CN103709163B - Xanthine derivative, Preparation Method And The Use - Google Patents

Xanthine derivative, Preparation Method And The Use Download PDF

Info

Publication number
CN103709163B
CN103709163B CN201210375253.8A CN201210375253A CN103709163B CN 103709163 B CN103709163 B CN 103709163B CN 201210375253 A CN201210375253 A CN 201210375253A CN 103709163 B CN103709163 B CN 103709163B
Authority
CN
China
Prior art keywords
methyl
xanthine
aminopiperidin
formula
chloromethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201210375253.8A
Other languages
Chinese (zh)
Other versions
CN103709163A (en
Inventor
陈栋
范传文
何绪军
程哲
李成龙
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
QILU PHARMACEUTICAL (HAINAN) CO Ltd
Original Assignee
Qilu Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Qilu Pharmaceutical Co Ltd filed Critical Qilu Pharmaceutical Co Ltd
Priority to CN201210375253.8A priority Critical patent/CN103709163B/en
Priority to PCT/CN2013/083096 priority patent/WO2014048243A1/en
Publication of CN103709163A publication Critical patent/CN103709163A/en
Application granted granted Critical
Publication of CN103709163B publication Critical patent/CN103709163B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a class xanthine derivative, its pharmaceutically acceptable salt, the solvate of described derivant, the solvate of pharmaceutically acceptable salt, its chemoproection form or prodrug and its production and use；Further relate to the midbody compound for preparing described xanthine derivative and described midbody compound preparation method.Described xanthine derivative and pharmaceutical composition thereof effectively suppress DPP lV activity, it is possible to for the medicine of preparation with dipeptidyl peptidase (DPP IV) relevant disease.

