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WO2014048243A1 - Xanthine derivative, preparation method and use thereof - Google Patents

Xanthine derivative, preparation method and use thereof Download PDF

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Publication number
WO2014048243A1
WO2014048243A1 PCT/CN2013/083096 CN2013083096W WO2014048243A1 WO 2014048243 A1 WO2014048243 A1 WO 2014048243A1 CN 2013083096 W CN2013083096 W CN 2013083096W WO 2014048243 A1 WO2014048243 A1 WO 2014048243A1
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WO
WIPO (PCT)
Prior art keywords
methyl
formula
chloromethyl
pharmaceutically acceptable
piperidin
Prior art date
Application number
PCT/CN2013/083096
Other languages
French (fr)
Chinese (zh)
Inventor
陈栋
范传文
何绪军
程哲
李成龙
Original Assignee
齐鲁制药有限公司
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Publication of WO2014048243A1 publication Critical patent/WO2014048243A1/en

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a novel class of xanthine derivatives, a preparation method and use thereof, and to an intermediate compound for preparing the xanthine derivative and a preparation method of the intermediate compound.
  • the xanthine derivative and the pharmaceutical composition thereof are effective for inhibiting dipeptidyl peptidase (DPP-IV) activity, and can be used for the preparation of a medicament for preventing or treating a disease associated with DPP-IV.
  • DPP-IV dipeptidyl peptidase
  • Dipeptidyl peptidase can be classified into I, III, IV, 6, 7, 8, 9, and 10 types.
  • Dipeptidyl peptidase-8 belongs to a member of the peptidase SB9 and is a small family of dipeptidyl peptidases. It encodes a protein gene similar to the highly expressed dipeptidyl peptidase-IV (DPP-IV) and has the same hydrolyzed substrate.
  • Dipeptidyl peptidase-9 belongs to the serine protease SC class S9B family. It cleaves the Xaa-Pro dipeptide from the N-terminus of the protein, showing activity with a proline dipeptidase.
  • DPP-IV binds to the membrane through a hydrophobic helix formed by a highly glycosylation region and a cysteine-rich region of the amino acid.
  • the carboxy-terminal serine protease region ⁇ / ⁇ is homologous to the hydrolase; DPP-IV can be rapid and specific a cleavage peptide chain at the N-terminal second proline or alanine residue, the substrate of which includes two incretins that play an important role in the type II diabetes immune response signal transduction: pancreatic Glucose-like peptide (GLP-1) fragment and intestinal depression Peptide peptide ((GGIIPP)). .
  • the GGLLPP--11 and GGIIPP fractions are derived from the gastric and gastric mucosal membrane LL cells and the KK cells, which are in response to the ingestion of the carbon-carbon hydration complexes and And the fat and fat of the intestines, which are secreted and secreted, and the blood glucose, glycosidin, and the two of them are used for the pancreatic pancreatic gland to enhance the induction of glucose and glucose.
  • the pancreatic islet is secreted and secreted, and the concentration of blood glucose and glucose is adjusted from this, and DDPPPP--11VV can hydrolyze its water to produce NN corresponding to the phase.
  • DDPPPP--IIVV inhibitory preparation may be used for treatment, pre-prevention or prevention of diarrhea, urinary glucosuria, hyperglycemia, obesity or Or pancreatic isletin to resist disease resistance and the like and diseases related to DDPPPP--IVVV. .
  • DDPPPP--88 and DDPPPP--99 are two or two classes of egg whites with catalyzed activity in the DDPPPP family. .
  • the source of DDPPPP-88 and the egg white sequence of DDPPPP-99 have the same homologous origin, DDPPPP-88 and DDPPPP--99 and DDPPPP-- There were 22666% homologous homology between the 44s. .
  • DDPPPP--88 and DDPPPP--99 have no extracellular extracellular catalytic structure domain. .
  • DDPPPP-88 is higher than that of live-activated TT cells
  • DDPPPP99 is higher than that of cancer cells, skeletal and skeletal muscle cells. , cardiac myocytes, and the liver and liver.
  • DDPPPP-88 and DDPPPP--99 are expressed in the blood cells, lymphocytes, and mononuclear cells.
  • DDPPPP--88 and DDPPPP-99 there may be a possibility that the activity of weak TT cells will be reduced, and the effect of immune system is affected. Functional ability. .
  • the inhibitory force is weak, and the DDPPPP--IIVV inhibitory preparation with better selectivity is safer and more complete. , the potential potential in the use of poisonous deputy vices to use small. .
  • DDPPPP--IVVV inhibitory preparation inhibits the activity of DDPPPP--IVVV, and can resist the rapid and rapid degradation of the degradation of the degraded material and stabilize it. The bioactive activity of the endogenous source is stabilized, and the therapeutic effect of the sway response can be achieved.
  • the DDPPPP--IIVV inhibitory preparation agent is also recognized as a cytokine factor in various various types of cells ((thorn stimulates hematopoietic blood cell cells), growth factors, and The nerves of the gods play a role in the splitting and cleavage of the peptide peptides. .
  • DDDDPP--IIVV can reduce the degradation of the factorization factor CCXXCCLL1122//SSDDFF--llaa ((the matrix-derived cell-derived derivative factor) , can specifically bind to the receptor CXCR4 expressing hematopoietic stem/progenitor cells, and CXCL12 is thought to be involved in the homing of hematopoietic stem cells [Ludwig A, J.
  • DDP-IV inhibitors may play a decisive role in stabilizing the hematopoietic environment, mobilization of hematopoietic stem cells from osteophytes, and hematopoietic reconstitution, and are expected to be used in the treatment of ischemic myocarditis and angiogenic diseases.
  • DPP-1V inhibitors have become a new direction in drug research, and there have been many DPP-IV inhibitors have been successfully marketed, such as Merck's Sitegliptin (WO03004498), Novartis's Vildagliptin (WO09819998), Bristol-Myers Squibb's Saxagliptin (WO00168603), Takeda's Alogliptin (WO2005095381), and Boehringer Ingelheim's BI- 1356 ( WO2004018468 , the chemical name of BI-1356 is: 8-[(3R)-3-amino-1-piperidinyl b-7-( 2 -butynyl)-3,7-dihydro-3-methyl 1-[( 4 -methyl- 2 -quinazolinyl)methylbu-1H-indole-2,6-dione) and the like. Although these drugs have good pharmacodynamic properties, it is still necessary to develop more new compounds with higher activity and
  • a first aspect of the invention provides a xanthine derivative of the formula I, a pharmaceutically acceptable salt, a solvate thereof, a solvate of a pharmaceutically acceptable salt, a chemically protected form thereof or a prodrug:
  • R 3 , R 5 each independently selected from hydrogen, a halogen atom, a straight or branched chain of 1 to 5 halogen atoms substituted or unsubstituted d- 6 alkyl, straight or branched 1 ⁇ a substituted or unsubstituted d- 6 alkoxy group, an aryl group or a hydroxy group;
  • X is independently selected from O or S;
  • n is selected from 1 or 2.
  • the xanthine derivative of the formula I according to the first aspect of the invention a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt, and a chemistry thereof Protection form or prodrug, wherein
  • R 3 , R 5 , and Re are each independently selected from the group consisting of hydrogen, a gas atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an isopropyl group, a ft ⁇ , an ft ⁇ , a trifluoromethyl group, and a trifluoromethyl group.
  • L ⁇ , or hydroxyl.
  • R 3 , R 5 , Re are each independently selected from the group consisting of hydrogen, chlorine atom, methyl group, methyl group #L ⁇ , and in a specific embodiment, the xanthine derivative of formula I according to the first aspect of the invention Or a pharmaceutically acceptable salt, a solvate thereof, a solvate of a pharmaceutically acceptable salt, a chemically protected form thereof, or a prodrug thereof,
  • R 3 is selected from the group consisting of hydrogen, methyl,
  • R 5 is selected from the group consisting of hydrogen, chlorine, methyl, and A
  • Re is selected from the group consisting of hydrogen, chlorine atom, methyl group, and methyl group.
  • the xanthine derivative of the formula I according to the first aspect of the invention a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt, and A chemically protected form or prodrug selected from Formula 1 (A), Formula 1 (B) or Formula I (C):
  • R 2 , R 3 , , R 5 , R 6 , m, X have the same meanings as defined above.
  • the xanthine derivative of the formula I according to the first aspect of the invention a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt, and A chemically protected form or prodrug selected from the following compounds:
  • a second aspect of the invention provides a xanthine derivative, a pharmaceutically acceptable salt, a solvate thereof, a pharmaceutically acceptable salt of the formula I according to the first aspect of the invention.
  • R 2 , R 3 , , R 5 , R6, X, m are as defined in the first aspect of the invention;
  • Y is a halogen;
  • the suitable acid is selected from the group consisting of trifluoroacetic acid, formic acid, hydrochloric acid, and acetic acid, preferably trifluoroacetic acid, hydrochloric acid, and most preferably trifluoroacetic acid.
  • a third aspect of the invention provides a compound of formula II,
  • R 3 , R 5 each independently selected from hydrogen, a halogen atom, a straight or branched chain of 1 to 5 halogen atoms substituted or unsubstituted d- 6 alkyl, straight or branched 1 ⁇ a substituted or unsubstituted d- 6 alkoxy group, an aryl group or a hydroxy group;
  • X is independently selected from O or S;
  • n 1 or 2;
  • the compound of the third aspect of the invention which is selected from the group consisting of 11 (A),
  • R 3 , R 4 , R 5 , R 6 , X, m are as defined in the first aspect of the invention; and when 1 16 is hydrogen, X is not o.
  • the compound of the third aspect of the invention is selected from the group consisting of:
  • a fourth aspect of the invention provides a method of preparing a compound of the formula ⁇ according to the third aspect of the invention, comprising the steps of:
  • the basic substance is selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, preferably potassium carbonate, sodium carbonate, sodium hydroxide, most preferably Potassium carbonate.
  • the substituted benzofuran or benzothiophene compound represented by formula III (C) is cyclized with a halogenated acetonitrile to give a compound of formula II (C); wherein R 3 , R 5 and Re are as defined The definition in requirement 1;
  • X is independently selected from O or S;
  • Y is a halogen
  • a fifth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the xanthine derivative of the formula I according to the first aspect of the invention, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable salt a solvate, a chemically protected form thereof or a prodrug, and a pharmaceutically acceptable excipient or carrier.
  • the xanthine derivative of the formula I the pharmaceutically acceptable salt, the solvate thereof, the pharmaceutically acceptable salt solvate of the formula I, and the chemical protection thereof are provided.
  • the use of the sixth aspect of the invention Characterizing that the disease associated with DPP-I is selected from the group consisting of diabetes, hyperglycemia, obesity or insulin resistance, ischemic myocarditis or angiogenic disease; preferably, said
  • the DPP-I related diseases are selected from the group consisting of diabetes and hyperglycemia.
  • a seventh aspect of the invention provides the use of the compound of the third aspect of the invention for the preparation of the baicalin derivative of claim 1.
  • An eighth aspect of the present invention provides a method for treating, preventing, and ameliorating a disease associated with DPP-I, which comprises the above-described huangzhiling derivative of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, and a solvent
  • a disease associated with DPP-I which comprises the above-described huangzhiling derivative of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, and a solvent
  • the solvate of the pharmaceutically acceptable salt, its chemically protected form, and the prodrug are administered to an individual in need thereof.
  • halogen or halo as used herein means fluoro, chloro, bromo or iodo, and the preferred halo group is fluoro, chloro or bromo.
  • alkyl as used in the present invention means a saturated straight or branched monovalent hydrocarbon group having from 1 to 6 (i.e., C1-6 alkyl), preferably from 1 to 4 (i.e., C1-4 alkyl),
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-, iso-, neopentyl, 2-methyl Butyl, n-hexyl, 4-methyl ⁇ , 3-methylpentyl, 2-methyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,
  • the alkyl group is preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
  • alkane as used in the present invention means a saturated linear or branched alkane having 1 to 6 moles.
  • An oxy group preferably an alkoxy group of 1 to 4 carbon atoms, an alkoxy group of 1 to 3 carbon atoms or an alkoxy group of 1 to 2 carbon atoms; examples of the alkane include, but are not limited to, ft ⁇ , ft ⁇ , n-propyl Ft ⁇ , isopropyl ft ⁇ , ⁇ #L ⁇ , Iso Ding#L ⁇ , ⁇ #L ⁇ , ⁇ #L ⁇ , Isoparm #L ⁇ , 2-Methyl Ding#L ⁇ , Xinwu ft ⁇ , , 4-methylpentan #L ⁇ , 3-methylpentan #L ⁇ , 2-methylpentan #L ⁇ , 1-methylpentyloxy, 3,3-dimethylbutyl #L ⁇ , 2,2-Dimethylbutyl #L ⁇ , 1,1-dimethylbutene #L
  • the xanthine derivative of the formula I of the present invention includes isomers, racemates, enantiomers, diastereomers, enantiomers, oximes, solvates and esters thereof; the compounds of the formula I according to the invention Its isomers, racemates, enantiomers, diastereomers, enantiomeric enrichments, gas substitutes, solvates and esters may also form solvates such as hydrates, alcoholates and the like.
  • the derivative may also be in the form of a prodrug or a dry release of the active ingredient after metabolic changes in the body.
  • the preparation of a suitable prodrug derivative is well known to those skilled in the art.
  • a solvate form of a pharmaceutically acceptable solvent such as water, ethanol or the like is equivalent to the unsolvated form.
  • the compound of the formula I of the present invention can be used in the form of a pharmaceutically acceptable salt derived from a mineral acid or an organic acid.
  • pharmaceutically acceptable salts means that it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and with reasonable effects within the scope of reliable medical judgment.
  • a pharmaceutically acceptable salt is well known in the art. The salt can be reacted with a suitable organic or inorganic acid by a compound of the invention.
  • the xanthine derivative of the formula I of the present invention is reacted with an organic acid or an inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the xanthine derivative, for example, a hydrohalide salt such as a hydrochloride or a hydrobromide salt.
  • a hydrohalide salt such as a hydrochloride or a hydrobromide salt.
  • Hydrogenated acid salts; other inorganic acids and their corresponding salts such as sulfates, nitrates, phosphates, etc.; and alkyl and monoarylsulfonates, such as ethanesulfonate, tosylate and acid salts
  • other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
  • Further acid addition salts of the invention include, but are not limited to: adipate, alginate, arginine, aspartate, hydrogen sulfate, bisulfite, bromide, butyrate, camphor Acid salt, camphor sulfonate, octoate, chloride, chlorobenzoate, cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecane Sulfate, fumarate, galactose salt (galacterateX from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerol phosphate, hemisuccinate , hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, edetate, isethionate, Isobutyrate, lactate, lacto
  • the xanthine derivative of the formula I of the present invention is reacted with the following organic or inorganic acid to prepare a pharmaceutically acceptable salt thereof: hydrochloric acid, sulfuric acid, phosphoric acid, malic acid, maleic acid, fumaric acid, lactic acid, benzene Formic acid, methanesulfonic acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid; preferably a hydrochloride, benzoate or trifluoroacetate salt.
  • the compound of the formula I of the present invention may be used alone as a therapeutic drug, or may be used in combination with one or more other DPP-I drugs having the same or synergistic mechanism. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
  • the compounds of formula I of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salts means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and with reasonable effects/ A pharmaceutically acceptable salt is well known in the art.
  • each active ingredient in the pharmaceutical compositions of the present invention can be varied so that the resulting amount of active compound is effective to provide the desired therapeutic response to the particular patient, composition, and mode of administration.
  • the dosage level must be based on the activity of the specific compound, the route of administration, and the treatment The severity of the condition and the condition of the patient to be treated and the previous medical history were chosen. However, it is the practice in the art that the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
  • a therapeutically and/or prophylactically effective amount of a compound of the invention may be administered in pure form, or in the form of a pharmaceutically acceptable salt, ester or prodrug. (in the case of these forms) application.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest and one or more pharmaceutically acceptable excipients.
  • therapeutic and/or prophylactically effective amount refers to a sufficient amount of the compound to treat the disorder in a reasonable effect/risk ratio suitable for any medical treatment and/or prophylaxis.
  • the total daily usage of the compounds of formula I of the present invention and pharmaceutical compositions thereof will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dosage level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; Patient's age, weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drug used in combination with or concurrent with the particular compound employed; Similar factors are known in the medical field. For example, it is the practice in the art to start at a dose lower than that required to achieve the desired therapeutic effect, gradually increasing the dosage until the desired effect is achieved.
  • the dose of the compound of the formula I according to the invention for use in mammals, especially humans may range from 0.001 to 1000 mg/kg body weight per day, for example from 0.01 to 100 mg/kg body weight per day, for example between 0.01 and 10 Mg/kg body weight/day.
  • compositions containing an effective amount of a compound of the invention can be prepared using pharmaceutical carriers well known to those skilled in the art.
  • the invention therefore also provides a pharmaceutical composition comprising a compound of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form for parenteral injection or for rectal administration.
  • the pharmaceutical composition can be formulated into a plurality of dosage forms for ease of administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions, Or an injectable dry powder, which can be immediately added by injecting water before injection. use).
  • oral preparations such as tablets, capsules, solutions or suspensions
  • injectable preparations such as injectable solutions or suspensions, Or an injectable dry powder, which can be immediately added by injecting water before injection. use.
  • the carrier of the pharmaceutical composition comprises: a binder for oral preparation (such as starch, usually corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone) , diluents (eg lactose, dextrose, sucrose, mannitol, behenyl alcohol, cellulose and/or glycerol), lubricants (eg silica, talc, stearic acid or its salts, usually stearic acid) Magnesium or calcium stearate, and/or polyethylene glycol), and if desired, a disintegrating agent, such as starch, agar, alginic acid or a salt thereof, usually sodium alginate, and/or an effervescent mixture, Solubilizers, stabilizers, suspending agents, pigments, flavoring agents, etc., preservatives, solubilizers, stabilizers, etc.
  • a binder for oral preparation such as starch
  • compositions for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations.
  • the pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.
  • the pharmaceutical composition of the present invention can be administered orally, rectally, parenterally, vaginally, topically (e.g., by powder, chondridine or drops), to humans and other mammals, or as an oral spray. Or nasal spray.
  • parenteral refers to a method of administration including intravenous, intramuscular, internal, intrasternal, subcutaneous, and intra-articular injections and infusions.
  • compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for the preparation of sterile injectable solutions or dispersions.
  • suitable aqueous or nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (such as olive oil), injectable organic esters such as oleic acid. Ethyl esters and suitable mixtures thereof.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms is ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, benzophenone, behenic acid and the like.
  • isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form is achieved by the use of substances which delay absorption, such as aluminum monostearate and gelatin.
  • Suspensions may contain suspending agents in addition to the active compound, such as ethoxylated isostearyl alcohol, polyoxyethylene behenyl alcohol and polyoxyethylene sorbitol ester, microcrystalline cellulose, aluminum hydroxide , bentonite, agar and tragacanth or a mixture of these substances.
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene behenyl alcohol and polyoxyethylene sorbitol ester, microcrystalline cellulose, aluminum hydroxide , bentonite, agar and tragacanth or a mixture of these substances.
  • the rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form.
  • delayed absorption of the parenterally administered drug form is accomplished by dissolving or suspend
  • the injectable depot form can be prepared by forming a microcapsule matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide.
  • a biodegradable polymer such as polylactide-polyglycolide.
  • the drug dry release rate can be controlled based on the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides.
  • Injectable depot formulations are also prepared by embedding the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable preparation can be sterilized, for example, by filtration with a bacteriophage or by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterilized form before use. Injectable medium.
  • the compounds of the invention or compositions thereof may be administered orally or parenterally.
  • the form for oral administration may be a tablet, a capsule, a coating, and an enteral preparation, an injection, a suppository, and the like. These formulations are prepared according to methods familiar to those skilled in the art. Excipients used in the manufacture of tablets, capsules, and coatings are conventional excipients such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils (such as corn). Oil, peanut oil, olive oil, etc.).
  • the dosage of the compound of the formula I according to the invention in tablets, capsules, coatings, injections and suppositories is calculated as the amount of the compound present in the unit dosage form.
  • the compound of the formula I according to the invention is generally present in an amount of from 0.1 to 1000 mg, preferably in a unit dosage form containing from 1 to 100 mg, more preferably in a unit dosage form containing from 5 to 20 mg e
  • solid dosage forms for oral administration which may be provided by the present invention include capsules, tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or the following: a) filler or extender such as starch, Lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyethylene Pyrrolidone, sucrose and gum arabic; C) humectants such as glycerin; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate
  • Solid compositions of a similar type may be used as fillers in soft and hard capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other materials well known in the art of pharmaceutical preparations. These solid dosage forms may optionally contain opacifying agents, and may be formulated such that they are only or preferentially dried in a certain portion of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and waxes. If appropriate, the active compound may also be formulated in microencapsulated form with one or more of the above excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain, in addition to the active compound, an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid.
  • Benzyl ester propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, Fatty acid esters of polyethylene glycol and dehydrated kaempferol and mixtures thereof.
  • the oral compositions may contain, in addition to the inert diluent, excipients such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and flavoring agents.
  • the compounds of the invention and compositions thereof are also contemplated for topical administration.
  • Dosage forms for topical administration of a compound of the invention include powders, sprays, cholestases and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any of the required preservatives, buffers or propellants.
  • Ophthalmic formulations, ocular cartilage agents, powders and solutions are also contemplated as being within the scope of the invention.
  • the compounds of the invention may also be administered in the form of liposomes.
  • liposomes are typically prepared using phospholipids or other lipid materials. Liposomes consist of a single layer dispersed in an aqueous medium Or formed by multiple layers of hydrated liquid crystal. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the composition of the present invention in the form of a liposome may contain, in addition to the compound of the present invention, a stabilizer, a preservative, an excipient or the like.
  • Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), which may be used singly or in combination. Methods of forming liposomes are well known in the art. detailed description
  • the temperature is expressed in degrees Celsius (.c), and the operation is carried out at room temperature; the room temperature has a meaning well known in the art, specifically, 10-35. C, preferably 15-30. C, most preferably 20-25. C;
  • the organic solvent is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure by a rotary evaporator, and the bath temperature is not higher than 60.
  • C The reaction process is followed by thin layer chromatography (TLC);
  • TLC thin layer chromatography
  • the obtained solid intermediate or final product is subjected to vacuum drying at a temperature not higher than 60 °C.
  • the final product has satisfactory proton nuclear magnetic resonance spectroscopy (H-NMR) and mass spectrometry (MS) data.
  • 4-Acetylaminoindan (5.0 g, 29 mmol) was added to a 250 mL round bottom flask. Add 150 mL of acetone, stir well, add 40 mL of 15% by mass aqueous solution of MgS0 4 and cool to 0. C, potassium permanganate (13.7 g, 87 mmol) was added, followed by stirring at room temperature for 15 hours.
  • reaction liquid was poured into 20 mL of ice water to precipitate a solid, which was filtered with suction, and the filter cake was purified by column chromatography to obtain white solid 0.25 g, yield: 67.6 % ES-API (m/z): [M+H] + 613.1 .
  • reaction mixture was evaporated to dryness eluted eluted elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut
  • 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxygJ)-pyridin-1-yl]xanthine 0.33 g, 0.8 mmol), potassium carbonate (0.17 g, 1.2 mmol) and 2-chloromethyl-4-methyl thiophene [3,2-d]pyrimidine (0.22 g, 0.9 mmol) were added to a 50 mL circle
  • 10 mL of N,N-dimethylformamide was added and the temperature was raised to 90.
  • 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy-oxinyl)-bran-1-yl] (0.42 g, 1.0 mmol)
  • potassium carbonate (0.17 g, 1.2 mmol)
  • 2-chloromethyl-5,6,7,8-tetrahydro-4-trifluoromethylquinidine (0.27 g, l. 1 mmol) was added to a 50 mL round bottom flask, and 10 ml of L N,N-dimethylformamide was added, and the temperature was raised to 90.
  • Example 12 14 ⁇ 7-A fL3 ⁇ 4>-4,5-dihydrocyclopentene "de quinazolin-2-yl)methyl 3-methyl-7- (trans-2-butan-1-yl) -8-i3-iR)-(pyridin-1-yl) ruthenium (compound 12)
  • Example 13 14(5,6,7,8-tetrahydro-4,6-dimethylquinazolin-2-yl)methyl 3-methyl-7- (trans-2-butanthene-1 - yl) -8-i3-iR) - preparation of ⁇ l-yl) purine yellow Li (compound 13) (1) _-chloro-2-methyl-5, 6, 7, 8-tetrahydro _ 4 _, _ two 6 Preparation of methyl quinazoline (intermediate 11(A) -4 )
  • DPP-IV/DPP-8/DPP-9 degradable substrate Ala-Pro-AMC produces product AMC (7-J ⁇ -4-methylcoumarin), AMC is produced by 355 nm UV light at 460 nm Emitting light.
  • the activity of DPP-IV/DPP-8/DPP-9 was measured by using Scanlab varioSCAN to dynamically measure the rise in fluorescence of AMC at 460 nm.
  • Test compound Compound 1 to Compound 20 prepared in Examples 1 to 20, tested in a concentration range of 0.64 to 200 nmol/L every three times concentration gradient
  • enzyme DPP-IV/DPP
  • -8/DPP-9 initial concentration of 0.1 ng / L
  • the enzyme reaction substrate initial concentration of 5 mol / L
  • the fluorescence value at 460 nm was continuously measured for 5 min.
  • V sample represents the initial velocity of each concentration group of the sample
  • V DMSO represents the initial velocity of the DMSO group
  • BI-1356 was proposed as a positive control for the test. It can be seen from the data in Table 1 that the compound of the present invention has a good inhibitory activity against DPP-I, and the selectivity to DPP-8 and DPP-9 is comparable to that of BI-1356; in particular, Compound 1, Compound 2 The DPP-I inhibitory activity of Compound 3, Compound 5, Compound 7, and Compound 10 was significantly stronger than that of BI-1356, which was 2 to 10 times stronger than that of BI-1356. Therefore, the compound of the present invention has superior biological activity.
  • the compound of the formula I of the present invention is excellent for inhibiting DPP-IV and can be used for the treatment, prevention and alleviation of diseases related to DPP-I, such as diabetes, hyperglycemia, obesity or insulin resistance, A disease such as ischemic myocarditis or an angiogenic disease.

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Abstract

The present invention relates to a xanthine derivative, a pharmaceutically acceptable salt thereof, a solvate of the derivative, a solvate of the pharmaceutically acceptable salt, a chemically protected form or prodrug thereof and a preparation method and a use thereof; and also relates to an intermediate compound used for preparing the xanthine derivative and a preparation method of the intermediate compound. The xanthine derivative and a pharmaceutical composition thereof effectively inhibit the activity of DPP-IV, and can be used for preparing a drug for diseases associated with dipeptidyl peptidase (DPP-IV).

Description

黄瞟呤衍生物、 其制备方法及用途 技术领域  Astragalus derivative, preparation method and use thereof
本发明属于医药技术领域， 具体涉及一类新的黄嚟呤衍生物、 其 制备方法及用途， 还涉及用于制备所述黄嚟呤衍生物的中间体化合物 及所述中间体化合物的制备方法。 所述黄嚟呤衍生物及其药物组合物 能有效抑制二肽基肽酶（DPP-IV )活性， 能够用于制备预防或治疗与 DPP-IV相关疾病的药物。 背景技术  The invention belongs to the technical field of medicine, and particularly relates to a novel class of xanthine derivatives, a preparation method and use thereof, and to an intermediate compound for preparing the xanthine derivative and a preparation method of the intermediate compound. The xanthine derivative and the pharmaceutical composition thereof are effective for inhibiting dipeptidyl peptidase (DPP-IV) activity, and can be used for the preparation of a medicament for preventing or treating a disease associated with DPP-IV. Background technique
二肽基肽酶（Dipeptidyl peptidase )可以分为 I、 III、 IV、 6、 7、 8、 9、 10等型。  Dipeptidyl peptidase can be classified into I, III, IV, 6, 7, 8, 9, and 10 types.
二肽基肽酶 -8 ( Dipeptidyl peptidase-8, DPP-8 )属于肽酶 SB9 的一员， 是二肽基肽酶中的一个小家族。 它编码的蛋白基因与高表达 的二肽基肽酶 -IV ( Dipeptidyl peptidase-IV ， DPP-IV )相似， 且水 解底物也相同。  Dipeptidyl peptidase-8 (DPP-8) belongs to a member of the peptidase SB9 and is a small family of dipeptidyl peptidases. It encodes a protein gene similar to the highly expressed dipeptidyl peptidase-IV (DPP-IV) and has the same hydrolyzed substrate.
二肽基肽酶 -9 ( Dipeptidyl peptidase-9, DPP-9 )属于丝氨酸蛋白 酶 SC类 S9B家族。 它可以从蛋白质的 N-末端裂解 Xaa-Pro二肽， 显 示出具有脯氨酸二肽酶的活性。  Dipeptidyl peptidase-9 (DPP-9) belongs to the serine protease SC class S9B family. It cleaves the Xaa-Pro dipeptide from the N-terminus of the protein, showing activity with a proline dipeptidase.
二肽基肽酶 -IV ( Dipeptidyl peptidase-IV, DPP-IV )是一种存在 于多种人体组织和器官的跨膜丝氨酸蛋白水解酶。 人类 DPP-IV的单 链由 766个氛基酸组成， 分为 5个结构区域： 这些区域的长度稍有差 异。可溶性 DPP-IV是一种大约为 210-290K的同型二聚体，也能聚合 高达 900K的复合物。  Dipeptidyl peptidase-IV (DPP-IV) is a transmembrane serine proteolytic enzyme found in a variety of human tissues and organs. The single strand of human DPP-IV consists of 766 amino acids divided into five structural regions: the length of these regions varies slightly. Soluble DPP-IV is a homodimer of approximately 210-290 K and can also polymerize complexes up to 900K.
