing EP 4 receptor-related diseases and/or (iii) EP 4 Use in receptor antagonists.
  • the EP 4 receptor-related diseases include diseases mediated by prostaglandin E2 and/or prostaglandin EP 4 receptors.
  • the EP 4 receptor related disease is selected from the group consisting of acute and chronic pain, inflammatory pain, diseases associated with inflammation, osteoarthritis and rheumatoid arthritis, cancer, migraine and endometriosis.
  • a method of treating or preventing EP 4 receptor-related diseases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as described in the first aspect or A pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof, or a pharmaceutical composition as described in the second aspect.
  • the subject in need refers to a subject identified or diagnosed as having an EP 4 receptor-related disease.
  • a method for inhibiting EP4 receptor activity in a cell or a subject comprising contacting the cell or administering to the subject a first A compound of the aspect, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof, or a pharmaceutical composition of the second aspect.
  • the cells are mammalian cells.
  • the method when the method is used to inhibit EP 4 receptor activity in cells, the method is non-therapeutic in vitro.
  • the subject is a mammal, preferably a human.
  • the present inventors unexpectedly found a class of compounds with novel structures that have better EP 4 receptor inhibitory activity.
  • the inventors also found that these compounds with novel structures have good pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been completed.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-C6 refers to one to six carbon atoms).
  • the alkyl group generally contains 1-6 carbon atoms (ie, C1-6 alkyl), more preferably, 1-3 carbon atoms, ie, C1-3 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups.
  • One or more (eg, 1-4) positions in the alkyl group can be optionally substituted, and such substitution can occur at any position in the group.
  • haloalkyl is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl propyl and heptachloropropyl.
  • haloalkyl groups also include "fluoroalkyl groups” having branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more fluorine atoms.
  • cycloalkyl is meant to include saturated monocyclic, bicyclic or polycyclic cyclic alkyl groups, such as C3-C8 or C3-C12 cycloalkyl groups.
  • C3-C8 cycloalkyl is meant to include C3, C4, C5, C6, C7, or C8 cycloalkyl.
  • Cycloalkyl groups may also include cycloalkyl groups with structures such as spiro, bridged, and paracyclic structures.
  • Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
  • substituted or unsubstituted cycloalkyl groups such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included in the definition of "cycloalkyl".
  • C5-C12 fused bicyclic refers to include C5, C6, C7, C8, C9, C10, C11, C12 bicycloalkyl, including but not limited to: Wait.
  • C5-C12 spirobicyclic refers to include C5, C6, C7, C8, C9, C10, C11, C12 bicycloalkyl, including but not limited to: Wait.
  • the cycloalkyl group is preferably a monocyclic cycloalkyl group containing 3 to 5 carbon atoms (ie, C 3-5 ), such as cyclopropyl, cyclobutyl, cyclopentyl.
  • halo or halogen includes fluorine, chlorine, bromine and iodine.
  • cyano refers to -CN.
  • the above-mentioned groups such as alkyl, haloalkyl and the like may be substituted or unsubstituted.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1 -C6 ureido group, etc.
  • a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to Alkyleneoxy, etc.
  • the terms "compound of the present invention” or “active ingredient of the present invention” are used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope thereof Compounds (eg, deuterated compounds) or prodrugs. The term also includes racemates, optical isomers.
  • the compound of the present invention has the structure shown in formula I
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.
  • R 1 and R 2 are each independently selected from hydrogen, C 1-3 alkyl, or R 1 and R 2 together form a cyclopropyl;
  • R 3 and R 4 are each independently selected from hydrogen, fluorine, C 1 -C 3 alkyl, or R 3 and R 4 together form a cyclopropyl;
  • R 5 and R 6 are each independently selected from hydrogen or C 1-3 alkyl
  • R 7 is selected from hydrogen, halogen, cyano, trifluoromethyl
  • R 8 is selected from hydrogen, C 1-3 alkyl
  • n 0, 1 or 2;
  • R1 is hydrogen and R2 is methyl or R1 and R2 together form a cyclopropyl ;
  • R3 and R4 are independently selected from hydrogen, fluoro, methyl or are taken together to form a cyclopropyl
  • R 5 and R 6 are each independently selected from hydrogen or methyl
  • R 7 is hydrogen
  • R8 is hydrogen
  • n is 2.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt".
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties or moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lac
  • Certain compounds of the present invention may contain acidic moieties or moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (eg, organic amines) such as benzathine, dicyclohexylamine , Hepamine (salt with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.
  • hydrate refers to a complex formed by the coordination of a compound of the present invention with water, such as a monohydrate.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds (also referred to as isotopic compounds), which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds.
  • the term "stable" refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out at room temperature to 90°C under the protection of inert gas and in a suitable solvent, and the reaction time is usually 2-24 hours.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 have the definitions described in the present invention.