Description

Xanthine derivative, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel xanthine derivative, a preparation method and application thereof, and also relates 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 can effectively inhibit the activity of dipeptidyl peptidase (DPP-IV) and can be used for preparing medicines for preventing or treating diseases related to DPP-IV.
Background
Dipeptidyl peptidases (Dipeptidyl peptidases) can be classified into types I, III, IV, 6,7,8, 9, 10, and the like.
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 high-expression dipeptidyl peptidase-IV (DPP-IV), and the hydrolysis substrate is the same.
Dipeptidyl peptidase-9 (DPP-9) belongs to the SC class of serine proteases S9B family. It cleaves Xaa-Pro dipeptides from the N-terminus of proteins and shows proline dipeptidase activity.
Dipeptidyl peptidase-IV (DPP-IV) is a transmembrane serine proteolytic enzyme present in a variety of human tissues and organs. The single chain of human DPP-IV consists of 766 amino acids, divided into 5 structural regions: the lengths of these regions differ slightly. Soluble DPP-IV is a homodimer of approximately 210-290K and is also capable of polymerizing complexes up to 900K.
DPP-IV is combined with a membrane through a hydrophobic helix formed by a hyperglycosylation area and a cysteine enrichment area of amino acid, and a serine protease area alpha/at a carboxyl terminal is homologous with hydrolase; DPP-IV can rapidly and specifically cleave the proline or alanine residue at the second N-terminal position of the peptide chain, and its substrates include two incretins which play an important role in the signal transduction process of the immune response to type II diabetes: a glucagon-like peptide (GLP-1) fragment and a Gastric Inhibitory Peptide (GIP). GLP-1 and GIP are incretins secreted by L cells and k cells of the gastric mucosa in response to ingested carbohydrates and fats, respectively, and both regulate blood glucose concentration by acting on the pancreas to enhance glucose-induced insulin secretion, while DPP-lV hydrolyzes them to produce the corresponding N-terminal cleaved forms GLP-19-36 and GIP3-42, both of which lose insulin-inducing activity [ Expert opin. investing. drugs,2004,13(9):1091-1102 ]. Therefore, by inhibiting DDP-IV activity, it is possible to inhibit the degradation of various active peptides including GLP-1, thereby prolonging the action time, reducing the synthesis of glucose in the liver, and controlling the blood glucose level. The DPP-IV inhibitor can be used for treating, preventing or relieving diseases related to DPP-IV, such as diabetes, hyperglycemia, obesity or insulin resistance.
DPP-8 and DPP-9 are two classes of proteins with catalytic activity in the DPP family. The protein sequence of human DPP-8 and DPP-9 have 61% homology, and the protein sequence of DPP-8 and DPP-9 and DPP-4 have 26% homology. Unlike DPP-IV, DPP-8 and DPP-9 do not have extracellular catalytic domains. Wherein DPP-8 is highly expressed in activated T cells and DPP9 is highly expressed in cancer cells, skeletal muscle cells, cardiac muscle cells and liver. In both blood lymphocytes and monocytes, DPP-8 and DPP-9 are expressed. Inhibition of human DPP-8 and DPP-9 may weaken T cell activity and affect immune function. The DPP-IV inhibitor has weak DPP-8 and DPP-9 inhibitory activity and good selectivity, and has high safety and small potential toxic and side effects.
The DPP-IV inhibitor is used for inhibiting the activity of DPP-IV, can prevent the rapid degradation of degraded substances and stabilize the endogenous biological activity of the degraded substances, thereby playing a responsive therapeutic role. DPP-IV inhibitors are also thought to play a role in the cleavage of various cytokines (stimulating hematopoietic cells), growth factors and neuropeptides. For example, DDP-IV is capable of degrading the chemokines CXCL12/SDF-1a (stromal cell derived factor a), SDF is released from bone marrow stromal cells and specifically binds to receptor CXCR4 expressing hematopoietic stem/progenitor cells, CXCL12 is thought to be involved in the homing of hematopoietic stem cells [ Ludwig A, J.LeukocBiol,2002,72(1):183 + 191 ], therefore, DDP-IV inhibitors may play a decisive role in stabilizing the hematopoietic environment, mobilizing hematopoietic stem cells from the bone marrow and in hematopoietic reconstitution, and are expected to be used in the treatment of ischemic myocarditis and angiogenic diseases.
DPP-lV inhibitors have become a new direction for pharmaceutical research, and several DPP-IV inhibitors have been successfully marketed, such as Sitagliptin from Merck (WO 03004498), Vildagliptin from Novartis (WO 09819998), Saxagliptin from Bristol-Myers Squibb (WO 00168603), Alogliptin from Takeda (WO 2005095381), BI-1356 from Boehringer Ingelheim (WO 2004018468, chemical name of BI-1356: 8- [ (3R) -3-amino-1-piperidinyl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione). Although the drugs have good pharmacodynamic properties, more novel compounds with higher activity and lower toxicity are still needed to be developed, and a wider drug selection space is provided for treating DPP-IV related diseases.
Disclosure of Invention
The invention aims to provide a compound which can inhibit DPP-lV activity and can be used for treating or relieving DPP-IV related diseases.
In a first aspect, the present invention provides a xanthine derivative, a pharmaceutically acceptable salt, solvate of a pharmaceutically acceptable salt, a chemically protected form or a prodrug thereof, represented by formula I:
formula I
Wherein,
R1selected from:
R2selected from 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyn-1-yl;
R3、R5、R6each independently selected from hydrogen, halogen atom, straight chain or branched chain C substituted or not substituted by 1-5 halogen atoms1-6Alkyl, straight or branched C substituted or unsubstituted with 1 to 5 halogen atoms1-6Alkoxy, cyano or hydroxy;
R4selected from methyl or trifluoromethyl;
x is independently selected from O or S;
m is selected from 1 or 2.
In a specific embodiment, the xanthine derivative, pharmaceutically acceptable salt, solvate of pharmaceutically acceptable salt, chemically protected form or prodrug thereof shown in formula I according to the first aspect of the present invention,
R3、R5、R6each independently selected from hydrogen, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano or hydroxy.
Preferably R3、R5、R6Each independently selected from hydrogen, chlorine atom, methyl, methoxy and cyano.
In a specific embodiment, the xanthine derivative, pharmaceutically acceptable salt, solvate of pharmaceutically acceptable salt, chemically protected form or prodrug thereof shown in formula I according to the first aspect of the present invention,
R3selected from hydrogen, methyl, cyano;
R5selected from hydrogen, chlorine atom, methyl and methoxy;
R6selected from hydrogen, chlorine atom, methyl and methoxy.
In a specific embodiment, the xanthine derivative represented by formula I, the pharmaceutically acceptable salt, the solvate of the pharmaceutically acceptable salt, and the chemically protected form or the prodrug thereof according to the first aspect of the present invention is selected from formula I (a), formula I (b), or formula I (c):
formula I (A)
Formula I (B)
Formula I (C)
Wherein: r2、R3、R4、R5、R6M and X are as defined above.
In a specific embodiment, the xanthine derivative represented by formula I, the pharmaceutically acceptable salt, the solvate of the pharmaceutically acceptable salt, and the chemically protected form or the prodrug thereof according to the first aspect of the present invention are selected from the following compounds:
1- [ (4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (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- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (4-methylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (4-methylbenzofuran [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-methylbenzothiophen [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4-trifluoromethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (6-chloro-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
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-methoxy-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4, 6-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4, 7-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4-methyl-6-cyanoquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
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-methyl-8-chlorobenzofuran [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, 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-methyl-7-methoxybenzothiophene [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine.
A second aspect of the present invention provides a process for the preparation of a xanthine derivative, a pharmaceutically acceptable salt, solvate of a pharmaceutically acceptable salt, chemically protected form or prodrug thereof, of formula I as described in the first aspect of the present invention, which comprises the steps of:
(1) r shown in formula II1Substituted halomethanes (R)1-CH2Y) and 3-methyl-7-substituted-8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl group represented by the formula IV]Xanthine to form intermediate i (a);
(2) intermediate I (a) removing tert-butyloxycarbonyl (abbreviated as Boc) in the presence of a suitable acid to obtain a compound represented by formula I;
wherein R is1、R2、R3、R4、R5、R6X, m are as defined in the first aspect of the invention; y is halogen;
the suitable acid is selected from trifluoroacetic acid, formic acid, hydrochloric acid, acetic acid, preferably trifluoroacetic acid, hydrochloric acid, most preferably trifluoroacetic acid.
In a third aspect the present invention provides a compound of formula II,
wherein: r1Selected from:
R2selected from 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyn-1-yl;
R3、R5、R6each independently selected from hydrogen, halogen atom, straight chain or branched chain C substituted or not substituted by 1-5 halogen atoms1-6Alkyl, straight or branched C substituted or unsubstituted with 1 to 5 halogen atoms1-6Alkoxy, cyano or hydroxy;
R4selected from methyl or trifluoromethyl;
x is independently selected from O or S;
m is selected from 1 or 2;
and when R is6When hydrogen, X is not O.
In a particular embodiment, the compound of the third aspect of the invention is selected from formula ii (a), (ii) (b) or formula ii (c):
wherein R is3、R4、R5、R6X, m are as defined in the first aspect of the invention; and when R is6When hydrogen, X is not O.
In a particular embodiment, the compound according to the third aspect of the invention is selected from the following compounds:
2-chloromethyl-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) — 1);
2-chloromethyl-5, 6,7, 8-tetrahydro-4-methylquinazoline (intermediate ii (a) -1);
2-chloromethyl-4-methylbenzofuran [3,2-d ] pyrimidine (intermediate II (C) -1);
2-chloromethyl-4-methylbenzothiophene [3,2-d ] pyrimidine (intermediate II (C) -2);
2-chloromethyl-6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidine (intermediate ii (a) -2);
2-chloromethyl-5, 6,7, 8-tetrahydro-4-trifluoromethylquinazoline (intermediate ii (a) -3);
2-chloromethyl-6-chloro-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -2);
2-chloromethyl-7-methyl-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -3);
2-chloromethyl-7-methoxy-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -4);
2-chloromethyl-5, 6,7, 8-tetrahydro-4, 6-dimethylquinazoline (intermediate ii (a) -4);
2-chloromethyl-5, 6,7, 8-tetrahydro-4, 7-dimethylquinazoline (intermediate ii (a) -5);
2-chloromethyl-5, 6,7, 8-tetrahydro-4-methyl-6-cyanoquinazoline (intermediate ii (a) -6);
2-chloromethyl-6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ] pyrimidine (intermediate ii (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-methoxybenzothiophene [3,2-d ] pyrimidine (intermediate II (C) -6).
In a fourth aspect, the present invention provides a process for the preparation of a compound of formula II according to the third aspect of the invention, which process comprises the steps of:
when R is1Is composed ofWhen the temperature of the water is higher than the set temperature,
r shown in formula III (A)3Reacting substituted cycloalkanone with halogenated acetamidine hydrochloride in the presence of alkaline substances to obtain a compound shown in II (A);
the alkaline substance is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium methoxide and sodium ethoxide, preferably potassium carbonate, sodium carbonate and sodium hydroxide, and most preferably potassium carbonate.
When R is1Is composed ofWhen the temperature of the water is higher than the set temperature,
(1) r shown in formula III (B)5Hydrolyzing the substituted 7-acetamido-indanone to obtain 7-amino-1-indanone;
(2) cyclizing 7-amino-1-indanone and halogenated acetonitrile to obtain a compound shown in II (B).
When R is1Is composed ofWhen the temperature of the water is higher than the set temperature,
r shown in formula III (C)4Substituted benzofurans orCyclizing a benzothiophene compound and halogenated acetonitrile to obtain a compound shown in a formula II (C); wherein R is3、R4、R5、R6Is as defined in claim 1;
x is independently selected from O or S;
and when R is6When hydrogen, X is not O;
y is halogen.
In a fifth aspect, the present invention provides a pharmaceutical composition, which comprises the xanthine derivative represented by formula I, the pharmaceutically acceptable salt, the solvate of the pharmaceutically acceptable salt, the chemically protected form or the prodrug thereof, according to the first aspect of the present invention, and a pharmaceutically acceptable excipient or carrier.
In a sixth aspect, the present invention provides a xanthine derivative represented by formula I, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt, a chemically protected form, a prodrug thereof, or a composition according to the fifth aspect, wherein the xanthine derivative is used as described in the first aspect of the present invention, and the composition is used for preparing medicines for treating, preventing and relieving diseases related to DPP-iv.
In a specific embodiment of the invention, the use according to the sixth aspect of the invention is characterized in that the DPP-iv-associated disease is selected from diabetes, hyperglycemia, obesity or insulin resistance, ischemic myocarditis or angiogenic diseases; preferably, the DPP-IV related disease is selected from diabetes and hyperglycemia.
A seventh aspect of the invention provides the use of a compound according to the third aspect of the invention for the preparation of a xanthine derivative according to claim 1.