DPP-IV通过氨基酸的一个高度糖基化区和半胱氨酸富集区形成 的疏水性螺旋与膜结合， 羧基端的丝氨酸蛋白酶区域 α/δ与水解酶同 源； DPP-IV可以迅速且特异性的裂解肽链 N-端第二位的脯氨酸或丙 氨酸残基， 其作用底物包括在 II型糖尿病免疫应答信号转导过程中起 重要作用的两种肠促胰岛素： 胰高血糖样肽（ GLP-1 ) 片段和肠抑胃 肽肽（（ GGIIPP ))。。 GGLLPP--11和和 GGIIPP分分别别是是由由胃胃粘粘膜膜 LL细细胞胞及及 kk细细胞胞为为了了应应答答 摄摄入入的的碳碳水水化化合合物物及及脂脂肪肪而而分分泌泌的的肠肠降降血血糖糖素素，， 二二者者通通过过作作用用于于胰胰腺腺 增增强强葡葡萄萄糖糖诱诱导导的的胰胰岛岛素素分分泌泌，， 从从而而调调节节血血糖糖浓浓度度，， 而而 DDPPPP--11VV能能将将 其其水水解解，， 产产生生相相应应的的 NN--端端切切断断形形式式 GGLLPP--1199--3366和和 GGIIPP33--4422,, 该该产产物物均均 丧丧失失了了姨姨岛岛素素诱诱导导活活性性 [[EExxppeerrtt OOppiinn.. IInnvveessttiinngg.. DDrruuggss,, 22000044，， 1133((99)):: 11009911--11110022】】。。 因因此此，， 通通过过抑抑制制 DDDDPP--IIVV活活性性，， 能能够够抑抑制制包包括括 GGLLPP--11在在 内内的的多多种种活活性性肽肽的的降降解解，， 从从而而延延长长作作用用时时间间，， 并并减减少少肝肝脏脏葡葡萄萄糖糖的的合合 成成，，控控制制血血糖糖水水平平。。 DDPPPP--IIVV抑抑制制剂剂可可以以用用于于治治疗疗、、预预防防或或緩緩解解糖糖尿尿病病、、 高高血血糖糖症症、、 肥肥胖胖症症或或胰胰岛岛素素抵抵抗抗症症等等与与 DDPPPP--IIVV相相关关的的疾疾病病。。 DPP-IV binds to the membrane through a hydrophobic helix formed by a highly glycosylation region and a cysteine-rich region of the amino acid. The carboxy-terminal serine protease region α/δ is homologous to the hydrolase; DPP-IV can be rapid and specific a cleavage peptide chain at the N-terminal second proline or alanine residue, the substrate of which includes two incretins that play an important role in the type II diabetes immune response signal transduction: pancreatic Glucose-like peptide (GLP-1) fragment and intestinal depression Peptide peptide ((GGIIPP)). . The GGLLPP--11 and GGIIPP fractions are derived from the gastric and gastric mucosal membrane LL cells and the KK cells, which are in response to the ingestion of the carbon-carbon hydration complexes and And the fat and fat of the intestines, which are secreted and secreted, and the blood glucose, glycosidin, and the two of them are used for the pancreatic pancreatic gland to enhance the induction of glucose and glucose. The pancreatic islet is secreted and secreted, and the concentration of blood glucose and glucose is adjusted from this, and DDPPPP--11VV can hydrolyze its water to produce NN corresponding to the phase. - The end-cutting cut-off form GGLLPP--1199--3366 and GGIIPP33--4422, both of which have lost the loss of the induction activity of the 姨姨 岛 素 诱 [ [ [ [ [ EExxppeerrtt OOppiinn.. IInnvveessttiinngg.. DDrruuggss,, 22000044,, 1133((99)):: 11009911--11110022]]. . Therefore, by inhibiting the activity of DDDDPP--IVVV by inhibition, it can suppress the degradation of a variety of active peptide peptides including GGLLPP--11. Solution, from the time to extend the duration of the long-term effect, and reduce the synthesis of less liver and liver glucosamine sugar, control, control blood sugar level. . DDPPPP--IIVV inhibitory preparation may be used for treatment, pre-prevention or prevention of diarrhea, urinary glucosuria, hyperglycemia, obesity or Or pancreatic isletin to resist disease resistance and the like and diseases related to DDPPPP--IVVV. .
DDPPPP--88和和 DDPPPP--99是是 DDPPPP家家族族中中具具有有催催化化活活性性的的两两类类蛋蛋白白。。 人人源源 DDPPPP--88与与 DDPPPP--99 的的蛋蛋白白序序列列有有 6611%%的的同同源源性性，， DDPPPP--88和和 DDPPPP--99与与 DDPPPP--44之之间间有有 2266%%的的同同源源性性。。 与与 DDPPPP--IIVV不不同同，， DDPPPP--88和和 DDPPPP--99没没有有 胞胞外外催催化化结结构构域域。。 其其中中 DDPPPP--88高高表表达达于于活活化化的的 TT细细胞胞，， 而而 DDPPPP99高高表表 达达于于癌癌细细胞胞、、 骨骨骼骼肌肌细细胞胞、、 心心肌肌细细胞胞和和肝肝脏脏中中。。 在在血血液液淋淋巴巴细细胞胞和和单单 核核细细胞胞中中，， DDPPPP--88和和 DDPPPP--99均均有有表表达达。。 对对人人 DDPPPP--88和和 DDPPPP--99的的抑抑制制，， 有有可可能能会会减减弱弱 TT细细胞胞活活性性，， 影影响响机机体体免免疫疫功功能能。。 对对 DDPPPP--88和和 DDPPPP--99 抑抑制制力力弱弱、、 选选择择性性较较好好的的 DDPPPP--IIVV抑抑制制剂剂，， 安安全全性性较较高高，， 潜潜在在毒毒副副作作 用用小小。。  DDPPPP--88 and DDPPPP--99 are two or two classes of egg whites with catalyzed activity in the DDPPPP family. . The source of DDPPPP-88 and the egg white sequence of DDPPPP-99 have the same homologous origin, DDPPPP-88 and DDPPPP--99 and DDPPPP-- There were 22666% homologous homology between the 44s. . Unlike DDPPPP--IIVV, DDPPPP--88 and DDPPPP--99 have no extracellular extracellular catalytic structure domain. . Among them, the expression of DDPPPP-88 is higher than that of live-activated TT cells, while the expression of DDPPPP99 is higher than that of cancer cells, skeletal and skeletal muscle cells. , cardiac myocytes, and the liver and liver. . DDPPPP-88 and DDPPPP--99 are expressed in the blood cells, lymphocytes, and mononuclear cells. . For the inhibition system of DDPPPP--88 and DDPPPP-99, there may be a possibility that the activity of weak TT cells will be reduced, and the effect of immune system is affected. Functional ability. . For DDPPPP--88 and DDPPPP--99, the inhibitory force is weak, and the DDPPPP--IIVV inhibitory preparation with better selectivity is safer and more complete. ,, the potential potential in the use of poisonous deputy vices to use small. .
用用 DDPPPP--IIVV抑抑制制剂剂抑抑制制 DDPPPP--IIVV的的活活性性，， 能能够够阻阻止止被被降降解解物物质质的的 迅迅速速降降解解并并且且稳稳定定了了其其内内源源性性的的生生物物活活性性，， 从从而而能能够够发发挥挥响响应应的的治治疗疗 作作用用。。 DDPPPP--IIVV抑抑制制剂剂还还被被认认为为在在各各种种细细胞胞因因子子 （（刺刺激激造造血血细细胞胞）） 、、 生生长长因因子子和和神神经经肽肽的的裂裂解解中中发发挥挥作作用用。。 如如 DDDDPP--IIVV能能够够降降解解趋趋化化因因子子 CCXXCCLL1122//SSDDFF--llaa ((基基质质细细胞胞衍衍生生因因子子 aa
Figure imgf000003_0001
，， 能与表达造血干 /祖细胞的受体 CXCR4特异性结合， CXCL12被认为 与造血干细胞的归巢有关 [Ludwig A, J. Leukoc Biol, 2002， 72(1):183-191.] , 因此， DDP-IV抑制剂在稳定造血内环境， 造血干细 胞从骨髄中的动员以及造血重建的过程中可能扮演决定性的角色， 有 望用于与缺血性心肌炎和血管生成性疾病的治疗中。 The use of DDPPPP--IVVV inhibitory preparation inhibits the activity of DDPPPP--IVVV, and can resist the rapid and rapid degradation of the degradation of the degraded material and stabilize it. The bioactive activity of the endogenous source is stabilized, and the therapeutic effect of the sway response can be achieved. . The DDPPPP--IIVV inhibitory preparation agent is also recognized as a cytokine factor in various various types of cells ((thorn stimulates hematopoietic blood cell cells), growth factors, and The nerves of the gods play a role in the splitting and cleavage of the peptide peptides. . For example, DDDDPP--IIVV can reduce the degradation of the factorization factor CCXXCCLL1122//SSDDFF--llaa ((the matrix-derived cell-derived derivative factor)
Figure imgf000003_0001
, can specifically bind to the receptor CXCR4 expressing hematopoietic stem/progenitor cells, and CXCL12 is thought to be involved in the homing of hematopoietic stem cells [Ludwig A, J. Leukoc Biol, 2002, 72(1): 183-191.] Therefore, DDP-IV inhibitors may play a decisive role in stabilizing the hematopoietic environment, mobilization of hematopoietic stem cells from osteophytes, and hematopoietic reconstitution, and are expected to be used in the treatment of ischemic myocarditis and angiogenic diseases.
目前， DPP-1V抑制剂已成为药物研究的一个新方向， 已经有多个 DPP-IV抑制剂成功上市，如 Merck公司的 Sitagliptin( WO03004498 )、 Novartis公司的 Vildagliptin ( WO09819998 )、 Bristol-Myers Squibb 公司的 Saxagliptin ( WO00168603 ) 、 Takeda 公司的 Alogliptin ( WO2005095381 ) 、 Boehringer Ingelheim 公司 的 BI-1356 ( WO2004018468 , BI-1356 的化学名称为： 8-[(3R)-3-氨基 -1-哌啶 基卜 7-(2-丁炔基 )-3，7-二氢 -3-甲基 -1-[(4-甲基 -2-喹唑啉基)甲基卜 1H-嚟 呤 -2,6-二酮）等。 虽然上述这些药物具备良好的药效学性质， 但仍有 必要开发出更多活性较高、 毒性较低的新的化合物， 为 DPP-IV相关 疾病的治疗提供更广的药物选择空间。 发明内容 At present, DPP-1V inhibitors have become a new direction in drug research, and there have been many DPP-IV inhibitors have been successfully marketed, such as Merck's Sitegliptin (WO03004498), Novartis's Vildagliptin (WO09819998), Bristol-Myers Squibb's Saxagliptin (WO00168603), Takeda's Alogliptin (WO2005095381), and Boehringer Ingelheim's BI- 1356 ( WO2004018468 , the chemical name of BI-1356 is: 8-[(3R)-3-amino-1-piperidinyl b-7-( 2 -butynyl)-3,7-dihydro-3-methyl 1-[( 4 -methyl- 2 -quinazolinyl)methylbu-1H-indole-2,6-dione) and the like. Although these drugs have good pharmacodynamic properties, it is still necessary to develop more new compounds with higher activity and lower toxicity, providing a wider choice of drugs for the treatment of DPP-IV related diseases. Summary of the invention
本发明的目的是提供一类具有抑制 DPP-1V 活性并且可用于 DPP-IV相关疾病的治疗或緩解性药物的化合物。  It is an object of the present invention to provide a class of compounds having a therapeutic or palliative drug which inhibits DPP-1V activity and which can be used for DPP-IV related diseases.
本发明的第一方面提供一种式 I所示的黄嚟呤衍生物、其药学上可 接受的盐、 溶剂合物、 药学上可接受的盐的溶剂合物、 其化学保护形式 或者前药：  A first aspect of the invention provides a xanthine derivative of the formula I, a pharmaceutically acceptable salt, a solvate thereof, a solvate of a pharmaceutically acceptable salt, a chemically protected form thereof or a prodrug:
Figure imgf000004_0001
Figure imgf000004_0001
其中，  among them,
选自：
Figure imgf000004_0002
From:
Figure imgf000004_0002
选自 2-丁烯- 1-基、 3-甲基- 2-丁烯- 1-基或 2-丁炔- 1 -基； Selected from 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyne-1-yl;
R3、 R5、 各自独立的选自氢、 卤素原子， 直链或支链的被 1 ~ 5 个卤素原子取代或未被取代的 d-6烷基、直链或支链的被 1 ~ 5个卤素原 子取代或未被取代的 d-6烷氧基、 氛基或羟基； R 3 , R 5 , each independently selected from hydrogen, a halogen atom, a straight or branched chain of 1 to 5 halogen atoms substituted or unsubstituted d- 6 alkyl, straight or branched 1 ~ a substituted or unsubstituted d- 6 alkoxy group, an aryl group or a hydroxy group;
选自甲^ ^三氟甲基； X独立的选自 O或 S; Selected from methyl trifluoromethyl; X is independently selected from O or S;
m选自 1或 2。  m is selected from 1 or 2.
在一个具体的实施方案中， 本发明第一方面所述的式 I所示的黄 嚟呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学上可接受的盐的溶 剂合物、 其化学保护形式或者前药， 其中，  In a specific embodiment, the xanthine derivative of the formula I according to the first aspect of the invention, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt, and a chemistry thereof Protection form or prodrug, wherein
R3、 R5、 Re各自独立的选自氢、 氣原子、 氯原子、 溴原子、 甲基、 乙基、 异丙基、 甲 ft^、 乙 ft^、 三氟甲基、 三氟甲 #L^、 或羟基。 R 3 , R 5 , and Re are each independently selected from the group consisting of hydrogen, a gas atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an isopropyl group, a ft^, an ft^, a trifluoromethyl group, and a trifluoromethyl group. L^, or hydroxyl.
优选地 R3、 R5、 Re各自独立的选自氢、 氯原子、 甲基、 甲 #L^、 在一个具体的实施方案中， 本发明第一方面所述的式 I所示的黄 嚟呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学上可接受的盐的溶 剂合物、 其化学保护形式或者前药， 其中， Preferably, R 3 , R 5 , Re are each independently selected from the group consisting of hydrogen, chlorine atom, methyl group, methyl group #L^, and in a specific embodiment, the xanthine derivative of formula I according to the first aspect of the invention Or a pharmaceutically acceptable salt, a solvate thereof, a solvate of a pharmaceutically acceptable salt, a chemically protected form thereof, or a prodrug thereof,
R3选自氢、 甲基、 R 3 is selected from the group consisting of hydrogen, methyl,
R5选自氢、 氯原子、 甲基、 甲 R 5 is selected from the group consisting of hydrogen, chlorine, methyl, and A
Re选自氢、 氯原子、 甲基、 甲 。  Re is selected from the group consisting of hydrogen, chlorine atom, methyl group, and methyl group.
在一个具体的实施方案中，本发明第一方面所述的式 I所示的黄嚟 呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学上可接受的盐的溶剂 合物、 及其化学保护形式或者前药， 其选自式 1 (A) 、 式 1 (B)或式 I (C)：
Figure imgf000005_0001
In a specific embodiment, the xanthine derivative of the formula I according to the first aspect of the invention, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt, and A chemically protected form or prodrug selected from Formula 1 (A), Formula 1 (B) or Formula I (C):
Figure imgf000005_0001
式 I (Α)  Formula I (Α)
Figure imgf000005_0002
Figure imgf000005_0002
式 I (Β)
Figure imgf000006_0001
Formula I (Β)
Figure imgf000006_0001
式 1(C)  Equation 1(C)
其中： R2、 R3、 、 R5、 R6、 m、 X的定义同上。 Wherein: R 2 , R 3 , , R 5 , R 6 , m, X have the same meanings as defined above.
在一个具体的实施方案中， 本发明第一方面所述的式 I所示的黄 嚟呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学上可接受的盐的溶 剂合物、 及其化学保护形式或者前药， 其选自下列的化合物：  In a specific embodiment, the xanthine derivative of the formula I according to the first aspect of the invention, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt, and A chemically protected form or prodrug selected from the following compounds:
1-[(4,5-二氢环戊 [de】喹唑啉 _2_基）甲基】 _3_甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(4,5-dihydrocyclopenta[de]quinazoline- 2 -yl)methyl] _ 3 _methyl-7-(2-butyn-1-yl)-8-(3- (R)-J>piperidin-1-yl)xanthine;
1-[(4，5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤；  1-[(4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)- 8-(3-(R)-J>piperidin-1-yl)xanthine;
1-[(5,6,7,8-四氢 _4_甲基喹唑啉 _2-基）甲基】 -3-甲基 _7_(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(5,6,7,8-tetrahydro- 4 -methyl- 2 -quinazoline- 2 -yl)methyl]-3-methyl- 7 ( 2- ( 2 -butyn-1-yl)-8 -(3-(R)-J>piperidin-1-yl)xanthine;
1-[(5，6，7，8-四氢 -4-甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤；  1-[(5,6,7,8-tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butene-1 -yl)-8-(3-(R)-J>piperidin-1-yl)xanthine;
1-[(4-甲基苯并呋喃 [3，2-d】嘧啶 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤；  1-[(4-methylbenzofuran[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 -(R)-J>piperidin-1-yl)xanthine;
1-[(4-甲基苯并呋喃 [3,2-d]嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤；  1-[(4-methylbenzofuran[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl) 8-(3-(R)-J>piperidin-1-yl)xanthine;
1-[(4-甲基苯并噻吩 [3，2_d】嘧啶 _2_基）甲基】 _3_甲基 _7_(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(4-Methylbenzothiophene [ 3 , 2 _d]pyrimidin- 2 -yl)methyl] _ 3 _methyl _ 7 _( 2 -butyn-1-yl) -8-(3- (R)-J>piperidin-1-yl)xanthine;
1—[(6，7-二氢 -4-甲基 -5 -环戊 [d】嘧啶 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤；  1-[(6,7-dihydro-4-methyl-5-cyclopenta[d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) 8-(3-(R)-J>piperidin-1-yl)xanthine;
1-[(5，6，7，8-四氢 _4_三氟甲基喹唑啉 -2-基)甲基】 -3-甲基 _7_(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[( 5 ,6, 7 ,8-tetrahydro 4 4 -trifluoromethylquinazolin-2-yl)methyl]-3-methyl- 7- ( 2 -butyn-1-yl) 8-(3-(R)-J>piperidin-1-yl)xanthine;
1-[(6-氯 -4,5-二氢环戊 [de】喹唑啉 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤；  1-[(6-chloro-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 -(3-(R)-J>piperidin-1-yl)xanthine;
1-[(7-甲基 -4,5-二氢环戊 [de】喹唑啉 -2-基)甲基卜 3-甲基 -7-(3-甲基 -2- 丁烯 -1-基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤； 1-[(7-Methyl-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl-3-methyl-7-(3-methyl-2- Buten-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine;
1-[(7-曱氧基 -4,5-二氢环戊 [de]喹唑啉 -2-基)曱基] -3-曱基 -7- (反 -2-丁 烯 _1_基 )_8-(3-(R)-氨基哌啶 -1-基)黄嘌呤；  1-[(7-decyloxy-4,5-dihydrocyclopenta[de]quinazolin-2-yl)indolyl]-3-indolyl-7- (trans-2-butene_1_ )8-(3-(R)-aminopiperidin-1-yl)xanthine;
1 - [(5，6，7，8-四氢 -4， 6-二曱基喹唑啉 -2-基)曱基] -3-甲基 -7- (反 -2-丁烯 -1-基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤；  1-[(5,6,7,8-tetrahydro-4,6-dimercaptoquinazolin-2-yl)indolyl]-3-methyl-7- (trans-2-butene-1 -yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine;
1-[(5，6，7，8-四氢 -4,7-二曱基喹唑啉 -2-基）曱基] -3-甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤；  1-[(5,6,7,8-tetrahydro-4,7-diamidinoquinazolin-2-yl)indolyl]-3-methyl-7-(2-butyn-1-yl) -8-(3-(R)-Aminopiperidin-1-yl)xanthine;
1 - [(5,6,7,8-四氢 -4-曱基 -6-氰基喹唑啉 -2-基）曱基] -3-曱基 -7- (反 -2-丁 烯 _1_基 )_8-(3-(R)-氨基哌啶 -1-基)黄嘌呤；  1-[(5,6,7,8-tetrahydro-4-indolyl-6-cyanoquinazolin-2-yl)indolyl]-3-indolyl-7- (trans-2-butene) _1_yl)_8-(3-(R)-aminopiperidin-1-yl)xanthine;
1-[(6，7-二氢 -4,6-二曱基 环戊 [d]嘧啶 -2-基)曱基] -3-曱基 -7-(2-丁 炔 _1_基 )_8-(3-(R)-氨基哌啶 -1-基)黄嘌呤；  1-[(6,7-Dihydro-4,6-dimercaptocyclopenta[d]pyrimidin-2-yl)indolyl]-3-indolyl-7-(2-butyn-1-yl) _8-(3-(R)-Aminopiperidin-1-yl)xanthine;
1-[(4，8-二曱基苯并呋喃 [3，2-d]嘧啶 -2-基）曱基] -3-甲基 -7-(3-曱基 -2- 丁烯 -1-基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤；  1-[(4,8-Dimercaptobenzofuran[3,2-d]pyrimidin-2-yl)indolyl]-3-methyl-7-(3-indolyl-2-butene-1 -yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine;
1 - [(4-曱基 -8-氯苯并呋喃 [3，2-d]嘧啶 -2-基)曱基] -3-甲基 -7-(3-曱基 -2- 丁烯 -1-基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤；  1-[(4-Mercapto-8-chlorobenzofuran [3,2-d]pyrimidin-2-yl)indolyl]-3-methyl-7-(3-indolyl-2-butene- 1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine;
1·[(4，8-二曱基苯并噻吩 [3，2-d]嘧啶 -2-基）曱基] -3-曱基 -7-(2-丁炔 -1- 基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤；  1·[(4,8-Dimercaptobenzothiophene[3,2-d]pyrimidin-2-yl)indolyl]-3-indolyl-7-(2-butyn-1-yl)-8 -(3-(R)-aminopiperidin-1-yl)xanthine;
1 - [(4-曱基 -7-曱氧基苯并噻吩 [3，2-d]嘧啶 -2-基)曱基] -3-曱基 -7-(2-丁 炔 _1_基 )_8-(3-(R)-氨基哌啶 -1-基)黄嘌呤。  1-[(4-Mercapto-7-methoxybenzothiophene [3,2-d]pyrimidin-2-yl)indolyl]-3-indolyl-7-(2-butynyl-1-yl) ) 8-(3-(R)-Aminopiperidin-1-yl)xanthine.
本发明的第二方面提供一种制备本发明第一方面所述的式 I 所示 的黄嘌呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学上可接受的盐  A second aspect of the invention provides a xanthine derivative, a pharmaceutically acceptable salt, a solvate thereof, a pharmaceutically acceptable salt of the formula I according to the first aspect of the invention.
Figure imgf000007_0001
Figure imgf000007_0001
( 1 )将式 II所示的 取代的卤代曱烷（ -(:Η2Υ ) 与式 IV所示 的 3-曱基 -7-取代 -8-[(R)-3- (叔丁氧羰基胺基)哌啶 -1-基]黄嘌呤反应， 生 成中间体 I ( a ) ； (1) A substituted halodecane represented by the formula II (-(:Η 2 Υ )) and a 3-mercapto-7-substituted-8-[(R)-3-(tert-butyl) group represented by the formula IV Oxycarbonylamino)piperidin-1-yl]xanthine reacts to form intermediate I (a);
( 2 )中间体 I( a )在适宜酸存在下脱除叔丁氧羰基（简写为： Boc )， 得到式 I所示的化合物； (2) The intermediate I(a) is decoupled from the tert-butoxycarbonyl group (abbreviated as Boc) in the presence of a suitable acid, Obtaining a compound of formula I;
其中， R2、 R3、 、 R5、 R6、 X、 m的定义同本发明第一方面 的定义； Y为卤素； Wherein R 2 , R 3 , , R 5 , R6, X, m are as defined in the first aspect of the invention; Y is a halogen;
所述的适宜酸选自三氟乙酸、 甲酸、盐酸、 乙酸，优选为三氟乙酸、 盐酸， 最优选为三氟乙酸。  The suitable acid is selected from the group consisting of trifluoroacetic acid, formic acid, hydrochloric acid, and acetic acid, preferably trifluoroacetic acid, hydrochloric acid, and most preferably trifluoroacetic acid.
本发明的第三方面提供式 II所示化合物，  A third aspect of the invention provides a compound of formula II,
其中： 选自：
Figure imgf000008_0001
； 选自 2-丁烯- 1-基、 3-甲基- 2-丁烯- 1-基或 2-丁炔- 1 -基；Of which: From:
Figure imgf000008_0001
; selected from 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyne-1-yl;
R3、 R5、 各自独立的选自氢、 卤素原子， 直链或支链的被 1 ~ 5 个卤素原子取代或未被取代的 d-6烷基、直链或支链的被 1 ~ 5个卤素原 子取代或未被取代的 d-6烷氧基、 氛基或羟基； R 3 , R 5 , each independently selected from hydrogen, a halogen atom, a straight or branched chain of 1 to 5 halogen atoms substituted or unsubstituted d- 6 alkyl, straight or branched 1 ~ a substituted or unsubstituted d- 6 alkoxy group, an aryl group or a hydroxy group;
选自甲^ ^三氟甲基；  Selected from methyl trifluoromethyl;
X独立的选自 O或 S;  X is independently selected from O or S;
m选自 1或 2;  m is selected from 1 or 2;
并且当 116为氢时， X不为 o。 And when 11 6 is hydrogen, X is not o.
在一个具体的实施方案中， 本发明第三方面所述的化合物， 其选 自 11(A),
Figure imgf000008_0002
In a specific embodiment, the compound of the third aspect of the invention, which is selected from the group consisting of 11 (A),
Figure imgf000008_0002
II (A) 11(B) II (0  II (A) 11(B) II (0
其中， R3、 R4、 R5、 R6、 X、 m的定义同本发明第一方面的定义; 并且当 116为氢时， X不为 o。 Wherein R 3 , R 4 , R 5 , R 6 , X, m are as defined in the first aspect of the invention; and when 1 16 is hydrogen, X is not o.
在一个具体的实施方案中， 本发明第三方面所述的化合物， 其选 自以下化合物：  In a specific embodiment, the compound of the third aspect of the invention is selected from the group consisting of:
2-氯甲基 -4,5-二氢环戊 [de】喹唑啉（中间体 Π(Β)-1 ) ；  2-Chloromethyl- 4,5-dihydrocyclopenta[de]quinazoline (intermediate Π(Β)-1);
2-氯甲基 -5,6,7,8-四氢 -4-甲基喹唑啉（中间体 II(A)-l ) ； 2-氯甲基 -4-甲基苯并呋喃 [3，2-d】嘧啶（中间体 II(C)-l ) ； 2-chloromethyl-5,6,7,8-tetrahydro-4-methylquinazoline (intermediate II (A)-l); 2-chloromethyl-4-methylbenzofuran [3,2-d]pyrimidine (intermediate II (C)-l);
2-氯甲基 -4-甲基苯并噻吩 [3，2-d】嘧啶（中间体 II(C)-2 ) ；  2-chloromethyl-4-methylbenzothiophene [3,2-d]pyrimidine (intermediate II(C)-2);
2-氯甲基 -6,7-二氢 -4-甲基 环戊 [d】嘧啶（中间体 Π(Α)-2 ) ； 2-氯甲基 -5,6,7,8-四氢 -4-三氟甲基喹唑啉（中间体 Π(Α)-3 ) ；  2-Chloromethyl-6,7-dihydro-4-methylcyclopenta[d]pyrimidine (intermediate Π(Α)-2); 2-chloromethyl-5,6,7,8-tetrahydro -4-trifluoromethylquinazoline (intermediate Π(Α)-3);
2-氯甲基 -6氯 -4,5-二氢环戊 [de】喹峻啉 (中间体 Π(Β)-2 ) ；  2-Chloromethyl-6-chloro- 4,5-dihydrocyclopenta [de] quinoline (intermediate Π(Β)-2);
2-氯甲基 -7-甲基 -4,5-二氢环戊 [de】喹唑啉（中间体 Π(Β)-3 )；  2-chloromethyl-7-methyl-4,5-dihydrocyclopenta [de]quinazoline (intermediate Π(Β)-3);
2-氯甲基 -7-甲 1¾>-4，5-二氢环戊 [de】喹唑啉（中间体 Π(Β)-4 )；  2-chloromethyl-7-methyl 13⁄4>-4,5-dihydrocyclopenta[de]quinazoline (intermediate Π(Β)-4);
2-氯甲基 -5，6，7，8-四氢 -4，6-二甲基喹峻啉（中间体 11(A)-4 )； 2-chloromethyl-5,6,7,8-tetrahydro-4,6-dimethylquinoline (intermediate 11(A) -4 );
2-氯甲基 -5，6，7，8-四氢 -4，7-二甲基喹峻啉（中间体 11(A)-5 )； 2-chloromethyl-5,6,7,8-tetrahydro-4,7-dimethylquinoline (intermediate 11(A) -5 );
2-氯甲基 -5，6，7，8-四氢 -4-甲基 -6- 1^喹唑啉（中间体 Π(Α)-6 )；  2-Chloromethyl-5,6,7,8-tetrahydro-4-methyl-6- 1^quinazoline (intermediate Π(Α)-6);
2-氯甲基 -6,7-二氢 -4,6-二甲基 -5Η-环戊 [d]嘧啶（中间体 II(A)-7 )； 2-氯甲基 -4，8-二甲 并呋喃 [3，2-d】嘧啶（中间体 II(C)-3 )；  2-Chloromethyl-6,7-dihydro-4,6-dimethyl-5Η-cyclopenta[d]pyrimidine (Intermediate II(A)-7); 2-Chloromethyl-4,8- Dimethylfuran [3,2-d]pyrimidine (Intermediate II (C)-3);
2-氯甲基 -4-甲基 -8-氯苯并呋喃 [3，2-d】嘧啶（中间体 11(C)-4 )； 2-chloromethyl-4-methyl-8-chlorobenzofuran [3,2-d]pyrimidine (intermediate 11 (C) -4 );
2-氯甲基 -4，8-二甲^并噻吩 [3，2-d】嘧啶（中间体 II(C)-5 )；  2-chloromethyl-4,8-dimethylthiophene [3,2-d]pyrimidine (intermediate II(C)-5);
2-氯甲基 -4-甲基 -7-甲氧基苯并噻吩 [3，2-d】嘧啶（中间体 II(C)-6 )。 本发明的第四方面提供一种制备本发明第三方面所述的式 Π所示 化合物的 该方法包括以下步骤：  2-Chloromethyl-4-methyl-7-methoxybenzothiophene [3,2-d]pyrimidine (Intermediate II(C)-6). A fourth aspect of the invention provides a method of preparing a compound of the formula 所述 according to the third aspect of the invention, comprising the steps of:
当 Ri
Figure imgf000009_0001
When Ri
Figure imgf000009_0001
HI (A) II (A)  HI (A) II (A)
将式 III ( A )所示的 R3取代的环烷酮与卤代乙脒盐酸盐在碱性物 质存在条件下反应， 得到 II ( A )所示的化合物； The R 3 -substituted cycloalkanone of the formula III (A) and the haloacetic acid hydrochloride are reacted in the presence of a basic substance to obtain a compound represented by II (A);
所述碱性物质选自碳酸钾、 碳酸钠、 碳酸氢钾、 碳酸氢钠、 氢氧 化钾、 氢氧化钠、 甲醇钠、 乙醇钠， 优选为碳酸钾、 碳酸钠、 氢氧化 钠， 最优选为碳酸钾。 当 为
Figure imgf000010_0001
The basic substance is selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, preferably potassium carbonate, sodium carbonate, sodium hydroxide, most preferably Potassium carbonate. When
Figure imgf000010_0001
( 1 )将式 111(B)所示的 R5取代的 7-乙酰氣基茚酮进行水解得到 7- 茚酮； (1) hydrolyzing the R 5 -substituted 7-acetyl ketone ketone represented by formula 111 (B) to give 7-fluorenone;
( 2 ) 卤代乙腈环合得到 11(B)所示的化合物。  (2) Halogenated acetonitrile is cyclized to give a compound represented by 11 (B).
当 Ri
Figure imgf000010_0002
When Ri
Figure imgf000010_0002
将式 III ( C )所示的 取代的苯并呋喃或苯并噻吩化合物与卤代 乙腈环合得到式 II ( C )所示的化合物； 其中， R3、 、 R5、 Re的定义 同权利要求 1中的定义； The substituted benzofuran or benzothiophene compound represented by formula III (C) is cyclized with a halogenated acetonitrile to give a compound of formula II (C); wherein R 3 , R 5 and Re are as defined The definition in requirement 1;
X独立的选自 O或 S;  X is independently selected from O or S;
并且当 116为氢时， X不为 O; And when 11 6 is hydrogen, X is not O;
Y为卤素。  Y is a halogen.