  • the method includes the following steps:
  • Compound 1-3 is reacted with p-pentafluorothiobenzyl bromide derivative in an inert solvent (eg DMF) to form compound 1-4; preferably, in the presence of Cs 2 CO 3 .
  • an inert solvent eg DMF
  • reaction solvent reaction temperature, reaction time, catalyst, etc.
  • reaction time reaction time, catalyst, etc.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent EP 4 receptor inhibitory activity and is an EP 4 receptor antagonist
  • the pharmaceutical compositions of the present invention are used to prevent and/or treat or alleviate EP 4 receptor-related diseases such as prostaglandin E 2 / prostaglandin EP 4 receptor mediators leading to diseases including: acute and chronic pain, inflammatory pain, conditions associated with inflammation, osteoarthritis and rheumatoid arthritis, cancer, migraine and endometriosis.
  • the compounds of the present invention have analgesic and anti-inflammatory activity.
  • the compounds of the present invention are used as analgesics.
  • they are useful in the treatment of: chronic joint pain (eg, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis), musculoskeletal pain; Back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other Pain associated with viral infections such as the common cold; rheumatic fever; functional bowel disorders such as pain associated with non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; postoperative pain; headache ; toothache; and dysmenorrhea.
  • chronic joint pain eg, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis
  • Neuropathic pain syndrome may develop after damage to neurons, and the pain may persist for months or years even after the initial damage has healed. Neuronal damage can occur in peripheral nerves, dorsal roots, spinal cord, or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that causes them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; nonspecific low back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; postherpetic neuralgia; trigeminal neuralgia; Pain from amputation, cancer, toxins, or chronic inflammatory conditions.
  • neuropathic pain are varied and are often described as natural shooting pain and stabbing or burning pain.
  • pain associated with normally non-painful sensations such as "tingling" (paraesthesia and dysesthesia), increased sensitivity to touch (hyperesthesia), pain sensations following innocuous stimuli ( dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (hot, cold, mechanical hyperalgesia), persistent pain sensation after removal of the stimulus (hyperalgesia) or Absence or deficiency of selective sensory pathways (hypoalgesia).
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to substances that aid in the formulation and/or administration and/or absorption of an active agent by an individual, and may be included in the compositions of the present disclosure without causing significant adverse toxicological effects in the individual.
  • Non-limiting examples of pharmaceutically acceptable carriers and excipients include water, NaCl, physiological saline solution, lactated Ringer's, conventional sucrose, conventional dextrose, binders, fillers, disintegrants, lubricants, Coatings, sweeteners, flavors, saline solutions (eg Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrole alkanes and pigments, etc.
  • Such formulations can be sterilized and, if desired, with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers that do not deleteriously react with or interfere with the activity of the compounds provided herein , a mixture of salts, buffers, colorants and/or fragrances that affect osmotic pressure.
  • adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers that do not deleteriously react with or interfere with the activity of the compounds provided herein , a mixture of salts, buffers, colorants and/or fragrances that affect osmotic pressure.
  • compositions of the present invention may be in solid or liquid form.
  • compositions in solid form may contain suitable excipients such as fillers, lubricants, binders, wetting agents, disintegrating agents, coloring and flavoring agents and mixtures thereof.
  • suitable excipients such as fillers, lubricants, binders, wetting agents, disintegrating agents, coloring and flavoring agents and mixtures thereof.
  • tablets may contain pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, talc, lactose, magnesium stearate, sucrose, stearic acid, mannitol.
  • compositions in liquid form can be solutions, suspensions, emulsions, syrups, elixirs.
  • compositions in liquid form may contain suspending agents, emulsifying agents, carriers, preservatives and coloring, flavoring agents.
  • compositions of the present invention can be administered by parenteral, oral, buccal, sublingual, nasal, rectal, topical, or transdermal administration.
  • Pharmaceutical compositions for oral administration are generally preferred.
  • compositions of the present invention suitable for oral administration will typically be discrete units in solid form, such as in the form of tablets, capsules, cachets, powders, granules, lozenges, patches, suppositories, pills, or In liquid form, eg, liquid preparations, injectable or infusible solutions or suspensions.
  • the precise amount of compound to provide a therapeutically effective amount of the compound to an individual will depend on the mode of administration, the type and severity of the disease and/or disorder, and the characteristics of the individual, such as general health, age, sex, weight, and tolerance to the drug . Those of ordinary skill in the art will be able to determine appropriate dosages based on these and other factors. When administered in combination with other therapeutic agents, the "therapeutically effective amount" of any other therapeutic agent will depend on the type of drug used.