In an eighth aspect, the present invention provides a method for treating, preventing and alleviating the diseases associated with DPP-IV, which comprises administering the xanthine derivative, the pharmaceutically acceptable salt, the solvate of the pharmaceutically acceptable salt, the chemically protected form thereof and the prodrug of the xanthine derivative according to the first aspect of the present invention to a subject in need thereof.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control.
The various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even then, it is intended that the present invention not be limited to the specific meanings and expressions employed herein as are inconsistent with such known meanings.
The term "halogen" or "halo" as used herein means fluoro, chloro, bromo or iodo, with the preferred halogen group being fluoro, chloro or bromo.
The term "alkyl" as used herein refers to a saturated straight or branched chain monovalent hydrocarbon radical having 1 to 6 carbon atoms (i.e., C1-6 alkyl), preferably 1 to 4 carbon atoms (i.e., C1-4 alkyl), 1 to 3 carbon atoms (i.e., C1-3 alkyl), or 1 to 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-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like, and in one embodiment, alkyl is preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
The "alkoxy" in the present invention means a saturated straight or branched chain alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, 1 to 3 carbon atoms or 1 to 2 carbon atoms; examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-dimethylbutoxy, 2-dimethylbutoxy, 1-dimethylbutoxy, 1, 2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2-ethylbutoxy, 1, 2-dimethylpropoxy, cyclopropoxy, cyclobutoxy, 1-methylcyclobutoxy, cyclopentoxy, cyclohexyloxy and the like; in one embodiment, the alkoxy group is preferably selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy.
The xanthine derivative shown in the formula I comprises isomers, racemes, enantiomers, diastereomers, enantiomer enrichments, deuterons, solvates and esters thereof; the compound of the formula I and the isomer, racemate, enantiomer, diastereomer, enantiomer enrichment, deuteron, solvate and ester thereof can also form solvate, such as hydrate, alcoholate and the like. The derivatives may also be prodrugs or forms which release the active ingredient upon metabolic changes in the body. The selection and preparation of suitable prodrug derivatives is well known to those skilled in the art. Generally for the purposes of the present invention, the solvate forms of pharmaceutically acceptable solvents such as water, ethanol, etc. are equivalent to the non-solvate forms.
The compounds of formula I of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts may be prepared by reacting a compound of the invention with a suitable organic or inorganic acid.
Reacting the xanthine derivative shown as the formula I with an organic acid or an inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the xanthine derivative, such as a hydrohalide salt, for example, a hydrochloride, a hydrobromide, a hydroiodide; other inorganic acids and their corresponding salts, such as sulfates, nitrates, phosphates, and the like; and alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; 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 present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galactarate (galac) (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, monobutyrate phosphate, camphorate, caprylate, capryl, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, oleates, embonate salts, pectates, persulfates, phenylacetates, 3-phenylpropionates, phosphates, phosphonates and phthalates. It will be appreciated that the free base forms will generally differ somewhat in physical properties from their respective salt forms, for example solubility in polar solvents, but for the purposes of the present invention, salts are equivalent to their respective free base forms.
Preferably, the xanthine derivative represented by formula I of the present invention is reacted with the following organic acid or inorganic acid to prepare a pharmaceutically acceptable salt thereof: hydrochloric acid, sulfuric acid, phosphoric acid, malic acid, maleic acid, fumaric acid, lactic acid, benzoic acid, methanesulfonic acid, citric acid, tartaric acid, acetic acid, or trifluoroacetic acid; preferably hydrochloride, benzoate or trifluoroacetate.
The compounds of formula I of the present invention may be used alone as therapeutic agents or in combination with one or more other DPP-IV drugs having a similar or synergistic mechanism of action. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The compounds of formula I of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
The actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is common practice in the art to start doses of the compounds at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
When used in the above-described treatment and/or prophylaxis or other treatment and/or prophylaxis, a therapeutically and/or prophylactically effective amount of one of the compounds of the present invention may be employed in pure form or, where present, in the form of a pharmaceutically acceptable salt, ester or prodrug. Alternatively, the compounds may be administered in a pharmaceutical composition comprising the subject compound together with one or more pharmaceutically acceptable excipients. The phrase "therapeutically and/or prophylactically effective amount" of a compound of the present invention refers to a sufficient amount of the compound to treat a disorder at a reasonable benefit/risk ratio applicable to any medical treatment and/or prophylaxis. It will be appreciated, however, that the total daily amount of a compound of formula I and pharmaceutical compositions thereof of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. In general, the dosage of the compounds of formula I of the present invention for use in mammals, especially humans, may be between 0.001 to 1000mg/kg body weight/day, such as between 0.01 to 100mg/kg body weight/day, such as between 0.01 to 10mg/kg body weight/day.
Pharmaceutical compositions containing effective amounts of the compounds of the present invention may be prepared using pharmaceutical carriers well known to those skilled in the art. The invention therefore also provides pharmaceutical compositions comprising a compound of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specifically formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.
The pharmaceutical compositions can be formulated in a variety of dosage forms for ease of administration, for example, oral formulations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are ready for use by addition of water for injection prior to injection). The carrier in the pharmaceutical composition comprises: binders for oral formulations (e.g., starch, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone), diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol), lubricants (e.g., silicon dioxide, talc, stearic acid or salts thereof, typically magnesium or calcium stearate, and/or polyethylene glycol), and, if desired, disintegrating agents, such as starch, agar, alginic acid or salts thereof, typically sodium alginate, and/or effervescent mixtures, solubilizing agents, stabilizers, suspending agents, pigments, flavoring agents, and the like, preservatives for injectable formulations, solubilizers, stabilizers, and the like; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
More specifically, the pharmaceutical compositions of the present invention may be administered orally, rectally, parenterally, intravaginally, topically (such as by powders, ointments, or drops), buccally to humans and other mammals, or as an oral or nasal spray. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example sugars, sodium chloride and the like, are also included. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of substances delaying absorption, for example, aluminum monostearate and gelatin.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
In some cases, to prolong the effect of a 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 crystalline or amorphous material which is poorly water soluble. Thus, the rate of absorption of the drug is dependent on its rate of dissolution, which in turn may be dependent on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms can be prepared by forming a microcapsule matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending 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 may also be prepared by embedding the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use.
The compounds of the present invention or compositions thereof may be administered orally or parenterally. The oral administration form can be tablet, capsule, coating agent, and intestinal tract external preparation such as injection and suppository. These formulations are prepared according to methods familiar to those skilled in the art. The adjuvants used for the manufacture of tablets, capsules, coatings are the customary adjuvants, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils (e.g. corn oil, peanut oil, olive oil, etc.). The preparation containing the compound of the invention also comprises other auxiliary materials, such as a surfactant, a lubricant, a disintegrating agent, a preservative, a flavoring agent, a pigment and the like. The dosage of the compounds of formula I containing the present invention in tablets, capsules, coatings, injections and suppositories is calculated as the amount of compound present in the unit dosage form. The compound of formula I of the present invention is generally present in an amount of from 0.1 to 1000mg in a unit dosage form, preferably a unit dosage form containing from 1 to 100mg, more preferably a unit dosage form containing from 5 to 20 mg.
In particular, the present invention may provide solid dosage forms for oral administration including 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: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, buffers may also be included in the dosage forms.
Solid compositions of a similar type, using excipients such as lactose and high molecular weight polyethylene glycols and the like, can also be used as fillers in soft and hard capsules.
Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. These solid dosage forms may optionally contain opacifying agents and may also be of such a composition that they release the active ingredient(s) only, or preferentially, at a site in the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. If appropriate, the active compounds can also be formulated in microencapsulated form with one or more of the abovementioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may contain, in addition to inert diluents, adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
The compounds of the present invention and compositions thereof are also contemplated for topical administration. Dosage forms for topical administration of the compounds of the present invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers, or propellants. Ophthalmic formulations, ocular ointments, powders, and solutions are also contemplated within the scope of the invention.
The compounds of the invention may also be administered in the form of liposomes. As is well known in the art, liposomes are typically made with phospholipids or other lipid materials. Liposomes are formed from single or multiple layers of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions of the present invention in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), which may be used alone or in combination. Methods of forming liposomes are well known in the art.
Detailed Description
The present invention is further illustrated by the following specific preparation examples and biological experiments; however, it should be understood that these examples and biological experiments are only for the purpose of specifically illustrating the present invention in more detail, and should not be construed as limiting the present invention in any way.
Although the materials and methods of operation are well known in the art for the purposes of this invention, the invention is nevertheless described in detail herein as is practicable. It is clear to the person skilled in the art that, in the following, the methods of operation are well known to the person skilled in the art, if not specified; the materials used are those skilled in the art which, on the basis of the published literature or the prior art, can be prepared by customary methods or are commercially available.
In the present invention, unless otherwise specified, wherein: (i) the temperature is expressed in degrees centigrade (DEG C), and the operation is carried out in a room temperature environment; said room temperature has the meaning well known in the art, in particular 10-35 ℃, preferably 15-30 ℃, most preferably 20-25 ℃; (ii) drying the organic solvent with anhydrous sodium sulfate, evaporating the solvent by a rotary evaporator under reduced pressure, and keeping the bath temperature not higher than 60 ℃; (iii) the reaction process was followed by Thin Layer Chromatography (TLC); (iv) and drying the obtained solid intermediate or final product in vacuum at the drying temperature of not higher than 60 ℃. (v) The final product has satisfactory proton NMR spectrum (1H-NMR) and Mass Spectrometry (MS) data.
Example 1:1- [ (4, 5-dihydrocyclopenta [ de ]]Quinazolin-2-yl) methyl]-3-methyl-7- (2-butyn-1-yl) - Preparation of 8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 1)
(1) Preparation of 3-methyl-7- (2-butyn-1-yl) -8-bromoxanthine
8-bromo-3-methyl-3, 7-dihydro-purine-2, 6-dione (24.5g, 100mmol) was suspended in 150mL of N, N-dimethylformamide (abbreviated as DMF) at room temperature, diisopropylethylamine (27mL, 150mmol) was added thereto, the mixture was mechanically stirred for 10 minutes, a solution of 1-bromo-2-butyne (15g, 110mmol) in N, N-dimethylformamide (50mL) was added dropwise thereto, and after completion of the addition, the mixture was stirred at room temperature for 10 to 12 hours. After the reaction, the reaction solution was poured into ice water, and solid was precipitated by stirring, filtered, and dried under vacuum to obtain 25g of pale yellow solid with a yield of 84.1%. ES-API (M/z) [ M + H ]]+297.0，299.0。