本发明的第五方面提供一种药物组合物， 其包含本发明第一方面所 述的式 I所示的黄嚟呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学 上可接收的盐的溶剂合物、其化学保护形式或者前药， 以及药学上可接 受的赋形剂或载体。  A fifth aspect of the invention provides a pharmaceutical composition comprising the xanthine derivative of the formula I according to the first aspect of the invention, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable salt a solvate, a chemically protected form thereof or a prodrug, and a pharmaceutically acceptable excipient or carrier.
本发明的第六方面提供本发明第一方面所述的式 I所示的黄嚟呤衍 生物、其药学上可接受的盐、溶剂合物、药学上可接收的盐的溶剂合物、 其化学保护形式、 前药或者本发明第五方面所述的组合物的用途， 在用 于制备治疗、 预防以及緩解与 DPP-I 相关的疾病的药物的用途。  According to a sixth aspect of the present invention, the xanthine derivative of the formula I, the pharmaceutically acceptable salt, the solvate thereof, the pharmaceutically acceptable salt solvate of the formula I, and the chemical protection thereof are provided. Use of a form, a prodrug or a composition of the fifth aspect of the invention, for the manufacture of a medicament for the treatment, prevention and alleviation of a disease associated with DPP-I.
在本发明的一个具体实施方案中， 本发明第六方面所述的用途， 其 特征在于， 所述与 DPP-I 相关的疾病选自糖尿病、 高血糖症、 肥胖症 或胰岛素抵抗症、 缺血性心肌炎或血管生成性疾病； 优选地， 所述与In a particular embodiment of the invention, the use of the sixth aspect of the invention, Characterizing that the disease associated with DPP-I is selected from the group consisting of diabetes, hyperglycemia, obesity or insulin resistance, ischemic myocarditis or angiogenic disease; preferably, said
DPP-I 相关的疾病选自糖尿病和高血糖症。 The DPP-I related diseases are selected from the group consisting of diabetes and hyperglycemia.
本发明的第七方面提供本发明第三方面所述的化合物在用于制备 权利要求 1所述的黄嚟玲衍生物中的用途。  A seventh aspect of the invention provides the use of the compound of the third aspect of the invention for the preparation of the baicalin derivative of claim 1.
本发明的第八方面提供一种治疗、 预防以及緩解与 DPP-I 相关的 疾病的方法， 该方法是将本发明第一方面所述的黄嚟玲衍生物、 其药学 上可接受的盐、 溶剂合物、 药学上可接收的盐的溶剂合物、 其化学保护 形式、 前药施用给有需要的个体。  An eighth aspect of the present invention provides a method for treating, preventing, and ameliorating a disease associated with DPP-I, which comprises the above-described huangzhiling derivative of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, and a solvent The solvate of the pharmaceutically acceptable salt, its chemically protected form, and the prodrug are administered to an individual in need thereof.
本发明所引述的所有文献， 它们的 4^5内容通过引用并入本文， 并 且如果这些文献所表达的含义与本发明不一致时， 以本发明的表述为 准。  All of the documents cited in the present invention, their contents are incorporated herein by reference, and if the meanings expressed by these documents are inconsistent with the present invention, the expression of the present invention shall prevail.
本发明使用的各种术语和短语具有本领域技术人员公知的一般含 义， 即便如此， 本发明仍然希望在此对这些术语和短语作更详尽的说明 和解释， 提及的术语和短语如有与公知含义不一致的， 以本发明所表述 的含义为准。  The various terms and phrases used in the present invention have the ordinary meanings known to those skilled in the art, and even though the present invention is intended to provide a more detailed description and explanation of the terms and phrases herein, the terms and phrases are In the event of a known inconsistency, the meaning expressed in the present invention shall prevail.
本发明所用的术语"卤素，，或 "卤代" 是指氟、 氯、 溴或碘， 优选的 卤素基团为氟、 氯或溴。  The term "halogen," or "halo" as used herein means fluoro, chloro, bromo or iodo, and the preferred halo group is fluoro, chloro or bromo.
本发明中使用的术语 "烷基"是指饱和的直链或支链一价烃基， 具有 1-6个^ ^子（即 C1-6烷基） ， 优选 1-4个^ ^子（即 C1-4烷基） 、 The term "alkyl" as used in the present invention means a saturated straight or branched monovalent hydrocarbon group having from 1 to 6 (i.e., C1-6 alkyl), preferably from 1 to 4 (i.e., C1-4 alkyl),
1- 3碳原子（即 C1-3烷基）或 1-2个碳原子（即 C1-2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、 异丁基、 叔丁基、 正^、 异^、 新戊基、 2-甲基丁基、 正己基、 4-甲基^、 3-甲基戊基、 2-甲基 、 1-甲基戊基、 3，3-二甲基丁基、 2，2-二甲基丁 基、 1，1-二甲基丁基、 1，2-二甲基丁基、 1，3-二甲基丁基、 2，3-二甲基丁基、1- 3 carbon atoms (i.e., C1-3 alkyl) or 1-2 carbon atoms (i.e., C1-2 alkyl). Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-, iso-, neopentyl, 2-methyl Butyl, n-hexyl, 4-methyl^, 3-methylpentyl, 2-methyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,
2-乙基丁基、 1,2-二甲基丙基等， 在一个实施例中， 烷基优选自甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 正戊基、 异戊基、 新戊基、 正己基。 2-ethylbutyl, 1,2-dimethylpropyl, etc. In one embodiment, the alkyl group is preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
本发明所述"烷 是指具有 1-6个^ ^子的饱和直链或支链的烷 氧基，优选 1-4个碳原子烷氧基、 1-3碳原子烷氧基或 1-2个碳原子烷氧 基； 烷 的实例包括但不限于甲 ft^、 乙 ft^、正丙 ft^、异丙 ft^、 正丁 #L^、 异丁 #L^、叔丁 #L^、正戊 #L^、 异戊 #L^、 2-甲基丁 #L^、 新戊 ft^、 、 4-甲基戊 #L^、 3-甲基戊 #L^、 2-甲基戊 #L^、 1-甲基戊氧 基、 3，3-二甲基丁 #L^、 2，2-二甲基丁 #L^、 1，1-二甲基丁 #L^、 1，2-二甲 基丁 #L^、 1，3-二甲基丁 #U>、 2，3-二甲基丁 #U>、 2-乙基丁氧基、 1,2- 二甲基丙 ft基、 环丙氧基、 环丁氧基、 1-甲基环丁氧基、 环戊氧基、 环 己 等； 在一个实施例中，烷 优选自甲 #L^、 乙 #L^、正丙 #L^、 异丙氧基、 正丁氧基、 异丁氧基、 叔丁氧基、 正戊氧基、 正己氧基。 The "alkane" as used in the present invention means a saturated linear or branched alkane having 1 to 6 moles. An oxy group, preferably an alkoxy group of 1 to 4 carbon atoms, an alkoxy group of 1 to 3 carbon atoms or an alkoxy group of 1 to 2 carbon atoms; examples of the alkane include, but are not limited to, ft^, ft^, n-propyl Ft^, isopropyl ft^, 正丁#L^, Iso Ding#L^, 叔丁#L^, 正戊#L^, Isoparm #L^, 2-Methyl Ding#L^, Xinwu ft ^, , 4-methylpentan #L^, 3-methylpentan #L^, 2-methylpentan #L^, 1-methylpentyloxy, 3,3-dimethylbutyl #L^, 2,2-Dimethylbutyl #L^, 1,1-dimethylbutene #L^, 1,2-dimethylbutene #L^, 1,3-dimethylbutan #U>, 2, 3-dimethylbutan #U>, 2-ethylbutoxy, 1,2-dimethylpropanyl, cyclopropoxy, cyclobutoxy, 1-methylcyclobutoxy, cyclopentyl Oxyl, cyclohexene, etc.; in one embodiment, the alkane is preferably selected from the group consisting of A#L^, B#L^, n-propyl #L^, isopropoxy, n-butoxy, isobutoxy, tert-butoxy Base, n-pentyloxy, n-hexyloxy.
本发明式 I所示黄嚟呤衍生物包括其异构体、 消旋体、 对映体、 非 对映体、 对映体富集物、 氘代物、 溶剂合物和酯； 本发明式 I化合物以 及它的异构体、 消旋体、 对映体、 非对映体、 对映体富集物、 氣代物、 溶剂合物和酯还可以形成溶剂合物， 例如水合物、 醇合物等。 所述衍生 物还可以是前药或可在体内代谢变化后幹放出所述活性成分的形式。选 # ^制备适当的前药衍生物是本领域技术人员^技术。一^ f于本发 明的目的来说， 药学上可接受的溶剂如水、 乙醇等的溶剂合物形式与非 溶剂合物形式相当。  The xanthine derivative of the formula I of the present invention includes isomers, racemates, enantiomers, diastereomers, enantiomers, oximes, solvates and esters thereof; the compounds of the formula I according to the invention Its isomers, racemates, enantiomers, diastereomers, enantiomeric enrichments, gas substitutes, solvates and esters may also form solvates such as hydrates, alcoholates and the like. The derivative may also be in the form of a prodrug or a dry release of the active ingredient after metabolic changes in the body. The preparation of a suitable prodrug derivative is well known to those skilled in the art. For the purposes of the present invention, a solvate form of a pharmaceutically acceptable solvent such as water, ethanol or the like is equivalent to the unsolvated form.
本发明的式 I化合物可以以衍生自无机酸或有机酸的药学上可接受 的盐的形式使用。 术语"药学上可接受的盐，，指在可靠的医学判断范围 内，适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、 过敏反应等，且与合理的效果 /风险比相称的盐。药学上可接受的盐是本 领域公知的。 所述盐可通过使本发明化合物与合适的有机酸或无机酸反 应。  The compound of the formula I of the present invention can be used in the form of a pharmaceutically acceptable salt derived from a mineral acid or an organic acid. The term "pharmaceutically acceptable salts" means that it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and with reasonable effects within the scope of reliable medical judgment. A pharmaceutically acceptable salt is well known in the art. The salt can be reacted with a suitable organic or inorganic acid by a compound of the invention.
本发明式 I所示的黄嚟呤衍生物与有机酸或无机酸反应， 得到所述 黄嚟呤衍生物的药学上可接受的酸加成盐，例如氢卤酸盐，例如盐酸盐、 氢溴酸盐、 氢埃酸盐； 其他无机酸和它们对应的盐， 例如硫酸盐、 硝酸 盐、 磷酸盐等； 和烷基与一芳基磺酸盐， 例如乙磺酸盐、 甲苯磺酸盐和 酸盐； 和其他有机酸和它们对应的盐， 例如乙酸盐、 酒石酸盐、 马 来酸盐、 琥珀酸盐、 柠檬酸盐、 苯甲酸盐、 水杨酸盐和抗坏血酸盐。 本发明的进一步酸加成盐包括但不限于： 己二酸盐、藻酸盐、精氨酸盐、 天冬氨酸盐、 硫酸氢盐、 亚硫酸氢盐、 溴化物、 丁酸盐、 樟脑酸盐、 樟 脑磺酸盐、 辛酸盐、 氯化物、 氯苯甲酸盐、 环戊烷丙酸盐、二葡糖酸盐、 磷酸二氢 盐、 二硝基苯甲酸盐、 十二烷基硫酸盐、 富马酸盐、 半乳糖 二酸盐 （galacterateX来自粘酸)、 半乳糖醛酸盐、 葡庚酸盐、 葡糖酸盐、 谷氛酸盐、甘油磷酸盐、 半琥珀酸盐、 半硫酸盐、庚酸盐、 己酸盐、 马 尿酸盐、 盐酸盐、 氢溴酸盐、 氢碘酸盐、 2-羟基乙磺酸盐、 埃化物、 羟 乙基磺酸盐、 异丁酸盐、 乳酸盐、 乳糖酸盐、 苹果酸盐、 丙二酸盐、 扁 桃酸盐、 偏磷酸盐、 甲磺酸盐、 甲 甲酸盐、 磷酸一氢盐、 2- 酸 盐、 烟酸盐、 硝酸盐、 草酸盐、 油酸盐、 朴酸盐、 果胶酸盐、 过硫酸盐、 苯基乙酸盐、 3-苯基丙酸盐、 磷酸盐、 膦酸盐和邻苯二甲酸 盐。 应当 认识到， 游离碱形式通常将在物理性质上多少不同于它们各自的盐形 式， 例如在极性溶剂中的溶解度， 但是出于本发明的目的， 盐等价于它 们各自的游离碱形式。 The xanthine derivative of the formula I of the present invention is reacted with an organic acid or an inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the xanthine derivative, for example, a hydrohalide salt such as a hydrochloride or a hydrobromide salt. Hydrogenated acid salts; other inorganic acids and their corresponding salts, such as sulfates, nitrates, phosphates, etc.; and alkyl and monoarylsulfonates, such as ethanesulfonate, tosylate and acid salts And other organic acids and their corresponding salts, such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts of the invention include, but are not limited to: adipate, alginate, arginine, aspartate, hydrogen sulfate, bisulfite, bromide, butyrate, camphor Acid salt, camphor sulfonate, octoate, chloride, chlorobenzoate, cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecane Sulfate, fumarate, galactose salt (galacterateX from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerol phosphate, hemisuccinate , hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, edetate, isethionate, Isobutyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, mesylate, carboxamate, monohydrogen phosphate, 2-acidate, Nicotinate, Nitrate, Oxalate, Oleate, Park Salt, Pectate, Persulfate, Phenyl Acetate, 3-Phenyl , Phosphate, phosphonate and phthalate. It will be appreciated that the free base forms will generally differ in physical properties from their respective salt forms, such as solubility in polar solvents, but for the purposes of the present invention, salts are equivalent to their respective free base forms.
优选地， 本发明式 I所示的黄嚟呤衍生物与下列有机酸或无机酸反 应制备其药学上可接受的盐： 盐酸、 硫酸、 磷酸、 苹果酸、 马来酸、 富 马酸、 乳酸、 苯甲酸、 甲磺酸、 杵檬酸、 酒石酸、 乙酸或三氟乙酸； 优 选为盐酸盐、 苯甲酸盐或三氟乙酸盐。  Preferably, the xanthine derivative of the formula I of the present invention is reacted with the following organic or inorganic acid to prepare a pharmaceutically acceptable salt thereof: hydrochloric acid, sulfuric acid, phosphoric acid, malic acid, maleic acid, fumaric acid, lactic acid, benzene Formic acid, methanesulfonic acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid; preferably a hydrochloride, benzoate or trifluoroacetate salt.
本发明式 I所示的化合物可以单独作为治疗药物使用， 或者可以 与一种或多种其他具有同类或协同作用机制的 DPP-I 类药物联合使 用。 联合治疗通过将各个治疗组分同时、 顺序或隔开给药来实现。  The compound of the formula I of the present invention may be used alone as a therapeutic drug, or may be used in combination with one or more other DPP-I drugs having the same or synergistic mechanism. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
本发明的式 I化合物可以以衍生自无机酸或有机酸的药学上可接 受的盐的形式使用。 术语"药学上可接受的盐，，指在可靠的医学判断范 围内， 适合用于与人类和低等动物的组织接触而不出现过度的毒性、 刺激、 过敏反应等， 且与合理的效果 /风险比相称的盐。 药学上可接受 的盐是本领域公知的。  The compounds of formula I of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salts" means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and with reasonable effects/ A pharmaceutically acceptable salt is well known in the art.
可改变本发明药物组合物中各活性成分的实际剂量水平， 以便所 得的活性化合物量能有效针对具体患者、 组合物和给药方式得到所需 的治疗反应。 剂量水平须根据具体化合物的活性、 给药途径、 所治疗 病况的严重程度以及待治疗患者的病况和既往病史来选定。 但是， 本 领域的做法是， 化合物的剂量从低于为得到所需治疗效果而要求的水 平开始， 逐渐增加剂量， 直到得到所需的效果。 The actual dosage level of each active ingredient in the pharmaceutical compositions of the present invention can be varied so that the resulting amount of active compound is effective to provide the desired therapeutic response to the particular patient, composition, and mode of administration. The dosage level must be based on the activity of the specific compound, the route of administration, and the treatment The severity of the condition and the condition of the patient to be treated and the previous medical history were chosen. However, it is the practice in the art that the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
当用于上述治疗和 /或预防或其他治疗和 /或预防时， 治疗和 /或预 防有效量的一种本发明化合物可以以纯形式应用， 或者以药学上可接 受的盐、 酯或前药形式 (在存在这些形式的情况下)应用。 或者， 所述 化合物可以以含有该目标化合物与一种或多种药物可接受赋形剂的药 物组合物给药。词语"治疗和 /或预防有效量 "的本发明化合物指以适用 于任何医学治疗和 /或预防的合理效果 /风险比治疗障碍的足够量的化 合物。 但应认识到， 本发明式 I化合物和其药物组合物的总日用量须 由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者， 具体的治疗有效剂量水平须根据多种因素而定， 所述因素包括所治疗 的障碍和该障碍的严重程度； 所采用的具体化合物的活性； 所采用的 具体组合物； 患者的年龄、 体重、 一般健康状况、 性别和饮食； 所采 用的具体化合物的给药时间、 给药途径和排泄率； 治疗持续时间； 与 所采用的具体化合物组合使用或同时使用的药物； 及医疗领域公知的 类似因素。 例如， 本领域的做法是， 化合物的剂量从低于为得到所需 治疗效果而要求的水平开始， 逐渐增加剂量， 直到得到所需的效果。 一般说来， 本发明式 I化合物用于哺乳动物特别是人的剂量可以介于 0.001 - 1000 mg/kg体重 /天， 例如介于 0.01 ~ 100 mg/kg体重 /天， 例 如介于 0.01 ~ 10 mg/kg体重 /天。  When used in the above treatment and/or prophylaxis or other treatments and/or prophylaxis, a therapeutically and/or prophylactically effective amount of a compound of the invention may be administered in pure form, or in the form of a pharmaceutically acceptable salt, ester or prodrug. (in the case of these forms) application. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest and one or more pharmaceutically acceptable excipients. The phrase "therapeutic and/or prophylactically effective amount" of a compound of the invention refers to a sufficient amount of the compound to treat the disorder in a reasonable effect/risk ratio suitable for any medical treatment and/or prophylaxis. It will be appreciated, however, that the total daily usage of the compounds of formula I of the present invention and pharmaceutical compositions thereof will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; Patient's age, weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drug used in combination with or concurrent with the particular compound employed; Similar factors are known in the medical field. For example, it is the practice in the art to start at a dose lower than that required to achieve the desired therapeutic effect, gradually increasing the dosage until the desired effect is achieved. In general, the dose of the compound of the formula I according to the invention for use in mammals, especially humans, may range from 0.001 to 1000 mg/kg body weight per day, for example from 0.01 to 100 mg/kg body weight per day, for example between 0.01 and 10 Mg/kg body weight/day.
运用本领域技术人员熟悉的药物载体可以制备成含有效剂量的本 发明化合物的药物组合物。 因此本发明还提供包含与一种或多种无毒 药物可接受载体配制在一起的本发明化合物的药物组合物。 所述药物 组合物可特别专门配制成以固体或液体形式供口服给药、 供胃肠外注 射或供直肠给药。  Pharmaceutical compositions containing an effective amount of a compound of the invention can be prepared using pharmaceutical carriers well known to those skilled in the art. The invention therefore also provides a pharmaceutical composition comprising a compound of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form for parenteral injection or for rectal administration.
所述的药物组合物可配制成许多剂型， 便于给药， 例如， 口服制 剂 (如片剂、 胶囊剂、 溶液或混悬液)； 可注射的制剂（如可注射的溶液 或混悬液， 或者是可注射的干燥粉末， 在注射前加入注射水可立即使 用）。 所述的药物组合物中载体包括： 口服制剂使用的粘合剂 (如淀粉， 通常是玉米、 小麦或米淀粉， 明胶、 甲基纤维素、 羧甲基纤维素钠和 / 或聚乙烯吡咯烷酮）， 稀释剂 (如乳糖、 右旋糖、 蔗糖、 甘露醇、 山椠 醇、 纤维素和 /或甘油)， 润滑剂 (如二氧化硅、 滑石、 硬脂酸或其盐， 通常是硬脂酸镁或硬脂酸钙， 和 /或聚乙二醇)， 以及如果需要， 还含 有崩解剂， 如淀粉、 琼脂、 海藻酸或其盐， 通常是藻酸钠， 和 /或泡腾 混合物， 助溶剂、 稳定剂、 悬浮剂、 色素、 矫味剂等， 可注射的制剂 使用的防腐剂、 加溶剂、 稳定剂等； 局部制剂用的基质、 稀幹剂、 润 滑剂、 防腐剂等。 药物制剂可以经口服或胃肠外方式 (例如静脉内、 皮 下、 腹膜内或局部)给药， 如果某些药物在胃部条件下是不稳定的， 可 以将其配制成肠衣片剂。 The pharmaceutical composition can be formulated into a plurality of dosage forms for ease of administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions, Or an injectable dry powder, which can be immediately added by injecting water before injection. use). The carrier of the pharmaceutical composition comprises: a binder for oral preparation (such as starch, usually corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone) , diluents (eg lactose, dextrose, sucrose, mannitol, behenyl alcohol, cellulose and/or glycerol), lubricants (eg silica, talc, stearic acid or its salts, usually stearic acid) Magnesium or calcium stearate, and/or polyethylene glycol), and if desired, a disintegrating agent, such as starch, agar, alginic acid or a salt thereof, usually sodium alginate, and/or an effervescent mixture, Solubilizers, stabilizers, suspending agents, pigments, flavoring agents, etc., preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.
更具体地说， 本发明的药物组合物可通过口服、 直肠、 胃肠外、 阴道内、 局部 (如通过散剂、 软骨剂或滴剂）、 口颊给予人类和其他哺 乳动物，或者作为口腔喷雾剂或鼻腔喷雾剂给予。本文所用术语 "胃肠 外"指包括静脉内、 肌肉内、 内、 胸骨内、 皮下和关节内注射和输 液的给药方式。  More specifically, the pharmaceutical composition of the present invention can be administered orally, rectally, parenterally, vaginally, topically (e.g., by powder, chondridine or drops), to humans and other mammals, or as an oral spray. Or nasal spray. The term "parenteral" as used herein, refers to a method of administration including intravenous, intramuscular, internal, intrasternal, subcutaneous, and intra-articular injections and infusions.
适合于胃肠外注射的组合物可包括生理上可接受的无菌含水或非 水溶液剂、 分散剂、 混悬剂或乳剂， 及供重构成无菌可注射溶液剂或 分散剂的无菌散剂。 合适的含水或非水载体、 稀释剂、 溶剂或媒介物 的实例包括水、 乙醇、多元醇 (丙二醇、聚乙二醇、甘油等)、植物油 (如 橄榄油）、 可注射有机酯如油酸乙酯及它们的合适混合物。  Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for the preparation of sterile injectable solutions or dispersions. . Examples of suitable aqueous or nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (such as olive oil), injectable organic esters such as oleic acid. Ethyl esters and suitable mixtures thereof.
这些组合物也可含有辅料， 如防腐剂、 湿润剂、 乳化剂和分散剂。 通过各种抗细菌剂和抗真菌剂， 例如尼泊金酯类、 三氯叔丁醇、 苯盼、 山椠酸等， 可确保防止微生物的作用。 还包括等渗剂， 例如糖类、 氯 化钠等。 通过使用能延迟吸收的物质， 例如单硬脂酸铝和明胶， 可达 到可注射药物形式的延长吸收。  These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms is ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, benzophenone, behenic acid and the like. Also included are isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form is achieved by the use of substances which delay absorption, such as aluminum monostearate and gelatin.
混悬剂中除活性化合物外还可含有悬浮剂， 例如乙氧基化异十八 醇、 聚氧乙烯山椠醇和聚氧乙烯失水山椠糖醇酯、 微晶纤维素、 偏氢 氧化铝、 膨润土、 琼脂和黄蓍胶或者这些物质的混合物等。 在一些情况下， 为延长药物的作用， 期望减慢皮下或肌内注射药 物的吸收。 这可通过使用水溶性差的晶体或无定形物质的液体混悬剂 来实现。 这样， 药物的吸收速度取决于其溶解速度， 而溶解速度又可 取决于晶体大小和晶型。 或者， 胃肠外给药的药物形式的延迟吸收通 过将该药物溶解于或悬浮于油媒介物中来实现。 Suspensions may contain suspending agents in addition to the active compound, such as ethoxylated isostearyl alcohol, polyoxyethylene behenyl alcohol and polyoxyethylene sorbitol ester, microcrystalline cellulose, aluminum hydroxide , bentonite, agar and tragacanth or a mixture of these substances. In some cases, in order to prolong the action of the drug, it is desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of poorly water-soluble crystals or amorphous materials. Thus, the rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
可注射贮库制剂形式可通过在生物可降解聚合物如聚丙交酯-聚 乙交酯中形成药物的微胶囊基质来制备。 可根据药物与聚合物之比和 所采用的具体聚合物的性质， 对药物幹放速度加以控制。 其他生物可 降解聚合物的实例包括聚原酸酯类和聚酐类。 可注射贮库制剂也可通 过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。  The injectable depot form can be prepared by forming a microcapsule matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. The drug dry release rate can be controlled based on the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot formulations are also prepared by embedding the drug in liposomes or microemulsions which are compatible with body tissues.
可注射制剂可例如通过用滤菌器过滤或通过掺入无菌固体组合物 形式的灭菌剂来灭菌， 所述固体组合物可在临用前溶解或分散于无菌 水或其他无菌可注射介质。  The injectable preparation can be sterilized, for example, by filtration with a bacteriophage or by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterilized form before use. Injectable medium.
本发明化合物或其组合物可用口服方法或非胃肠道给药方式。 口 服给药形式可以是片剂、 胶囊剂、 包衣剂， 肠道外用药制剂有注射剂 和栓剂等。 这些制剂是按照本领域的技术人员所熟悉的方法制备的。 为了制造片剂、 胶囊剂、 包衣剂所用的辅料是常规用的辅料， 例如淀 粉、 明胶、 阿拉伯胶， 硅石， 聚乙二醇， 液体剂型所用的溶剂如水、 乙醇、 丙二醇、 植物油 (如玉米油、 花生油、 橄榄油等)。 含有本发明 化合物的制剂中还有其它辅料， 例如表面活性剂， 润滑剂， 崩解剂， 防腐剂， 矫味剂和色素等。 在片剂、 胶囊剂、 包衣剂、 注射剂和栓剂 中含有本发明式 I化合物的剂量是以单元剂型中存在的化合物量计算 的。 在单元剂型中本发明式 I化合物一般含量为 0.1 - lOOOmg, 优选 的单元剂型含有 1 - lOOmg, 更优选的单元剂型含有 5 - 20mge The compounds of the invention or compositions thereof may be administered orally or parenterally. The form for oral administration may be a tablet, a capsule, a coating, and an enteral preparation, an injection, a suppository, and the like. These formulations are prepared according to methods familiar to those skilled in the art. Excipients used in the manufacture of tablets, capsules, and coatings are conventional excipients such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils (such as corn). Oil, peanut oil, olive oil, etc.). There are other adjuvants in the formulation containing the compound of the present invention, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents and pigments. The dosage of the compound of the formula I according to the invention in tablets, capsules, coatings, injections and suppositories is calculated as the amount of the compound present in the unit dosage form. In a unit dosage form the compound of the formula I according to the invention is generally present in an amount of from 0.1 to 1000 mg, preferably in a unit dosage form containing from 1 to 100 mg, more preferably in a unit dosage form containing from 5 to 20 mg e
具体地说，本发明可以提供的供口服给药的固体剂型包括胶囊剂、 片剂、 丸剂、 散剂和颗粒剂。 在此类固体剂型中， 活性化合物可与至 少一种惰性的药物可接受赋形剂或载体如柠檬酸钠或磷酸二钙和 /或 以下物质混合： a)填充剂或增量剂如淀粉、 乳糖、 蔗糖、 葡萄糖、 甘 露糖醇和硅酸； b)粘合剂如羧甲基纤维素、 海藻酸盐、 明胶、 聚乙烯 吡咯烷酮、 蔗糖和阿拉伯树胶； C)保湿剂如甘油； d)崩解剂如琼脂、 碳酸钙、 马铃薯或木薯淀粉、 海藻酸、 某些硅酸盐和碳酸钠； e)溶液 阻滞剂如石蜡； f)吸收加速剂如季铵化合物； g)湿润剂如鲸蜡醇和甘油 单硬脂酸酯； h)吸附剂如高岭土和膨润土以及 i)润滑剂如滑石粉、 硬 脂酸钙、硬脂酸镁、 固体聚乙二醇、 十二烷基硫酸钠和它们的混合物。 在胶囊剂、 片剂和丸剂的情况下， 所述剂型中也可包含緩冲剂。 In particular, solid dosage forms for oral administration which may be provided by the present invention include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or the following: a) filler or extender such as starch, Lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyethylene Pyrrolidone, sucrose and gum arabic; C) humectants such as glycerin; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite and i) lubricants such as talc, calcium stearate, stearic acid Magnesium hydride, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, buffers may also be included in the dosage form.
相似类型的固体组合物使用赋形剂例如乳糖及高分子量聚乙二醇 等， 也可用作软胶囊和硬胶囊中的填充物。  Solid compositions of a similar type may be used as fillers in soft and hard capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like.
片剂、 糖衣丸剂、 胶囊剂、 丸剂和颗粒剂的固体剂型可与包衣和 壳料如肠溶衣材和医药制剂领域公知的其他衣材一起制备。 这些固体 剂型可任选含有遮光剂， 且其组成还可使其只是或优先地在肠道的某 个部位任选以延迟方式幹放活性成分。 可以使用的包埋组合物的实例 包括高分子物质和蜡类。 如果适合， 活性化合物也可与一种或多种上 述赋形剂配成微囊形式。  The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other materials well known in the art of pharmaceutical preparations. These solid dosage forms may optionally contain opacifying agents, and may be formulated such that they are only or preferentially dried in a certain portion of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and waxes. If appropriate, the active compound may also be formulated in microencapsulated form with one or more of the above excipients.
供口服给药的液体剂型包括药学上可接受的乳剂、 溶液剂、 混悬 剂、 糖浆剂和酏剂。 液体剂型除含有活性化合物外还可含有本领域常 用的惰性稀幹剂， 例如水或其他溶剂， 增溶剂和乳化剂例如乙醇、 异 丙醇、 碳酸乙酯、 乙酸乙酯、 苄醇、 苯甲酸苄酯、 丙二醇、 1,3-丁二 醇、 二甲基甲酰胺、 油类 (特别是棉籽油、 花生油、 玉米油、 胚芽油、 橄榄油、 蓖麻油和芝麻油)、 甘油、 四氢糠醇、 聚乙二醇和脱水山椠糖 醇的脂肪酸酯及它们的混合物。 口服组合物除包含惰性稀释剂外还可 包含辅料， 例如湿润剂、 乳化剂和悬浮剂、 甜味剂、 矫味剂和香味剂。  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. The liquid dosage form may contain, in addition to the active compound, an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid. Benzyl ester, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, Fatty acid esters of polyethylene glycol and dehydrated kaempferol and mixtures thereof. The oral compositions may contain, in addition to the inert diluent, excipients such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and flavoring agents.