  • Appropriate doses are known for the approved therapeutics and can be adjusted by one of ordinary skill in the art according to the individual's condition, the type of disorder being treated, and the amount of the compound of the invention used, for example, as reported in the literature and in Dosage recommended in Physician's Desk Reference (57th ed., 2003).
  • the content of the active ingredient is usually 0.000001-1 wt %, preferably 0.00001-1 wt %, and most preferably 0.0001-0.1 wt %.
  • subjects to which the pharmaceutical composition or therapeutic agent of the present invention is administered include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates and stereoisomers are mixed to form a pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , stereoisomers, or administer the pharmaceutical composition of the present invention for selectively inhibiting EP 4 receptors.
  • the compounds of the present invention have excellent inhibitory activity against EP4 receptors.
  • the compounds of the present invention have better pharmacodynamics and pharmacokinetics.
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 NMR spectrometers, and the determination solvent contained deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) And deuterated methanol (CD 3 OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in units of one millionth (ppm).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 COCD 3 deuterated acetone
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass spectrometry
  • TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • THF tetrahydrofuran
  • MeOH methanol
  • HCl hydrochloric acid
  • Pd(PPh 3 ) 4 palladium tetrakistriphenylphosphine
  • K 2 CO 3 potassium carbonate
  • AcOK potassium acetate
  • NaOH sodium hydroxide
  • H 2 O water
  • TEA triethylamine
  • DIEA N,N-diisopropylethylamine
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • Py pyridine
  • DCE 1,2-Dichloroethane
  • DMSO dimethyl sulfoxide
  • TFA trifluoroacetic acid
  • NaBH(AcO) 3 sodium triacetylborohydride
  • Sn 2 (Bu-n) 6 hexahexylditin
  • AlCl 3 aluminum trichloride
  • CuI cuprous io
  • 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid 0.5 g, 1.96 mmol
  • 4-(1-aminocyclopropyl)-benzoic acid methyl The ester (0.37 g, 1.96 mmol), HATU (0.74 g, 1.96 mmol) and DIEA (0.76 g, 5.88 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 5 hours.
  • the compounds of the present invention have excellent EP4 receptor binding activity and excellent EP4 receptor inhibitory ability.
  • the compound of the present invention has better pharmacodynamics and pharmacokinetics.