(2) Preparation of 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Under nitrogen, 3-methyl-7- (2-butyn-1-yl) -8-bromoxanthine (3.0g, 10mmol), potassium carbonate (2.0g, 15mmol) and 3- (R) -tert-butoxycarbonyl-aminopiperidine (2.2g, 11mmol) were added to a 50mL round-bottomed flask, 10mL of N, N-dimethylformamide was added, and the mixture was heated to 95 ℃ and stirred for 5 hours; after the reaction, the reaction solution was cooled to room temperature, and the reaction solution was poured into ice water to precipitate a solid, which was filtered and vacuum-dried to obtain a pale yellow solid 3.1g with a yield of 74.5%. ES-API (M/z) [ M + H ]]+417.1。
(3) Preparation of 4-acetamidoindane
Adding 4-aminoindan (13.5g, 101mmol) into a 500mL round-bottom flask, adding 50mL ethanol, stirring to dissolve, cooling to 0 ℃, adding 200mL ethanol solution dissolved with acetic anhydride (19mL, 201mmol), and stirring at room temperature for 12 hours; after the reaction is finished, the solvent is removed by reduced pressure evaporation to obtain17.0g of white solid, 97.1% yield. ES-API (M/z) [ M + H ]]+176.0。
(4) Preparation of 7-acetamido-1-indanone
Adding 4-acetamidoindane (5.0g, 29mmol) into a 250mL round-bottom flask, adding 150mL acetone, stirring well, adding 40mL MgSO 15% by mass4The aqueous solution was cooled to 0 ℃ and potassium permanganate (13.7g, 87mmol) was added, followed by stirring at room temperature for 15 hours. After the reaction, the reaction solution was filtered through celite, the filter cake was washed with chloroform and water in this order, the aqueous phase was separated from the filtrate, and extracted once with 50mL of chloroform, the organic phases were combined, washed once with 70mL of saturated saline, dried over anhydrous sodium sulfate for 10 hours, filtered, and the solvent was distilled off from the filtrate to obtain 4.2g of a white solid, with a yield of 76.6%. ES-API (M/z) [ M + H ]]+190.0。
(5) Preparation of 7-amino-2, 3-dihydro-1-indanone
Adding 7-acetamido-1-indanone (4.0g, 21mmol) into a 100mL round-bottom flask, then adding 50mL of 6mol/L hydrochloric acid, heating to 90 ℃, and stirring for 4 h; after the reaction, the reaction solution was cooled to 0 ℃ and the pH of the reaction solution was adjusted to 8 with 2mol/L aqueous NaOH solution, the reaction solution was extracted with ethyl acetate (30 mL) (3 times for the total extraction), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2.8g of a yellow solid with a yield of 90.7%. ES-API (M/z) [ M + H ]]+148.0。
(6) Preparation of 2-chloromethyl-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -1)
Intermediate II (B) -1
7-amino-2, 3-dihydro-1-indanone (1.5g, 10mmol) is dissolved in 20mL of 1, 4-dioxane, the solution is cooled to 10 ℃, then hydrogen chloride gas is introduced, after 2 hours, chloroacetonitrile (0.9g, 12mmol) in 1, 4-dioxane is added dropwise, and the mixture is stirred at room temperature for 5 hours. After the reaction, 50mL of ice water was added, the pH of the reaction mixture was adjusted to 8 with 2mol/L aqueous NaOH, ethyl acetate was used for extraction (30mL, 2 times of extraction), the organic phases were combined, washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated off by rotary evaporation to give 1.9g of a white solid with a yield of 92.2%. ES-API (M/z) [ M + H ]]+207.0。
(7) Preparation of 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
Under the protection of nitrogen, 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butyloxycarbonylamino) piperidine-1-yl]Xanthine (0.21g, 0.5mmol), potassium carbonate (0.11g, 0.8mmol) and 2-chloromethyl-4, 5-dihydrocyclopenta [ de ]]Quinazoline (0.13g, 0.6mmol) was added to a 50mL round bottom flask, 10mL of N, N-dimethylformamide was added, the temperature was raised to 90 ℃ and stirred for 5 hours; after the reaction, the reaction solution is poured into 20mL of ice water to precipitate solid, the solid is filtered, and the filter cake is purified by column chromatography to obtain 0.20g of light yellow solid, the yield is 68.5 percent, and the ES-API (M/z): M + H]+585.0。
(8) Preparation of 1- [ (4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 1)
Compound 1
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 (0.17g, 0.3mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 2mL of trifluoroacetic acid and stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off, 20mL of ice water was added, the pH of the reaction solution was adjusted to 8 with 2mol/L of NaOH aqueous solution, dichloromethane was extracted (20mL, 3 times of extraction), the organic phases were combined, washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give a pale yellow solid, which was purified by column chromatography to give 0.10g of a white solid (Compound 1), with a yield of 68.9%.
ES-API(m/z):[M+H]+485.3。
1H-NMR(600MHz,CDCl3,ppm)：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: 1- [ (4, 5-dihydrocyclopenta [ de ]]Quinazolin-2-yl) methyl]-3-methyl-7- (3-methyl-2-butane) Preparation of en-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthines (Compound 2)
(1) Preparation of 3-methyl-7- (3-methyl-2-buten-1-yl) -8-bromoxanthine
8-bromo-3-methyl-3, 7-dihydro-purine-2, 6-dione (24.5g, 100mmol) was suspended in 150mL of N-dimethylformamide (abbreviated as DMF) at room temperature, diisopropylethylamine (27mL, 150mmol) was added thereto, the mixture was mechanically stirred for 10 minutes, 50mL of a solution of 1-bromo-3-methyl-2-butene (16.5g, 110mmol) in N, N-dimethylformamide was added dropwise thereto, and the mixture was added dropwiseAfter the addition, the mixture is stirred for 10 to 12 hours at room temperature. After the reaction, the reaction solution was poured into 300ml of ice water to precipitate a solid, which was filtered and vacuum-dried to obtain 28.5g of a pale yellow solid with a yield of 91.1%. ES-API (M/z) [ M + H ]]+313.0，315.0。
(2) Preparation of 3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Under nitrogen, 3-methyl-7- (3-methyl-2-buten-1-yl) -8-bromoxanthine (5.0g, 16mmol), potassium carbonate (3.3g, 24mmol) and 3- (R) -tert-butoxycarbonyl-aminopiperidine (3.5g, 18mmol) were added to a 100mL round-bottomed flask, 40mL of N, N-dimethylformamide was added, and the mixture was heated to 95 ℃ and stirred for 5 hours. After the reaction, the reaction solution was poured into 50mL of ice water to precipitate a solid, which was filtered and dried in vacuo to give 5.6g of a pale yellow solid with a yield of 81.2%. ES-API (M/z) [ M + H ]]+433.1。
(3) Preparation of 1- [ (4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Under the protection of nitrogen, 3-methyl-7- (3-methyl-2-butene-1-yl) -8- [ (R) -3- (tert-butyloxycarbonylamino) piperidine-1-yl]Xanthine (0.31g, 0.7mmol), potassium carbonate (0.15g, 1.1mmol) and 2-chloromethyl-4, 5-dihydrocyclopenta [ de ]]Quinazoline (prepared according to steps (3) - (6) of example 1) (0.17g, 0.8mmol) was added to a 50mL round bottom flask, 10mL of N, N-dimethylformamide was added, and the mixture was stirred at 90 ℃ for 7 hours. After the reaction, the reaction solution was poured into ice water to precipitate a solid, which was filtered, and the filter cake was purified by column chromatography to obtain a pale yellow solid 0.32g, with a yield of 76.2%. ES-API (M/z) [ M + H ]]+601.0。
(4) Preparation of 1- [ (4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 2)
Compound 2
1- [ (4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.30g, 0.5mmol) was dissolved in a mixed solution of 10mL of methylene chloride and 2mL of trifluoroacetic acid and stirred at room temperature for 1 hour; after the reaction, the solvent was distilled off under reduced pressure, 20mL of ice water was added, the pH of the reaction solution was adjusted to 8 with 2mol/L of NaOH aqueous solution, dichloromethane was extracted (20mL, 3 times of extraction), the organic phases were combined, washed once with 30mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow solid, which was purified by column chromatography to give 0.18g of a white solid (Compound 2), with a yield of 72.0%.
ES-API(m/z):[M+H]+501.4。
1H-NMR(600MHz,CDCl3,ppm)：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: 1- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl]-3-methyl-7- (2-butyne-1-) Preparation of yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 3)
(1) Preparation of 2-chloromethyl-5, 6,7, 8-tetrahydro-4-methylquinazoline (intermediate II (A) -1)
Intermediate II (A) -1
2-Acetylcyclohexanone (2.8g, 20mmol), potassium carbonate (4.1g, 30mmol) and chloroacetamidine hydrochloride (2.8g, 22mmol) were added to 30mL of n-butanol, and stirred under reflux for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was poured into 50mL of water, extracted with ethyl acetate (30mL, 3 times), the organic phases were combined, washed once with 30mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a yellow solid, which was purified by column chromatography (eluent: petroleum ether/ethyl acetate =9:1) to give 2.3g of a pale yellow liquid, with a yield of 58.9%. ES-API (M/z) [ M + H ]]+197.1。
(2) Preparation of 1- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Under the protection of nitrogen, 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butyloxycarbonylamino) piperidine-1-yl]Xanthine (see steps (1) - (2) of example 1 for preparation method) (0.17g, 0.4mmol), potassium carbonate (83mg, 0.6mmol) and 2-chloromethyl-5, 6,7, 8-tetrahydro-4-methyl quinazoline (0.10g, 0.5mmol) were added to a 50mL round bottom flask, 10mL of N, N-dimethylformamide was added, and the mixture was heated to 90 ℃ and stirred for 6 hours. After the reaction is finished, pouring the reaction solution into 30mL of ice water to separate out a solid, performing suction filtration, and purifying a filter cake by column chromatography to obtain 0.17g of a white solid with the yield of 73.9%. ES-API (M/z) [ M + H ]]+577.1。
(3) Preparation of 1- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 3)
Compound 3
1- [ (5,6,7, 8-tetrahydro-4-methyl-quinazolin-2-yl) methyl]-3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine (0.15g, 0.26mmol) was dissolved in a mixed solution of 10mL of methylene chloride and 2mL of trifluoroacetic acid, and stirred at room temperature for 1 hour; after the reaction, the solvent was distilled off, 20mL of ice water was added, the pH was adjusted to 8 with 2mol/L aqueous NaOH solution, dichloromethane was extracted (20mL, 2 times of extraction), the organic phases were combined, washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow solid, which was purified by column chromatography to give 89mg of a white solid (Compound 3) with a yield of 71.8%. ES-API (M/z) [ M + H ]]+477.3。
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 4- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl]-3-methyl-7- (3-methyl-2- Preparation of buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 4)
(1) Preparation of 1- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (preparation method see steps (1) - (2) of example 2) (0.26g, 0.6mmol), potassium carbonate (0.12g, 0.9mmol) and 2-chloromethyl-5, 6,7, 8-tetrahydro-4-methylquinazoline (preparation method see step (1) of example 3) (0.14g, 0.7mmol) were added to a 50mL round-bottomed flask under nitrogen protection, 10mL of N, N-dimethylformamide was added, nitrogen was replaced three times, and the mixture was stirred at 95 ℃ for 6 hours. After the reaction, the reaction solution was poured into 30mL of ice water to precipitate a solid, which was filtered, and the filter cake was purified by silica gel column to obtain a pale yellow solid (0.27g, yield 76.1%)
ES-API(m/z):[M+H]+593.1
(2) Preparation of 1- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 4)
Compound 4
1- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.25g, 0.4mmol) was dissolved in a mixed solution of 20mL of methylene chloride and 2mL of trifluoroacetic acid and stirred at room temperature for 1 hour; after the reaction, the solvent was distilled off, 20mL of ice water was added, the pH was adjusted to 8 with 2mol/L of NaOH aqueous solution, dichloromethane extraction (20mL, extraction 3 times) was performed, the organic phases were combined, 20mL of saturated brine was added for washing, anhydrous sodium sulfate was used for drying, the solvent was distilled off under reduced pressure to obtain a pale yellow solid, which was purified by a silica gel column to obtain 0.15g of a white solid (Compound 4), with a yield of 76.1%. ES-API (M/z) [ M + H ] + 493.3.
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 5- [ (4-methylbenzofuran [3,2-d ]]Pyrimidin-2-yl) methyl]-3-methyl-7- (2-butyne-1-) Base) -8- (3- (R) -aminopiperidin-1-yl) Preparation of xanthine (Compound 5)
(1) Preparation of 2- (2-oxopropoxy) benzonitrile
O-hydroxybenzonitrile (12.0g, 100mmol), potassium carbonate (27.6g, 200mmol) and potassium iodide (20.0g, 120mmol) were added to 150mL acetone, stirred at room temperature for 0.5 h, bromoacetone (15.1g, 110mmol) was added, and heated under reflux for 3 h; after the reaction was completed, it was cooled to room temperature, and it was filtered with suction, the filtrate was concentrated, and the residue was added to 150mL of water, extracted with ethyl acetate (100 mL, 2 times), the organic phases were combined, washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 16.1g of a brown solid after drying, in a yield of 92.0%. ES-API (M/z) [ M + H ] + 176.0.
(2) Preparation of 2-acetyl-3-aminobenzofuran
2- (2-oxopropoxy) benzonitrile (15.0g, 86mmol) was dissolved in 200mL of methanol, sodium methoxide (5.1g, 95mmol) was added, and the mixture was stirred at room temperature for 10-12 hours; after the reaction, the solvent was distilled off under reduced pressure, 150mL of water was added, followed by extraction with methylene chloride (100 mL, 3 times), and the organic phases were combined, washed once with 150mL of saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 14.1g of a yellow solid in a yield of 96.7%. ES-API (M/z) [ M + H ] + 176.1.
(3) Preparation of 2-chloromethyl-4-methylbenzofuran [3,2-d ] pyrimidine (intermediate II (c) -1)
Intermediate II (C) -1
Dissolving 2-acetyl-3-aminobenzofuran (6.0g, 34mmol) in 100mL of 1, 4-dioxane, cooling the solution to 10 ℃, introducing hydrogen chloride gas, dropwise adding a 1, 4-dioxane solution of chloroacetonitrile (3.1g, 41mmol) after 2 hours, and stirring at room temperature for 7 hours; after the reaction, 100mL of ice water was added, then the pH of the reaction solution was adjusted to 8 with 2mol/L aqueous NaOH solution, extracted with ethyl acetate (100 mL, 2 times), the organic phases were combined, washed once with 100mL of saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5.8g of a white solid in 73.4% yield. ES-API (M/z) [ M + H ] + 233.1.