本发明的化合物及其组合物还考虑用于局部给药。 供局部给予本 发明化合物的剂量形式包括散剂、 喷雾剂、 软骨剂和吸入剂。 在无菌 条件下将活性化合物与药学上可接受的载体和任何所需的防腐剂、 緩 冲剂或推进剂混合。 眼用制剂、 眼软骨剂、 散剂和溶液剂也被考虑在 本发明范围内。  The compounds of the invention and compositions thereof are also contemplated for topical administration. Dosage forms for topical administration of a compound of the invention include powders, sprays, cholestases and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any of the required preservatives, buffers or propellants. Ophthalmic formulations, ocular cartilage agents, powders and solutions are also contemplated as being within the scope of the invention.
本发明化合物也可以脂质体形式给药。 如本领域所公知， 脂质体 通常用磷脂或其他脂类物质制得。 脂质体由分散于含水介质中的单层 或多层水化液晶所形成。 任何能够形成脂质体的无毒、 生理上可接受 和可代谢的脂质均可使用。 脂质体形式的本发明组合物除含有本发明 化合物外， 还可含有稳定剂、 防腐剂、 赋形剂等。 优选的脂类是天然 和合成的磷脂和磷脂酰胆碱 (卵磷脂）， 它们可单独或者混合使用。 形 成脂质体的方法是本领域公知的。 具体实施方式 The compounds of the invention may also be administered in the form of liposomes. As is known in the art, liposomes are typically prepared using phospholipids or other lipid materials. Liposomes consist of a single layer dispersed in an aqueous medium Or formed by multiple layers of hydrated liquid crystal. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The composition of the present invention in the form of a liposome may contain, in addition to the compound of the present invention, a stabilizer, a preservative, an excipient or the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), which may be used singly or in combination. Methods of forming liposomes are well known in the art. detailed description
下面通过具体的制备实施例和生物学实验进一步说明本发明； 但 是， 应当理解， 这些实施例和生物学实验仅仅是用于更详细具体地说 明本发明之用， 而不应将其理解为用于以任何形式限制本发明。  The invention is further illustrated by the following specific examples of preparation and biological experiments; however, it should be understood that these examples and biological experiments are merely used to describe the invention in more detail, and should not be construed as The invention is limited in any way.
虽然为实现本发明目的所使用的材料和操作方法是本领域公知 的， 但是本发明仍然在此作尽可能详细描述。 本领域技术人员清楚， 在下文中， 如果未特别说明， 操作方法是本领域技术人员公知的； 所 可以制备得到， 或者可以通过市场购买得到。  While the materials and methods of operation used to accomplish the objectives of the present invention are well known in the art, the present invention is still described in detail herein. It will be apparent to those skilled in the art that, hereinafter, the method of operation is well known to those skilled in the art unless otherwise specified; it may be prepared, or may be commercially available.
在本发明中， 除非另外说明， 其中： （i)温度以摄氏度 (。c)表示， 操 作在室温环境下进行； 所述室温具有本技术领域公知的含义， 具体地， 是指 10-35。C， 优选 15-30。C， 最优选 20-25。C; (ii)有机溶剂用无水硫酸 钠干燥， 溶剂的蒸除通过旋转蒸发仪减压蒸发， 浴温不高于 60。C; (iii) 反应过程用薄层色谱 (TLC)跟踪；（iv)所得固体中间体或终产物均进行真 空干燥， 干燥温度不高于 60°C。 （V)终产物具有满意的质子核磁共振光 谱 H-NMR)和质谱 (MS)数据。  In the present invention, unless otherwise stated, wherein: (i) the temperature is expressed in degrees Celsius (.c), and the operation is carried out at room temperature; the room temperature has a meaning well known in the art, specifically, 10-35. C, preferably 15-30. C, most preferably 20-25. C; (ii) The organic solvent is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure by a rotary evaporator, and the bath temperature is not higher than 60. C; (iii) The reaction process is followed by thin layer chromatography (TLC); (iv) the obtained solid intermediate or final product is subjected to vacuum drying at a temperature not higher than 60 °C. (V) The final product has satisfactory proton nuclear magnetic resonance spectroscopy (H-NMR) and mass spectrometry (MS) data.
实施例 1: 14(4,5-二氢环戊 idel喹峻啉 -2-基)甲基 1-3-甲基 -7-(2-丁炔 -1-基) -8-i3-iR)- ^哌啶 -1-基)黃嚟呤（化合物 1 ) 的制备  Example 1: 14(4,5-Dihydrocyclopentad idel quinoline-2-yl)methyl 1-3-methyl-7-(2-butyn-1-yl)-8-i3-iR Preparation of -^piperidin-1-yl)xanthine (Compound 1)
( 1 ) 3
Figure imgf000018_0001
( 1 ) 3
Figure imgf000018_0001
室温条件下，将 8-溴 -3-甲基 -3，7-二氢 -嚟呤 -2，6-二酮 (24.5g， lOOmmol) 混悬于 150mL N，N-二甲基甲酰胺（缩写为： DMF ) 中， 加入二异丙基 乙胺 (27mL， 150mmol)， 机械搅拌 10分钟， 然后滴加溶有 1-溴 -2-丁炔 (15g, llOmmol)的 N，N-二甲基甲酰胺溶液 (50mL)， 滴加完毕后， 室温 搅拌 10-12小时。 反应完毕， 将反应液倒入冰水中， 搅拌析出固体， 抽 滤， 真空干燥得淡黄色固体 25g， 产率 84.1 %。 ES-API (m/z): [M+H]+ 297.0, 299.0。 8-Bromo-3-methyl-3,7-dihydro-indole-2,6-dione (24.5 g, 100 mmol) at room temperature Suspension in 150 mL of N,N-dimethylformamide (abbreviation: DMF), addition of diisopropylethylamine (27 mL, 150 mmol), mechanical stirring for 10 minutes, then dropwise addition of 1-bromo-2- A solution of butyne (15 g, llO mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 10-12 hours. After the completion of the reaction, the reaction mixture was poured into ice water, and the solid was evaporated, filtered, and dried in vacuo to give a pale yellow solid (25 g). ES-API (m/z): [M+H] + 297.0, 299.0.
( 2 ) 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧!^胺基)哌啶 -1-基】 黄嚟呤的制
Figure imgf000019_0001
(2) 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]
Figure imgf000019_0001
在氮气保护下， 将 3-甲基 -7-(2-丁炔 -1-基) -8-溴黄嚟呤 (3.0g， 10mmol)、 碳酸钾 (2.0g， 15mmol)和 3-(R)-叔丁 ^^啶 (2.2g, llmmol)加入到 50mL的圆底烧瓶中， 加入 10mL N，N-二甲基甲酰胺， 升温至 95。C搅拌 5小时； 反应完毕， 冷却至室温， 将反应液倒入冰水中 析出固体，抽滤、真空干燥，得浅黄色固体 3.1g，产率 74.5 %。 ES-API (m/z): [M+H】+ 417.1。 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (3.0 g , 10 mmol), potassium carbonate (2.0 g, 15 mmol) and 3-(R)- under nitrogen protection Tert-butyl pyridine (2.2 g, ll mmol) was added to a 50 mL round bottom flask, and 10 mL of N,N-dimethylformamide was added and the mixture was warmed to 95. C was stirred for 5 hours; after completion of the reaction, the mixture was cooled to room temperature, and the mixture was poured into ice water to give a solid, which was filtered and dried in vacuo to give a pale-yellow solid (3.1 g). ES-API (m/z): [M+H]+ 417.1.
( 3 ) 4-乙酰氣
Figure imgf000019_0002
(3) 4 -acetylene
Figure imgf000019_0002
将 4-氛基茚满 (13.5g， lOlmmol)加入到 500mL的圆底烧瓶中， 加 入 50mL 乙醇， 搅拌溶解并降温到 0。C， 然后加入溶有醋酸酐 (19mL， 201mmol)的乙醇溶液 200mL， 室温搅拌 12小时； 反应完毕， 减压蒸除 溶剂， 得白色固体 17.0g, 产率 97.1 %。 ES-API (m/z): [M+H]+ 176.0。 4-Alkyl indane (13.5 g, 10 mmol) was added to a 500 mL round bottom flask, 50 mL of ethanol was added, stirred to dissolve and cooled to 0. Then, 200 mL of an ethanol solution in which acetic anhydride (19 mL, 201 mmol) was dissolved was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to give a white solid (17.0 g, yield: 97.1%). ES-API (m/z): [M+H] + 176.0.
( 4 ) 7-乙酰
Figure imgf000019_0003
(4) 7-acetyl
Figure imgf000019_0003
将 4-乙酰氨基茚满 (5.0g， 29mmol)加入到 250 mL的圆底烧瓶中， 加入 150 mL丙酮， 搅拌均匀后加入 40mL质量分数为 15 %的 MgS04 水溶液， 降温到 0。C， 加入高锰酸钾 (13.7 g, 87mmol)， 然后室温搅拌 15小时。反应完毕，将反应液经硅藻土过滤，滤饼依次用氯仿和水洗涤， 滤液分出水相， 并用 50mL氯仿萃取一次， 合并有; N«， 70mL饱和食 盐水洗涤一次， 无水硫酸钠干燥 10小时， 过滤、 滤液蒸出溶剂得白色 固体 4.2g， 产率 76.6 %。 ES-API (m/z): [M+H】+ 190.0。 4-Acetylaminoindan (5.0 g, 29 mmol) was added to a 250 mL round bottom flask. Add 150 mL of acetone, stir well, add 40 mL of 15% by mass aqueous solution of MgS0 4 and cool to 0. C, potassium permanganate (13.7 g, 87 mmol) was added, followed by stirring at room temperature for 15 hours. After the reaction is completed, the reaction solution is filtered through celite, and the filter cake is washed with chloroform and water, and the filtrate is separated from the aqueous phase and extracted once with 50 mL of chloroform, and combined; N«, 70 mL of saturated brine is washed once, dried over anhydrous sodium sulfate After 10 hours, the solvent was evaporated, and the solvent was evaporated to give a white solid (yield: 4.2 g). ES-API (m/z): [M+H] + 190.0.
( 5 ) 7- J^-2，3- -1-茚酮的制备
Figure imgf000020_0001
(5) Preparation of 7-J^-2,3--1-indanone
Figure imgf000020_0001
将 7-乙酰 茚酮 (4.0g， 21mmol)加入到 lOOmL的圆底烧瓶中， 然后加入 50mL 6 mol/L盐酸， 升温至 90。C搅拌 4h; 反应完毕， 冷却至 0 °C,用 2mol/L NaOH 7j溶液调节反应液 pH值到 8， 乙酸乙酯（30mL ) 萃取反应液（共萃取 3次）， 合并有 ^ 目， 饱和食盐水洗涤， 无水硫酸 钠干燥， 减压蒸出溶剂得黄色固体 2.8g， 产率 90.7 %。 ES-API (m/z): 7-Acetyl ketone (4.0 g, 21 mmol) was added to a 100 mL round bottom flask, then 50 mL of 6 mol/L hydrochloric acid was added and the temperature was raised to 90. C stirring for 4h; After the reaction is completed, cool to 0 °C, adjust the pH of the reaction solution to 8 with 2mol/L NaOH 7j solution, extract the reaction solution with ethyl acetate (30mL) (3 times total extraction), combine with the mesh, saturate washed with brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give a yellow solid 2.8 g, 90.7% yield. ES-API (m/z):
[M+H】+ 148.0。 [M+H] + 148.0.
( 6 ) 2-氯甲 -4,5-二氢环戊 [de】喹峻啉 (中间体 Π(Β)-1 ) 的制备
Figure imgf000020_0002
(6) Preparation of 2-chloromethyl-4,5-dihydrocyclopenta[de]quinoline (intermediate Π(Β)-1 )
Figure imgf000020_0002
中间体 Π(Β)-1  Intermediate Π(Β)-1
将 7- ^-2，3-二氢 -1-茚酮 (1.5g， lOmmol)溶于 20mL 1，4-二氧六环 中，将溶液冷却至 10。C，然后通入氯化氢气体， 2小时后滴加氯乙腈 (0.9g， 12mmol)的 1，4-二氧六环溶液，室温下搅拌 5小时。反应完毕，加入 50mL 冰水， 用 2mol/L NaOH 7j溶液调节反应液 pH值到 8， 乙酸乙酯萃取 ( 30mL, 萃取 2次）， 合并有 t f， 20mL饱和食盐水洗涤， 无水硫酸 钠干燥， 旋蒸出溶剂得白色固体 1.9g， 产率 92.2 %。 ES-API (m/z): 7-^-2,3-Dihydro-1-indanone (1.5 g, 10 mmol) was dissolved in 20 mL of 1,4-dioxane and the solution was cooled to 10. C, hydrogen chloride gas was then introduced, and after 2 hours, a solution of chloroacetonitrile (0.9 g , 12 mmol) in 1,4-dioxane was added dropwise, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, 50 mL of ice water was added, and the pH of the reaction solution was adjusted to 8 with 2 mol/L NaOH 7j solution, extracted with ethyl acetate (30 mL, extracted twice), combined with tf, washed with 20 mL of brine, dried over anhydrous sodium sulfate. The solvent was distilled off to give a white solid 1.9 g, yield 92.2%. ES-API (m/z):
[M+H】+ 207.0。 [M+H] + 207.0.
( 7 ) 1-[(4，5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-[(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤的制备
Figure imgf000021_0001
(7) 1-[(4,5-Dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- Preparation of [(R)-3-(tert-butoxy!(amino)piperidin-1-yl]xanthine
Figure imgf000021_0001
在氮气保护下，将 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧叛^ ^基) 旅啶 -1-基】黄嚟呤 (0.21g， 0.5mmol)、 碳酸钾 (O.llg, 0.8mmol)和 2-氯甲 基 -4，5-二氢环戊 [de】喹唑淋 (0.13g， 0.6mmol)加入至 50mL 的圆底烧瓶 中，加入 10mL N，N-二甲基甲酰胺，升温至 90。C搅拌 5小时；反应完毕， 将反应液倒入 20mL冰水中析出固体， 抽滤， 滤饼经柱层析纯化， 得浅 黄色固体 0.20g， 产率 68.5 %， ES-API (m/z): [M+H]+ 585.0。 Under the protection of nitrogen, 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy-oxinyl)-bran-1-yl] (0.21 g, 0.5 mmol), potassium carbonate (O.llg, 0.8 mmol) and 2-chloromethyl-4,5-dihydrocyclopenta[de]quinazoline (0.13 g, 0.6 mmol) were added to 50 mL In a round bottom flask, 10 mL of N,N-dimethylformamide was added and the temperature was raised to 90. After stirring for 5 hours; the reaction was completed, and the reaction mixture was poured into 20 mL of ice water to precipitate a solid, which was filtered with suction, and the filter cake was purified by column chromatography to give a pale-yellow solid 0.20 g, yield 6.58 %, ES-API (m/z) : [M+H] + 585.0.
( 8 ) 1-[(4，5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)- J^哌啶 -1-基)黄嚟呤（化合物 1 )的制备  (8) 1-[(4,5-Dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- Preparation of (3-(R)-J^piperidin-1-yl)xanthine (Compound 1)
Figure imgf000021_0002
Figure imgf000021_0002
化合物 1  Compound 1
将 1-[(4，5-二氢环戊 [de】喹唑啉 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-[(R)-3- (叔丁氧羰基胺基)哌啶 -1-基】黄嚟呤 (0.17g， 0.3mmol)溶于 10mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时。反应 完毕， 蒸出溶剂， 加入 20mL冰水， 用 2mol/L NaOH水溶液调节反应 液 pH值到 8， 二氯甲烷萃取（20mL， 萃取 3次）， 合并有机相， 30mL 饱和食盐水洗涤， 无 酸钠干燥， 蒸出溶剂得淡黄色固体， 经柱层析 纯化得白色固体 (化合物 1) 0.10g, 产率 68.9 %。  1-[(4,5-Dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[( R)-3-(tert-Butoxycarbonylamino)piperidin-1-yl]xanthine (0.17 g, 0.3 mmol) was dissolved in a mixed solution of 10 mL of dichloromethane and 2 mL of trifluoroacetic acid, and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, 20 mL of ice water was added, and the pH of the reaction mixture was adjusted to 8 with 2 mol/L NaOH aqueous solution, extracted with dichloromethane (20 mL, extracted 3 times), combined organic phase, washed with 30 mL of saturated brine, acid-free The organic layer was dried (MgSO4).
ES-API (m/z): [M+H】+ 485.3。  ES-API (m/z): [M+H] + 485.3.
^ NMR (600MHz, CDC13, δρριη): 7.78(d, 1H)， 7.61 (d, 1H)， 7.37(d, 1H)， 5.60(s, 2H)， 4.90(d, 2H)， 3.57-3.71 (m, 2H)， 3.55 (s, 3H), 3.40(m, 2H) 3.38 (m, 2H)， 3.11 (m, 2H)， 2.93 (m, 1H)， 2.01 (m, 1H)， 1.89 (m, 1H)， 1.80 (s, 3H), 1.73(m, 1H)， 1.39(m, 1H)。 实施例 2: 14(4,5-二氢环戊 idel喹峻啉 -2-基)甲基 1-3-甲基 -7-(3-甲基 ■2—丁烯小基 )_8_i3_iR)_ ^旅^ 基)黄嚟呤（化合物 2 ) 的制备 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 7.78(d, 1H), 7.61 (d, 1H), 7.37(d, 1H), 5.60(s, 2H), 4.90(d, 2H), 3.57-3.71 (m, 2H), 3.55 (s, 3H), 3.40 (m, 2H) 3.38 (m, 2H), 3.11 (m, 2H), 2.93 (m, 1H), 2.01 (m, 1H), 1.89 (m , 1H), 1.80 (s, 3H), 1.73 (m, 1H), 1.39 (m, 1H). Example 2: 14(4,5-dihydrocyclopentan idel quinoline-2-yl)methyl 1-3-methyl-7-(3-methyl-2-isobutenyl)_ 8 _ Preparation of i3 _ iR) _ ^旅^ base) Astragalus (Compound 2)
( 1 ) 3-甲基 -7-(3-甲基 -2-  (1) 3-methyl-7-(3-methyl-2-
Figure imgf000022_0001
Figure imgf000022_0001
室温下，将 8-溴 -3-甲基 -3，7-二氢 -嚟呤 -2，6-二酮 (24.5g， lOOmmol) 混 悬于 150mL N，N-二甲基甲酰胺（缩写为： DMF ) 中， 后加入二异丙基 乙胺 (27mL， 150mmol)， 机械搅拌 10分钟， 然后滴加溶有 1-溴 -3-甲基 -2-丁烯 (16.5g， llOmmol)的 N，N-二甲基甲酰胺溶液 50mL，滴加完毕后， 室温搅拌 10-12小时。反应完毕，将反应液倒入 300ml冰水中析出固体， 抽滤，真空干燥得淡黄色固体 28.5g，产率 91.1 %。 ES-API (m/z): [M+H]+ 313.0, 315.0。 8-Bromo-3-methyl-3,7-dihydro-indole-2,6-dione (24.5 g, 100 mmol) was suspended in 150 mL of N,N-dimethylformamide at room temperature (abbreviation To: DMF), followed by the addition of diisopropylethylamine (27 mL, 150 mmol), mechanical stirring for 10 minutes, then dropwise addition of 1-bromo-3-methyl-2-butene (16.5 g, llOmmol) 50 mL of N,N-dimethylformamide solution was added, and after stirring, it was stirred at room temperature for 10-12 hours. After the completion of the reaction, the reaction mixture was poured into 300 ml of ice water to precipitate a solid, which was filtered and dried in vacuo to give a pale yellow solid (28.5 g). ES-API (m/z): [M+H] + 313.0, 315.0.
( 2 ) 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧！^胺基)哌 啶 -1-基】黄  (2) 3-Methyl-7-(3-methyl-2-buten-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl Yellow
Figure imgf000022_0002
Figure imgf000022_0002
在氮气保护下， 将 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-溴黄嚟呤 (5.0g， 16mmol)、 碳酸钾 (3.3g， 24mmol)和 3-(R)-叔丁 旅啶 (3.5g， 18mmol)加入到 lOOmL的圆底烧瓶中， 加入 40mL N，N-二甲基甲酰胺， 升温至 95。C搅拌 5小时。反应完毕，将反应液倒入 50mL冰水中析出固 体， 抽滤， 真空干燥得浅黄色固体 5.6g， 产率 81.2 %。 ES-API (m/z): 3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromoxanthine (5.0 g , 16 mmol), potassium carbonate (3.3 g, 24 mmol) and 3 under nitrogen -(R)-tert-Butidine (3.5 g, 18 mmol) was added to a 100 mL round bottom flask, and 40 mL of N,N-dimethylformamide was added and the mixture was warmed to 95. C was stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 50 mL of ice water to precipitate a solid, which was filtered, and dried in vacuo to give 5.6 g of pale yellow solid. ES-API (m/z):
[M+H】+ 433.1。 [M+H] + 433.1.
( 3 ) 1-[(4，5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2- 丁婦 _1 _基) _8- [(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤的制备
Figure imgf000023_0001
(3) 1-[(4,5-Dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butanyl _ Preparation of _8-[(R)-3-(tert-butoxy!(amino)piperidin-1-yl]xanthine
Figure imgf000023_0001
在氮气保护下， 将 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧 胺基)哌啶 -1-基】黄嚟呤 (0.31g， 0.7mmol)、 碳酸钾 (0.15g， l.lmmol) 和 2-氯甲基 -4,5-二氢环戊 [de】喹峻啉 (按实施例 1中步骤（ 3 ) - ( 6 )制 备） (0.17g, 0.8mmol)加入至 50mL的圆底烧瓶中， 加入 10mL N，N-二 甲基甲酰胺， 升温至 90。C搅拌 7小时。反应完毕， 将反应液倒入冰水中 析出固体，抽滤，滤饼经柱层析纯化 s得浅黄色固体 0.32g，产率 76.2 %。 3-methyl-7-(3-methyl-2-buten-1-yl)-8-[(R)-3-(tert-butoxyamino)piperidin-1- under nitrogen protection Astragalus (0.31 g, 0.7 mmol), potassium carbonate (0.15 g, 1.1 mmol) and 2-chloromethyl-4,5-dihydrocyclopenta[de]quinoline (according to the procedure in Example 1 ( 3) - (6) Preparation) (0.17 g, 0.8 mmol) was added to a 50 mL round bottom flask, and 10 mL of N,N-dimethylformamide was added and the temperature was raised to 90. C was stirred for 7 hours. After the reaction, the reaction solution was poured into ice-water and chromatographed s 0.32 g of a pale yellow solid, a yield of 76.2% solids precipitated, filtered off with suction, the filter cake was purified by column.
ES-API (m/z): [M+H】+ 601.0。 ES-API (m/z): [M+H] + 601.0.
( 4 ) 1-[(4，5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁 烯 -1-  (4) 1-[(4,5-Dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butene-1-
Figure imgf000023_0002
Figure imgf000023_0002
化合物 2  Compound 2
将 1-[(4，5-二氢环戊 [de】喹峻啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁 fUtiJ^基)哌啶 -1-基】黄嚟呤 (0.30g， 0.5mmol)溶于 10mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时；反应 完毕， 减压蒸出溶剂， 加入 20mL冰水， 用 2mol/L NaOH 7j溶液调节 反应液 pH值到 8， 二氯甲烷萃取（20mL， 萃取 3次） ， 合并有 t «， 30mL饱和食盐水洗涤一次， 无水硫酸钠干燥， 减压蒸出溶剂得淡黄色 固体， 经柱层析纯化得白色固体 (化合物 2) 0.18g， 产率 72.0 %。  1-[(4,5-Dihydrocyclopenta[de]quinolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl) -8-[(R)-3-(tert-butyl-fUtiJ^yl)piperidin-1-yl]xanthine (0.30 g, 0.5 mmol) was dissolved in a mixed solution of 10 mL of dichloromethane and 2 mL of trifluoroacetic acid, stirred at room temperature 1 hour; the reaction is completed, the solvent is distilled off under reduced pressure, 20 mL of ice water is added, the pH of the reaction solution is adjusted to 8 with 2 mol/L NaOH 7j solution, extracted with dichloromethane (20 mL, extracted 3 times), combined with t «, 30 mL The mixture was washed with saturated brine and dried over anhydrous sodium sulfate]]]]]]]]]]
ES-API (m/z): [M+H】+ 501.4。  ES-API (m/z): [M+H] + 501.4.
^ NMR (600MHz, CDC13, δρριη): 7.78(d, 1H)， 7.61 (d, 1H)， 7.37(d, 1H)， 5.60(s, 2H)， 5.43(t, 1H)， 4.73(m, 2H)， 3.56(s, 3H), 3.52(m, 1H)， 3.38- 3.42(m, 5H)， 2.97-3.09 (m, 2H)， 2.82 (m, 1H)， 2.01 (m, 1H)， 1.85 (m, 1H)， 1.70-1.75 (m， 7H)， 1.36(m, 1H)。 实施例 3: 14(5,6,7,8-四氢 -4-甲基喹唑啉 -2-基)甲基卜 3-甲基 -7-g-丁 炔 -1-基) -8-(3-iR)- J ^啶 -1-基)黄嚟呤（化合物 3 )的制备 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 7.78(d, 1H), 7.61 (d, 1H), 7.37(d, 1H), 5.60(s, 2H), 5.43(t, 1H), 4.73(m , 2H), 3.56(s, 3H), 3.52(m, 1H), 3.38- 3.42(m, 5H), 2.97-3.09 (m, 2H), 2.82 (m, 1H), 2.01 (m, 1H), 1.85 (m, 1H), 1.70-1.75 (m, 7H), 1.36 (m, 1H). Example 3: 14(5,6,7,8-tetrahydro-4-methylquinazolin-2-yl)methyl-3-methyl-7-g-butyn-1-yl)-8 -(3-iR)-J ^pyridin-1-yl) Preparation of xanthine (Compound 3)
( 1 ) 2- Π(Α)-1 )的制备
Figure imgf000024_0001
Preparation of ( 1 ) 2 - Π(Α)-1 )
Figure imgf000024_0001
中间体 Π(Α)-1  Intermediate Π(Α)-1
将 2-乙酰基环己酮 (2.8g， 20mmol)、 碳酸钾 (4.1g， 30mmol)和盐酸氯乙 脒 (2.8g， 22mmol)加入至 30mL正丁醇中， 回流搅拌 5小时。反应完毕， 减压蒸出溶剂， 剩余物倒入 50mL水中， 乙酸乙酯萃取 (30mL， 萃取 3 次)， 合并有 W«， 30mL饱和食盐水洗涤一次， 无水硫酸钠干燥， 减压 蒸出溶剂得黄色固体， 经柱层析纯化 (洗脱剂： 石油醚 /乙酸乙酯 =9:1)得 淡黄色液体 2.3g,产率 58.9 %。 ES-API (m/z): [M+H]+ 197.1„ 2-Acetylcyclohexanone (2.8 g, 20 mmol), potassium carbonate (4.1 g, 30 mmol) and chloroacetic acid hydrochloride (2.8 g, 22 mmol) were added to 30 mL of n-butanol and stirred under reflux for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was poured into 50 ml of water, ethyl acetate (30 mL, extracted 3 times), washed with W «, 30 mL of brine, dried over anhydrous sodium sulfate and evaporated. The solvent was obtained as a yellow solid, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 9:1). ES-API (m/z): [M+H] + 197.1„
( 2 ) 1-[(5，6，7，8-四氢 -4-甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-  (2) 1-[(5,6,7,8-Tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-
Figure imgf000024_0002
Figure imgf000024_0002
在氮气保护下，将 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧叛^ ^基) 旅啶 -1-基】黄嚟呤（制备方法参见实施例 1 步骤（1 ) - ( 2 ) ) (0.17g, 0.4mmol)、 碳酸钾 (83mg， 0.6mmol)和 2-氯甲基 -5，6，7，8-四氢 -4-甲基喹 唑淋 (0.10g， 0.5mmol)加入至 50mL的圆底烧瓶中， 加入 10mL N，N-二 甲基甲酰胺， 升温至 90。C搅拌 6小时。 反应完毕， 将反应液倒入 30mL 冰水中析出固体， 抽滤， 滤饼经柱层析纯化， 得白色固体 0.17g， 产率 73.9 %。 ES-API (m/z): [M+H]+ 577.1„ Under the protection of nitrogen, 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy-oxinyl)-bran-1-yl] (For the preparation method, see Example 1 Step (1) - (2)) (0.17 g, 0.4 mmol), potassium carbonate (83 mg, 0.6 mmol) and 2-chloromethyl-5,6,7,8-tetrahydro- 4-Methylquinazoline (0.10 g, 0.5 mmol) was added to a 50 mL round bottom flask, and 10 mL of N,N-dimethylformamide was added and the mixture was warmed to 90. C was stirred for 6 hours. After the completion of the reaction, the reaction mixture was poured into 30 mL of ice water to precipitate a solid, which was filtered, and then filtered and purified by column chromatography to give a white solid (0.17 g). ES-API (m/z): [M+H] + 577.1„
( 3 ) 1-[(5，6，7，8-四氢 -4-甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1- 基) - 3 )的制备
Figure imgf000024_0003
(3) 1-[(5,6,7,8-Tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) ) - 3) preparation
Figure imgf000024_0003
化合物 3 将 1- [(5，6，7，8-四氢 -4-甲基喹唑啉 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-[(R)-3- (叔丁氧！ ^胺基)哌啶 -1-基】黄嚟呤 (0.15g， 0.26mmol)溶于 10mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时；反应 完毕， 蒸出溶剂， 加入 20mL冰水， 用 2mol/L NaOH水溶液调 pH值 到 8， 二氯甲烷萃取（20mL， 萃取 2次） ， 合并有 t «， 30mL饱和食 盐水洗涤， 无水硫酸钠干燥， 减压蒸出溶剂得淡黄色固体， 经柱层析纯 化， 得白色固体 (化合物 3) 89 mg, 产率 71.8 %。 ES-API (m/z): [M+H]+ 477.3。 Compound 3 1-[(5,6,7,8-Tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]xanthine (0.15 g, 0.26 mmol) dissolved in 10 mL of dichloromethane and 2 mL of trifluoroacetic acid in a mixture at room temperature Stir for 1 hour; after completion of the reaction, distill off the solvent, add 20 mL of ice water, adjust the pH to 8 with 2 mol/L NaOH aqueous solution, extract with dichloromethane (20 mL, extract 2 times), combine with t «, 30 mL of saturated brine to wash The residue was dried over anhydrous sodium sulfate. ES-API (m/z): [M+H] + 477.3.
^ NMR (600MHz, CDC13, δρριη): 5.32(d, 2H)， 4.98(m, 2H)， 3.62 (m， 1H)， 3.49-3.53 (m, 4H)， 2.74 (s, 2H)， 2.55(s, 2H),2.30 (s, 3H), 2.01 (m, 2H) 1.88 (m, 1H)，1.81 (s, 3H), 1.79(m, 8H)。 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 5.32(d, 2H), 4.98(m, 2H), 3.62 (m, 1H), 3.49-3.53 (m, 4H), 2.74 (s, 2H), 2.55 (s, 2H), 2.30 (s, 3H), 2.01 (m, 2H) 1.88 (m, 1H), 1.81 (s, 3H), 1.79 (m, 8H).
