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WO2017031918A1 - Inhibiteur de dipeptidyl-peptidase-iv à action prolongée, ses applications, et un procédé de préparation d'un intermédiaire de celui-ci - Google Patents

Inhibiteur de dipeptidyl-peptidase-iv à action prolongée, ses applications, et un procédé de préparation d'un intermédiaire de celui-ci Download PDF

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Publication number
WO2017031918A1
WO2017031918A1 PCT/CN2016/000478 CN2016000478W WO2017031918A1 WO 2017031918 A1 WO2017031918 A1 WO 2017031918A1 CN 2016000478 W CN2016000478 W CN 2016000478W WO 2017031918 A1 WO2017031918 A1 WO 2017031918A1
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Prior art keywords
group
compound
alkyl
tert
pyran
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PCT/CN2016/000478
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English (en)
Chinese (zh)
Inventor
谢益农
游泽金
何云
宋占波
王亚军
张绍华
李路
王浩东
张继超
朱军
曾宏
宋宏梅
齐伟
王利春
王晶翼
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四川科伦药物研究院有限公司
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Priority to CN201680008006.0A priority Critical patent/CN107250135B/zh
Publication of WO2017031918A1 publication Critical patent/WO2017031918A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to compounds as dipeptidyl peptidase-IV (DPP-4) inhibitors and their use in the treatment and prevention of DPP-4 related diseases including diabetes, especially type II diabetes.
  • the invention further relates to a process for the preparation of the above compounds and intermediates thereof.
  • the present invention relates to pharmaceutical compositions comprising these compounds, and the use of these compositions in the prevention or treatment of diseases associated with DPP-4.
  • Diabetes is a chronic metabolic disease caused by various factors such as genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, and mental factors. Clinically, hyperglycemia is the main symptom. It can be divided into type I diabetes (insulin dependent), type II diabetes (non-insulin dependent), gestational diabetes and other special types of diabetes. In diabetic patients, the proportion of type 2 diabetes is about 90%.
  • Non-Patent Document 1 Non-Patent Document 1
  • Dipeptidyl peptidase-IV is a serine protease.
  • DPP-4 can block the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave the N-terminal group-propadipeptide enzyme of GLP-1 from the active form of GLP- 1 (7-36) NH 2 degrades into inactive GLP-1 (9-36) NH 2 (Non-Patent Document 2).
  • GLP-1 Glucagon-like peptide-1
  • GLP-1 is a hormone secreted by islet ⁇ -cells and intestinal L-cells, which has glucose-dependent insulin secretion and increases insulin biosynthesis. Therefore, GLP- is used.
  • GLP-1 The treatment of diabetes has caused great interest among scientists. In addition to promoting insulin secretion, GLP-1 also promotes ⁇ -cell proliferation, anti- ⁇ -cell apoptosis, inhibits glucagon and glycogen production, suppresses appetite, reduces gastrointestinal emptying rate, and protects nerve cells. And other physiological functions. These characteristics of GLP-1 make it an ideal treatment for diabetes. However, GLP-1 has a half-life in vivo of only a few minutes, and is rapidly degraded by endogenous dipeptidyl peptidase-IV (DPP-4) (removing the N-terminal dipeptide), thereby losing insulin secretion-promoting activity (Non-Patent Document 3) ).
  • DPP-4 endogenous dipeptidyl peptidase-IV
  • DPP-4 is widely distributed in human body and is the main metabolic enzyme of GLP-1, which plays an important role in regulating GLP-1 activity.
  • a DPP-4 inhibitor enhances the action of GLP-1.
  • DPP-4 inhibitors also promote ⁇ -cell proliferation, anti- ⁇ -cell apoptosis, inhibit glucagon and glycogen production, suppress appetite, increase body weight, reduce gastrointestinal emptying rate, Protect nerve cells and other effects. Therefore, DPP-4 inhibitors can also be used for the treatment of various diseases associated with dipeptidyl peptidases such as obesity and hyperlipidemia (Non-Patent Document 4).
  • DPP-4 inhibitors Since the crystal structure of DPP-4 was reported in 2003, a number of new structural types of DPP-4 inhibitors have been listed in recent years, such as sitagliptin phosphate developed by Merck (sitagliptin phosphate, in the United States in October 2006). Listing).
  • Non-Patent Document 1 Medicinal Research Review, 2009, 29(1), 125-195
  • Non-Patent Document 3 Expert Opin. Investing. Drugs, 2004, 13(9): 1091-1102
  • An object of the present invention is to provide a compound as a dipeptidyl peptidase-IV (DPP-4) inhibitor, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or Prodrugs, which are useful in the treatment and prevention of DPP-4 related diseases including the treatment of diabetes, especially type 2 diabetes.
  • the present invention provides a novel compound having a novel substituted 3-aminotetrahydropyran structure, a high inhibitory activity against dipeptidyl peptidase-IV, and excellent drug metabolism properties.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier or excipient for treating various diseases associated with dipeptidyl peptidase-IV. .
  • the therapeutic agent in particular the dipeptidyl peptidase-IV inhibitor, has an excellent activity for treating diabetes, has markedly improved solubility, and has good activity and bioavailability in animals, and low toxicity, and is suitable for use in A preparation for treating diabetes is prepared.