(4) Preparation of 1- [ (4-methylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Under nitrogen, 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.25g, 0.6mmol), potassium carbonate (0.11g, 0.8mmol) and 2-chloromethyl-4-methylbenzofuran [3,2-d ] pyrimidine (0.16g, 0.7mmol) were added to a 50mL round-bottomed flask, 10mL of N, N-dimethylformamide was added, and the mixture was heated to 90 ℃ and stirred for 5 hours; after the reaction is finished, pouring the reaction solution into 20mL of ice water to separate out a solid, performing suction filtration, and purifying a filter cake by column chromatography to obtain 0.25g of white solid, wherein the yield of the ES-API (M/z) is 67.6 percent [ M + H ] + 613.1.
(5) Preparation of 1- [ (4-methylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 5)
Compound 5
1- [ (4-methylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.20g, 0.3mmol) was dissolved in a mixed solution of 20mL of dichloromethane and 2mL of trifluoroacetic acid and stirred at room temperature for 1 hour; after the reaction, the solvent was distilled off under reduced pressure, 20mL of ice water was added, the pH was adjusted to 8 with 2mol/L aqueous NaOH solution, dichloromethane was extracted (20mL, 2 times of extraction), the organic phases were combined, washed once with 20mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow solid, which was purified by column chromatography to give 0.12g of a white solid (Compound 5) with a yield of 70.6%. ES-API (M/z) [ M + H ] + 513.2.
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 6- [ (4-methylbenzofuran [3,2-d ]]Pyrimidin-2-yl) methyl]-3-methyl-7- (3-methyl-2- Preparation of buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 6)
(1) Preparation of 1- [ (4-methylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.43g, 1.0mmol, preparation method see steps (1) - (2) of example 2), potassium carbonate (0.21g, 1.5mmol) and 2-chloromethyl-4-methylbenzofuran [3,2-d ] pyrimidine (0.26g, 1.1mmol, preparation method see steps (1) - (3) of example 5) were added to a 50mL round-bottomed flask under nitrogen protection, 10mL of N, N-dimethylformamide was added, and the mixture was stirred at 90 ℃ for 8 hours; after the reaction is finished, pouring the reaction liquid into 20mL of ice water to separate out a solid, performing suction filtration, and purifying a filter cake by column chromatography to obtain 0.51g of a white solid with the yield of 81.0%. ES-API (M/z) [ M + H ] + 629.1.
(2) Preparation of 1- [ (4-methylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 6)
Compound 6
1- [ (4-methylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.33g, 0.5mmol) was dissolved in a mixed solution of 20mL of methylene chloride and 2mL of trifluoroacetic acid and stirred at room temperature for 1 hour; after the reaction, 20mL of ice water was added, the pH of the reaction solution was adjusted to 8 with 2mol/L NaOH aqueous solution, dichloromethane was used for extraction (20mL, 2 times of extraction), the organic phases were combined, washed once with 20mL of saturated saline, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a pale yellow solid, which was purified by column chromatography to give 0.21g of a white solid (Compound 6), with a yield of 79.2%. ES-API (M/z) [ M + H ] + 529.3.
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 7- [ (4-methylbenzothiophene [3,2-d ]]Pyrimidin-2-yl) methyl]-3-methyl-7- (2-butyne-1-) Preparation of yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 7)
(1) Preparation of 2- (benzylthio) benzonitrile
Dissolving o-nitrobenzonitrile (7.5g, 50mmol) and benzylmercaptan (6.2g, 50mmol) in 50mLN, N-dimethylformamide, cooling the solution to 0 ℃, adding dropwise 15mL of an aqueous solution of potassium hydroxide (5.0g, 90mmol), and stirring at room temperature for 2 hours; after the reaction, the reaction solution was poured into 100mL of ice water to precipitate a solid, which was filtered and dried under vacuum to obtain 9.5g of a yellow solid with a yield of 84.4%. ES-API (M/z) [ M + H ] + 226.0.
(2) Preparation of 2-mercaptobenzonitrile
Mixing AlCl3(8.6g, 65mmol) is added into 50mL of toluene, 50mL of toluene solution dissolved with 2- (benzylthio) benzonitrile (9.0g, 40mmol) is added dropwise under the protection of nitrogen, and after the dropwise addition is finished, the mixture is stirred for 48 hours at room temperature; after the reaction, 100mL of ice water was added to the reaction mixture, the organic phase was separated and washed successively with water and 5% sodium hydroxide solution (50mL) (twice), the aqueous layer was acidified to pH 3, extracted with dichloromethane (100 mL, 3 times), the organic phases were combined, washed once with 150mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 5.0g of a brown liquid with a yield of 92.6%. ES-API (M/z) [ M + H ]]+136.0。
(3) Preparation of 2-acetyl-3-aminobenzothiophene
2-mercaptobenzonitrile (4.0g, 30mmol), potassium carbonate (8.3g, 60mmol) and potassium iodide (5.8g, 35mmol) were added to 50mL of acetone, stirred at room temperature for 0.5 h, bromoacetone (4.6g, 34mmol) was added, and the mixture was refluxed at elevated temperature for 5 h; after the reaction, it was cooled to room temperature, filtered under suction, the filtrate was concentrated, the residue was added to 100mL of water, extracted with ethyl acetate (50mL, 3 times), the organic phases were combined, washed once with 100mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 5.0g of a brown solid with a yield of 87.7%. ES-API (M/z) [ M + H ] + 192.1.
(4) Preparation of 2-chloromethyl-4-methylbenzothiophene [3,2-d ] pyrimidine (intermediate II (C) -2)
Intermediate II (C) -2
Dissolving 2-acetyl-3-aminobenzothiophene (4.0g, 20mmol) in 100mL of 1, 4-dioxane, cooling the solution to 10 ℃, introducing hydrogen chloride gas, dropwise adding a 1, 4-dioxane solution of chloroacetonitrile (1.7g, 22mmol) after 2 hours, and stirring at room temperature for 6 hours; after the reaction, 100mL of ice water was added, the pH of the reaction mixture was adjusted to 8 with 2mol/L aqueous NaOH solution, extracted with ethyl acetate (100 mL, 2 times), the organic phases were combined, washed once with 100mL of saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a yellow solid, which was purified by column chromatography (gradient elution, petroleum ether/ethyl acetate =10: 1-5: 1) to give 3.8g of a yellow solid with a yield of 76.6%. ES-API (M/z) [ M + H ] + 249.2.
(5) Preparation of 1- [ (4-methylbenzothiophen [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Under nitrogen, 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.33g, 0.8mmol), potassium carbonate (0.17g, 1.2mmol) and 2-chloromethyl-4-methylbenzothiophene [3,2-d ] pyrimidine (0.22g, 0.9mmol) were added to a 50mL round-bottomed flask, 10mL of N, N-dimethylformamide was added, and the mixture was heated to 90 ℃ and stirred for 5 hours; after the reaction is finished, pouring the reaction solution into 20mL of ice water to precipitate a solid, performing suction filtration, and purifying a filter cake by using a silica gel column (gradient elution, dichloromethane/methanol =100: 1-60: 1) to obtain 0.41g of a light yellow solid, wherein the yield is 81.9%, and the ES-API (M/z): M + H ] + 629.1.
(6) Preparation of 1- [ (4-methylbenzothiophen [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 7)
Compound 7
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]Xanthine (0.32g, 0.5mmol) was dissolved in a mixed solution of 20mL of methylene chloride and 2mL of trifluoroacetic acid, and the reaction was stirred at room temperature for 1 hour, whereupon the reaction was completed. The solvent was distilled off under reduced pressure, 20mL of ice water was added, the pH of the reaction solution was adjusted to 8 with 2mol/L aqueous NaOH solution, dichloromethane extraction (20mL, 2 times of extraction) was performed, the organic phases were combined, washed once with 20mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a yellow solid, which was purified by column chromatography to give 0.21g of a yellow solid (Compound 7) with a yield of 79.5%. ES-API (M/z) [ M + H ]]+529.2
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 8- [ (6, 7-dihydro-4-methyl-5H-cyclopenta [ d ]]Pyrimidin-2-yl) methyl]-3-methyl-7- (2-butane) Preparation of alkyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 8)
(1) Preparation of 2-chloromethyl-6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidine (intermediate II (A) -2)
Intermediate II (A) -2
2-Acetylcyclopentanone (5.0g, 40mmol), potassium carbonate (6.9g, 50mmol) and chloroacetamidine hydrochloride (6.5g, 50mmol) were added to 50mL of n-butanol, and stirred at 120 ℃ for 5 hours; after the reaction, the solvent was removed under reduced pressure, the residue was poured into 100mL of water, extracted with ethyl acetate (50mL, 3 times), the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a yellow solid which was purified by column chromatography to give 1.5g of a pale yellow liquid with a yield of 20.5%. ES-API (M/z) [ M + H ]]+183.1。
(2) Preparation of 1- [ (6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Under nitrogen, 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.25g, 0.6mmol), potassium carbonate (0.11g, 0.8mmol) and 2-chloromethyl-6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidine (0.13g, 0.7mmol) were added to a 50mL round-bottomed flask, 10mL of N, N-dimethylformamide was added, and the mixture was stirred at 90 ℃ for 5 hours; after the reaction is finished, pouring the reaction solution into 20mL of ice water to precipitate a solid, performing suction filtration, and purifying a filter cake by column chromatography (gradient elution, dichloromethane/methanol =100: 1-50: 1) to obtain 0.29g of a white solid with the yield of 85.3%. ES-API (M/z) [ M + H ] + 563.1.
(3) Preparation of 1- [ (6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 8)
Compound 8
1- [ (6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.22g, 0.4mmol) was dissolved in a mixed solution of 10mL of methylene chloride and 2mL of trifluoroacetic acid and stirred at room temperature for 1 hour; after the reaction, the solvent was distilled off under reduced pressure, 20mL of ice water was added, the pH of the reaction solution was adjusted to 8 with 2mol/L aqueous NaOH, dichloromethane was extracted (20mL, 2 times of extraction), the organic phases were combined, washed once with 20mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow solid, which was purified by column chromatography to give 0.14g of a pale yellow solid (compound 8) with a yield of 75.6%. ES-API (M/z) [ M + H ] + 463.2.
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 9: 1- [ (5,6,7, 8-tetrahydro-4-trifluoromethylquinazolin-2-yl) methyl]-3-methyl-7- (2-butane) Preparation of alkyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 9)
(1) Preparation of 2-chloromethyl-5, 6,7, 8-tetrahydro-4-trifluoromethylquinazoline (intermediate II (A) -3)
Intermediate II (A) -3
2-trifluoroacetylcyclohexanone (5.0g, 26mmol), potassium carbonate (4.6g, 33mmol) and chloroacetamidine hydrochloride (4.0g, 31mmol) were added to 30mL of isopropanol and stirred at 50 ℃ for 3 hours; after the reaction, the solvent was distilled off under reduced pressure, the residue was poured into 100mL of water, extracted with ethyl acetate (100 mL, 2 times), the organic phases were combined, washed once with 100mL of saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a yellow solid, which was purified by column chromatography to give 4.6g of a pale yellow solid with a yield of 70.8%. ES-API (M/z) [ M + H ] + 251.1.
(2) Preparation of 1- [ (5,6,7, 8-tetrahydro-4-trifluoromethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Under nitrogen, 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.42g, 1.0mmol), potassium carbonate (0.17g, 1.2mmol) and 2-chloromethyl-5, 6,7, 8-tetrahydro-4-trifluoromethylquinazoline (0.27g, 1.1mmol) were added to a 50mL round-bottomed flask, 10mL of N, N-dimethylformamide was added, and the mixture was stirred at 90 ℃ for 6 hours; after the reaction is finished, pouring the reaction liquid into 20mL of ice water to separate out a solid, performing suction filtration, and purifying a filter cake by column chromatography to obtain 0.56g of a white solid with the yield of 88.9%. ES-API (M/z) [ M + H ] +631.1
(3) Preparation of 1- [ (5,6,7, 8-tetrahydro-4-trifluoromethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 9)
Compound 9
1- [ (5,6,7, 8-tetrahydro-4-trifluoromethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine (0.32g, 0.5mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 2mL of trifluoroacetic acid, and stirred at room temperature for 1 hour; after the reaction, the solvent was distilled off under reduced pressure, 20mL of ice water was added, the pH was adjusted to 8 with 2mol/L of NaOH aqueous solution, dichloromethane extraction (20mL, 2 times of extraction) was performed, the organic phases were combined, washed once with 20mL of saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow solid, which was purified by column chromatography to give 0.16g of a white solid (Compound 9) with a yield of 60.4%. ES-API (M/z) [ M + H ] + 531.3.
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 10- [ (6-chloro-4, 5-dihydrocyclopenta [ de ]]Quinazolin-2-yl) methyl]-3-methyl-7- (2-butyne-) Preparation of 1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 10)
(1) Preparation of 2-chloromethyl-6-chloro-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -2)
Intermediate II (B) -2
Prepared from 4-chloro-7-amino-2, 3-dihydro-1-indanone in 86.5% yield by a method similar to that of example 1 (6). ES-API (M/z) [ M + H ]]+239.3。
(2) Preparation of 1- [ (6-chloro-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
By a method similar to example 1 (7), starting from 2-chloromethyl-6-chloro-4, 5-dihydrocyclopenta [ de ]]Quinazoline and 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butyloxycarbonyl)Amino) piperidin-1-yl]Xanthine was prepared in 71.6% yield. ES-API (M/z) [ M + H ]]+619.3。
(3) Preparation of 1- [ (6-chloro-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 10)
Compound 10
Prepared in a similar manner to example 1 (8) from 1- [ (6-chloro-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 84.6% yield.
ES-API(m/z):[M+H]+519.2。
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 11- [ (7-methyl-4, 5-dihydrocyclopenta [ de ]]Quinazolin-2-yl) methyl]-3-methyl-7- (3-methyl) Preparation of the radical-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 11)
(1) Preparation of 2-chloromethyl-7-methyl-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -3)
Intermediate II (B) -3
By a method similar to that of example 1 (6), starting from 5-methyl-7-amino-2, 3-dihydro-1-indanone preparation with a yield of 79.6%. ES-API (M/z) [ M + H ]]+219.1。
(2) Preparation of 1- [ (7-methyl-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
By a method similar to example 2 (3), starting from 2-chloromethyl-7-methyl-4, 5-dihydrocyclopenta [ de ]]Quinazoline and 3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 77.8% yield. ES-API (M/z) [ M + H ]]+615.3。