实施例 4: 14(5,6,7,8-四氢 -4-甲基喹唑啉 -2-基)甲基〗 -3-甲基 -7-ί3-甲 基 -2-丁烯 -1-基) -8-(3-iR)- J ^啶 -1-基)黄嚟呤（化合物 4 )的制备  Example 4: 14(5,6,7,8-tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-ί3-methyl-2-butene- Preparation of 1-yl)-8-(3-iR)-J^--1-yl)xanthine (Compound 4)
( 1 ) 1-[(5，6，7，8-四氢 -4-甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2- 丁 _1 _基) _8- [(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤的制备  (1) 1-[(5,6,7,8-Tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butyl _1 _ base) _8- [(R)-3-(tert-butoxy!^amino)piperidin-1-yl] Preparation of astragalus
Figure imgf000025_0001
Figure imgf000025_0001
在氮气保护下， 将 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧 胺基)哌啶 -1-基】黄嚟呤（制备方法参见实施例 2步骤（ 1 ) - ( 2 ) ) (0.26g, 0.6mmol)、 碳酸钾 (0.12g， 0.9mmol)和 2-氯甲基 -5，6，7，8-四氢 -4- 甲基喹唑啉 (制备方法参见实施例 3步骤（ 1 ) ) (0.14g， 0.7mmol)加入 至 50mL的圆底烧瓶中，加入 10mL N，N-二甲基甲酰胺，置换氮气三次， 升温至 95。C搅拌 6小时。反应完毕，将反应液倒入 30mL冰水中析出固 体， 抽滤， 滤饼经硅胶柱纯化， 得浅黄色固体 (0.27g， 产率 76.1 %  3-methyl-7-(3-methyl-2-buten-1-yl)-8-[(R)-3-(tert-butoxyamino)piperidin-1- under nitrogen protection Astragalus (for the preparation method, see Step 2 (1) - (2)) (0.26 g, 0.6 mmol), potassium carbonate (0.12 g, 0.9 mmol) and 2-chloromethyl-5,6,7,8 - tetrahydro-4-methylquinazoline (for the preparation method, see step 3 (1) of Example 3) (0.14 g, 0.7 mmol) was added to a 50 mL round bottom flask, and 10 mL of N,N-dimethylformamide was added. Replace the nitrogen three times and raise the temperature to 95. C was stirred for 6 hours. After the completion of the reaction, the reaction mixture was poured into 30 mL of ice water to precipitate a solid, which was filtered, and filtered, and then purified on silica gel column to obtain a pale yellow solid (0.27 g, yield 76.1 %
ES-API (m/z): [M+H] + 593.1  ES-API (m/z): [M+H] + 593.1
( 2 ) 1-[(5，6，7，8-四氢 -4-甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2- 丁烯 -1-基) -8-(3-(R)- J ^啶 -1-基)黄嚟呤（化合物 4 )的制备 CF.COOH (2) 1-[(5,6,7,8-Tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butyl Preparation of alken-1-yl)-8-(3-(R)-J^pyridin-1-yl)xanthine (Compound 4) CF.COOH
CH2C12 CH 2 C1 2
NHBoc I I 丽：  NHBoc I I Li:
化合物 4  Compound 4
将 1- [(5，6，7，8-四氢 -4-甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁 烯 -1-基) -8-[(R)-3- (叔丁氧叛基胺基)哌啶 -1-基】黄嚟呤 (0.25g， 0.4mmol) 溶于 20mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时； 反应完毕， 蒸出溶剂， 加入 20mL冰水， 用 2mol/L NaOH水溶液调 pH 值到 8， 二氯甲烷萃取 (20mL， 萃取 3次)， 合并有 t f， 加入 20ml饱 和食盐水洗涤， 无水硫酸钠干燥， 减压蒸出溶剂得淡黄色固体， 经硅胶 柱纯化， 得白色固体 (化合物 4) 0.15g, 产率 76.1 %。 ES-API (m/z): 1-[(5,6,7,8-Tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butene- 1-yl)-8-[(R)-3-(tert-butoxysylamino)piperidin-1-yl]xanthine (0.25 g, 0.4 mmol) dissolved in 20 mL of dichloromethane and 2 mL of trifluoroacetic acid In the mixed solution, stir at room temperature for 1 hour; after completion of the reaction, distill off the solvent, add 20 mL of ice water, adjust the pH to 8 with 2 mol/L NaOH aqueous solution, extract with dichloromethane (20 mL, extract 3 times), combine with tf, add 20ml saturated brine, dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure to give a pale yellow solid which was purified by silica gel column to give a white solid (compound 4) 0.15g, yield 76 .1%. ES-API (m/z):
[M+H】+ 493.3。 [M+H] + 493.3.
1H-NMR (600MHz, CDC13, 5ppm): 5.41(t, 1H)， 5.33(s, 2H)， 4.73(m, 2H)， 3.53-3.56 (m, 4H)， 3.19-3.34 (m, 2H)， 2.95-3.04 (m, 2H)， 2.74 (s, 2H)， 2.55(s, 2H),2.30 (s, 3H), 2.03 (m, 1H)， 1.85 (m, 1H)， 1.71-1.79(m, 11H)， 1.51(m, 1H)。  1H-NMR (600MHz, CDC13, 5ppm): 5.41(t, 1H), 5.33(s, 2H), 4.73 (m, 2H), 3.53-3.56 (m, 4H), 3.19-3.34 (m, 2H), 2.95-3.04 (m, 2H), 2.74 (s, 2H), 2.55 (s, 2H), 2.30 (s, 3H), 2.03 (m, 1H), 1.85 (m, 1H), 1.71-1.79 (m, 11H), 1.51 (m, 1H).
实施例 5: 1-『 -甲絲并呋喃『3,2-d〗嘧啶 -2-基)甲基〗 -3-甲基 -7- -丁 炔 -1-基) -8-i3-iR)- ^啶 -1-基)黃嚟呤（化合物 5 )的制备  Example 5: 1-"-Methyl-furfuran "3,2-d-pyridin-2-yl)methyl"-3-methyl-7-butyne-1-yl)-8-i3-iR Preparation of -(pyridin-1-yl)xanthine (Compound 5)
( 1 ) 2-(2-氧代丙 #
Figure imgf000026_0001
(1) 2 -( 2 -oxo-propion #
Figure imgf000026_0001
将邻羟基苯甲腈 (12.0g， 100mmol)、 碳酸钾 (27.6g， 200mmol)和碘 化钾 (20.0g， 120mmol)加至 150mL丙酮中， 室温搅拌 0.5小时， 加入溴 丙酮 (15.1g， HOmmol), 升温回流 3小时； 反应完毕， 冷却至室温， 抽 滤， 浓缩滤液， 剩余物加入至 150mL水中， 用乙酸乙酯萃取（lOOmL, 萃取 2次） ， 合并有; W«， lOOmL饱和食盐水洗涤， 无水硫酸钠干燥， 减压蒸出溶剂， 干燥后棕色固体 16.1g, 产率 92.0 %。 ES-API (m/z):  O-hydroxybenzonitrile (12.0 g, 100 mmol), potassium carbonate (27.6 g, 200 mmol) and potassium iodide (20.0 g, 120 mmol) were added to 150 mL of acetone, stirred at room temperature for 0.5 hour, and bromoacetone (15.1 g, HO mmol) was added. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and then dried, brown solid, 16.1 g, yield 92.0%. ES-API (m/z):
[M+H] + 176.0。 2-乙 ¾^-3- ^苯并呋喃的制备
Figure imgf000027_0001
[M+H] + 176.0. Preparation of 2-ethyl 3⁄4^-3-^benzofuran
Figure imgf000027_0001
将 2-(2-氧代丙 苯甲腈 (15.0g， 86mmol)溶于 200mL 甲醇中， 加入甲醇钠 (5.1g， 95mmol)， 室温搅拌 10-12小时； 反应完毕， 减压蒸 除溶剂， 加入 150mL水， 然后用二氯甲烷萃取（lOOmL, 萃取 3次） ， 合并有; t «， 用 150mL饱和食盐水洗涤一次， 无水硫酸钠干燥。 减压 蒸出溶剂得黄色固体 14.1 g,产率 96.7 %。 ES-API (m/z): [M+H] + 176.1„ ( 3 ) 2-氯甲基 -4-甲基苯并呋喃 [3，2-d】嘧啶（中间体 II(c)-l ) 的制 备
Figure imgf000027_0002
2-(2-oxopropenzonitrile (15.0 g, 86 mmol) was dissolved in 200 mL of methanol, and sodium methoxide (5.1 g, 95 mmol) was added and stirred at room temperature for 10-12 hours; After adding 150 mL of water, and then extracting with dichloromethane (100 mL, extracting 3 times), and combining; t «, washed once with 150 mL of brine, dried over anhydrous sodium sulfate. The rate is 96.7 %. ES-API (m/z): [M+H] + 176.1 „( 3 ) 2-Chloromethyl-4-methylbenzofuran [3,2-d]pyrimidine (Intermediate II ( Preparation of c)-l)
Figure imgf000027_0002
中间体 II(C)-1  Intermediate II(C)-1
将 2-乙酰基 -3- J ^并呋喃 (6.0g， 34mmol)溶于 lOOmL 1，4-二氧六 环中， 将溶液冷却至 10。C， 然后通入氯化氢气体， 2小时后滴加氯乙腈 (3.1g, 41mmol)的 1,4-二氧六环溶液， 室温下搅拌 7小时； 反应完毕， 加入 lOOmL冰水， 然后再用 2mol/L NaOH 7j溶液调节反应液 pH值到 8， 乙酸乙酯萃取（lOOmL, 萃取 2次） ， 合并有机相， 用 lOOmL饱和 食盐水洗一次， 无 酸钠干燥。 减压蒸出溶剂得白色固体 5.8g， 产率 73.4 %。 ES-API (m/z): [M+H] + 233.1。  2-Acetyl-3-J^furan (6.0 g, 34 mmol) was dissolved in 100 mL of 1,4-dioxane and the solution was cooled to 10 . C, then hydrogen chloride gas was introduced, and after 2 hours, a solution of chloroacetonitrile (3.1 g, 41 mmol) in 1,4-dioxane was added dropwise, and stirred at room temperature for 7 hours; after completion of the reaction, 100 mL of ice water was added, and then 2 mol was used. /L NaOH 7j solution adjust the pH of the reaction solution to 8, extract ethyl acetate (100 mL, extract twice), combine the organic phase, wash once with 100 mL of saturated brine, dry without sodium. The solvent was evaporated under reduced pressure to give a white solid (yel. ES-API (m/z): [M+H] + 233.1.
( 4 ) 1-[(4-甲基苯并呋喃 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤的制备
Figure imgf000027_0003
(4) 1-[(4-Methylbenzofuran[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 -[(R)-3-(tert-butoxy!-amino)piperidin-1-yl] Preparation of Astragalus
Figure imgf000027_0003
在氮气保护下，将 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧叛^ ^基) 旅啶 -1-基】黄嚟呤（0.25g， 0.6mmol)、碳酸钾 (O.llg, 0.8mmol)和 2-氯甲 基 -4-甲^^并呋喃 [3，2-d】嘧啶 (0.16g， 0.7mmol)加入至 50mL的圆底烧 瓶中， 加入 10mL N，N-二甲基甲酰胺， 升温至 90。C搅拌 5小时； 反应完 毕， 将反应液倒入 20mL冰水中析出固体， 抽滤， 滤饼经柱层析纯化， 得白色固体 0.25g, 产率 67.6 % ES-API (m/z): [M+H] + 613.1。 Under the protection of nitrogen, 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy-oxinyl)-bran-1-yl] (0.25 g, 0.6 mmol), potassium carbonate (O.llg, 0.8 mmol) and 2-chloromethyl-4-methylbenzofuran [3,2-d]pyrimidine (0.16 g, 0.7 mmol) were added to 50 mL In a round bottom flask, 10 mL of N,N-dimethylformamide was added and the temperature was raised to 90. C stirring for 5 hours; reaction is complete After completion, the reaction liquid was poured into 20 mL of ice water to precipitate a solid, which was filtered with suction, and the filter cake was purified by column chromatography to obtain white solid 0.25 g, yield: 67.6 % ES-API (m/z): [M+H] + 613.1 .
( 5 ) 1-[(4-甲基苯并呋喃 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-
Figure imgf000028_0001
(5) 1-[(4-Methylbenzofuran [3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-
Figure imgf000028_0001
化合物 5  Compound 5
将 1-[(4-甲基苯并呋喃 [3，2-d】嘧啶 -2-基)甲基】 _3_甲基 _7_(2-丁炔 -1- 基) -8-[(R)-3- (叔丁氧羰基胺基)哌啶 -1-基】黄嚟呤 (0.20g， 0.3mmol)溶于 20mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时；反应 完毕， 减压蒸出溶剂， 加入 20mL冰水， 用 2mol/L NaOH水溶液调 pH 值到 8， 二氯甲烷萃取（20mL， 萃取 2次） ， 合并有 t f， 20mL饱和 食盐水洗^ "次， 无 酸钠干燥， 减压蒸出溶剂得淡黄色固体， 经柱 层析纯化， 得白色固体 (化合物 5) 0.12g, 产率 70.6 %。 ES-API (m/z): 1 - [(4 - methylbenzofuran [3, 2 -d] pyrimidin - 2 - yl) methyl] _ _ 3 _ 7 _ methyl (2 - butyn-1-yl) -8- [ (R)-3-(tert-Butoxycarbonylamino)piperidin-1-yl]xanthine (0.20 g, 0.3 mmol) was dissolved in a mixed solution of 20 mL of dichloromethane and 2 mL of trifluoroacetic acid, and stirred at room temperature for 1 hour; After completion of the reaction, the solvent was distilled off under reduced pressure, and 20 mL of ice water was added thereto, and the pH was adjusted to 8 with 2 mol/L NaOH aqueous solution, extracted with dichloromethane (20 mL, extracted twice), and combined with tf, 20 mL of saturated brine for washing. Drying without sodium sulfate, the solvent was evaporated to dryness crystals crystals crystals crystals crystalsssssssssssssssssssss
[M+H】+ 513.2。 [M+H] + 513.2.
1H-NMR (600MHz, CDC13, 5ppm): 8.16(d, 1H)， 7.60-7.64(m, 2H)， 7.39(m, 1H)， 5.58(s, 2H)， 4.87-4.94 (m， 2H)， 3.70 (d, 1H)， 3.54-3.60 (m， 4H)， 3.09-3.16 (m, 2H)， 2.96 (m, 1H)， 2.74(s, 3H), 2.01 (m， 1H)， 1.90 (m, 1H)， 1.79(m, 3H), 1.74(m, 1H)， 1.40(m， 1H)。  1H-NMR (600MHz, CDC13, 5ppm): 8.16(d, 1H), 7.60-7.64 (m, 2H), 7.39 (m, 1H), 5.58 (s, 2H), 4.87-4.94 (m, 2H), 3.70 (d, 1H), 3.54-3.60 (m, 4H), 3.09-3.16 (m, 2H), 2.96 (m, 1H), 2.74(s, 3H), 2.01 (m, 1H), 1.90 (m, 1H), 1.79 (m, 3H), 1.74 (m, 1H), 1.40 (m, 1H).
实施例 6: 1-『 -甲^^并呋喃『3,2-dl嘧啶 -2-基)甲基 1-3-甲基 -7-(3-甲 基 -2-丁烯 -1-基) -8-(3-iR)- J ^啶 -1-基)黄嚟呤（化合物 6 )的制备  Example 6: 1-"-Methane^furan"3,2-dl-pyrimidin-2-yl)methyl 1-3-methyl-7-(3-methyl-2-buten-1-yl Preparation of 8-(3-iR)-J(pyridin-1-yl)xanthine (Compound 6)
(1) 1-[(4-甲基苯并呋喃 [3，2-d】嘧啶 -2-基)甲基】 _3_甲基 -7_(3_甲基 -2- 丁婦 _1 _基) _8- [(R) (1) 1-[(4-Methylbenzofuran[ 3 , 2 -d]pyrimidin-2-yl)methyl] _ 3 _methyl- 7 _( 3 _methyl- 2 - 丁妇_1 _ base) _8- [(R)
Figure imgf000028_0002
Figure imgf000028_0002
在氮气保护下， 将 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧 胺基)哌啶 -1-基】黄嚟呤 (0.43g， l.Ommol, 制备方法参见实施例 2步 骤（ 1 )-( 2 ))、碳酸钾 (0.21g， 1.5mmol)和 2-氯甲基 -4-甲^:并呋喃 [3，2-d】 嘧啶 (0.26g， l.lmmol, 制备方法参加实施例 5步骤（ 1 ) - ( 3 ) )加入至 50mL的圆底烧瓶中， 加入 10mL N，N-二甲基甲酰胺， 升温至 90。C搅拌 8小时； 反应完毕， 将反应液倒入 20mL冰水中析出固体， 抽滤， 滤饼 经柱层析纯化，得白色固体 0.5lg，产率 81·0 %。 ES-API (m/z): [M+H] + 629.1„ 3-methyl-7-(3-methyl-2-buten-1-yl)-8-[(R)-3-(tert-butoxyamino)piperidin-1- under nitrogen protection Astragalus (0.43 g , l.Ommol, see Method 2 for the preparation method) (1)-(2)), potassium carbonate (0.21 g , 1.5 mmol) and 2-chloromethyl-4-methyl^-furan [3,2-d]pyrimidine (0.26 g, 1.1 mmol, prepared Method The steps (1) - (3) of Example 5 were added to a 50 mL round bottom flask, 10 mL of N,N-dimethylformamide was added, and the temperature was raised to 90. C for 8 hours; completion of the reaction, the reaction solution was poured into 20mL of ice water to precipitate solid was purified by chromatography, suction filtered, the filter cake was purified by column to give a white solid 0. 5 lg, yield 81 · 0%. ES-API (m/z): [M+H] + 629.1„
( 2 ) 1-[(4-甲基苯并呋喃 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2  ( 2 ) 1-[(4-Methylbenzofuran [3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(3-methyl-2
Figure imgf000029_0001
Figure imgf000029_0001
化合物 6  Compound 6
将 1-[(4-甲基苯并呋喃 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁 烯 -1-基) -8-[(R)-3- (叔丁氧叛基胺基)哌啶 -1-基】黄嚟呤 (0.33g， 0.5mmol) 溶于 20mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时； 反应完毕， 加入 20mL冰水， 用 2mol/L NaOH 7j溶液调节反应液 pH 值到 8， 二氯甲烷萃取（20mL， 萃取 2次） ， 合并有 t f， 20mL饱和 食盐水洗^ "次， 无 酸钠干燥， 减压蒸出溶剂得淡黄色固体， 经柱 层析纯化， 得白色固体 (化合物 6) 0.21g, 产率 79.2 %。 ES-API (m/z):  1-[(4-Methylbenzofuran [3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl -8-[(R)-3-(tert-butoxysylamino)piperidin-1-yl]xanthine (0.33 g, 0.5 mmol) dissolved in a mixed solution of 20 mL of dichloromethane and 2 mL of trifluoroacetic acid After stirring at room temperature for 1 hour; after completion of the reaction, add 20 mL of ice water, adjust the pH of the reaction solution to 8 with 2 mol/L NaOH 7j solution, extract with dichloromethane (20 mL, extract 2 times), combine with tf, wash with 20 mL of saturated brine. The reaction mixture was evaporated to dryness eluted eluted elut elut elut elut elut elut elut elut elut elut
[M+H】+ 529.3。 [M+H] + 529.3.
1H-NMR (600MHz, CDC13, 5ppm): 8.18(d, 1H)， 7.60-7.64(m, 2H)， 7.40(m, 1H)， 5.61(s, 2H)， 5.38(t, 1H)， 4.74-4.81 (m, 2H)， 3.74 (m, 1H)， 3.65 (m, 1H)， 3.56-3.62(m, 4H)， 3.19-3.24 (m, 2H)， 2.80(s, 3H), 2.14 (m, 1H)， 1.96 (m, 1H)， 1.69-1.74 (m, 7H)， 1.43(m, 1H)。  1H-NMR (600MHz, CDC13, 5ppm): 8.18 (d, 1H), 7.60-7.64 (m, 2H), 7.40 (m, 1H), 5.61 (s, 2H), 5.38 (t, 1H), 4.74- 4.81 (m, 2H), 3.74 (m, 1H), 3.65 (m, 1H), 3.56-3.62 (m, 4H), 3.19-3.24 (m, 2H), 2.80(s, 3H), 2.14 (m, 1H), 1.96 (m, 1H), 1.69-1.74 (m, 7H), 1.43 (m, 1H).
实施例 7: 1-『 -甲^^并噻吩『3,2-dl嘧啶 -2-基)甲基 1-3-甲基 -7- -丁 炔 -1-基) -8-i3-iR)- ^啶 -1-基)黃嚟呤（化合物 7 )的制备  Example 7: 1-"-Methane^thiophene "3,2-dl-pyrimidin-2-yl)methyl 1-3-methyl-7--butyn-1-yl)-8-i3-iR Preparation of -(pyridin-1-yl)xanthine (Compound 7)
( 1 ) 2- (苄^ J 苯甲腈的制备
Figure imgf000029_0002
将邻硝基苯甲腈 (7.5g， 50mmol)、苄硫醇 (6.2g， 50mmol)溶于 50mL N，N-二甲基甲酰胺中，将溶液冷却至 0。C，滴加氢氧化钾 (5.0g， 90mmol) 的水溶液 15mL， 室温搅拌 2小时； 反应完毕， 将反应液倒入 lOOmL冰 水中析出固体，抽滤，真空干燥，得黄色固体 9.5g，产率 84.4 %。 ES-API (m/z): [M+H】+ 226.0。 (1) Preparation of 2-(benzyl^J benzonitrile)
Figure imgf000029_0002
O-Nitrobenzonitrile (7.5 g, 50 mmol) and benzyl mercaptan (6.2 g, 50 mmol) were dissolved in 50 mL of N,N-dimethylformamide and the solution was cooled to 0. C, 15 mL of an aqueous solution of potassium hydroxide (5.0 g, 90 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into 100 mL of ice water to precipitate a solid, which was filtered and dried in vacuo to give 9.5 g of a yellow solid. 84.4%. ES-API (m/z): [M+H]+ 226.0.
( 2 ) 2-巯羞
Figure imgf000030_0001
(2) 2- shame
Figure imgf000030_0001
将 AlCl3(8.6g， 65mmol)加入至 50mL 甲苯中， 氮气的保护下滴加 50mL溶有 2- (苄¾^)苯甲腈 (9.0g， 40mmol)的甲苯溶液， 滴加完毕， 室 温搅拌 48小时； 反应完毕， 向反应液中加入 lOOmL冰水， 分出有机相 并依次用水、 5%氢氧化钠溶液 (50mL)洗涤（共洗涤两次） ， 7J层被酸 化至 pH-3后， 用二氯甲烷萃取（lOOmL, 萃取 3次） ， 合并有机相， 150mL饱和食盐水洗涤一次，无水硫酸钠干燥，减压蒸出溶剂得棕色液 体 5.0g，产率 92.6 %。 ES-API (m/z): [M+H】+ 136.0。 Add AlCl 3 (8.6 g, 65 mmol) to 50 mL of toluene, and add 50 mL of a toluene solution containing 2-(benzyl 3⁄4^)benzonitrile (9.0 g, 40 mmol) dropwise under a nitrogen atmosphere. After 48 hours; after the reaction was completed, 100 mL of ice water was added to the reaction solution, and the organic phase was separated and washed successively with water, 5% sodium hydroxide solution (50 mL) (two times in total), and the 7J layer was acidified to pH-3. It was extracted with dichloromethane (100 mL, extracted 3 times), and the organic phase was combined, washed twice with 150 mL of brine, dried over anhydrous sodium sulfate, and evaporated. ES-API (m/z): [M+H]+ 136.0.
( 3 ) 2-乙 -3- ^苯并噻吩的制备 o (3) Preparation of 2-ethyl-3-^benzothiophene o
Figure imgf000030_0002
Figure imgf000030_0002
将 2-巯^ ^甲腈 (4.0g， 30mmol)、 碳酸钾 (8.3g， 60mmol)和^匕钾 (5.8g， 35mmol)加入至 50mL丙酮中， 室温搅拌 0.5小时， 加入溴丙酮 (4.6g， 34mmol), 升温回流 5小时； 反应完毕， 冷却至室温， 抽滤， 浓 缩滤液， 剩余物加入 lOOmL水中， 乙酸乙酯萃取（50mL， 萃取 3次）， 合并有; t «， lOOmL饱和食盐水洗涤一次， 无水硫酸钠干燥， 减压蒸出 溶剂得棕色固体 5.0g，产率 87.7 %。 ES-API (m/z): [M+H】+ 192.1。  2-巯^^carbonitrile (4.0 g, 30 mmol), potassium carbonate (8.3 g, 60 mmol) and potassium (5.8 g, 35 mmol) were added to 50 mL of acetone, stirred at room temperature for 0.5 hour, and bromoacetone (4.6 g) was added. , 34mmol), refluxing for 5 hours; after completion of the reaction, cooling to room temperature, suction filtration, concentration of the filtrate, the residue was added to 100 mL of water, ethyl acetate extraction (50 mL, extraction 3 times), combined; t «, lOOmL saturated brine The mixture was washed once, dried over anhydrous sodium sulfate, and evaporated. ES-API (m/z): [M+H] + 192.1.
( 4 ) 2-氯甲基 -4-甲基苯并噻吩 [3，2-d】嘧啶（中间体 11(C)-2 )的制 备
Figure imgf000030_0003
Preparation of (4) 2 -chloromethyl- 4 -methylbenzothiophene [ 3 , 2 -d]pyrimidine (Intermediate 11(C) -2 )
Figure imgf000030_0003
中间体 II(C)-2 将 2-乙酰基 -3- J ^并塞哈 (4.0g， 20mmol)溶于 lOOmL 1，4-二氧六 环中， 将溶液冷却至 10。C， 然后通入氯化氢气体， 2小时后滴加氯乙腈 (1.7g， 22mmol)的 1,4-二氧六环溶液， 室温下搅拌 6小时； 反应完毕， 加入 lOOmL冰水，然后用 2mol/L NaOH 7j溶液调节反应液 pH值到 8， 乙酸乙酯萃取（lOOmL, 萃取 2次）， 合并有机相， lOOmL饱和食盐水 洗涤一次， 无水硫酸钠干燥。 减压蒸出溶剂得黄色固体， 经柱层析纯化 (梯度洗脱，石油醚 /乙酸乙酯 =10:1~5:1)得黄色固体 3.8g，产率 76.6 %。 ES-API (m/z): [M+H】+ 249.2。 Intermediate II (C)-2 2-Acetyl-3-J^ and Seyja (4.0 g, 20 mmol) was dissolved in 100 mL of 1,4-dioxane and the solution was cooled to 10. C, then hydrogen chloride gas was introduced, and after 2 hours, a solution of chloroacetonitrile (1.7 g, 22 mmol) in 1,4-dioxane was added dropwise, and stirred at room temperature for 6 hours; after completion of the reaction, 100 mL of ice water was added, followed by 2 mol/ The pH of the reaction solution was adjusted to 8 by L NaOH 7j solution, ethyl acetate was extracted (100 mL, extracted twice), and the organic phase was combined, washed once with 100 mL of brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to dryness crystals crystals crystals crystals ES-API (m/z): [M+H]+ 249.2.
( 5 ) 1-[(4-甲基苯并噻吩 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧^ ^基)哌啶 -1-基】黄噪呤的制备
Figure imgf000031_0001
(5) 1-[(4-Methylbenzothiophene [3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 -[(R)-3-(tert-Butoxy)-piperidin-1-yl] Preparation of Yellow Noise
Figure imgf000031_0001
在氮气保护下，将 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧 gJ^基) 派啶 -1-基】黄嚟呤 (0.33g， 0.8mmol)、 碳酸钾 (0.17g， 1.2mmol)和 2-氯甲 基 -4-甲^^并噻吩 [3，2-d】嘧啶 (0.22g， 0.9mmol)加入至 50mL的圆底烧 瓶中， 加入 10mL N，N-二甲基甲酰胺， 升温至 90。C搅拌 5小时； 反应完 毕， 将反应液倒入 20mL水水中析出固体，抽滤， 滤饼经硅胶柱纯化 (梯 度洗脱，二氯甲烷 /甲醇 =100:1~60:1)，得淡黄色固体 0.41g，产率 81.9 %， ES-API (m/z): [M+H]+ 629.1„ Under the protection of nitrogen, 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxygJ)-pyridin-1-yl]xanthine 0.33 g, 0.8 mmol), potassium carbonate (0.17 g, 1.2 mmol) and 2-chloromethyl-4-methyl thiophene [3,2-d]pyrimidine (0.22 g, 0.9 mmol) were added to a 50 mL circle In a bottom flask, 10 mL of N,N-dimethylformamide was added and the temperature was raised to 90. C is stirred for 5 hours; after the reaction is completed, the reaction liquid is poured into 20 mL of water to precipitate a solid, which is filtered with suction, and the filter cake is purified by silica gel column (gradient elution, dichloromethane/methanol = 100:1 to 60:1). Yellow solid 0.41 g , yield 81.9%, ES-API (m/z): [M+H]+ 629.1 „
( 6 ) 1-[(4-甲基苯并噻吩 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-
Figure imgf000031_0002
(6) 1-[(4-Methylbenzothiophene[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyne-1-
Figure imgf000031_0002
化合物 7  Compound 7
将 1-[(4-甲基苯并噻吩 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-[(R)-3- (叔丁氧羰基胺基)哌啶 -1-基】黄噪呤 (0.32g， 0.5mmol)溶于 20mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时，反应 完毕。 减压蒸出溶剂， 加入 20mL冰水， 用 2mol/L NaOH 7j溶液调节 反应液 pH值到 8， 二氯甲烷萃取（20mL， 萃取 2次） ， 合并有 t «， 20mL饱和食盐水洗涤一次， 无水硫酸钠干燥， 减压蒸出溶剂得黄色固 体， 经柱层析纯化， 得黄色固体 (化合物 7) 0.21g， 产率 79.5 %。 ES-API (m/z): [M+H】+ 529.2 1-[( 4 -Methylbenzothiophene[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[ (R)-3-(tert-Butoxycarbonylamino)piperidin-1-yl] yellow noise (0.32 g, 0.5 mmol) was dissolved in a mixture of 20 mL of dichloromethane and 2 mL of trifluoroacetic acid and stirred at room temperature 1 In hours, the reaction is complete. Evaporate the solvent under reduced pressure, add 20 mL of ice water, and adjust with 2 mol/L NaOH 7j solution. The pH of the reaction mixture was adjusted to 8, and the mixture was extracted with dichloromethane (20 mL, extracted twice). The mixture was washed with EtOAc EtOAc. Purification gave 0.21 g of a yellow solid (Comp. 7). ES-API (m/z): [M+H]+ 529.2
^ NMR (600MHz, CDC13, δρριη): 8.37(d, 1H)， 7.86(d, 1H)， 7.61 (m， 1H)， 7.48(m, 1H)， 5.61(s, 2H)， 4.91(m， 2H)， 3.72(m, 1H)， 3.57-3.62(m, 4H). 3.12 (m, 2H)， 2.95 (m, 1H)， 2.74(s, 3H), 2.01 (m, 1H)， 1.90 (m, 1H)， 1.73-1.76(m, 4H)， 1.39(m, 1H)。 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 8.37(d, 1H), 7.86(d, 1H), 7.61 (m, 1H), 7.48(m, 1H), 5.61(s, 2H), 4.91(m , 2H), 3.72(m, 1H), 3.57-3.62(m, 4H). 3.12 (m, 2H), 2.95 (m, 1H), 2.74(s, 3H), 2.01 (m, 1H), 1.90 ( m, 1H), 1.73-1.76 (m, 4H), 1.39 (m, 1H).