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Abstract

提供了一种式I化合物及其制备方法和应用，包括所述化合物作为活性成分的药物组合物或其药学上可接受的盐。还提供了式I化合物在治疗和预防EP 4受体相关疾病的用途。

Description

环胺衍生物及其制备方法和应用 技术领域
本发明属于医药化学领域，具体涉及一种环胺衍生物及其制备方法和应用。
背景技术
前列腺素E 2(PGE 2)是前列腺素类家族的成员，具有多种生理效果，包括黏膜保护、胃中的胃酸分泌的诱导、发热的产生、痛觉过敏、炎症和免疫。PGE 2的四个受体EP 1、EP 2、EP 3和EP 4广泛分布于各种组织中。
EP 4受体的特征在于与其他前列腺素类受体相比时具有最长的细胞内C末端环。EP 4受体与G蛋白耦联，并介导环状单磷酸腺苷浓度升高。EP 4受体的表达受各种生理性和病理生理性过程控制，因为该受体参与排卵与受精、诱导骨形成、T细胞因子信号传导、预防炎症性肠病、促进朗格汉斯细胞迁移与成熟，并且在胶原诱导的关节炎模型中介导关节炎症以及其他过程。
现有研究表明PGE 2抑制蛋白聚糖合成并且通过EP 4受体刺激骨关节炎软骨细胞中的基质降解。靶向EP 4可能可以代表未来的用于骨关节炎疾病修改的策略。此外还有研究表明前列腺素类EP 4受体的药学阻断可以代表骨关节炎和/或类风湿性关节炎的体征和症状缓解中的新的疗法策略。
综上所述，本领域仍然迫切需要能够在体外和体内有效且可靠地抑制EP 4的新型化合物。
发明内容
本发明的目的是提供一类新型的具有EP 4受体抑制活性和/或具有良好药效学/药代动力学性能的可作为EP 4受体拮抗剂的新颖化合物及其可药用盐，和以它们作为活性成分的药物组合物，以及其在治疗或减轻EP 4受体相关疾病如前列腺素EP 4受体介导的疾病中的用途。
在本发明的第一方面中，提供了一种式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药；
Figure PCTCN2022074190-appb-000001
其中，
R 1和R 2各自独立选自下组：氢、C 1-3烷基，或者，R 1和R 2以及与它们相连的碳原子共同形成C 3-5环烷基(如环丙基)；
R 3和R 4各自独立选自下组：氢、卤素(如氟)、C 1-3烷基；或者，R 3和R 4以及与它们相连的碳原子共同形成C 3-5环烷基(如环丙基)；
R 5和R 6各自独立选自下组：氢、C 1-3烷基；或者，R 5和R 6以及与它们相连的碳原子共同形成C 3-5环烷基(如环丙基)；
R 7为无或选自下组的取代基：卤素、氰基、C 1-3烷基、C 1-3卤代烷基(如三氟甲基)；
R 8选自下组：氢、C 1-3烷基；
n为0、1或2；
并且，所述烷基、环烷基还能任选地被一个或多个(如1、2或3该)选自下组的取代基取代：卤素、C 1-3烷基、C 1-3卤代烷基。
在另一优选例中，
R 1和R 2各自独立选自下组：氢、C 1-3烷基，或者，R 1和R 2以及与它们相连的碳原子共同形成环丙基；
R 3和R 4各自独立选自下组：氢、氟、C 1-3烷基，或R 3和R 4以及与它们相连的碳原子共同形成环丙基；
R 5和R 6各自独立选自下组：氢或C 1-3烷基；
R 7为无或选自下组的取代基：卤素、氰基、三氟甲基；
R 8选自下组：氢、C 1-3烷基；
n为0、1或2。
在另一优选例中，其中R 1是氢且R 2是甲基，或者，R 1和R 2以及与它们相连的碳原子共同形成一个环丙基。
在另一优选例中，其中R 3和R 4独立地选自下组：氢、氟、甲基；或者R 3和R 4以及与它们相连的碳原子共同形成环丙基。
在另一优选例中，其中R 5和R 6各自独立为氢或甲基。
在另一优选例中，R 7不为无时，R 7位于-SF 5的邻位或间位。
在另一优选例中，其中R 7为无。
在另一优选例中，其中R 8为氢。
在另一优选例中，其中n为2。
在另一优选例中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和n各自独立地为实施例化合物(如表1中所列出的化合物)中对应的基团。
在另一优选例中，所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，所述化合物选自下组：
Figure PCTCN2022074190-appb-000002
在本发明的第二方面中，提供了一种药物组合物，其包含如第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，以及药学上可接受的载体或稀释剂。
在本发明的第三方面中，提供了一种如第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，或如第二方面所述的药物组合物在制备(i)用于抑制EP 4受体活性的药物和/或(ii)用于治疗或预防EP 4受体相关疾病的药物和/或(iii)EP 4受体拮抗剂中的用途。
在另一优选例中，所述EP 4受体相关疾病包括前列腺素E2和/或前列腺素EP 4受体介导的疾病。
在另一优选例中，所述EP 4受体相关疾病选自下组：急性和慢性疼痛、炎性疼痛、与炎症相关联的疾患、骨关节炎和类风湿性关节炎、癌症、偏头痛和子宫内膜异位的。
在本发明的第四方面，提供了一种治疗或预防EP 4受体相关疾病的方法，所述方法包括给予有需要的受试者治疗有效量的如第一方面所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，或如第二方面所述的药物组合物。
在另一优选例中，有需要的受试者是指被鉴定或诊断为具有EP 4受体相关疾病的受 试者。
在本发明的第五方面中，提供了一种用于抑制细胞或受试者中的EP 4受体活性的方法，所述方法包括使所述细胞接触或向所述受试者施用第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药或第二方面所述的药物组合物的步骤。
在另一优选例中，所述细胞为哺乳动物细胞。
在另一优选例中，当所述方法用于抑制细胞中的EP 4受体活性时，所述方法是体外非治疗性的。