(3) Preparation of 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 (Compound 11)
Compound 11
Prepared in a similar manner to example 2 (4) from 1- [ (7-methyl-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 79.6% yield.
ES-API(m/z):[M+H]+515.3。
1H-NMR(600MHz,CDCl3,ppm)：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),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)。
Example 12: 1- [ (7-methoxy-4, 5-dihydrocyclopenta [ de ]]Quinazolin-2-yl) methyl]-3-methyl-7- (trans- Preparation of 2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 12)
(1) Preparation of 3-methyl-7- (trans-2-buten-1-yl) -8-bromoxanthine
Prepared from 8-bromo-3-methyl-3, 7-dihydro-purine-2, 6-dione and (E) -1-bromo-2-butene in a yield of 92.6% by a method similar to that of example 1 (1). ES-API (M/z) [ M + H ]]+298.1，300.1。
(2) Preparation of 3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Prepared in a similar manner to example 1 (2) from 3-methyl-7- (trans-2-buten-1-yl) -8-bromoxanthine and 3- (R) -tert-butoxycarbonyl-aminopiperidine in 82.8% yield. ES-API (M/z) [ M + H ]]+419.1。
(3) Preparation of 2-chloromethyl-7-methoxy-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -4)
Intermediate II (B) -4
Prepared from 5-methoxy-7-amino-2, 3-dihydro-1-indanone in 79.6% yield by a method similar to that of example 1 (6). ES-API (M/z) [ M + H ]]+235.1。
(4) Preparation of 1- [ (7-methoxy-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
By a method similar to example 2 (3), starting from 2-chloromethyl-7-methyl-4, 5-dihydrocyclopenta [ de ]]Quinazoline with 3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 76.8% yield. ES-API (M/z) [ M + H ]]+617.3。
(5) Preparation of 1- [ (7-methoxy-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 12)
Compound 12
Prepared in a similar manner to example 2 (4) from 1- [ (7-methoxy-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 71.6% yield.
ES-API(m/z):[M+H]+517.3。
1H-NMR(600MHz,CDCl3,ppm)：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: 1- [ (5,6,7, 8-tetrahydro-4, 6-dimethylquinazolin-2-yl) methyl group]-3-methyl-7- (trans-2-) Buten-1-yl) -8- (3- (R) -aminoPreparation of PIPERIDIN-1-YL) xanthine (Compound 13)
(1) Preparation of 2-chloromethyl-5, 6,7, 8-tetrahydro-4, 6-dimethylquinazoline (intermediate II (A) -4)
Intermediate II (A) -4
Prepared from 2-acetyl-4-methylcyclohexanone and chloroacetamidine hydrochloride in a yield of 61.6% in a similar manner to example 3 (1). ES-API (M/z) [ M + H ]]+211.1。
(2) Preparation of 1- [ (5,6,7, 8-tetrahydro-4, 6-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Using a method similar to that in example 3 (2), starting from 2-chloromethyl-5, 6,7, 8-tetrahydro-4, 6-dimethylquinazoline and 3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 71.1% yield. ES-API (M/z) [ M + H ]]+593.3。
(3) Preparation of 1- [ (5,6,7, 8-tetrahydro-4, 6-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 13)
Compound 13
Prepared in a similar manner to example 3 (3) from 1- [ (5,6,7, 8-tetrahydro-4, 6-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 80.2% yield.
ES-API(m/z):[M+H]+493.3。
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 14: 1- [ (5,6,7, 8-tetrahydro-4, 7-dimethylquinazolin-2-yl) methyl group]-3-methyl-7- (2-butane) Preparation of alkyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 14)
(1) Preparation of 2-chloromethyl-5, 6,7, 8-tetrahydro-4, 7-dimethylquinazoline (intermediate II (A) -5)
Intermediate II (A) -5
Prepared from 2-acetyl-5-methylcyclohexanone and chloroacetamidine hydrochloride in a yield of 70.7% by a similar method to that of example 3 (1). ES-API (M/z) [ M + H ]]+211.1。
(2) Preparation of 1- [ (5,6,7, 8-tetrahydro-4, 7-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Using a method similar to that in example 3 (2), starting from 2-chloromethyl-5, 6,7, 8-tetrahydro-4, 7-dimethylquinazoline and 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 72.6% yield. ES-API (m)/z):[M+H]+591.3。
(3) Preparation of 1- [ (5,6,7, 8-tetrahydro-4, 7-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 14)
Compound 14
Prepared in a similar manner to example 3 (3) from 1- [ (5,6,7, 8-tetrahydro-4, 7-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 77.2% yield.
ES-API(m/z):[M+H]+491.3。
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 15: 1- [ (5,6,7, 8-tetrahydro-4-methyl-6-cyanoquinazolin-2-yl) methyl group]-3-methyl-7- Preparation of (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 15)
(1) Preparation of 2-chloromethyl-5, 6,7, 8-tetrahydro-4-methyl-6-cyanoquinazoline (intermediate II (A) -6)
Intermediate II (A) -6
Prepared from 2-acetyl-4-cyanocyclohexanone and chloroacetamidine hydrochloride in a yield of 60.1% using a method similar to that of example 3 (1). ES-API (M/z) < M +H]+222.1。
(2) Preparation of 1- [ (5,6,7, 8-tetrahydro-4-methyl-6-cyanoquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
Using a method similar to example 3 (2), starting from 2-chloromethyl-5, 6,7, 8-tetrahydro-4-methyl-6-cyanoquinazoline and 3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 75.8% yield. ES-API (M/z) [ M + H ]]+604.3。
(3) Preparation of 1- [ (5,6,7, 8-tetrahydro-4-methyl-6-cyanoquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 15)
Compound 15
Prepared in a similar manner to example 3 (3) from 1- [ (5,6,7, 8-tetrahydro-4-methyl-6-cyanoquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in a yield of 76.0%.
ES-API(m/z):[M+H]+504.3。
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 16: 1- [ (6, 7-dihydro-4, 6-dimethyl-5H-cyclopentyl)[d]Pyrimidin-2-yl) methyl]-3-methyl-7- Preparation of (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 16)
(1) Preparation of 2-chloromethyl-6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ] pyrimidine (intermediate II (A) -7)
Intermediate II (A) -7
Prepared from 2-acetyl-4-methylcyclopentanone and chloroacetamidine hydrochloride in a yield of 26.4% using a similar method to example 8 (1). ES-API (M/z) [ M + H ]]+197.1。
(2) Preparation of 1- [ (6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
By a method similar to that in example 8 (2), from 2-chloromethyl-6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ]]Pyrimidine and 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 78.1% yield. ES-API (M/z) [ M + H ]]+577.3。
(3) Preparation of 1- [ (6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 16)
Compound 16
Prepared in a similar manner to example 8 (3) from 1- [ (6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 74.3% yield.
ES-API(m/z):[M+H]+477.3。
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 17: 1- [ (4, 8-Dimethylbenzofuran [3,2-d ]]Pyrimidin-2-yl) methyl]-3-methyl-7- (3-methyl) Preparation of the radical-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 17)
(1) Preparation of 2-chloromethyl-4, 8-dimethylbenzofuran [3,2-d ] pyrimidine (intermediate II (C) -3)
Intermediate II (C) -3
Prepared from 2-acetyl-3-amino-5-methylbenzofuran and chloroacetonitrile in a yield of 81.5% by a similar method to that of example 5 (3). ES-API (M/z) [ M + H ]]+247.1。
(2) Preparation of 1- [ (4, 8-dimethylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
By a method similar to that in example 6 (1), from 2-chloromethyl-4, 8-dimethylbenzofuran [3,2-d ]]Pyrimidines and 3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl group]Xanthine was prepared in 73.2% yield. ES-API (M/z) [ M + H ]]+643.3。
(3) Preparation of 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 (Compound 17)
Compound 17
Prepared in a similar manner to example 6 (2) from 1- [ (4, 8-dimethylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in a yield of 72.9%.
ES-API(m/z):[M+H]+543.3
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 18: 1- [ (4-methyl-8-chlorobenzofuran [3,2-d ]]Pyrimidin-2-yl) methyl]-3-methyl-7- (3-methyl) Preparation of the radical-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (compound 18)
(1) Preparation of 2-chloromethyl-4-methyl-8-chlorobenzofuran [3,2-d ] pyrimidine (intermediate II (C) -4)
Intermediate II (C) -4
Prepared from 2-acetyl-3-amino-5-chlorobenzofuran and chloroacetonitrile in a similar manner to example 5 (3) at a yield of 76.5%. ES-API (M/z) [ M + H ]]+267.1。
(2) Preparation of 1- [ (4-methyl-8-chlorobenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
By a method similar to example 6 (1), from 2-chloromethyl-4-methyl-8-chlorobenzofuran [3,2-d]Pyrimidine and 3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 78.8% yield. ES-API (M/z) [ M + H ]]+663.2。
(3) Preparation of 1- [ (4-methyl-8-chlorobenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 18)
Compound 18
Prepared in a similar manner to example 6 (2) from 1- [ (4-methyl-8-chlorobenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 71.8% yield.
ES-API(m/z):[M+H]+563.2
1H-NMR(600MHz,CDCl3,ppm)：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)。
Example 19: 1- [ (4, 8-dimethylbenzothiophene [3,2-d ]]Pyrimidin-2-yl) methyl]-3-methyl-7- (2-butane) Preparation of alkyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 19)
(1) Preparation of 2-chloromethyl-4, 8-dimethylbenzothiophene [3,2-d ] pyrimidine (intermediate II (C) -3)
Intermediate II (C) -5
Prepared from 2-acetyl-3-amino-5-methylbenzothiophene and chloroacetonitrile in a yield of 77.6% by a similar method to that of example 7 (4). ES-API (M/z) [ M + H ]]+263.0。
(2) Preparation of 1- [ (4, 8-dimethylbenzothiophene [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
By a method similar to example 7 (5), from 2-chloromethyl-4, 8-dimethylbenzothiophene [3,2-d ]]Pyrimidine and 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 86.1% yield. ES-API (M/z) [ M + H ]]+643.3。
(3) Preparation of 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 (Compound 19)
Compound 19
Prepared in a similar manner to example 7 (6) from 1- [ (4, 8-dimethylbenzothiophene [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 70.8% yield.
ES-API(m/z):[M+H]+543.2
1H-NMR(600MHz,CDCl3,ppm)：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- [ (4-methyl-7-methoxybenzothiophene [3,2-d ]]Pyrimidin-2-yl) methyl]-3-methyl-7- Preparation of (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 20)
(1) Preparation of 2-chloromethyl-4-methyl-7-methoxybenzothiophene [3,2-d ] pyrimidine (intermediate II (C) -6)
Intermediate II (C) -6
Prepared from 2-acetyl-3-amino-6-methoxybenzothiophene and chloroacetonitrile in a yield of 75.8% by a similar method to that of example 7 (4). ES-API (M/z) [ M + H ]]+279.0。
(2) Preparation of 1- [ (4-methyl-7-methoxybenzothiophen [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine
By a method similar to example 7 (5), starting from 2-chloromethyl-4-methyl-7-methoxybenzothiophene [3,2-d]Pyrimidine and 3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl]Xanthine was prepared in 82.7% yield. ES-API (M/z) [ M + H ]]+659.2。
(3) Preparation of 1- [ (4-methyl-7-methoxybenzothiophen [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine (Compound 20)
Compound 20
Prepared in a similar manner to example 7 (6) from 1- [ (4-methyl-7-methoxybenzothiophene [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl ] xanthine in 76.0% yield.
E S-API(m/z):[M+H]+559.2
1H-NMR(600MHz,CDCl3,ppm)：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
Experimental example: determination of DPP-IV/DPP-8/DPP-9 inhibitory Activity
DPP-IV/DPP-8/DPP-9 (from BPS-Bioscience, Cat.80040, 80080, 80090) is a pure enzyme expressed using a baculovirus expression system and purified, the reaction system is performed in a buffer solution (from BPS-Bioscience, Cat.80300) at pH =7.5, and the enzyme reaction substrate is alanine-proline-7-amino-4-methylcoumarin (Ala-Pro-AMC) (from BPS-Bioscience, Cat.80305).
DPP-IV/DPP-8/DPP-9 degrades a substrate Ala-Pro-AMC to produce a product AMC (7-amino-4-methylcoumarin), which is excited by 355nm ultraviolet light to produce 460nm emitted light. The activity of DPP-IV/DPP-8/DPP-9 was determined by dynamic measurement of the rate of increase of fluorescence value of AMC at 460nm using Scanlab varioSCAN.
The determination method comprises the following steps: test compounds (compounds 1 to 20 prepared in examples 1 to 20, tested at a concentration range of 0.64 to 200nmol/L every three times of a concentration gradient), an enzyme (DPP-IV/DPP-8/DPP-9, initial concentration 0.1 ng/. mu.L) and a reaction buffer solution were mixed well, pre-incubated at 37 ℃ for 15min, an enzyme reaction substrate (initial concentration 5. mu. mol/L) was added to initiate a reaction, and a 460nm fluorescence value was continuously measured for 5 min. A blank control group without substrate, a solvent control group with DMSO (Dimethyl sulfoxide) instead of the test compound, and a positive control group of BI-1356[ see Journal of Medicinal Chemistry,2007, 26, 6450-. All final volumes were 100. mu.L. Each sample concentration was 3 replicates.
The increase in fluorescence intensity (unit: RFU/sec) in the initial period of the enzyme reaction (substrate consumption of 20% or less, substrate consumption being linear with time) was first calculated to represent the initial velocity of the enzyme (amount of product produced per unit time in the initial period of the enzyme reaction), and then the percentage of activity of each concentration group of the sample was calculated, as follows:
wherein VSample (I)Indicates the initial velocity, V, of each concentration group of the sampleDMSOThe initial velocity of the DMSO group is shown.
Using concentration value as abscissa and activity value as ordinate, then adopting GRAPHPADPRISM 5 software to make dose-effect curve fitting, calculating to obtain IC50The value is obtained. Determination of the biological Activity of a part of the Compounds of the formula IThe test results are shown in Table 1.
TABLE 1 inhibitory Activity of some of the Compounds of formula I on DPP-IV/DPP-8/DPP-9
Note: "/" indicates that the compound was not tested for efficacy
Among them, BI-1356 was proposed as a positive control for the test. The data in the table 1 show that the compound of the invention has better inhibitory activity to DPP-IV, and the selectivity to DPP-8 and DPP-9 is equivalent to that of BI-1356; particularly, DPP-IV inhibitory activity of the compound 1, the compound 2, the compound 3, the compound 5, the compound 7 and the compound 10 is obviously stronger than that of BI-1356 and is 2-10 times stronger than that of BI-1356, so that the compound has better biological activity.
In conclusion, the compound shown in the formula I can well inhibit DPP-IV, and can be used for treating, preventing and relieving diseases related to DPP-IV, such as diabetes, hyperglycemia, obesity or insulin resistance, ischemic myocarditis or angiogenic diseases.