实施例 8: 14(6,7-二氢 -4-甲基 -5ff-环戊 idl嘧啶 -2-基)甲基 1-3-甲基 -7-(2-丁炔 -1-基) -8-i3-iR)- ^哌啶 -1-基)黃嚟呤（化合物 8 ) 的制备  Example 8: 14(6,7-Dihydro-4-methyl-5ff-cyclopentidylididin-2-yl)methyl 1-3-methyl-7-(2-butyn-1-yl) Preparation of -8-i3-iR)-^piperidin-1-yl)xanthine (Compound 8)
( 1 ) 2-氯甲基 -6,7-二氢 -4-甲基 -5 -环戊 [d】嘧啶（中间体 Π(Α)-2 ) 的制备
Figure imgf000032_0001
(1) Preparation of 2-chloromethyl-6,7-dihydro-4-methyl-5-cyclopenta[d]pyrimidine (intermediate Π(Α)-2)
Figure imgf000032_0001
中间体 Π(Α)-2  Intermediate Π(Α)-2
将 2-乙酰基环戊酮 (5.0g， 40mmol)、 碳酸钾 (6.9g， 50mmol)和盐酸 氯乙脒 (6.5g， 50mmol)加入至 50mL正丁醇中， 120。C搅拌 5小时； 反应 完毕， 减压除去溶剂， 剩余物倒入 lOOmL水中， 乙酸乙酯萃取（50mL， 萃取 3次）， 合并有; W«， 饱和食盐水洗涤一次， 无水硫酸钠干燥， 减 压蒸出溶剂得黄色固体， 经柱层析纯化， 得淡黄色液体 1.5g， 产率 20.5 %。 ES-API (m/z): [M+H]+ 183.1„ 2-Acetylcyclopentanone (5.0 g, 40 mmol), potassium carbonate (6.9 g, 50 mmol) and chloroacetic acid hydrochloride (6.5 g, 50 mmol) were added to 50 mL of n-butanol, 120. After stirring for 5 hours; the reaction was completed, the solvent was removed under reduced pressure, and the residue was poured into 100 mL of water, ethyl acetate (50 mL, extracted 3 times), and combined; W«, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a white solid. ES-API (m/z): [M+H] + 183.1„
( 2 ) 1-[(6，7-二氢 -4-甲基 -5 -环戊 [d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2- 丁 -1 -基) -8- [(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤的制备
Figure imgf000032_0002
(2) 1-[(6,7-Dihydro-4-methyl-5-cyclopenta[d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyl-1 - Preparation of -8-[(R)-3-(tert-butoxy!(amino)piperidin-1-yl]xanthine
Figure imgf000032_0002
在氮气保护下，将 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧叛^ ^基) 旅啶 -1-基】黄嚟呤 (0.25g， 0.6mmol)、 碳酸钾 (O.llg, 0.8mmol)和 2-氯甲 基 -6，7-二氢 -4-甲基 -5 -环戊 [d】嘧 (0.13g， 0.7mmol)加入至 50mL圆底 烧瓶中， 加入 10mL N，N-二甲基甲酰胺， 升温至 90。C搅拌 5小时； 反应 完毕， 将反应液倒入 20mL冰水中析出固体， 抽滤， 滤饼经柱层析纯化 (梯度洗脱，二氯甲烷 /甲醇 =100:1~50:1)，得白色固体 0.29g，产率 85.3 %。 ES-API (m/z): [M+H】+ 563.1。 Under the protection of nitrogen, 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy-oxinyl)-bran-1-yl] (0.25 g, 0.6 mmol), potassium carbonate (O.llg, 0.8 mmol) and 2-chloromethyl-6,7-dihydro-4-methyl-5-cyclopenta[d]pyrimidine (0.13 g, 0.7 Mm) added to a 50mL round bottom Into the flask, 10 mL of N,N-dimethylformamide was added and the temperature was raised to 90. C is stirred for 5 hours; after the reaction is completed, the reaction solution is poured into 20 mL of ice water to precipitate a solid, which is filtered with suction, and the filter cake is purified by column chromatography (gradient elution, dichloromethane/methanol = 100:1 to 50:1). The white solid was 0.29 g, and the yield was 85.3%. ES-API (m/z): [M+H]+ 563.1.
( 3 ) 1-[(6，7-二氢 -4-甲基 -5 -环戊 [d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2- 丁炔 -
Figure imgf000033_0001
(3) 1-[(6,7-Dihydro-4-methyl-5-cyclopenta[d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyne-
Figure imgf000033_0001
化合物 8  Compound 8
将 1-[(6，7-二氢 -4-甲基 -5 -环戊 [d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁 炔 -1-基) -8-[(R)-3- (叔丁氧叛基胺基)哌啶 -1-基】黄嚟呤 (0.22g， 0.4mmol) 溶于 10mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时； 反应完毕， 减压蒸出溶剂， 加入 20mL冰水， 用 2mol/L NaOH水溶液 调节反应液 pH值到 8， 二氯甲烷萃取（20mL， 萃取 2次）， 合并有机 相， 20mL饱和食盐水洗涤一次， 无水硫酸钠干燥， 减压蒸出溶剂得淡 黄色固体， 经柱层析纯化得淡黄色固体（化合物 8 ) 0.14g，产率 75.6 %。 ES-API (m/z): [M+H】+ 463.2。 1-[(6,7-Dihydro- 4 -methyl-5-cyclopenta[d]pyrimidin-2-yl)methyl]-3-methyl-7-( 2 -butyn-1-yl) -8-[(R)-3-(tert-butoxysylamino)piperidin-1-yl]xanthine (0.22 g, 0.4 mmol) dissolved in a mixed solution of 10 mL of dichloromethane and 2 mL of trifluoroacetic acid After stirring at room temperature for 1 hour; after completion of the reaction, the solvent was evaporated under reduced pressure, 20 mL of ice water was added, and the pH of the reaction mixture was adjusted to 8 with 2 mol/L NaOH aqueous solution, extracted with dichloromethane (20 mL, extracted twice), and the organic phase was combined. The mixture was washed with EtOAc (3 mL). ES-API (m/z): [M+H]+ 463.2.
1H-NMR (600MHz, CDC13, 5ppm): 5.38(d, 2H)， 4.98-5.05(m, 2H)， 3.47-3.61 (m, 5H)， 2.72 (m, 2H)， 2.50(m， 2H)，2.28 (s, 3H), 1.86-1.97(m, 3H),1.81 (s, 3H), 1.70-1.76(m, 6H)。  1H-NMR (600MHz, CDC13, 5ppm): 5.38 (d, 2H), 4.98-5.05 (m, 2H), 3.47-3.61 (m, 5H), 2.72 (m, 2H), 2.50 (m, 2H), 2.28 (s, 3H), 1.86-1.97 (m, 3H), 1.81 (s, 3H), 1.70-1.76 (m, 6H).
实施例 9: 14(5,6,7,8-四氢 -4-三氟甲基喹峻啉 -2-基)甲基卜 3-甲基 -7-(2-丁炔 -1-基) -8-i3-iR)- ^哌啶 -1-基)黃嚟呤（化合物 9 ) 的制备  Example 9: 14(5,6,7,8-tetrahydro-4-trifluoromethylquinolin-2-yl)methyl-3-methyl-7-(2-butyn-1-yl) Preparation of -8-i3-iR)-^piperidin-1-ylxanthine (Compound 9)
( 1 ) 2-氯甲基 -5,6,7,8-四氢 -4-三氟甲基喹峻啉 (中间体 Π(Α)-3 ) 的制备
Figure imgf000033_0002
(1) Preparation of 2-chloromethyl-5,6,7,8-tetrahydro-4-trifluoromethylquinoline (intermediate Π(Α)-3)
Figure imgf000033_0002
中间体 Π(Α)-3  Intermediate Π(Α)-3
将 2-三氟乙酰基环己酮 (5.0g， 26mmol)、 碳酸钾 (4.6g， 33mmol)和 盐酸氯乙脒 (4.0g， 31mmol)加入至 30mL异丙醇中， 50。C搅拌 3小时； 反应完毕， 减压蒸出溶剂， 剩余物倒入 lOOmL 水中， 乙酸乙酯萃取 ( lOOmL, 萃取 2次）， 合并有 t f， lOOmL饱和食盐水洗涤一次， 无 酸钠干燥， 减压蒸出溶剂得黄色固体， 经柱层析纯化， 得淡黄色固 体 4.6g,产率 70.8 % 。 ES-API (m/z): [M+H] + 251.1。 2-Trifluoroacetylcyclohexanone (5.0 g, 26 mmol), potassium carbonate (4.6 g, 33 mmol) and Chloroacetic acid hydrochloride (4.0 g, 31 mmol) was added to 30 mL of isopropanol, 50. C stirring for 3 hours; After the reaction is completed, the solvent is distilled off under reduced pressure, and the residue is poured into 100 mL of water, extracted with ethyl acetate (100 mL, extracted twice), washed with tf, 100 mL of saturated brine, dried without sodium, minus The solvent was evaporated to give a yellow solid, which was purified by column chromatography. ES-API (m/z): [M+H] + 251.1.
( 2 ) 1-[(5，6，7，8_四氢 -4-三氟甲基喹唑啉 -2-基)甲基】 _3_甲基 -7_(2- 丁炔 -1 -基) -8- [(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤的制备
Figure imgf000034_0001
( 2 ) 1-[( 5 , 6 , 7 , 8 _tetrahydro - 4 -trifluoromethylquinazolin- 2 -yl)methyl] _ 3 _methyl- 7 _( 2 -butyne-1 -Base) -8- [(R)-3-(tert-butoxy!-amino)piperidin-1-yl] Preparation of Astragalus
Figure imgf000034_0001
在氮气保护下，将 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧叛^ ^基) 旅啶 -1-基】黄嚟呤 (0.42g， 1.0mmol)、 碳酸钾 (0.17g， 1.2mmol)和 2-氯甲 基 -5,6,7,8-四氢 -4-三氟甲基喹峻淋 (0.27g， l.lmmol)加入至 50mL的圆底 烧瓶中， 加入 lOmlL N，N-二甲基甲酰胺， 升温至 90。C搅拌 6小时； 反 应完毕， 将反应液倒入 20mL冰水中析出固体， 抽滤， 滤饼经柱层析纯 化， 得白色固体 0.56g, 产率 88.9 % 。 ES-API (m/z): [M+H] + 631.1  Under the protection of nitrogen, 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy-oxinyl)-bran-1-yl] (0.42 g, 1.0 mmol), potassium carbonate (0.17 g, 1.2 mmol) and 2-chloromethyl-5,6,7,8-tetrahydro-4-trifluoromethylquinidine (0.27 g, l. 1 mmol) was added to a 50 mL round bottom flask, and 10 ml of L N,N-dimethylformamide was added, and the temperature was raised to 90. After stirring for 6 hours; after the reaction was completed, the reaction liquid was poured into 20 mL of ice water to precipitate a solid, which was suction filtered, and the filter cake was purified by column chromatography to obtain white solid (0.56 g, yield: 88.9 %). ES-API (m/z): [M+H] + 631.1
( 3 ) l-[(5，6,7,8-四氢 -4-三氟甲基喹唑啉 -2-基)甲基】 _3_甲基 -7_(2- 丁炔
Figure imgf000034_0002
(3) l-[( 5 , 6 , 7 , 8 -tetrahydro- 4- 4 -trifluoromethylquinazolin- 2 -yl)methyl] _ 3 _methyl- 7 _( 2 -butyne
Figure imgf000034_0002
化合物 9  Compound 9
将 1-[(5，6，7，8-四氢 -4-三氟甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁 fUtiJ^基)哌啶 -1-基】黄嚟呤 (0.32g，0.5mmol)溶于 10mL二氯甲烷和 2mL三氟乙酸的混合溶液中， 室温搅拌 1小时；反应 完毕， 减压蒸出溶剂， 加入 20mL冰水， 用 2mol/L NaOH水溶液调 pH 值到 8， 二氯甲烷萃取（20mL， 萃取 2次） ， 合并有 t f， 20mL饱和 食盐水洗^ "次， 无 酸钠干燥， 减压蒸出溶剂得淡黄色固体， 经柱 层析纯化， 得白色固体 (化合物 9) 0.16g, 产率 60.4 % 。 ES-API (m/z):  1-[(5,6,7,8-tetrahydro-4-trifluoromethylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) -8-[(R)-3-(tert-butyl-fUtiJ^yl)piperidin-1-yl]xanthine (0.32 g, 0.5 mmol) dissolved in 10 mL of dichloromethane and 2 mL of trifluoroacetic acid in a mixture at room temperature Stir for 1 hour; after completion of the reaction, distill off the solvent under reduced pressure, add 20 mL of ice water, adjust the pH to 8 with 2 mol/L NaOH aqueous solution, extract with dichloromethane (20 mL, extract 2 times), combine with tf, wash with 20 mL of saturated brine. ^", EtOAc (m/z): EtOAc: EtOAc:
[M+H】+ 531.3。 1H-NMR (600MHz, CDC13, 5ppm): 5.42(s, 2H)， 4.85-4.94(m, 2H)， 3.55-3.69(m, 5H)， 3.18(m, 2H)， 3.03(m, 1H)， 2.84-2.90(m, 4H)， 2.02 (m, 1H)， 1.90 (m, 1H)， 1.81-1.86(m, 8H)， 1.50(m， 1H)。 [M+H] + 531.3. 1H-NMR (600MHz, CDC13, 5ppm): 5.42 (s, 2H), 4.85-4.94 (m, 2H), 3.55-3.69 (m, 5H), 3.18 (m, 2H), 3.03 (m, 1H), 2.84-2.90 (m, 4H), 2.02 (m, 1H), 1.90 (m, 1H), 1.81-1.86 (m, 8H), 1.50 (m, 1H).
实施例 10: 1-ίί6-氯 -4,5-二氢环戊 idel喹唑啉 -2-基）甲基 1-3-甲基 Example 10: 1-ίί6-chloro-4,5-dihydrocyclopentene idel quinazolin-2-yl)methyl 1-3-methyl
-7- -丁炔 -1-基) -8-i3- )- ^哌啶 -1-基)黃嚟呤（化合物 to )的制备 Preparation of -7--butyne-1-yl)-8-i3-)-^piperidin-1-yl)xanthine (compound to )
( 1 ) 2-氯甲基 -6氯 -4,5-二氢环戊 [de】喹峻啉 (中间体 Π(Β)-2 ) 的 制备
Figure imgf000035_0001
(1) Preparation of 2-chloromethyl-6-chloro-4,5-dihydrocyclopenta[de]quinoline (intermediate Π(Β)-2)
Figure imgf000035_0001
中间体 Π(Β)-2  Intermediate Π(Β)-2
采用与实施例 1 ( 6 )相似的方法， 由 4-氯 -7- J>-2，3-二氢 -1-茚酮 制备， 产率 86.5 %。 ES-API (m/z): [M+H】+ 239.3。  Prepared from 4-chloro-7-J>-2,3-dihydro-1-indanone in a similar manner to Example 1 (6), yield 8.65 %. ES-API (m/z): [M+H]+ 239.3.
( 2 ) 1-[(6-氯 -4,5-二氢环戊 [de】喹峻啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔 制备
Figure imgf000035_0002
(2) 1-[(6-Chloro-4,5-dihydrocyclopenta[de]quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) ) -8-[(R)-3- (preparative preparation)
Figure imgf000035_0002
采用与实施例 1( 7 )相似的方法，由 2-氯甲基 -6氯 -4,5-二氢环戊 [de】 喹唑啉与 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧叛基胺基)哌啶 -1-基】 黄嚟呤制备， 产率 71.6 %。 ES-API (m/z): [M+H】+ 619.3。 In a similar manner to Example 1 (7), 2-chloromethyl-6-chloro-4,5-dihydrocyclopenta[de]quinazoline and 3-methyl-7-(2-butyne- 1-yl)-8-[(R)-3-(tert-butoxymethylamino)piperidin-1-yl] Astragalus was prepared in a yield of 71.6%. ES-API (m/z): [M+H] + 619.3.
( 3 ) 1-[(6-氯 -4,5-二氢环戊 [de】喹峻啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-(3-(R)- J^哌啶 -1-基)黄嚟呤（化合物 10 )的制备  (3) 1-[(6-Chloro-4,5-dihydrocyclopenta[de]quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) Preparation of 8-(3-(R)-J^piperidin-1-yl)xanthine (Compound 10)
Figure imgf000035_0003
Figure imgf000035_0003
化合物 10  Compound 10
采用与实施例 1 ( 8 )相似的方法， 由 1-[(6-氯 -4,5-二氢环戊 [de】喹 唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤制备， 产率 84.6 %。 ES-API (m/z): [M+H】 519.2。 In a similar manner to Example 1 (8), 1-[(6-chloro-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7 -(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]xanthine was prepared in a yield of 84.6 %. ES-API (m/z): [M+H] 519.2.
^ NMR (600MHz, CDC13, δρριη): 7.90(d, 1H)， 7.78 (s, 1H)， 5.56(s, 2H)， 4.91(d, 2H)， 3.60-3.71 (m, 2H)， 3.56 (s, 3H), 3.42(m, 2H)， 3.39 (m, 2H)， 3.10 (m, 2H)， 2.91 (m, 1H)， 1.91-2.00 (m, 2H)， 1.81 (s, 3H), 1.75(m, 1H)， 1.40 (m, 1H)。 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 7.90(d, 1H), 7.78 (s, 1H), 5.56(s, 2H), 4.91(d, 2H), 3.60-3.71 (m, 2H), 3.56 (s, 3H), 3.42 (m, 2H), 3.39 (m, 2H), 3.10 (m, 2H), 2.91 (m, 1H), 1.91-2.00 (m, 2H), 1.81 (s, 3H), 1.75 (m, 1H), 1.40 (m, 1H).
实施例 11: 14Γ7-甲基 -4,5-二氢环戊 idel喹唑啉 -2-基)甲基卜 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-(3-iR)- ^哌啶 -1-基)黄嚟呤（化合物 11 ) 的 制备  Example 11: 14Γ7-Methyl-4,5-dihydrocyclopentan idel quinazolin-2-yl)methyl-3-methyl-7-(3-methyl-2-buten-1-yl Preparation of 8-(3-iR)-piperidin-1-ylxanthine (Compound 11)
( 1 ) 2-氯甲基 -7-甲基 -4,5-二氢环戊 [de】喹峻啉 (中间体 Π(Β)-3 ) 的制备
Figure imgf000036_0001
(1) Preparation of 2-chloromethyl-7-methyl-4,5-dihydrocyclopenta[de]quinoline (intermediate Π(Β)-3)
Figure imgf000036_0001
中间体 Π(Β)-3  Intermediate Π(Β)-3
采用与实施例 1 ( 6 )相似的方法， 由 5-甲基 -7- J^-2，3-二氢 -1-茚 酮制备， 产率 79.6 %。 ES-API (m/z): [M+H】+ 219.1。  Prepared from 5-methyl-7-J^-2,3-dihydro-1-indanone in a similar manner to Example 1 (6), yield 7.69 %. ES-API (m/z): [M+H]+ 219.1.
( 2 ) 1-[(7-甲基 -4,5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7-(3- 甲基 -2-丁烯 -1-基) - 】黄嚟呤的制备  (2) 1-[(7-Methyl-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2- Buten-1-yl) - Preparation of Astragalus
Figure imgf000036_0002
采用与实施例 2 ( 3 )相似的方法， 由 2-氯甲基 -7-甲基 -4,5-二氢环 戊 [de】喹唑啉与 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧！ ^胺 基)哌啶 -1-基】黄嚟呤制备， 产率 77.8 %。 ES-API (m/z): [M+H]+ 615.3。
Figure imgf000036_0002
In a similar manner to Example 2 (3), 2-chloromethyl-7-methyl-4,5-dihydrocyclopenta[de]quinazoline and 3-methyl-7-(3-methyl) Benzyl-2-buten-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]xanthine was prepared in a yield of 77.8 %. ES-API (m/z): [M+H] + 615.3.
( 3 ) 1-[(7-甲基 -4,5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7-(3- 甲基 -2-丁烯 -1-基) -8-(3-(R)- J^哌啶 -1-基)黄嚟呤（化合物 11 )的制备
Figure imgf000037_0001
(3) 1-[(7-Methyl-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2- Preparation of buten-1-yl)-8-(3-(R)-J^piperidin-1-yl)xanthine (Compound 11)
Figure imgf000037_0001
化合物 11  Compound 11
采用与实施例 2 (4)相似的方法， 由 1-[(7-甲基 -4,5-二氢环戊 [de】 喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧!^ 胺基)哌啶 -1-基】黄嚟呤制备， 产率 79.6%。  In a similar manner to Example 2 (4), 1-[(7-methyl-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl- Preparation of 7-(3-methyl-2-buten-1-yl)-8-[(R)-3-(tert-butoxy!^amino)piperidin-1-yl]xanthine, yield 79.6% .
ES-API (m/z): [M+H] + 515.3。  ES-API (m/z): [M+H] + 515.3.
1H-NMR (600MHz, CDC13, 5ppm): 7.70(s, 1H)， 7.27(s, 1H), 5.55(s, 1H-NMR (600MHz, CDC13, 5ppm): 7.70(s, 1H), 7.27(s, 1H), 5.55(s,
2H)， 5.37(s, 1H)， 4.70-4.79(m, 2H)， 3.50-3.55(m, 4H)， 3.36- 3.41(m, 5H)，2H), 5.37(s, 1H), 4.70-4.79(m, 2H), 3.50-3.55(m, 4H), 3.36- 3.41(m, 5H),
2.95-3.06 (m, 2H)， 2.81 (m, 1H)， 2.51 (s, 3H), 2.00 (m, 1H)， 1.84-1.88 (m,2.95-3.06 (m, 2H), 2.81 (m, 1H), 2.51 (s, 3H), 2.00 (m, 1H), 1.84-1.88 (m,
2H)， 1.73(s, 3H), 1.71 (s, 3H), 1.37(m, 1H)。 2H), 1.73 (s, 3H), 1.71 (s, 3H), 1.37 (m, 1H).
实施例 12: 14Γ7-甲 fL¾>-4,5-二氢环戊『de〗喹唑啉 -2-基)甲基 3-甲 基 -7- (反 -2-丁浠 -1-基) -8-i3-iR)- ^啶 -1-基)黃嚟呤（化合物 12)的制 奎  Example 12: 14Γ7-A fL3⁄4>-4,5-dihydrocyclopentene "de quinazolin-2-yl)methyl 3-methyl-7- (trans-2-butan-1-yl) -8-i3-iR)-(pyridin-1-yl) ruthenium (compound 12)
(1) 3-甲基 -7- (反 -2-丁 -1-基) -8-溴黄嚟呤的制备  (1) Preparation of 3-methyl-7-(trans-2-but-1-yl)-8-bromoxanthine
Figure imgf000037_0002
Figure imgf000037_0002
采用与实施例 1(1)相似的方法，由 8-溴 -3-甲基 -3,7-二氢 -嚟呤 -2,6- 二酮和 (E)-l-溴 -2-丁烯制备，产率 92.6%。 ES-API(m/z): [M+H]+ 298.1, 道1。 Using a method similar to that of Example 1 (1), from 8-bromo-3-methyl-3,7-dihydro-indole-2,6-dione and (E)-l-bromo-2-butane The olefin was prepared in a yield of 92.6%. ES-API (m/z): [M+H] + 298.1, track 1.
( 2 ) 3-甲基 -7- (反 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧^ 基)哌啶 -1- 基】黄嚟呤的制备  (2) Preparation of 3-methyl-7-(trans-2-buten-1-yl)-8-[(R)-3-(tert-butoxy)piperidin-1-yl]xanthine
Figure imgf000037_0003
Figure imgf000037_0003
采用与实施例 1 (2)相似的方法， 由 3-甲基 -7- (反 -2-丁烯 -1-基) -8- 溴黄嚟呤和 3-(R)-叔丁氧叛基 啶制备，产率 82.8% oES-API (m/z): [M+H】 419.1。 Using a method similar to that of Example 1 (2), from 3-methyl-7-(trans-2-buten-1-yl)-8-bromoxanthine and 3-(R)-tert-butoxy-indenyl Preparation, yield 82.8% oES-API (m/z): [M+H] 419.1.
( 3 ) 2-氯甲基 -7-甲 #L^-4，5-二氢环戊 [de】喹峻啉 (中间体 Π(Β)-4 ) 的制备
Figure imgf000038_0001
(3) Preparation of 2-chloromethyl-7-methyl#L^-4,5-dihydrocyclopenta[de]quinoline (intermediate Π(Β)-4)
Figure imgf000038_0001
中间体 Π(Β)-4  Intermediate Π(Β)-4
采用与实施例 1 ( 6 )相似的方法， 由 5-甲氧基 -7- J^-2，3-二氢 -1- 茚酮制备， 产率 79.6 %。 ES-API (m/z): [M+H】+ 235.1。  Prepared from 5-methoxy-7-J^-2,3-dihydro-1-indanone in a similar manner to Example 1 (6), yield 7.96 %. ES-API (m/z): [M+H]+ 235.1.
( 4 ) 1-[(7-甲氧基 -4，5-二氢环戊 [de】喹唑啉 -2-基）甲基】 -3-甲基 (4) 1 - [(7-methoxy - 4-cyclopentyl-dihydro-5- [de] quinazolin - 2 - yl) methyl] -3-methyl
Figure imgf000038_0002
Figure imgf000038_0002
采用与实施例 2 ( 3 )相似的方法， 由 2-氯甲基 -7-甲基 -4,5-二氢环 戊 [de】喹唑啉与 3-甲基 -7- (反 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧 ItiJ^基)哌 啶 -1-基】黄嚟呤制备， 产率 76.8 %。 ES-API (m/z): [M+H】+ 617.3。 In a similar manner to Example 2 (3), 2-chloromethyl-7-methyl-4,5-dihydrocyclopenta[de]quinazoline and 3-methyl-7- (anti-2) -buten-1-yl)-8-[(R)-3-(tert-butoxy-ItiJ^)piperidin-1-yl]xanthine was prepared in a yield of 76.8 %. ES-API (m/z): [M+H] + 617.3.
( 5 ) 1-[(7-甲氧基 -4，5-二氢环戊 [de】喹唑啉 -2-基）甲基】 -3-甲基 -7- (反 -2-丁烯 -1-基) -8 （化合物 12 )的制备
Figure imgf000038_0003
(5) 1 - [(7-methoxy - 4-cyclopentyl-dihydro-5- [de] quinazolin - 2 - yl) methyl] -3-methyl-7- (2-butene Preparation of -1-yl)-8 (Compound 12)
Figure imgf000038_0003
化合物 12  Compound 12
采用与实施例 2( 4 )相似的方法，由 1-[(7-甲氧基 -4,5-二氢环戊 [de】 喹唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧!^胺基) 哌啶 -1-基】黄嚟呤制备， 产率 71.6 %。  In a similar manner to Example 2(4), 1-[(7-methoxy-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl -7-(trans-2-buten-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl] Astragalus was prepared in a yield of 71.6%.
ES-API (m/z): [M+H】 517.3。  ES-API (m/z): [M+H] 517.3.
^ NMR (600MHz, CDC13, δρριη): 7.61(s, 1H)， 7.11(s, 1H)， 5.56(s, 2H)， 5.44(s, 1H)， 5.32(s, 1H)， 4.70-4.78(m, 2H)， 3.81(s, 3H), 3.45-3.54(m, 4H)， 3.33- 3.40(m, 5H)， 2.94-3.03 (m, 2H)， 2.82 (m, 1H)， 2.01 (m, 1H)， 1.84-1.87 (m, 2H)， 1.73 (s, 3H), 1.36(m, 1H)。 实施例 13: 14(5,6,7,8-四氢 -4， 6-二甲基喹唑啉 -2-基)甲基 3-甲基 -7- (反 -2-丁浠 -1-基) -8-i3-iR)- ^啶 -1-基)黃嚟呤（化合物 13 )的制备 ( 1 ) 2_氯甲基 -5，6，7，8_四氢 _4，6_二甲基喹唑啉 (中间体 11(A)-4 )的 制备
Figure imgf000039_0001
^ NMR (600MHz, CDC1 3 , δ ρριη ): 7.61(s, 1H), 7.11(s, 1H), 5.56(s, 2H), 5.44(s, 1H), 5.32(s, 1H), 4.70-4.78 (m, 2H), 3.81(s, 3H), 3.45-3.54(m, 4H), 3.33- 3.40(m, 5H), 2.94-3.03 (m, 2H), 2.82 (m, 1H), 2.01 (m , 1H), 1.84-1.87 (m, 2H), 1.73 (s, 3H), 1.36 (m, 1H). Example 13: 14(5,6,7,8-tetrahydro-4,6-dimethylquinazolin-2-yl)methyl 3-methyl-7- (trans-2-butanthene-1 - yl) -8-i3-iR) - preparation of ^ l-yl) purine yellow Li (compound 13) (1) _-chloro-2-methyl-5, 6, 7, 8-tetrahydro _ 4 _, _ two 6 Preparation of methyl quinazoline (intermediate 11(A) -4 )
Figure imgf000039_0001
中间体 Π(Α)-4  Intermediate Π(Α)-4
采用与实施例 3 ( 1 )相似的方法， 由 2-乙酰基 -4-甲基环己酮和盐 酸氯乙脒制备， 产率 61.6 %。 ES-API (m/z): [Μ+Η】+ 211.1。  Prepared in a similar manner to Example 3 (1) from 2-acetyl-4-methylcyclohexanone and chloroacetic acid hydrochloride in a yield of 61.6 %. ES-API (m/z): [Μ+Η]+ 211.1.
( 2 ) 1-[(5，6，7，8-四氢 -4，6-二甲基喹唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2- 丁婦 _1 _基) _8- [(R)-3- 呤的制备  ( 2 ) 1-[(5,6,7,8-Tetrahydro-4,6-dimethylquinazolin-2-yl)methyl]-3-methyl-7- (trans-2-but Preparation of _8-[-(R)-3-呤
Figure imgf000039_0002
Figure imgf000039_0002
采用与实施例 3 ( 2 )相似的方法， 由 2-氯甲基 -5,6,7,8-四氢 -4,6-二 甲基喹唑啉和 3-甲基 -7- (反 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧!^胺基)哌 啶 -1-基】黄嚟呤制备， 产率 71.1 %。 ES-API (m/z): [M+H】+ 593.3。 In a similar manner to Example 3 (2), from 2-chloromethyl-5,6,7,8-tetrahydro-4,6-dimethylquinazoline and 3-methyl-7- (reverse 2-buten-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl] Astragalus was prepared in 71.1% yield. ES-API (m/z): [M+H] + 593.3.
( 3 ) 1-[(5，6，7，8-四氢 -4，6-二甲基喹唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2- 丁烯 -1-基) -8-(3-(R)- ^啶 -1-基)黄嚟呤（化合物 13 ) 的制备  (3) 1-[(5,6,7,8-Tetrahydro-4,6-dimethylquinazolin-2-yl)methyl]-3-methyl-7- (anti-2-butyl) Preparation of alken-1-yl)-8-(3-(R)-l-yl-1-yl)xanthine (Compound 13)
Figure imgf000039_0003
Figure imgf000039_0003
化合物 13  Compound 13
采用与实施例 3 ( 3 )相似的方法， 由 1-[(5，6，7，8-四氢 -4,6-二甲基喹 唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧羰基胺基) 哌啶 -1-基】黄嚟呤制备， 产率 80.2 %。 Using a method similar to that of Example 3 (3), from 1-[(5,6,7,8-tetrahydro-4,6-dimethylquinazolin- 2 -yl)methyl]-3-methyl The base 7-(trans- 2 -buten-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)piperidin-1-yl]xanthine was prepared in a yield of 80.2%.