在另一优选例中，所述受试者为哺乳动物，优选为人。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了一类具有较好的EP 4受体抑制活性的具有新颖结构的化合物。此外，发明人还发现这些具有新颖结构的化合物具有良好药效学/药代动力学性能。在此基础上，完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
如本文所用，术语“烷基”本身或作为另一取代基的一部分，是指具有指定的碳原子数的直链或支链烃基(即，C1-C6是指一个至六个碳原子)。优选地，烷基一般包含1-6个碳原子(即C 1-6烷基)，更优选地，包含1-3个碳原子即C 1-3烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。烷基中的一个或多个(如1-4个)位置可任选地被取代，所述的取代可在基团中的任何位置上进行。
如本文所有，术语“卤代烷基”指包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还 包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
术语“环烷基”是指包括饱和单环、双环或多环的环状烷基，例如C3-C8或C3-C12环烷基。C3-C8环烷基指包括C3、C4、C5、C6、C7、或C8环烷基。环烷基还可包括螺环、桥环、并环等结构的环烷基。本发明的代表性的环烷基包括但不限于：环丙基、环丁基、环戊基、环己基和降莰烷基。应理解，取代或未取代的环烷基，例如支化环烷基(如1-甲基环丙基和2-甲基环丙基)，均包括在“环烷基”的定义中。C5-C12稠合双环指包括C5、C6、C7、C8、C9、C10、C11、C12双环烷基，其包括但不限于：
Figure PCTCN2022074190-appb-000003
Figure PCTCN2022074190-appb-000004
等。C5-C12螺双环指包括C5、C6、C7、C8、C9、C10、C11、C12双环烷基，其包括但不限于：
Figure PCTCN2022074190-appb-000005
Figure PCTCN2022074190-appb-000006
等。在本发明中，环烷基优选为含有3至5个碳原子(即C 3-5)的单环环烷基，如环丙基、环丁基、环戊基。
术语“卤代”或“卤素”包括氟、氯、溴和碘。
术语“氰基”指-CN。
在本发明中，上述的烷基、卤代烷基等基团可以是取代的或未取代的。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧代(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e，P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e、NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中，R a可以独立表示氢、氘、烷基、环烷基、烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、 C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
活性成分
如本文所用，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式I化合物、或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物(如氘代化合物)或前药。该术语还包括外消旋体、光学异构体。
本发明化合物具有式I所示的结构
Figure PCTCN2022074190-appb-000007
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8如前定义。
优选地，R 1和R 2各自独立选自氢、C 1-3烷基，或R 1和R 2共同形成一个环丙基；
优选地，R 3和R 4各自独立选自氢、氟、C 1-C 3烷基，或R 3和R 4共同形成一个环丙基；
优选地，R 5和R 6各自独立选自氢或C 1-3烷基；
优选地，R 7选自氢、卤素、氰基、三氟甲基；
优选地，R 8选自氢、C 1-3烷基；
优选地，n为0、1或2；
优选地，其中R 1是氢且R 2是甲基或R 1和R 2共同形成一个环丙基；
优选地，其中R 3和R 4独立地选自氢、氟、甲基或被共同形成一个环丙基；
优选地，其中R 5和R 6各自独立选自氢或甲基；
优选地，其中R 7为氢；
优选地，其中R 8为氢。
优选地，其中n为2。
本发明的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化 合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段或部分，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段或部分，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物，如一水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物(也称为同位素化合物)，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本 发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
通常，在制备流程中，各反应通常惰性气体保护下，适当溶剂中，在室温到90℃下 进行，反应时间通常为2-24小时。
方法一:
Figure PCTCN2022074190-appb-000008
方法一中：R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8具有本发明所述的定义。所述方法包括以下步骤：