Claims (20)

1. A xanthine derivative of formula I or a pharmaceutically acceptable salt thereof:
wherein,
R1selected from:
R2selected from 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyn-1-yl;
R3、R5、R6each independently selected from hydrogen, halogen atom, straight chain or branched chain C substituted or not substituted by 1-5 halogen atoms1-6Alkyl, straight or branched C substituted or unsubstituted with 1 to 5 halogen atoms1-6Alkoxy, cyano or hydroxy;
R4selected from methyl or trifluoromethyl;
x is independently selected from O or S;
m is selected from 1 or 2.
2. The xanthine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein,
R3、R5、R6each independently selected from hydrogen, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano or hydroxy.
3. The xanthine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein,
R3、R5、R6each independently selected from hydrogen, chlorine atom, methyl, methoxy and cyano.
4. The xanthine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein,
R3selected from hydrogen, methyl, cyano;
R5selected from hydrogen, chlorine atom, methyl and methoxy;
R6selected from hydrogen, chlorine atom, methyl and methoxy.
5. A xanthine derivative of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the xanthine derivative of formula I is selected from formula I (a), formula I (b), or formula I (c):
wherein: r2、R3、R4、R5、R6M, X are as defined in claim 1.
6. The xanthine derivative of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, which is selected from the following compounds:
1- [ (4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (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- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (4-methylbenzofuran [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (4-methylbenzofuran [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-methylbenzothiophen [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4-trifluoromethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (6-chloro-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
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-methoxy-4, 5-dihydrocyclopenta [ de ] quinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4, 6-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4, 7-dimethylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (5,6,7, 8-tetrahydro-4-methyl-6-cyanoquinazolin-2-yl) methyl ] -3-methyl-7- (trans-2-buten-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
1- [ (6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine;
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-methyl-8-chlorobenzofuran [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, 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-methyl-7-methoxybenzothiophene [3,2-d ] pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) xanthine.
7. A process for the preparation of a xanthine derivative of formula I or a pharmaceutically acceptable salt thereof, which process comprises the steps of:
(1) r shown in formula II1Substituted methyl halide and 3-methyl-7-substituted-8- [ (R) -3- (tert-butoxycarbonylamino) piperidin-1-yl group represented by the formula IV]Xanthine reaction to produce intermediate i (a);
(2) removing tert-butyloxycarbonyl from the intermediate I (a) in the presence of a suitable acid to obtain a compound represented by formula I;
wherein R is1、R2、R3、R4、R5、R6X, m is as defined in claim 1; y is halogen;
the suitable acid is selected from trifluoroacetic acid, formic acid, hydrochloric acid, acetic acid.
8. The method of claim 7 wherein the suitable acid is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
9. The method of claim 7 wherein the suitable acid is trifluoroacetic acid.
10. A compound of the formula II,
wherein: r1Selected from:R3、R5、R6each independently selected from hydrogen, halogen atom, straight chain or branched chain C substituted or not substituted by 1-5 halogen atoms1-6Alkyl, straight or branched C substituted or unsubstituted with 1 to 5 halogen atoms1-6Alkoxy, cyano or hydroxy;
R4selected from methyl or trifluoromethyl;
x is independently selected from O or S;
y is halogen;
m is selected from 1 or 2;
and when R is6When hydrogen, X is not O.
11. The compound of formula II according to claim 10, which is selected from II (a), formula II (b) or formula II (c):
wherein R is3、R4、R5、R6X, m is as defined in claim 1; and when R is6When hydrogen, X is not O.
12. The compound of formula II according to claim 10, selected from the following compounds:
2-chloromethyl-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) — 1);
2-chloromethyl-5, 6,7, 8-tetrahydro-4-methylquinazoline (intermediate ii (a) -1);
2-chloromethyl-4-methylbenzothiophene [3,2-d ] pyrimidine (intermediate II (C) -2);
2-chloromethyl-6, 7-dihydro-4-methyl-5H-cyclopenta [ d ] pyrimidine (intermediate ii (a) -2);
2-chloromethyl-5, 6,7, 8-tetrahydro-4-trifluoromethylquinazoline (intermediate ii (a) -3);
2-chloromethyl-6-chloro-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -2);
2-chloromethyl-7-methyl-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -3);
2-chloromethyl-7-methoxy-4, 5-dihydrocyclopenta [ de ] quinazoline (intermediate II (B) -4);
2-chloromethyl-5, 6,7, 8-tetrahydro-4, 6-dimethylquinazoline (intermediate ii (a) -4);
2-chloromethyl-5, 6,7, 8-tetrahydro-4, 7-dimethylquinazoline (intermediate ii (a) -5);
2-chloromethyl-5, 6,7, 8-tetrahydro-4-methyl-6-cyanoquinazoline (intermediate ii (a) -6);
2-chloromethyl-6, 7-dihydro-4, 6-dimethyl-5H-cyclopenta [ d ] pyrimidine (intermediate ii (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-methoxybenzothiophene [3,2-d ] pyrimidine (intermediate II (C) -6).
13. A process for preparing a compound of formula II, comprising the steps of:
when R is1Is composed ofWhen the temperature of the water is higher than the set temperature,
r shown in formula III (A)3Reacting substituted cycloalkanone with halogenated acetamidine hydrochloride in the presence of alkaline substances to obtain a compound shown in II (A);
the alkaline substance is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium methoxide and sodium ethoxide;
when R is1Is composed ofWhen the temperature of the water is higher than the set temperature,
(1) r shown in formula III (B)5Hydrolyzing the substituted 7-acetamido-indanone to obtain 7-amino-1-indanone;
(2) cyclizing 7-amino-1-indanone and halogenated acetonitrile to obtain a compound shown in II (B);
when R is1Is composed ofWhen the temperature of the water is higher than the set temperature,
r shown in formula III (C)6Cyclizing the substituted benzofuran or benzothiophene compound and halogenated acetonitrile to obtain a compound shown as a formula II (C); wherein R is3、R4、R5、R6Is as defined in claim 1;
x is independently selected from O or S;
and when R is6When hydrogen, X is not O;
y is halogen.
14. The process of claim 13, wherein the alkaline substance is potassium carbonate, sodium hydroxide.
15. The process of claim 13, wherein the basic material is potassium carbonate.
16. A pharmaceutical composition comprising a xanthine derivative of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, and a pharmaceutically acceptable excipient or carrier.
17. Use of a xanthine derivative of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, or a composition according to claim 16, for the preparation of a medicament for the treatment, prevention and alleviation of DPP-iv related diseases.
18. The use according to claim 17, wherein the DPP-iv-related disease is selected from diabetes, hyperglycemia, obesity, insulin resistance, ischemic myocarditis, or angiogenic diseases.
19. The use according to claim 17, wherein the DPP-iv-related disease is selected from diabetes and hyperglycemia.
20. Use of a compound of formula II as defined in any one of claims 10 to 12 for the preparation of a xanthine derivative as defined in claim 1.
CN201210375253.8A 2012-09-29 2012-09-29 Xanthine derivative, Preparation Method And The Use Active CN103709163B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201210375253.8A CN103709163B (en) 2012-09-29 2012-09-29 Xanthine derivative, Preparation Method And The Use
PCT/CN2013/083096 WO2014048243A1 (en) 2012-09-29 2013-09-09 Xanthine derivative, preparation method and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201210375253.8A CN103709163B (en) 2012-09-29 2012-09-29 Xanthine derivative, Preparation Method And The Use