ES-API (m/z): [M+H】+ 493.3。 1H-NMR (600MHz, CDC13, 5ppm): 5.41-5.46(m, 2H)， 5.32(s, 2H)， 4.71(m, 2H)， 3.52-3.56 (m, 4H)， 3.17-3.26 (m, 2H)， 2.94-3.04 (m, 2H)， 2.72 (s, 2H)， 2.54(s, 2H)， 2.31 (s, 3H), 2.02 (m, 1H)， 1.86-1.92 (m, 2H)， 1.71-1.79(m, 6H)， 1.35-1.40(m, 4H)。 ES-API (m/z): [M+H]+ 493.3. 1H-NMR (600MHz, CDC13, 5ppm): 5.41-5.46(m, 2H), 5.32(s, 2H), 4.71(m, 2H), 3.52-3.56 (m, 4H), 3.17-3.26 (m, 2H ), 2.94-3.04 (m, 2H), 2.72 (s, 2H), 2.54 (s, 2H), 2.31 (s, 3H), 2.02 (m, 1H), 1.86-1.92 (m, 2H), 1.71- 1.79 (m, 6H), 1.35-1.40 (m, 4H).
实施例 14: 1-ίί5,6,7,8-四氢 -4,7-二甲基喹唑啉 -2-基)甲基 1-3-甲基 -7- -丁炔 -1-基) -8-(3-iR)- ^哌啶 -1-基)黄嚟呤（化合物 14 )的制备  Example 14: 1-ίί5,6,7,8-tetrahydro-4,7-dimethylquinazolin-2-yl)methyl 1-3-methyl-7-butyne-1-yl Preparation of 8-(3-iR)-piperidin-1-ylxanthine (Compound 14)
( 1 ) 2-氯甲基 -5，6，7，8_四氢 _4，7_二甲基喹唑啉 (中间体 11(A)-5 )的 制备
Figure imgf000040_0001
(1) 2 - chloro-5, 6, 7, 48-tetrahydro _ _, _ 7-dimethyl-quinazoline (Intermediate 11 (A) - 5) Preparation of
Figure imgf000040_0001
中间体 Π(Α)-5  Intermediate Π(Α)-5
采用与实施例 3 ( 1 )相似的方法， 由 2-乙酰基 -5-甲基环己酮和盐 酸氯乙脒制备， 产率 70.7 %。 ES-API (m/z): [Μ+Η】+ 211.1。  Prepared in a similar manner to Example 3 (1) from 2-acetyl-5-methylcyclohexanone and chloroacetic acid hydrochloride in a yield of 70.7 %. ES-API (m/z): [Μ+Η]+ 211.1.
( 2 ) 1-[(5，6，7，8-四氢 -4，7-二甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁 炔小基 )_8_[(R)_3_ ( 的制备 (2) 1-[(5,6,7,8-Tetrahydro-4,7-dimethylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne small yl) _ 8 _ [(R) _ 3 _ ( prepared
Figure imgf000040_0002
Figure imgf000040_0002
采用与实施例 3 ( 2 )相似的方法， 由 2-氯甲基 -5,6,7,8-四氢 -4,7-二 甲基喹唑啉和 3-甲基 -7-(2-丁炔 -1-基) -8- [(R)-3- (叔丁氧 胺基)哌啶 -1- 基】黄嚟呤制备， 产率 72.6 %。 ES-API (m/z): [M+H】+ 591.3。  In a similar manner to Example 3 (2), 2-chloromethyl-5,6,7,8-tetrahydro-4,7-dimethylquinazoline and 3-methyl-7-(2) -butyn-1-yl)-8-[(R)-3-(tert-butoxyamino)piperidin-1-yl]xanthine was prepared in a yield of 72.6 %. ES-API (m/z): [M+H]+ 591.3.
( 3 ) 1-[(5，6，7，8-四氢 -4，7-二甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁 炔小基) _8_(3_(R)_ ^ 小基)黄嚟呤（化合物 14 ) 的制备 (3) 1-[(5,6,7,8-Tetrahydro-4,7-dimethylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne small Preparation of _ 8 _ (3 _ (R) _ ^ small base) xanthine (Compound 14)
Figure imgf000040_0003
Figure imgf000040_0003
化合物 14  Compound 14
采用与实施例 3 ( 3 )相似的方法， 由 1-[(5，6，7，8-四氢 -4,7-二甲基喹 唑啉 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤制备， 产率 77.2 %。 ES-API (m/z): [M+H】 491.3。 Using a method similar to that of Example 3 (3), from 1-[(5,6,7,8-tetrahydro-4,7-dimethylquinazolin-2-yl)methyl]-3-methyl Preparation of 7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]xanthine, yield 77.2%. ES-API (m/z): [M+H] 491.3.
^ NMR (600MHz, CDC13, δρριη): 5.30(d, 2H)， 4.96(m, 2H)， 3.61 (m， 1H)， 3.58-3.56 (m, 4H)， 2.75 (s, 2H)， 2.56(s, 2H)， 2.31 (s, 3H), 1.92-2.00 (m， 3H), 1.80 (s, 3H), 1.70-1.76(m, 6H), 1.41(m， 1H)， 1.26(s, 3H)。 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 5.30(d, 2H), 4.96(m, 2H), 3.61 (m, 1H), 3.58-3.56 (m, 4H), 2.75 (s, 2H), 2.56 (s, 2H), 2.31 (s, 3H), 1.92-2.00 (m, 3H), 1.80 (s, 3H), 1.70-1.76 (m, 6H), 1.41 (m, 1H), 1.26 (s, 3H) ).
实施例 15: 14(5,6,7,8-四氢 -4-甲基 -6- ^喹唑啉 -2-基)甲基 3-甲 基 -7- (反 -2-丁烯 -1-基) -8-(3-iR)- J ^啶 -1-基)黄嚟呤（化合物 15 )的制 奎  Example 15: 14(5,6,7,8-tetrahydro-4-methyl-6-^ quinazolin-2-yl)methyl 3-methyl-7- (trans-2-butene- 1-ki)-8-(3-iR)-J^-l-yl) scutellaria (compound 15)
( 1 ) 2-氯甲基 -5，6，7，8-四氢 -4-甲基 喹唑啉 (中间体 Π(Α)-6 ) 的制备
Figure imgf000041_0001
(1) Preparation of 2-chloromethyl-5,6,7,8-tetrahydro-4-methylquinazoline (intermediate Π(Α)-6)
Figure imgf000041_0001
中间体 Π(Α)-6  Intermediate Π(Α)-6
采用与实施例 3 ( 1 )相似的方法， 由 2-乙酰基 -4-氛基环己酮和盐 酸氯乙脒制备， 产率 60.1 %。 ES-API (m/z): [Μ+Η】+ 222.1。  Prepared in a similar manner to Example 3 (1) from 2-acetyl-4-ylcyclohexanone and chloroacetic acid hydrochloride in a yield of 60.1%. ES-API (m/z): [Μ+Η] + 222.1.
( 2 ) 1-[(5，6，7，8-四氢 -4-甲基 喹唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2-丁烯 -1-基) -8-[(R 嚟呤的制备  (2) 1-[(5,6,7,8-Tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7- (trans-2-butene-1 -based) -8-[(Preparation of R 嚟呤
Figure imgf000041_0002
Figure imgf000041_0002
采用与实施例 3 ( 2 )相似的方法， 由 2-氯甲基 -5,6,7,8-四氢 -4-甲基 喹唑啉和 3-甲基 -7- (反 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧!^胺基) 哌啶 -1-基】黄嚟呤制备， 产率 75.8 %。 ES-API (m/z): [Μ+Η】 + 604·3。  In a similar manner to Example 3 (2), 2-chloromethyl-5,6,7,8-tetrahydro-4-methylquinazoline and 3-methyl-7- (anti-2- Buten-1-yl)-8-[(R)-3-(tert-butoxy!(amino)piperidin-1-yl]xanthine was prepared in a yield of 75.8 %. ES-API (m/z): [Μ+Η] + 604·3.
( 3 ) 1-[(5，6，7，8-四氢 -4-甲基 喹唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2-丁烯 -1-基) -8-(3-( 15 ) 的制备  (3) 1-[(5,6,7,8-Tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7- (trans-2-butene-1 -Base) Preparation of -8-(3-( 15 )
Figure imgf000041_0003
Figure imgf000041_0003
化合物 15  Compound 15
采用与实施例 3 ( 3 )相似的方法， 由 1-[(5，6，7，8-四氢 -4-甲基 -6-氡 基喹唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2-丁烯 -1-基) -8- [(R)-3- (叔丁氧!^胺 基)哌啶 -1-基】黄嚟呤制备， 产率 76.0 %。 Using a method similar to that of Example 3 (3), from 1-[(5,6,7,8-tetrahydro-4-methyl-6-oxime) Alkyl quinazolin-2-yl)methyl]-3-methyl-7-(trans-2-buten-1-yl)-8- [(R)-3-(tert-butoxy!! Piperidin-1-yl] Astragalus preparation, yield 76.0%.
ES-API (m/z): [M+H】+ 504.3。  ES-API (m/z): [M+H]+ 504.3.
^ NMR (600MHz, CDC13, δρριη): 5.40-5.46(m, 2H)， 5.31(s, 2H), 4.71(m, 2H)， 3.50-3.58 (m， 4H)， 3.18-3.27 (m， 4H)， 2.82-2.90 (m， 3H), 2.60(s, 2H)， 2.30 (s, 3H), 2.00 (m, 1H)， 1.84-1.92 (m, 2H)， 1.71-1.77(m, 6H ^ NMR (600MHz, CDC1 3 , δ ρριη ): 5.40-5.46(m, 2H), 5.31(s, 2H), 4.71(m, 2H), 3.50-3.58 (m, 4H), 3.18-3.27 (m, 4H), 2.82-2.90 (m, 3H), 2.60(s, 2H), 2.30 (s, 3H), 2.00 (m, 1H), 1.84-1.92 (m, 2H), 1.71-1.77 (m, 6H)
实施例 16: 1-『ί6,7-二氢 -4,6-二甲基 -5ff-环戊『dl嘧啶 -2-基)甲基卜 3- 甲基 -7- -丁炔 -1-基) -8-(3-iR)- ^哌啶 -1-基)黄嚟呤（化合物 16 ) 的制 奎  Example 16: 1-"ί6,7-Dihydro-4,6-dimethyl-5ff-cyclopenta"dl pyridin-2-yl)methylbu-3-methyl-7-butyne-1- Preparation of -8-(3-iR)-^piperidin-1-yl)xanthine (Compound 16)
( 1 ) 2-氯甲基 -6,7-二氢 -4,6-二甲基 环戊 [d】嘧啶 （中间体 Π(Α)-7 ) 的制备
Figure imgf000042_0001
(1) Preparation of 2-chloromethyl-6,7-dihydro-4,6-dimethylcyclopenta[d]pyrimidine (intermediate Π(Α)-7)
Figure imgf000042_0001
中间体 Π(Α)-7  Intermediate Π(Α)-7
采用与实施例 8 ( 1 )相似的方法， 由 2-乙酰基 -4-甲基环戊酮和盐 酸氯乙脒制备， 产率 26.4 %。 ES-API (m/z): [Μ+Η】+ 197.1。  Prepared in a similar manner to Example 8 (1) from 2-acetyl-4-methylcyclopentanone and chloroacetic acid hydrochloride in a yield of 26.4%. ES-API (m/z): [Μ+Η] + 197.1.
( 2 ) 1-[(6，7-二氢 -4，6-二甲基 环戊 [d】嘧啶 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-[( 】黄嚟呤的制备
Figure imgf000042_0002
采用与实施例 8 ( 2 )相似的方法， 由 2-氯甲基 -6,7-二氢 -4,6-二甲基 -5 -环戊 [d】嘧啶和 3-甲基 -7-(2-丁炔 -1-基) -8- [(R)-3- (叔丁氧叛^ 基)哌 啶 -1-基】黄嚟呤制备， 产率 78.1 %。 ES-API (m/z): [M+H】+ 577.3。 (2) 1 - [(6,7-dihydro - 4-methyl-6-cyclopentyl [d] pyrimidin - 2 - yl) methyl] -3-methyl-7- (2-butynyl -1 -base) -8-[(] Preparation of Astragalus
Figure imgf000042_0002
In a similar manner to Example 8 (2), 2-chloromethyl-6,7-dihydro-4,6-dimethyl-5-cyclopenta[d]pyrimidine and 3-methyl-7- (2-butyn-1-yl)-8-[(R)-3-(tert-butoxy-oxy)piperidin-1-yl]xanthine was prepared in a yield of 78.1%. ES-API (m/z): [M+H] + 577.3.
( 3 ) 1-[(6，7-二氢 -4，6-二甲基 环戊 [d】嘧啶 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-(3-(R)- J^哌啶 -1-基)黄嚟呤（化合物 16 )的制备
Figure imgf000043_0001
(3) 1 - [(6,7-dihydro - 4-methyl-6-cyclopentyl [d] pyrimidin - 2 - yl) methyl] -3-methyl-7- (2-butynyl -1 -Based on the preparation of 8-(3-(R)-J^piperidin-1-yl)xanthine (Compound 16)
Figure imgf000043_0001
化合物 16  Compound 16
采用与实施例 8 ( 3 )相似的方法， 由 1-[(6，7-二氢-4，6-二甲基-5 环戊 [d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8- [(R)-3- (叔丁氧!^胺 基)哌啶 -1-基】黄嚟呤制备， 产率 74.3 %。  In a similar manner to Example 8 (3), 1-[(6,7-dihydro-4,6-dimethyl-5cyclopenta[d]pyrimidin-2-yl)methyl]-3- Methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]xanthine was prepared in a yield of 74.3 %.
ES-API (m/z): [M+H】+ 477.3。  ES-API (m/z): [M+H]+ 477.3.
^ NMR (600MHz, CDC13, δρριη)： 5.30(d, 2H)， 4.97(m, 2H)， 3.49-3.59 (m， 5H)， 2.74 (s, 2H)， 2.55(s, 2H)， 2.31 (s, 3H), 2.01 (m， 2H)， 1.86 (m, 1H)， 1.81 (s, 3H), 1.71-1.79(m, 4H)， 1.38-1.42(m, 4H)。 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 5.30(d, 2H), 4.97(m, 2H), 3.49-3.59 (m, 5H), 2.74 (s, 2H), 2.55(s, 2H), 2.31 (s, 3H), 2.01 (m, 2H), 1.86 (m, 1H), 1.81 (s, 3H), 1.71-1.79 (m, 4H), 1.38-1.42 (m, 4H).
实施例 17: 1-『 ,8-二甲基苯并呋喃『3,2-d〗嘧啶 -2-基)甲基 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-(3-iR)- ^哌啶 -1-基)黄嚟呤（化合物 17 ) 的 制备  Example 17: 1-",8-Dimethylbenzofuran "3,2-d-pyrimidin-2-yl)methyl 3-methyl-7-(3-methyl-2-butene-1 -Base) Preparation of 8-(3-iR)-piperidin-1-yl)xanthine (Compound 17)
( 1 ) 2-氯甲基 -4,8-二甲基苯并呋喃 [3，2-d】嘧啶（中间体 II(C)-3 )的 制备
Figure imgf000043_0002
(1) Preparation of 2-chloromethyl-4,8-dimethylbenzofuran [3,2-d]pyrimidine (Intermediate II(C)-3)
Figure imgf000043_0002
中间体 II(C)-3  Intermediate II (C)-3
采用与实施例 5 ( 3 )相似的方法， 由 2-乙酰基 -3- J^-5-甲羞^：并 呋喃和氯乙腈制备， 产率 81.5 %。 ES-API (m/z): [Μ+Η】 + 247·1。 Prepared in a similar manner to Example 5 (3) from 2-acetyl-3-J^-5-methion^:furan and chloroacetonitrile in a yield of 81.5 %. ES-API (m/z): [Μ+Η] + 247·1.
( 2 ) 1-[(4，8-二甲^^并呋喃 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲 基 -2-丁烯 -1-基) -8-[ 嚟呤的制备  (2) 1-[(4,8-Dimethyl^furan[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butyl Preparation of ene-1-yl)-8-[
Figure imgf000043_0003
Figure imgf000043_0003
采用与实施例 6 ( 1 )相似的方法， 由 2-氯甲基 -4，8-二甲基苯并呋喃 [3，2-d】嘧啶和 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧 胺基) 哌啶 -1-基】黄嚟呤制备， 产率 73.2 %。 ES-API (m/z): [Μ+Η】 + 643·3。 ( 3 ) l-[(4，8-二甲^^并呋喃 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲 基 -2-丁烯 -1-基) -8 合物 17 )的制备 In a similar manner to Example 6 (1), 2-chloromethyl-4,8-dimethylbenzofuran [3,2-d]pyrimidine and 3-methyl-7-(3-methyl 2-buten-1-yl)-8-[(R)-3-(tert-butoxyamino)piperidin-1-yl]xanthine was prepared in a yield of 73.2%. ES-API (m/z): [Μ+Η] + 643·3. (3) l-[(4,8-Dimethyl^^furan[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butyl Preparation of alk-1-yl)-8 compound 17)
Figure imgf000044_0001
Figure imgf000044_0001
化合物 17  Compound 17
采用与实施例 6 ( 2 )相似的方法， 由 1-[(4，8-二甲^并呋喃 [3，2-d】 嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧！ ^胺 基)哌啶 -1-基】黄嚟呤制备， 产率 72.9 %。  In a similar manner to Example 6 (2), 1-[(4,8-dimethylfuran[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7- Preparation of (3-methyl-2-buten-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]xanthine, yield 7.29 %.
ES-API (m/z): [M+H】+ 543.3  ES-API (m/z): [M+H]+ 543.3
^ NMR (600MHz, CDC13, δρριη): 8.01(d, 1H)， 7.87 (s, 1H)， 7.40(d, 1H)， 5.60(s, 2H)， 5.36(t, 1H)， 4.74-4.80 (m, 2H)， 3.76 (m, 1H)， 3.56-3.65(m. 5H)， 3.18-3.22 (m, 2H)， 2.80(s, 3H), 2.49 (s, 3H), 2.14 (m, 1H)， 1.98 (m, 1H)， 1.68-1.74 (m, 7H)， 1.40(m， 1H)。 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 8.01(d, 1H), 7.87 (s, 1H), 7.40(d, 1H), 5.60(s, 2H), 5.36(t, 1H), 4.74-4.80 (m, 2H), 3.76 (m, 1H), 3.56-3.65 (m. 5H), 3.18-3.22 (m, 2H), 2.80(s, 3H), 2.49 (s, 3H), 2.14 (m, 1H) ), 1.98 (m, 1H), 1.68-1.74 (m, 7H), 1.40 (m, 1H).
实施例 18: 1-『 -甲基 -8-氯苯并呋喃『3,2-d〗嘧啶 -2-基)甲基〗 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-(3-iR)- ^哌啶 -1-基)黄嚟呤（化合物 18 ) 的 制备  Example 18: 1-"-Methyl-8-chlorobenzofuran "3,2-d-pyridin-2-yl)methyl"-3-methyl-7-(3-methyl-2-butyl Preparation of alken-1-yl)-8-(3-iR)-piperidin-1-ylxanthine (Compound 18)
( 1 ) 2-氯甲基 -4-甲基 -8-氯苯并呋喃 [3，2-d】嘧啶（中间体 II(C)-4 ) 的制备
Figure imgf000044_0002
(1) Preparation of 2-chloromethyl-4-methyl-8-chlorobenzofuran [3,2-d]pyrimidine (Intermediate II(C)-4)
Figure imgf000044_0002
中间体 II(C)-4  Intermediate II(C)-4
采用与实施例 5 ( 3 )相似的方法， 由 2-乙酰基 -3- J^-5-氯苯并呋 喃和氯乙腈制备， 产率 76.5 %。 ES-API (m/z): [Μ+Η】+ 267·1。 Prepared in a similar manner to Example 5 (3) from 2-acetyl-3-J^-5-chlorobenzofuran and chloroacetonitrile in a yield of 76.5 %. ES-API (m/z): [Μ+Η] + 267·1.
( 2 ) 1-[(4-甲基 -8-氯苯并呋喃 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(3- 甲基 -2-丁烯 -1-基) -8- [(R)-3- (叔丁氧^ 基)哌啶 -1-基】黄嚟呤的制备
Figure imgf000045_0001
( 2 ) 1-[( 4 -Methyl-8-chlorobenzofuran [3, 2 -d]pyrimidin- 2 -yl)methyl]-3-methyl-7-(3-methyl-2- Preparation of buten-1-yl)-8-[(R)-3-(tert-butoxy)piperidin-1-yl]xanthine
Figure imgf000045_0001
采用与实施例 6 ( 1 )相似的方法， 由 2-氯甲基 -4-甲基 -8-氯苯并呋 喃 [3，2-d】嘧啶和 3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8- [(R)-3- (叔丁氧 胺 基)旅啶 -1-基】黄嚟呤制备， 产率 78.8 %。 ES-API (m/z): [M+H】 + 663.2。 In a similar manner to Example 6 (1), 2-chloromethyl-4-methyl-8-chlorobenzofuran [3,2-d]pyrimidine and 3-methyl-7-(3-methyl 2-buten-1-yl)-8-[(R)-3-(tert-butoxyamino) bistidin-1-yl] Astragalus preparation, yield 78.8%. ES-API (m/z): [M+H] + 663.2.
( 3 ) 1-[(4-甲基 -8-氯苯并呋喃 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(3- 甲基 -2-丁烯 -1-基) - 合物 18 )的制备 (3) 1 - [(4 - methyl-8-chlorobenzofuran [3, 2 -d] pyrimidin - 2 - yl) methyl] -3-methyl-7- (3-methyl-2- Preparation of buten-1-yl)-form 18)
Figure imgf000045_0002
Figure imgf000045_0002
化合物 18  Compound 18
采用与实施例 6 ( 2 )相似的方法，由 1-[(4-甲基 -8-氯苯并呋喃 [3，2-d】 嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-[(R)-3- (叔丁氧！ ^胺 基)哌啶 -1-基】黄嚟呤制备， 产率 71.8 %。  In a similar manner to Example 6 (2), 1-[(4-methyl-8-chlorobenzofuran [3,2-d]pyrimidin-2-yl)methyl]-3-methyl- Preparation of 7-(3-methyl-2-buten-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]xanthine, yield 71.8 % .
ES-API (m/z): [M+H】+ 563.2  ES-API (m/z): [M+H]+ 563.2
1H-NMR (600MHz, CDC13, 5ppm): 8.20(d, 1H)， 7.59(d, 1H)， 7.47(d, 1H)， 5.61(s, 2H)， 5.36(t, 1H)， 4.74-4.82 (m, 2H)， 3.77 (m, 1H)， 3.66 (m, 1H)， 3.55-3.60(m, 4H)， 3.20-3.26 (m, 2H)， 2.81(s, 3H), 2.15 (m, 1H)， 1.96 (m, 1H)， 1.69-1.74 (m, 7H)， 1.42(m， 1H)。  1H-NMR (600MHz, CDC13, 5ppm): 8.20(d, 1H), 7.59(d, 1H), 7.47(d, 1H), 5.61(s, 2H), 5.36(t, 1H), 4.74-4.82 ( m, 2H), 3.77 (m, 1H), 3.66 (m, 1H), 3.55-3.60 (m, 4H), 3.20-3.26 (m, 2H), 2.81(s, 3H), 2.15 (m, 1H) , 1.96 (m, 1H), 1.69-1.74 (m, 7H), 1.42 (m, 1H).
实施例 19: 1-『 ,8-二甲基苯并噻吩『3,2-dl嘧啶 -2-基)甲基卜 3-甲基 -7-(2-丁炔 -1-基) -8-i3-iR)- ^哌啶 -1-基)黃嚟呤（化合物 19 )的制备  Example 19: 1-",8-Dimethylbenzothiophene "3,2-dl-pyrimidin-2-yl)methyl-3-methyl-7-(2-butyn-1-yl)-8 -i3-iR)-^piperidin-1-yl)xanthine (Compound 19) Preparation
( 1 ) 2-氯甲基 -4,8-二甲基苯并噻吩 [3，2-d】嘧啶（中间体 II(C)-3 )的 制备
Figure imgf000045_0003
(1) Preparation of 2-chloromethyl-4,8-dimethylbenzothiophene [3,2-d]pyrimidine (Intermediate II(C)-3)
Figure imgf000045_0003
中间体 II(C)-5  Intermediate II(C)-5
采用与实施例 7 ( 4 )相似的方法， 由 2-乙酰基 -3- J^-5-甲 ^^并 噻吩和氯乙腈制备， 产率 77.6 %。 ES-API (m/z): [Μ+Η】 + 263·0。 In a similar manner to Example 7 (4), from 2-acetyl-3-J^-5-methyl^ Preparation of thiophene and chloroacetonitrile in a yield of 77.6 %. ES-API (m/z): [Μ+Η] + 263·0.
( 2 ) 1-[(4，8-二甲^:并噻吩 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁 炔小基 )_8_[(R)_3_ 制备 ( 2 ) 1-[(4,8-Dimethyl^:thiophene [3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyne small group)_ 8 _[ (R) _ 3 _ preparation
Figure imgf000046_0001
Figure imgf000046_0001
采用与实施例 7 ( 5 )相似的方法， 由 2-氯甲基 -4，8-二甲基苯并噻吩  In a similar manner to Example 7 (5), from 2-chloromethyl-4,8-dimethylbenzothiophene
[3，2-d】嘧啶和 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧！ ^胺基)哌啶 -1- 基】黄嚟呤制备， 产率 86.1 %。 ES-API (m/z): [M+H】+ 643.3。 [3,2-d]pyrimidine and 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1- Base] Astragalus preparation, yield 86.1%. ES-API (m/z): [M+H] + 643.3.
( 3 ) 1-[(4，8-二甲^:并噻吩 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁 炔小基) _8_(3_(R)_ ) 的制备 (3) 1-[(4,8-Dimethyl^:thiophene[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyne small group) _ Preparation of 8 _ (3 _ (R) _ )
Figure imgf000046_0002
Figure imgf000046_0002
化合物 19  Compound 19
采用与实施例 7 ( 6 )相似的方法， 由 1-[(4，8-二甲基苯并噻吩 [3，2-d】 嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧!^胺基)哌啶 -1-基】黄嚟呤制备， 产率 70.8 %。  In a similar manner to Example 7 (6), 1-[(4,8-dimethylbenzothiophene[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7 -(2-butyn-1-yl)-8-[(R)-3-(tert-butoxy!-amino)piperidin-1-yl]xanthine was prepared in a yield of 70.8 %.
ES-API (m/z): [M+H】+ 543.2  ES-API (m/z): [M+H]+ 543.2
^ NMR (600MHz, CDC13, δρριη): 8.22(d, 1H)， 7.66(s, 1H)， 7.45 (d, 1H)， 5.60(s, 2H)， 4.91(m， 2H)， 3.71(m, 1H)， 3.56-3.61(m, 4H)， 3.10-3.15 (m, 2H)， 2.96 (m, 1H)， 2.72 (s, 3H), 2.46 (s, 3H), 2.00 (m, 1H)， 1.91 (m, 1H)， 1.72-1.76(m, 4H)， 1.38(m, 1H)。 实施例 20: 1-『 -甲基 -7-甲 fL¾>苯并噱吩『3,2-d〗嘧啶 -2-基)甲基 3- 甲基 -7- -丁炔 -1-基) -8-(3-iR)- ^哌啶 -1-基)黄嚟呤（化合物 20 ) 的制 奎 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 8.22(d, 1H), 7.66(s, 1H), 7.45 (d, 1H), 5.60(s, 2H), 4.91(m, 2H), 3.71(m , 1H), 3.56-3.61(m, 4H), 3.10-3.15 (m, 2H), 2.96 (m, 1H), 2.72 (s, 3H), 2.46 (s, 3H), 2.00 (m, 1H), 1.91 (m, 1H), 1.72-1.76 (m, 4H), 1.38 (m, 1H). Example 20: 1-"-Methyl-7-methylfL3⁄4>benzobenzophene "3,2-d-pyrimidin-2-yl)methyl 3-methyl-7-butyne-1-yl) -8-(3-iR)-(piperidin-1-yl)xanthine (Compound 20)
( 1 ) 2-氯甲基 -4-甲基 -7-甲氧基苯并噻吩 [3，2-d】嘧啶（中间体 II(C)-6 ) 的制备
Figure imgf000047_0001
(1) Preparation of 2-chloromethyl-4-methyl-7-methoxybenzothiophene [3,2-d]pyrimidine (Intermediate II(C)-6)
Figure imgf000047_0001
中间体 II(C)-6  Intermediate II (C)-6
采用与实施例 7 ( 4 )相似的方法， 由 2-乙酰基 -3- J^-6-甲氧基苯 并噻吩和氯乙腈制备， 产率 75.8 %。 ES-API (m/z): [Μ+Η】 + 279·0。  Prepared in a similar manner to Example 7 (4) from 2-acetyl-3-J^-6-methoxybenzothiophene and chloroacetonitrile in a yield of 75.8 %. ES-API (m/z): [Μ+Η] + 279·0.
( 2 ) 1-[(4-甲基 -7-甲氧基苯并噻吩 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) - 嚟呤的制备
Figure imgf000047_0002
(2) 1-[(4-Methyl-7-methoxybenzothiophene [3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyne- 1-base) - preparation of hydrazine
Figure imgf000047_0002
采用与实施例 7 ( 5 )相似的方法， 由 2-氯甲基 -4-甲基 -7-甲 并噻吩 [3，2-d】嘧啶和 3-甲基 -7-(2-丁炔 -1-基) -8-[(R)-3- (叔丁氧！^胺基) 哌啶 -1-基】黄嚟呤制备， 产率 82.7 %。 ES-API (m/z): [Μ+Η】 + 659·2。  In a similar manner to Example 7 (5), 2-chloromethyl-4-methyl-7-methylthiophene [3,2-d]pyrimidine and 3-methyl-7-(2-butyne) -1-yl)-8-[(R)-3-(tert-butoxy!(amino)piperidin-1-yl]xanthine was prepared in a yield of 82.7 %. ES-API (m/z): [Μ+Η] + 659·2.
( 3 ) 1-[(4-甲基 -7-甲氧基苯并噻吩 [3，2-d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8 物 20 )的制备
Figure imgf000047_0003
(3) 1-[(4-Methyl-7-methoxybenzothiophene [3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyne- Preparation of 1-base)-8-form 20)
Figure imgf000047_0003
化合物 20  Compound 20
采用与实施例 7 ( 6 )相似的方法， 由 1-[(4-甲基 -7-甲氧基苯并噻吩 [3，2-d】嘧啶 -2-基)甲基】 _3_甲基 _7_(2-丁炔 -1-基) _8-[(R)-3- (叔丁氧叛基胺 基)哌啶 -1-基】黄嚟呤制备， 产率 76.0 %。 In a similar manner to Example 7 (6), 1-[(4-methyl-7-methoxybenzothiophene [ 3 , 2 -d]pyrimidin- 2 -yl)methyl] _ 3 _ _ _ 7-yl (2 - butyn-1-yl) _ 8 - [(R) - 3 - ( tert betray ylamino) piperidin-1-yl] preparation yellow Li methotrexate, yield 76.0%.