(i)惰性溶剂(如DMF)中，化合物1-1中的羧基与4-(1-氨基环丙基)-苯甲酸甲酯中的氨基缩合生成化合物1-2；优选地，在HATU和DIEA的存在下进行反应；
(ii)在惰性溶剂如二氯甲烷中，酸性条件下(如HCl存在下)，化合物1-2脱保护基生成化合物1-3；
(iii)惰性溶剂(如DMF)中，化合物1-3与对五氟硫基苄溴衍生物生成化合物1-4；优选地，在Cs 2CO 3的存在下反应。
(iv)在有机溶剂如四氢呋喃和水的混合溶剂中，碱性条件下，化合物1-4酯键水解生成化合物1-5；优选地，在LiOH的存在下水解。
以上反应步骤中，反应溶剂、反应温度、反应时间、催化剂等可以根据具体的反应物进行选择。
药物组合物和施用方法
由于本发明的化合物具有优异的EP 4受体抑制活性，是EP 4受体拮抗剂，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物、溶剂合物、立体异构体、同位素化合物或前药等以及本发明所述的药物组合物用于预防和/或治疗或减轻EP 4受体相关的疾病如前列腺素E 2/前列腺素EP 4受体介导的疾病，这些疾病包括：急性 和慢性疼痛、炎性疼痛、与炎症相关联的疾患、骨关节炎和类风湿性关节炎、癌症、偏头痛和子宫内膜异位。特别地，本发明的化合物具有止痛的和抗炎的活性。
在某些实施例中，本发明的化合物用作止痛剂。例如，它们在以下疾病的治疗中是有用的：慢性关节疼痛(例如类风湿性关节炎、骨关节炎、类风湿性脊椎炎、痛风性关节炎和幼年型关节炎)，肌肉骨骼疼痛；下背和颈部疼痛；扭伤和劳损；神经性疼痛；交感神经维持性疼痛(sympathetically maintained pain)；与癌症和纤维组织肌痛相关的疼痛；与偏头痛相关的疼痛；与流行性感冒或其他的病毒性传染例如普通感冒相关的疼痛；风湿热；功能性肠紊乱例如非溃疡消化不良、非心脏病胸痛和肠易激综合征相关的疼痛；与心肌缺血相关的疼痛；手术后疼痛；头痛；牙痛；和痛经。
本发明的化合物在神经性疼痛的治疗中是有用的。神经元的损伤之后可能发展为神经性疼痛综合征，甚至在最初的损伤已经愈合之后疼痛可以持续几个月或几年。神经元的损伤可以在末梢神经、背根、脊髓或脑中的某些区中发生。神经性疼痛综合征传统地根据引起它们的疾病或事件来分类。神经性疼痛综合征包括：糖尿病神经病；坐骨神经痛；非特异性下背疼痛；多发性硬化疼痛；纤维组织肌痛；与HIV相关的神经病；疱疹后神经痛；三叉神经痛；以及来源于物理创伤、截肢、癌症、毒素或慢性炎症病症的疼痛。这些病症是难以治疗的，并且虽然多种药物已知具有有限的效力，但是完全的疼痛控制几乎不被实现。神经性疼痛的症状是多样化的，并且经常被描述为自然的射痛和刀刺性疼痛或烧灼疼痛。此外，存在与正常地非疼痛的感觉相关的疼痛，例如“发麻”(感觉倒错和感觉迟钝)、增加的对触摸的敏感性(感觉过敏)、在无害的刺激之后的疼痛感觉(动态的、静态的或热的异常性疼痛)、增加的对伤害性刺激的敏感性(热的、冷的、机械的痛觉过敏)、在刺激的除去之后的继续的疼痛感觉(痛觉过敏)或选择性的感觉传导路的不存在或缺陷(痛觉减退)。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药 效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022074190-appb-000009
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
“药学上可接受的赋形剂”和“药学上可接受的载体”是指有助于活性剂的配制和/或施用和/或被个体吸收的物质，并且可以包含在本公开的组合物中而不引起对该个体的显著不利的毒理作用。药学上可接受的载体和赋形剂的非限制性实例包括水、NaCl、生理盐水溶液、乳酸林格氏液、常规蔗糖、常规葡萄糖、粘合剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、风味剂、盐溶液(例如林格溶液)、醇、油、明胶、碳水化合物，诸如乳糖、直链淀粉或淀粉、脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷和颜料等。这样的制剂可以被灭菌，并且如果需要，与不会有害地与本文提供的化合物反应或干扰本文提供的化合物的活性的辅助剂例如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、影响渗透压的盐、缓冲剂、着色剂和/或芳香物质等混合。本领域普通技术人员将认识到其他药物载体和赋形剂适用于公开的化合物。
在某些实施例中，本发明的药物组合物可以以固体或液体形式。
固体形式的药物组合物可以含有适当的赋形剂例如填料、润滑剂、结合剂、润湿剂、崩解剂、着色剂和调味剂和其混合物。例如，片剂可以含有预糊化淀粉、微晶纤维素、乙醇酸钠淀粉、滑石、乳糖、硬脂酸镁、蔗糖、硬脂酸、甘露醇。
液体形式的药物组合物可以为溶液、悬浮液、乳液、糖浆、酏剂。典型地，以液体形式的组合物可以含有悬浮剂、乳化剂、载体、防腐剂和着色剂、调味剂。
本发明的药物组合物可以通过胃肠外的、口服的、颊的、舌下的、鼻的、直肠的、局部的、或经皮的施用被施用。用于口服施用的药物组合物通常是优选的。
适合于口服施用的本发明的药物组合物典型地将是以固体形式的离散单元，例如以片剂、胶囊、扁囊剂、粉末、颗粒、锭剂、贴片、栓剂、丸剂的形式，或以液体形式，例如液体制剂、可注射的或可输注的溶液或悬浮液。
向个体提供治疗有效量的化合物的精确量将取决于给药方式、疾病和/或病症的类型和严重程度以及个体的特征，例如一般健康状况、年龄、性别、体重和对药物的耐受性。本领域普通技术人员将能够根据这些和其他因素确定合适的剂量。当与其他治疗剂组合施用时，任何其他治疗剂的“治疗有效量”将取决于所用药物的类型。合适的剂量对于批准的治疗剂是已知的，并且可以由本领域普通技术人员根据个体的状况、 治疗的病症类型和通过以下使用的本发明化合物的量进行调整，例如，在文献中报道和在Physician’s Desk Reference(第57版，2003)中推荐的剂量。
本发明的药物组合物中，活性成分的含量通常为0.000001-1wt％，优选为0.00001-1wt％，最优选为0.0001-0.1wt％。