Publications (2)

Publication Number Publication Date
CN103709163A CN103709163A (en) 2014-04-09
CN103709163B true CN103709163B (en) 2016-12-21

Family

ID=50386973

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210375253.8A Active CN103709163B (en) 2012-09-29 2012-09-29 Xanthine derivative, Preparation Method And The Use

Country Status (2)

Country Link
CN (1) CN103709163B (en)
WO (1) WO2014048243A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6840931B2 (en) * 2015-03-09 2021-03-10 東ソー株式会社 Method for Producing Fused Ring Aromatic Compound
CN104844602B (en) * 2015-04-14 2018-07-20 威海迪素制药有限公司 A kind of preparation method of Li Gelieting
CN107216340B (en) * 2016-03-22 2021-05-04 中国科学院上海药物研究所 Salt form of DPPIV inhibitor and preparation method thereof
CN107216339B (en) * 2016-03-22 2021-05-04 中国科学院上海药物研究所 Polymorphism of DPPIV inhibitor maleate and preparation method thereof
CN110894198B (en) * 2018-09-13 2022-12-02 齐鲁制药有限公司 Xanthine compound and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1675212A (en) * 2002-08-21 2005-09-28 贝林格尔英格海姆法玛两合公司 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
CN1980930A (en) * 2004-02-18 2007-06-13 贝林格尔·英格海姆国际有限公司 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and the use in the form of a DPP-IV inhibitor

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1514552A4 (en) * 2002-06-06 2008-04-02 Eisai R&D Man Co Ltd Novel fused imidazole derivative
IT1403282B1 (en) * 2010-12-23 2013-10-17 Dipharma Francis Srl PROCEDURE FOR THE PREPARATION OF LINAGLIPTIN

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1675212A (en) * 2002-08-21 2005-09-28 贝林格尔英格海姆法玛两合公司 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
CN1980930A (en) * 2004-02-18 2007-06-13 贝林格尔·英格海姆国际有限公司 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and the use in the form of a DPP-IV inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RN：949877-52-5;ACS;《STN REGISTRY》;20071010;第1-3页 *

Also Published As

Publication number Publication date
CN103709163A (en) 2014-04-09
WO2014048243A1 (en) 2014-04-03

Similar Documents

Publication Publication Date Title
EP3188730B1 (en) Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
CN103709163B (en) Xanthine derivative, Preparation Method And The Use
CN101362765A (en) 5,7-diaminopyrazolo &#39;4,3-d!pyrimidines with PDE-5 inhibiting activity
EP2593456B1 (en) Aldose reductase inhibitors and uses thereof
EA030115B1 (en) Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
RU2672582C2 (en) Bicyclic inhibitors
EP2786998B1 (en) Thienyl [3, 2-d]pyrimidin-4-one compounds, preparation method, pharmaceutical compositions and use thereof
CN102827170A (en) Active treatment compositions and use method thereof
JP2006045156A (en) Condensed pyrazole derivative
CN104039784A (en) Substituted annellated pyrimidine and the use thereof
US20170022218A1 (en) Condensed 5-oxazolidinone derivative
CN103459382B (en) For suppressing the heterocyclic compound of PASK
CN111434662B (en) Haloallylamine compound and application thereof
JPWO2005021550A1 (en) Bicyclic pyrazole derivatives
EP3541376A1 (en) Indole derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
JPWO2005051949A1 (en) New condensed imidazole derivatives
EP2513108B1 (en) Novel (heterocycle/condensed piperidine)-(piperazinyl)-1-alcanone or (heterocycle/condensed pyrrolidine)-(piperazinyl)-1-alcanone derivatives, and use thereof as p75 inhibitors
JP2022543515A (en) plasma kallikrein inhibitor
US8785477B2 (en) Hexahydropyrrolo[3,4-b]pyrrole derivatives, preparation methods and pharmaceutical uses thereof
US20240158390A1 (en) Other heteroaromatic compounds having activity against rsv
CN103420981A (en) Substituted-pyrrolidinyl-contained thiomorpholine compounds
WO2023155004A1 (en) Pyrazolopyrimidines, compositions comprising them and uses thereof
WO2018102256A1 (en) Pyrrolidinone compounds
CN110256420B (en) Tetrahydropyridopyrimidine derivatives, their preparation and use
CN114671878B (en) Substituted nitrogen-containing bicyclic compounds and uses thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20201021

Address after: 570314 -A, Nanhai Avenue, national hi tech Development Zone, Hainan, Haikou, 273

Patentee after: QILU PHARMACEUTICAL (HAINAN) Co.,Ltd.

Address before: 250100 No. 243 industrial North Road, Licheng District, Shandong, Ji'nan

Patentee before: Qilu Pharmaceutical Co.,Ltd.

TR01 Transfer of patent right