ES-API (m/z): [M+H】+ 559.2  ES-API (m/z): [M+H]+ 559.2
^ NMR (600MHz, CDC13, δρριη): 7.96(d, 1H)， 7.51(s, 1H)， 7.06 (d, 1H)， 5.62(s, 2H)， 4.92(m， 2H)， 3.82(s, 3H), 3.70(m, 1H)， 3.56-3.61(m, 4H)， 3.11-3.15 (m, 2H)， 2.94 (m, 1H)， 2.76(s, 3H), 2.01 (m, 1H)， 1.88 (m, 1H)， 1.72-1.76(m, 4H)， 1.41(m， 1H)。 生物学评价 ^ NMR (600MHz, CDC1 3 , δ ρριη ): 7.96(d, 1H), 7.51(s, 1H), 7.06 (d, 1H), 5.62(s, 2H), 4.92(m, 2H), 3.82(s , 3H), 3.70(m, 1H), 3.56-3.61(m, 4H), 3.11-3.15 (m, 2H), 2.94 (m, 1H), 2.76(s, 3H), 2.01 (m, 1H), 1.88 (m, 1H), 1.72-1.76 (m, 4H), 1.41 (m, 1H). Biological evaluation
实验例： DPP-IV/DPP-8/DPP-9抑制活性的测定 DPP-IV/DPP-8/DPP-9 (购自 BPS-Bioscience， Cat. 80040, 80080， 80090)为应用杆状病毒表达系统表达并经纯化的纯酶， 反应体系在 PH=7.5的緩冲溶液 (购自 BPS-Bioscience， Cat. 80300 )中进行， 酶反应
Figure imgf000048_0001
甲基香豆素 （ Ala-Pro-AMC ) (购自Experimental example: Determination of inhibitory activity of DPP-IV/DPP-8/DPP-9 DPP-IV/DPP-8/DPP-9 (purchased from BPS-Bioscience, Cat. 80040, 80080, 80090) is a pure enzyme expressed and purified using a baculovirus expression system. The reaction system is buffered at pH=7.5. Solution (purchased from BPS-Bioscience, Cat. 80300), enzymatic reaction
Figure imgf000048_0001
Methyl coumarin (Ala-Pro-AMC) (purchased from
BPS-Bioscience, Cat. 80305 ) 。 BPS-Bioscience, Cat. 80305).
DPP-IV/DPP-8/DPP-9可降解底物 Ala-Pro-AMC生成产物 AMC( 7- J^-4-甲基香豆素） ， AMC被 355 nm的紫外光^ L产生 460nm的发 射光。使用 Scanlab varioSCAN动态测量 AMC在 460nm处荧光值的上 升速度来测定 DPP-IV/DPP-8/DPP-9的活' 14。  DPP-IV/DPP-8/DPP-9 degradable substrate Ala-Pro-AMC produces product AMC (7-J^-4-methylcoumarin), AMC is produced by 355 nm UV light at 460 nm Emitting light. The activity of DPP-IV/DPP-8/DPP-9 was measured by using Scanlab varioSCAN to dynamically measure the rise in fluorescence of AMC at 460 nm.
测定方法： 将受试化合物 (实施例 1至实施例 20制备的化合物 1 至化合物 20，在 0.64~200nmol/L浓度范围内， 每隔三倍浓度梯度进行 测试） 、 酶（DPP-IV/DPP-8/DPP-9, 初始浓度为 0.1ng/ L )和反应緩 冲溶液混 ， 在 37。C预孵 15 min , 加入酶反应底物 （初始浓度为 5 mol/L )启动反应， 连续测定 460nm荧光值 5min。 同时设置不加底 物的空白对照组、 以 DMSO (二甲羞 巩， Dimethyl sulfoxide )替代受 试化合物的溶剂对照组、 以及 BI-1356 [其制备方法参见 Journal of Medicinal Chemistry, 2007, 26, 6450- 6453】阳性对照组。所有反应^ ^积 均为 ΙΟΟμ 每个样品浓度 3个复孔。  Determination method: Test compound (Compound 1 to Compound 20 prepared in Examples 1 to 20, tested in a concentration range of 0.64 to 200 nmol/L every three times concentration gradient), enzyme (DPP-IV/DPP) -8/DPP-9, initial concentration of 0.1 ng / L) mixed with the reaction buffer solution, at 37. C pre-incubation for 15 min, the enzyme reaction substrate (initial concentration of 5 mol / L) was added to initiate the reaction, and the fluorescence value at 460 nm was continuously measured for 5 min. At the same time, a blank control group without a substrate, a solvent control group in which DMSO (Dimethyl sulfoxide) was substituted for the test compound, and BI-1356 were prepared [for the preparation method, see Journal of Medicinal Chemistry, 2007, 26, 6450). - 6453] Positive control group. All reactions were ΙΟΟμ 3 replicates per sample concentration.
首先计算酶的反应初始期（底物消耗 20%以下，底物消耗与时间呈 线性）内的荧光强度的增量（单位： RFU/秒），以此代表酶的初速度（酶 反应初始期单位时间内产物生成量）， 然后计算样品各浓度组的活性百 分数， 公式如下：  First, calculate the increase in fluorescence intensity (unit: RFU / sec) in the initial phase of the enzyme reaction (substrate consumption is less than 20%, substrate consumption is linear with time), which represents the initial velocity of the enzyme (initial phase of the enzyme reaction) The amount of product produced per unit time), and then calculate the percentage of activity of each concentration group of the sample, the formula is as follows:
其中 V 样品表示样品各浓度组的初速度， VDMSO表示 DMSO组的初 速度。 The V sample represents the initial velocity of each concentration group of the sample, and V DMSO represents the initial velocity of the DMSO group.
以浓度值为横坐标， 活性值为纵坐标， 然后采用 GRAPHPAD PRISM 5软件做剂量-效应曲线拟合， 计算得到 IC5。值。 部分式 I所示 化合物的生物活性测试结果见表 1。 表 1.部分式 I所示化合物对 DPP-IV/DPP-8/DPP-9抑制活性 The concentration value was plotted on the abscissa and the activity value was plotted on the ordinate. Then the dose-effect curve was fitted using GRAPHPAD PRISM 5 software to calculate IC 5 . value. The biological activity test results of some of the compounds of formula I are shown in Table 1. Table 1. Inhibitory activity of a compound of formula I on DPP-IV/DPP-8/DPP-9
Figure imgf000049_0001
Figure imgf000049_0001
注： "/" 表示未进行该化合物的该项药效试验  Note: "/" means that the drug has not been tested for this compound.
其中， BI-1356是作为试验的阳性对照而提出的。 由表 1中的数据 可以看出本发明的化合物对 DPP-I 的具有较好的抑制活性，对 DPP-8、 DPP-9的选择性与 BI-1356相当；特别是化合物 1、化合物 2、化合物 3、 化合物 5、 化合物 7、 化合物 10的 DPP-I 抑制活性明显强于 BI-1356, 比 BI-1356强 2 ~ 10倍， 因此， 本发明化合物具有更优的生物活性。 综上所述， 本发明的式 I化合物能很好地抑制 DPP-IV, 能够用 于治疗、 预防以及緩解与 DPP-I 相关的疾病， 例如糖尿病、 高血糖症、 肥胖症或胰岛素抵抗症、 缺血性心肌炎或血管生成性疾病等疾病。 Among them, BI-1356 was proposed as a positive control for the test. It can be seen from the data in Table 1 that the compound of the present invention has a good inhibitory activity against DPP-I, and the selectivity to DPP-8 and DPP-9 is comparable to that of BI-1356; in particular, Compound 1, Compound 2 The DPP-I inhibitory activity of Compound 3, Compound 5, Compound 7, and Compound 10 was significantly stronger than that of BI-1356, which was 2 to 10 times stronger than that of BI-1356. Therefore, the compound of the present invention has superior biological activity. In summary, the compound of the formula I of the present invention is excellent for inhibiting DPP-IV and can be used for the treatment, prevention and alleviation of diseases related to DPP-I, such as diabetes, hyperglycemia, obesity or insulin resistance, A disease such as ischemic myocarditis or an angiogenic disease.

Claims

权 利 要 求 Rights request
1、 式 I所示的黄嚟呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学上可接受的盐的溶剂合物、 其化学保护形式或者前药： 1. The xantholine derivative represented by Formula I, its pharmaceutically acceptable salts, solvates, solvates of pharmaceutically acceptable salts, its chemically protected forms or prodrugs:
Figure imgf000051_0001
Figure imgf000051_0001
其中， in,
Ri选自：
Figure imgf000051_0002
Ri is selected from:
Figure imgf000051_0002
R2选自 2-丁烯- 1-基、 3-甲基- 2-丁烯- 1-基或 2-丁炔- 1 -基； R 2 is selected from 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyn-1-yl;
R3、 R5、 各自独立的选自氢、 卤素原子， 直链或支链的被 1 ~ 5 个卤素原子取代或未被取代的 d-6烷基、直链或支链的被 1 ~ 5个卤素原 子取代或未被取代的 d-6烷氧基、 氛基或羟基； R 3 and R 5 are each independently selected from hydrogen, halogen atoms, linear or branched d-6 alkyl substituted by 1 to 5 halogen atoms or unsubstituted, linear or branched d- 6 alkyl group substituted by 1 to 5 halogen atoms, 5 halogen atoms substituted or unsubstituted d- 6 alkoxy, cyano or hydroxyl group;
选自甲^ ^三氟甲基； Selected from methyl, trifluoromethyl;
X独立的选自 O或 S; X is independently selected from O or S;
m选自 1或 2。 m is selected from 1 or 2.
2、 根据权利要求 1所述的式 I所示的黄嚟呤衍生物、 其药学上可 接受的盐、 溶剂合物、 药学上可接受的盐的溶剂合物、 其化学保护形式 或者前药， 其中， 2. The xanthine derivative represented by Formula I according to claim 1, its pharmaceutically acceptable salt, solvate, solvate of a pharmaceutically acceptable salt, its chemically protected form or prodrug, wherein ,
R3、 R5、 Re各自独立的选自氢、 氣原子、 氯原子、 溴原子、 甲基、 乙基、 异丙基、 甲 ft^、 乙 ft^、 三氟甲基、 三氟甲 #L^、 或羟基。 R 3 , R 5 , and Re are each independently selected from hydrogen, gas atom, chlorine atom, bromine atom, methyl, ethyl, isopropyl, methane, ethyl, trifluoromethyl, and trifluoromethyl. L^, or hydroxyl.
优选地 R3、 R5、 Re各自独立的选自氢、 氯原子、 甲基、 甲 #L^、 Preferably, R 3 , R 5 and Re are each independently selected from hydrogen, chlorine atom, methyl, methane,
3、 根据权利要求 1所述的式 I所示的黄嚟呤衍生物、 其药学上可 接受的盐、 溶剂合物、 药学上可接受的盐的溶剂合物、 其化学保护形式 或者前药， 其中， R3选自氢、 甲基、 3. The xanthine derivative represented by Formula I according to claim 1, its pharmaceutically acceptable salt, solvate, solvate of a pharmaceutically acceptable salt, its chemically protected form or prodrug, wherein , R 3 is selected from hydrogen, methyl,
R5选自氢、 氯原子、 甲基、 甲 R 5 is selected from hydrogen, chlorine atom, methyl, methyl
选自氢、 氯原子、 甲基、 甲 。 Selected from hydrogen, chlorine atom, methyl, and methyl.
4、 根据权利要求所述的式 I所示的黄嚟呤衍生物， 其药学上可接 受的盐、 溶剂合物、 药学上可接受的盐的溶剂合物、 其化学保护形式或 者前药， 其中所述式 I所示的黄嚟呤衍生物选自式 I ( Α ) 、 式 1 ( B ) 或式 I ( C )： 4. The xanthine derivative represented by Formula I according to claim 1, its pharmaceutically acceptable salt, solvate, solvate of a pharmaceutically acceptable salt, its chemically protected form or prodrug, wherein The xantholine derivative shown in formula I is selected from formula I (A), formula 1 (B) or formula I (C):
Figure imgf000052_0001
Figure imgf000052_0001
式 1(C) Formula 1(C)
其中： R2、 R3、 R4、 R5、 、 m、 X的定义同权利要求 1中的定义 。 Among them: R 2 , R 3 , R 4 , R 5 , , m and X have the same definitions as in claim 1.
5、根据权利要求 1至 4任何一项所述的式 I所示的黄嚟呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学上可接受的盐的溶剂合物、 及其 化学保护形式或者前药， 其选自下列的化合物： 5. The xantholine derivative represented by Formula I according to any one of claims 1 to 4, its pharmaceutically acceptable salts, solvates, solvates of pharmaceutically acceptable salts, and chemical protection thereof A form or prodrug selected from the following compounds:
1-[(4,5-二氢环戊 [de】喹唑啉 _2_基）甲基】 _3_甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(4,5-Dihydrocyclopenta[de]quinazoline_ 2 yl)methyl] _ 3 _methyl-7-(2-butyn-1-yl) -8-(3- (R)- J>piperidin-1-yl)xanthin;
1-[(4，5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； l-[(5,6,7,8-四氢 _4_甲基喹唑啉 _2-基）甲基】 -3-甲基 _7_(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(4,5-dihydrocyclopent[de]quinazolin-2-yl)methyl] -3-methyl-7-(3-methyl-2-buten-1-yl) - 8-(3-(R)- J>piperidin-1-yl)xanthin; l-[(5,6,7,8-tetrahydro_4_methylquinazolin_2-yl)methyl]-3-methyl_7_(2 - butyn - 1-yl)-8 -(3-(R)- J>piperidin-1-yl)xanthin;
1-[(5，6，7，8-四氢 -4-甲基喹唑啉 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(5,6,7,8-tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butene-1 -base) -8-(3-(R)- J>piperidin-1-yl)xanthin;
1-[(4-甲基苯并呋喃 [3，2-d】嘧啶 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(4-methylbenzofuran[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 -(R)- J>piperidin-1-yl)xanthin;
1-[(4-甲基苯并呋喃 [3,2-d]嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2-丁烯 -1-基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(4-methylbenzofuran[3,2-d]pyrimidin-2-yl)methyl] -3-methyl-7-(3-methyl-2-buten-1-yl) -8-(3-(R)- J>piperidin-1-yl)xanthin;
1-[(4-甲基苯并噻吩 [3，2_d】嘧啶 _2_基）甲基】 _3_甲基 _7_(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1 -[(4-methylbenzothiophene[ 3,2_d ]pyrimidin_2_yl)methyl] _3_methyl_7_ ( 2 -butyn- 1 -yl)-8-( 3- (R)- J>piperidin-1-yl)xanthin;
1—[(6，7-二氢 -4-甲基 -5 -环戊 [d】嘧啶 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1-基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(6,7-dihydro-4-methyl-5-cyclopent[d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) -8-(3-(R)- J>piperidin-1-yl)xanthin;
1-[(5，6，7，8-四氢 _4_三氟甲基喹唑啉 -2-基)甲基】 -3-甲基 _7_(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[( 5,6,7,8 -tetrahydro_4_trifluoromethylquinazolin- 2 -yl)methyl]-3- methyl_7_ ( 2 - butyn -1-yl) -8-(3-(R)- J>piperidin-1-yl)xanthin;
1-[(6-氯 -4,5-二氢环戊 [de】喹唑啉 -2-基）甲基】 -3-甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(6-chloro-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 -(3-(R)- J>piperidin-1-yl)xanthin;
1-[(7-甲基 -4,5-二氢环戊 [de】喹唑啉 -2-基)甲基卜 3-甲基 -7-(3-甲基 -2- 丁烯 -1-基) -8-(3-(R)- J^旅啶 -1-基)黄嚟呤； 1-[(7-methyl-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl-3-methyl-7-(3-methyl-2-butene-1) -base)-8-(3-(R)-J^ridin-1-yl)xanthin;
1-[(7-甲氧基 -4，5-二氢环戊 [de】喹唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2-丁 烯 -1-基) -8-(3-(R)- J ^^啶 -1-基)黄嚟呤； 1-[(7-methoxy-4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl] -3-methyl-7-(trans-2-butene-1- base) -8-(3-(R)-J^^din-1-yl)xanthin;
1-[(5，6，7，8-四氢 -4， 6-二甲基喹唑 基)甲基】 -3-甲基 -7- (反 -2-丁烯 -1-基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(5,6,7,8-tetrahydro-4,6-dimethylquinazolyl)methyl] -3-methyl-7- (trans-2-buten-1-yl) - 8-(3-(R)- J>piperidin-1-yl)xanthin;
1 - [(5,6,7,8-四氢 -4，7-二甲基喹唑啉 _2_基）甲基】 _3_甲基 _7_(2-丁炔 -1- 基) -8-(3-(R)- J>哌啶 -1-基)黄嚟呤； 1-[(5,6,7,8 - tetrahydro- 4,7 -dimethylquinazolin_2-yl ) methyl]_3_methyl_7_( 2 - butyn- 1 -yl ) -8-(3-(R)- J>piperidin-1-yl)xanthin;
1-[(5，6，7，8-四氢 -4-甲基 喹唑啉 -2-基)甲基】 -3-甲基 -7- (反 -2-丁 烯 -1-基) -8-(3-(R)- J ^^啶 -1-基)黄嚟呤； 1-[(5,6,7,8-tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(trans-2-buten-1-yl) -8-(3-(R)-J^^^din-1-yl)xanthin;
1—[(6，7-二氢 -4,6-二甲基 -5 -环戊 [d】嘧啶 -2-基)甲基】 -3-甲基 -7-(2-丁 炔 -1-基) -8-(3-(R)- J ^^啶 -1-基)黄嚟呤； 1-[(6,7-dihydro-4,6-dimethyl-5-cyclopent[d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyne-1 -base) -8-(3-(R)- J^^din-1-yl)xanthin;
1-[(4，8-二甲基苯并呋喃 [3,2-d]嘧啶 -2-基)甲基】 -3-甲基 -7-(3-甲基 -2- 丁烯 -1-基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤； 1-[(4,8-Dimethylbenzofuran[3,2-d]pyrimidin-2-yl)methyl] -3-methyl-7-(3-methyl-2- Buten-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine;
1 - [(4-曱基 -8-氯苯并呋喃 [3，2-d]嘧啶 -2-基)曱基] -3-甲基 -7-(3-曱基 -2- 丁烯 -1-基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤； 1-[(4-methyl-8-chlorobenzofuran[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butene- 1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine;
1-[(4，8-二曱基苯并噻吩 [3，2-d]嘧啶 -2-基）曱基] -3-甲基 -7-(2-丁炔 -1- 基) -8-(3-(R)-氨基哌啶 -1-基)黄嘌呤； 1-[(4,8-dimethylbenzothiophene[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 -(3-(R)-aminopiperidin-1-yl)xanthine;
1 - [(4-曱基 -7-曱氧基苯并噻吩 [3，2-d】嘧啶 -2-基)曱基] -3-曱基 -7-(2-丁 炔 _1_基 )_8-(3-(R)-氨基哌啶 -1-基)黄嘌呤。 1-[(4-methyl-7-methoxybenzothiophene[3,2-d]pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl )_8-(3-(R)-aminopiperidin-1-yl)xanthine.
6、 一种制备式 I所示的黄嘌呤衍生物、 其药学上可接受的盐、 溶 剂合物、 药学上可接受的盐的溶剂合物、 其化学保护形式或者前药的方 6. A method for preparing the xanthine derivative represented by formula I, its pharmaceutically acceptable salt, solvate, pharmaceutically acceptable salt solvate, its chemically protected form or prodrug.
Figure imgf000054_0001
Figure imgf000054_0001
( 1 )将式 II所示的 取代的卤代曱烷与式 IV所示的 3-曱基 -7- 取代 -8-[(R)-3- (叔丁氧羰基胺基)哌啶 -1-基]黄嘌呤反应， 生成中间体 I (1) Substituted halomethane represented by formula II and 3-methyl-7-substituted-8-[(R)-3-(tert-butoxycarbonylamino)piperidine- represented by formula IV 1-yl]xanthine reaction to generate intermediate I
( a ) ； (a);
( 2 ) 中间体 I ( a )在适宜酸存在下脱除叔丁氧羰基， 得到式 I所 示的化合物； (2) Intermediate I (a) removes the tert-butoxycarbonyl group in the presence of a suitable acid to obtain the compound represented by formula I;
其中， 、 R2、 R3、 ¾、 R5、 、 X、 m的定义同权利要求 1中定 义； Y为卤素； Among them, , R 2 , R 3 , ¾, R 5 , , X and m are as defined in claim 1; Y is halogen;
所述的适宜酸选自三氟乙酸、 曱酸、盐酸、 乙酸，优选为三氟乙酸、 盐酸， 最优选为三氟乙酸。 The suitable acid is selected from trifluoroacetic acid, formic acid, hydrochloric acid, and acetic acid, preferably trifluoroacetic acid and hydrochloric acid, and most preferably trifluoroacetic acid.
7、 式 II所示化合物， 7. Compounds represented by formula II,
R^Y R^Y
其中： 选自：
Figure imgf000054_0002
；Where: Selected from:
Figure imgf000054_0002
;
R2选自 2-丁烯 -1-基、 3-曱基 -2-丁烯 -1-基或 2-丁炔 -1-基； R 2 is selected from 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyn-1-yl;
R3、 R5、 Ri各自独立的选自氢、 卤素原子， 直链或支链的被 1 ~ 5 个卤素原子取代或未被取代的 d-6烷基、直链或支链的被 1 ~ 5个卤素原 子取代或未被取代的 d-6烷氧基、 氛基或羟基； R 3 , R 5 , Ri are each independently selected from hydrogen and halogen atoms, linear or branched by 1 to 5 d - 6 alkyl group substituted or unsubstituted by 1 to 5 halogen atoms, linear or branched d- 6 alkoxy group, cyano group or hydroxyl group substituted or unsubstituted by 1 to 5 halogen atoms;
选自甲^ ^三氟甲基； Selected from methyl, trifluoromethyl;
X独立的选自 O或 S; X is independently selected from O or S;
m选自 1或 2; m is selected from 1 or 2;
并且当 116为氢时， X不为 o。 And when 11 6 is hydrogen, X is not o.
8、 权利要求 7所述的式 II化合物， 其选自 Π(Α)、 式 11(B)或式 11(C):
Figure imgf000055_0001
 8. The compound of formula II according to claim 7, which is selected from Π(A), formula 11(B) or formula 11(C):
Figure imgf000055_0001
II (Α) 11(B) II (0 II (Α) 11(B) II (0
其中， R3、 R4、 R5、 R6、 X、 m的定义同权利要求 1中定义; 并且当 R6为氢时， X不为 0。 Among them, the definitions of R 3 , R 4 , R 5 , R 6 , X and m are the same as those in claim 1; and when R 6 is hydrogen, X is not 0.
9、 权利要求 7所述的式 II化合物， 其选自以下化合物： 9. The compound of formula II according to claim 7, which is selected from the following compounds:
2-氯甲基 -4,5-二氢环戊 [de】喹唑啉（中间体 Π(Β)-1 ) ； 2-Chloromethyl-4,5-dihydrocyclopenta[de]quinazoline (intermediate Π(Β)-1);
2-氯甲基 -5,6,7,8-四氢 -4-甲基喹唑啉（中间体 II(A)-l ) ； 2-Chloromethyl-5,6,7,8-tetrahydro-4-methylquinazoline (Intermediate II(A)-1);
2-氯甲基 -4-甲基苯并呋喃 [3，2-d】嘧啶（中间体 II(C)-l ) ； 2-Chloromethyl-4-methylbenzofuran[3,2-d]pyrimidine (Intermediate II(C)-1);
2-氯甲基 -4-甲基苯并噻吩 [3，2-d】嘧啶（中间体 II(C)-2 ) ； 2-Chloromethyl-4-methylbenzothiophene[3,2-d]pyrimidine (Intermediate II(C)-2);
2-氯甲基 -6,7-二氢 -4-甲基 -5H-环戊 [d】嘧啶（中间体 Π(Α)-2 ) ； 2-氯甲基 -5,6,7,8-四氢 -4-三氟甲基喹唑啉（中间体 Π(Α)-3 ) ； 2-Chloromethyl-6,7-dihydro-4-methyl-5H-cyclopenta[d]pyrimidine (intermediate Π(Α)-2); 2-chloromethyl-5,6,7,8 -Tetrahydro-4-trifluoromethylquinazoline (intermediate Π(Α)-3);
2-氯甲基 -6氯 -4,5-二氢环戊 [de】喹唑啉（中间体 Π(Β)-2 ) ； 2-Chloromethyl-6chloro-4,5-dihydrocyclopenta[de]quinazoline (intermediate Π(Β)-2);
2-氯甲基 -7-甲基 -4,5-二氢环戊 [de】喹唑啉（中间体 Π(Β)-3 ) ； 2-氯甲基 -7-甲氧基 -4,5-二氢环戊 [de】喹唑啉（中间体 Π(Β)-4 ) ； 2-氯甲基 -5,6,7,8-四氢 -4,6-二甲基喹唑啉（中间体 Π(Α)-4 ) ； 2-Chloromethyl-7-methyl-4,5-dihydrocyclopenta[de]quinazoline (intermediate Π(B)-3); 2-chloromethyl-7-methoxy-4, 5-dihydrocyclopenta[de]quinazoline (intermediate Π(B)-4); 2-chloromethyl-5,6,7,8-tetrahydro-4,6-dimethylquinazoline (Intermediate Π(Α)-4);
2-氯甲基 -5,6,7,8-四氢 -4,7-二甲基喹唑啉（中间体 Π(Α)-5 ) ； 2-Chloromethyl-5,6,7,8-tetrahydro-4,7-dimethylquinazoline (intermediate Π(Α)-5);
2-氯甲基 -5,6,7,8-四氢 -4-甲基 喹唑啉（中间体 Π(Α)-6 ) ； 2-氯甲基 -6,7-二氢 -4,6-二甲基 -5Η-环戊 [d】嘧啶（中间体 Π(Α)-7 )； 2-氯甲基 -4,8-二甲基苯并呋喃 [3，2-d】嘧啶（中间体 II(C)-3 ) ； 2-氯甲基 -4-甲基 -8-氯苯并呋喃 [3，2-d】嘧啶（中间体 II(C)-4 ) ； 2-氯甲基 -4,8-二甲基苯并噻吩 [3，2-d】嘧啶（中间体 II(C)-5 ) ； 2-氯甲基 -4-甲基 -7-甲氧基苯并噻吩 [3，2-d】嘧啶（中间体 II(C)-6 ) 2-Chloromethyl-5,6,7,8-tetrahydro-4-methylquinazoline (intermediate Π(Α)-6); 2-chloromethyl-6,7-dihydro-4, 6-Dimethyl-5H-cyclopenta[d]pyrimidine (intermediate Π(A)-7); 2-Chloromethyl-4,8-dimethylbenzofuran[3,2-d]pyrimidine ( Intermediate II(C)-3); 2-chloromethyl-4-methyl-8-chlorobenzofuran[3,2-d]pyrimidine (Intermediate II(C)-4); 2-Chloromethyl-4,8-dimethylbenzothiophene[3,2-d]pyrimidine (Intermediate II(C)-5); 2-Chloromethyl-4-methyl-7-methoxy Benzothiophene[3,2-d]pyrimidine (Intermediate II(C)-6)
10、 一种制备式 II所示化合物的方法， 该方法包括以下步骤： 10. A method for preparing a compound represented by formula II, the method comprising the following steps:
当 RiWhen Ri
Figure imgf000056_0001
Figure imgf000056_0001
III (A) (A) III (A) (A)
将式 III ( A )所示的 R3取代的环烷酮与卤代乙脒盐酸盐在碱性物 质存在条件下反应， 得到 II ( A )所示的化合物； The compound represented by II (A) is obtained by reacting the R3 - substituted cycloalkanone represented by formula III (A) and the haloacetamidine hydrochloride in the presence of alkaline substances;
所述碱性物质选自碳酸钾、 碳酸钠、 碳酸氢钾、 碳酸氢钠、 氢氧 化钾、 氢氧化钠、 甲醇钠、 乙醇钠， 优选为碳酸钾、 碳酸钠、 氢氧化 钠， 最优选 The alkaline substance is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, preferably potassium carbonate, sodium carbonate, and sodium hydroxide, and most preferably
当 为
Figure imgf000056_0002
as
Figure imgf000056_0002
ΙΙΙ(Β) 11(B) ΙΙΙ(Β) 11(B)
( 1 )将式 ΠΙ(Β)所示的 R5取代的 7-乙酰氣基茚酮进行水解得到 茚酮； (1) Hydrolyze the R 5 -substituted 7-acetylaminoindanone represented by formula II(B) to obtain indanone;
( 2 )将 7- J^-l-茚酮与卤代乙腈环合得到 11(B)所示的化合物； (2) Cycling 7-J^-l-indanone with haloacetonitrile to obtain the compound shown in 11(B);
当 Ri
Figure imgf000056_0003
When Ri
Figure imgf000056_0003
将式 III ( C )所示的 R4取代的苯并呋喃或苯并噻吩化合物与卤代 乙腈环合得到式 II ( C )所示的化合物； 其中， R3、 、 R5、 Re的定义 同权利要求 1中的定义； The R4-substituted benzofuran or benzothiophene compound represented by formula III (C) is mixed with a halogenated The compound represented by formula II (C) is obtained by cyclization of acetonitrile; wherein, the definitions of R 3 , R 5 and Re are the same as those in claim 1;
X独立的选自 O或 S; X is independently selected from O or S;
并且当 116为氢时， X不为 O; And when 11 6 is hydrogen, X is not O;
Y为卤素。 Y is halogen.
11、 一种药物组合物， 其包含权利要求 1-5任一项所述的式 I所示 的黄嚟呤衍生物、 其药学上可接受的盐、 溶剂合物、 药学上可接收的盐 的溶剂合物、其化学保护形式或者前药，以及药学上可接受的赋形剂或 载体。 11. A pharmaceutical composition comprising the xantholine derivative represented by Formula I according to any one of claims 1 to 5, its pharmaceutically acceptable salts, solvates, and solvents for pharmaceutically acceptable salts compounds, their chemically protected forms or prodrugs, and pharmaceutically acceptable excipients or carriers.
12、 权利要求 1-5任一项所述的式 I所示的黄嚟呤衍生物、其药学 上可接受的盐、 溶剂合物、 药学上可接收的盐的溶剂合物、 其化学保护 形式、 前药或者权利要求 11所述的组合物的用途， 在用于制备治疗、 预防以及緩解与 DPP-I 相关的疾病的药物的用途。 12. The xanthine derivative represented by Formula I according to any one of claims 1 to 5, its pharmaceutically acceptable salts, solvates, solvates of pharmaceutically acceptable salts, and its chemically protected forms, The use of the prodrug or the composition of claim 11 for the preparation of medicaments for the treatment, prevention and alleviation of diseases related to DPP-I.
13、 根据权利要求 12所述的用途， 其特征在于， 所述与 DPP-I 相 关的疾病选自糖尿病、 高血糖症、 肥胖症、 胰岛素抵抗症、 缺血性心肌 炎或血管生成性疾病； 优选地， 所述与 DPP-I 相关的疾病选自糖尿病 和高 jk 症。 13. The use according to claim 12, characterized in that the disease related to DPP-I is selected from diabetes, hyperglycemia, obesity, insulin resistance, ischemic myocarditis or angiogenic diseases; preferably Preferably, the disease associated with DPP-I is selected from the group consisting of diabetes and hypertensive disorders.
14、权利要求 7至 9任一项所述的式 II化合物在用于制备权利要求 1所述的黄嚟玲衍生物中的用途。 14. Use of the compound of formula II according to any one of claims 7 to 9 for the preparation of the Huanglin derivative according to claim 1.
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