本发明的药物组合物或治疗剂的给药对象的实例包括哺乳动物(例如，人、小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴等)。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体，或施用本发明所述的药物组合物，用于选择性地抑制EP 4受体。
本发明具有以下主要优点：
(1)本发明化合物对EP 4受体具有优良的抑制活性。
(2)本发明化合物具有较低的毒副作用。
(3)本发明化合物具有较好的药效学、药代动力学性能。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400和Bruker AVANCE-500核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Agilent 1260质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5micron C18 100x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
下列简写词的使用贯穿本发明
THF：四氢呋喃；MeOH：甲醇；HCl：盐酸；Pd(PPh 3) 4：四三苯基膦钯；K 2CO 3：碳酸钾；AcOK：醋酸钾；NaOH：氢氧化钠；H 2O：水；TEA：三乙胺；DIEA：N,N-二异丙基乙胺；DMF：N,N-二甲基甲酰胺；DMA：N,N-二甲基乙酰胺；Py：吡啶；DCE：1,2-二氯乙烷；DMSO：二甲基亚砜；TFA：三氟乙酸；NaBH(AcO) 3：三乙酰基硼氢化钠；Sn 2(Bu-n) 6：六己基二锡；AlCl 3：三氯化铝；CuI：碘化亚铜；DPPA：叠氮磷酸二苯酯；BuOH：叔丁醇；Cs 2CO 3：碳酸铯；K 3PO 4：磷酸钾；BnBr：苄溴；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；X-Phos：2-二环己基磷-2,4,6-三异丙基联苯；EA：乙酸乙酯；NaHCO 3：碳酸氢钠；DIPEA：N，N-二异丙基乙胺；HBr：溴化氢。
实施例
实施例1 化合物1的合成
Figure PCTCN2022074190-appb-000010
步骤1.合成5-(((1-(4-(甲氧基羰基)苯基)环丙基)氨基甲酰基)叔丁基6-氮杂螺[2.5]辛烷-6-羧酸酯
室温下，将6-(叔丁氧羰基)-6-氮杂螺[2.5]辛烷-5-羧酸(0.5g,1.96mmol)，4-(1-氨基环丙 基)-苯甲酸甲酯(0.37g,1.96mmol)、HATU(0.74g,1.96mmol)和DIEA(0.76g,5.88mmol)溶于DMF(10mL)中，室温下搅拌5小时。反应完全加水淬灭、然后用EA(20mL*2)萃取，有机相干燥，旋干，然后用PE:EA＝5:1柱层析得5-(((1-(4-(甲氧基羰基)苯基)环丙基)氨基甲酰基)叔丁基6-氮杂螺[2.5]辛烷-6-羧酸酯0.7g，MS m/z(ESI)：429.2[M+H] +。
步骤2.合成4-(1-(6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸甲酯
室温下，将5-(((1-(4-(甲氧基羰基)苯基)环丙基)氨基甲酰基)叔丁基6-氮杂螺[2.5]辛烷-6-羧酸酯(0.7g,1.63mmol)溶于DCM(10mL)中，然后降至0℃，再加入盐酸二氧六环(3mL，4mol/L)搅拌3小时。反应完全抽滤得到产物，不需要纯化直接投下一步。
步骤3.合成4-(1-(6-(4-(五氟硫基)苄基)-6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸甲酯
将4-(1-(6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸甲酯(0.3g,0.91mmol)，4-(五氟硫基)苄溴(0.27g,0.91mmol)，Cs 2CO 3(0.59g,1.82mmol)加入到单口瓶中，再加入DMF(10mL)，混合物在80℃下反应5小时，反应完全后，冷却到室温，加入水(10mL)，用EA(30mL*2)萃取，有机相干燥，旋干，然后PE:EA＝2:1柱层析得到4-(1-(6-(4-(五氟硫基)苄基)-6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸甲酯0.42g，MS m/z(ESI)：545.1[M+H] +。
步骤4.合成4-(1-(6-(4-(五氟硫基)苄基)-6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸
室温下，4-(1-(6-(4-(五氟硫基)苄基)-6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸甲酯(0.42g,0.72mmol)溶于1:2的MeOH/THF的(20mL),然后加入H 2O(5mL),氢氧化锂(56mg,2.3mmol),室温搅拌反应10小时，反应完全后移除有机溶剂，柠檬酸水溶液调节PH＝4-5,用DCM(30mL*2)萃取，有机相干燥，旋干，然后DCM:MeOH＝10:1柱层析得到4-(1-(6-(4-(五氟硫基)苄基)-6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸0.4g。MS m/z(ESI):531.5[M+H] +。通过手性柱分离可以得到两种不同构型的产物。
1H NMR(400MHz,DMSO)δ12.51(s,1H),10.01(d,J＝121.3Hz,1H),7.85(t,J＝70.0Hz,6H),7.21(s,2H),4.38(d,J＝27.6Hz,1H),4.08(s,1H),3.20(s,1H),2.09(d,J＝25.3Hz,2H),1.62–1.08(m,6H),0.84(dd,J＝8.7,2.2Hz,2H),0.68–0.18(m,4H).
实施例2
以与实施例1类似的方法制备表1中化合物1以外的其他化合物。
表1 化合物列表
Figure PCTCN2022074190-appb-000011
Figure PCTCN2022074190-appb-000012
生物活性测试例1：
(a)放射性配体EP4受体结合测定：
实验方法：在非结合96孔板内加入结合缓冲液(50mmol/L HEPES，pH 7.4，5mmol/L MgCl2，1mmol/L CaCl2，0.2％BSA)和不同浓度的待测化合物和对照化合物，将从过表达人EP4cDNA的Chem-1细胞制备的膜与1.8nmol/L[ 3H]_PGE和5μmol/L未标记的PGE2相混合，并在室温温育1-2h。在过滤之前，用0.33％聚乙烯亚胺包被GF/C96孔滤板30min，然后用50mmol/L HEPES(pH 7.4)、0.5％BSA洗涤。将结合反应物转移至滤板，并用洗涤缓冲液(每次洗涤，1mL/孔)洗涤3次。干燥所述板，并计数放射性。通过上述的放射性配体EP4受体结合测定确定的Ki值。
经测试，本发明的化合物具有优异的EP4受体的结合活性，具有优异的EP 4受体抑制能力。
(b)本发明化合物的PK的确定
在雄性Han Wistar大鼠中研究化合物的药物动力学。使用静脉内注射以及口服的方式给药(对于每个剂量途径n＝3)，在给药后的多个时间点进行取样。使用特异性的并 且灵敏的LC-MS/MS生物分析方法定量地分析血浆抽出物。
经测试，本发明的化合物具有较好的药效学、药代动力学性能。
(c)人肝微粒体中的代谢稳定性
以磷酸缓冲液(pH＝7.4,100mM)为孵育体系介质，分别加入人肝微粒体和目标化合物，使其终浓度分别为0.5mg/mL和1μM,预孵育5min后，加入终浓度为1mM的NADPH启动反应，于37℃分别孵育0、5、15、30和45min后加入含内标的冰乙腈终止反应。样品6000rpm离心15min，取上清80μL加入140μL超纯水稀释后，待LC-MS/MS进样分析。
(d)溶解度
精密称取约1mg的各化合物粉末，放入玻璃小瓶中(n＝3)，并加入PBS(pH 7.4)溶液使其浓度为1mg/mL。将样品25℃ 1,100rpm振摇24h后，转移到过滤板中，以负压装置过滤，并接收滤液。滤液以含有内标的超纯水和乙腈(1:1)的混合物稀释后，采用LC-MS/MS检测，通过随行的标准曲线计算浓度。结果如表2
表2
化合物编号 溶解度(μg/mL) 溶解度(μM)
对照化合物 826.00 1748.11
实施例1 1080.00 2035.62
Figure PCTCN2022074190-appb-000013
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药；
    Figure PCTCN2022074190-appb-100001
    其中，
    R 1和R 2各自独立选自下组：氢、C 1-3烷基；或者，R 1和R 2以及与它们相连的碳原子共同形成C 3-5环烷基；
    R 3和R 4各自独立选自下组：氢、卤素、C 1-3烷基；或者，R 3和R 4以及与它们相连的碳原子共同形成C 3-5环烷基；
    R 5和R 6各自独立选自下组：氢、C 1-3烷基；或者，R 5和R 6以及与它们相连的碳原子共同形成C 3-5环烷基；
    R 7为无或选自下组的取代基：卤素、氰基、C 1-3烷基、C 1-3卤代烷基；
    R 8选自下组：氢、C 1-3烷基；
    n为0、1或2；
    并且，所述烷基、环烷基还能任选地被一个或多个选自下组的取代基取代：卤素、C 1-3烷基、C 1-3卤代烷基。
  2. 如权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，
    R 1是氢且R 2是甲基；或者，R 1和R 2以及与它们相连的碳原子共同形成环丙基；和/或
    R 5和R 6各自独立为氢或甲基。
  3. 如权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，R 3和R 4各自独立地选自下组：氢、氟、甲基；或者，R 3和R 4以及与它们相连的碳原子共同形成环丙基。
  4. 如权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，R 7为无。
  5. 如权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，R 8为氢。
  6. 如权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，n为2。
  7. 如权利要求1所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2022074190-appb-100002
  8. 一种药物组合物，其特征在于，包含如权利要求1至7中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，以及药学上可接受的载体或稀释剂。
  9. 一种如权利要求1至7中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，或者如权利要求8所述的药物组合物在制备(i)用于抑制EP 4受体的药物和/或(ii)用于治疗或预防EP 4受体相关疾病的药物和/或(iii)EP 4受体拮抗剂中的用途。
  10. 如权利要求10所述的用途，其中，所述EP 4受体相关疾病包括：急性和慢性疼痛、炎性疼痛、与炎症相关联的疾患、骨关节炎和类风湿性关节炎、癌症、或偏头痛和子宫内膜异位。
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