  • the present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found that a specific compound having a 3-aminotetrahydropyran structure, that is, a compound represented by the following formula (I) has a higher
  • a specific compound having a 3-aminotetrahydropyran structure that is, a compound represented by the following formula (I) has a higher
  • the advantage of a glucose-dependent mechanism, thus reducing the risk of hypoglycemia, in addition to the existing DPP-4 inhibitors, the compounds of the invention have more favorable pharmacokinetic properties, longer durations
  • the present invention has been completed.
  • Ring A is an unsaturated ring, in the B ring Represents a single or double bond;
  • a 3 , A 4 , A 5 and A 6 are each independently selected from a carbon atom or a nitrogen atom, and at least 2 of A 3 , A 4 , A 5 and A 6 are carbon atoms;
  • R 3 is selected from a hydroxyl group, an alkyl group optionally substituted with a group selected from the substituent group a, a cycloalkyl group optionally substituted with a group selected from the substituent group a, optionally selected from a substituent a group-substituted amino group of group a, an amino C2-6 alkanoyl group optionally substituted with a group selected from substituent group a, an aminocarbonylamino group optionally substituted with a group selected from substituent group a, optionally a C6-10 aryl group substituted with a group selected from the substituent group a, a 5-11 membered heterocyclic group optionally substituted with a group selected from the substituent group a;
  • R 5 is a single bond or a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group;
  • R 6 is C1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
  • R 7 and R 8 are each independently hydrogen, hydroxy, C 1-6 alkyl optionally substituted with a group selected from substituent group a, C 3-8 optionally substituted with a group selected from substituent group a a cycloalkyl group, optionally substituted with a group selected from the group of substituent group a (provided that R 7 and R 8 are not hydrogen at the same time);
  • R 9 is a single bond, a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group.
  • R 1 and R 2 are not simultaneously a hydrogen atom; and when the B ring is a saturated ring and one of R 1 and R 2 is a hydrogen atom, the other of R 1 and R 2
  • One of the groups is not a C1-6 alkyl group optionally substituted with a substituent selected from a halogen atom and a C1-6 alkoxy group, a cyano group, an optionally substituted C1-6 alkoxy group, or an optionally substituted C3. -8 cycloalkyl, optionally substituted 5-11 membered heterocyclic group;
  • Ar is a C6-10 aryl group optionally substituted by 1 to 5 groups selected from the substituent group a;
  • a 3 is N, A 4 is C, A 5 is N, A 6 is C, or
  • a 3 is N, A 4 is C, A 5 is C, A 6 is C, or
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N, A 4 is C, A 5 is C, A 6 is N, or
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring.
  • a 3 is N, A 4 is C, A 5 is N, A 6 is C, or
  • a 3 is N, A 4 is C, A 5 is C, A 6 is C, or
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N, A 4 is C, A 5 is C, A 6 is N, or
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • a compound of the present invention which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof.
  • the ring A is an unsaturated ring
  • the ring B is a ring.
  • unsaturated ring As an unsaturated ring,
  • a 3 is N, A 4 is C, A 5 is N, A 6 is C, or
  • a 3 is N, A 4 is C, A 5 is C, A 6 is C, or
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N, A 4 is C, A 5 is C, A 6 is N, or
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the compound of the present invention which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or a prodrug thereof, wherein R 1 and R 2 are each independently a hydrogen atom or an amino group.
  • R 1 and R 2 are each independently a hydrogen atom or an amino group.
  • a compound of the present invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein Both represent a single button.
  • a compound according to the invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein Ar is optionally 1 to 5 selected from the group of substituents A group substituted with a phenyl group of a.
  • the compound of the present invention which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein the compound is selected from the following formula (a), ( Any one of b), (c), (d), (e) and (f),
  • Ar is a phenyl group optionally substituted by 1 to 5 halogen atoms
  • the compound of the present invention which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein the compound is a compound selected from the group consisting of
  • a compound of the present invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, for use as a dipeptidyl peptidase-IV inhibitor.
  • composition comprising a compound of the invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, and a pharmaceutically acceptable carrier or form Agent.
  • composition of the present invention further comprising other compounds which can be used in combination with the compound, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof Active substance.
  • composition according to the present invention wherein the other active substance is metformin or a salt thereof, or pioglitazone or the like.
  • the composition according to the invention contains 0.01 to 1000 mg of the compound according to the invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10-100 mg, most preferably 15-50 mg, for example 20 mg, 25 mg, 30 mg.
  • the pharmaceutical preparation of the present invention or the like may be in a unit dosage form, and the unit dose contains 0.01 to 1000 mg of the compound of the present invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10 to 100 mg, most It is preferably 15-50 mg, for example, 20 mg, 25 mg, 30 mg.
  • a pharmaceutical preparation suitable for administration to an animal, especially a mammal wherein the preparation comprises a compound of the invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or
  • the prodrug thereof is used as an active ingredient, and the preparation includes a solid preparation, a semisolid preparation, a liquid preparation, and a gaseous preparation.
  • a therapeutic or prophylactic agent for a disease associated with dipeptidyl peptidase-IV which comprises the compound, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof As an active ingredient.
  • the compound of the present invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, or a combination thereof with other active substances, is used for the preparation of a treatment Use in drugs for diseases associated with dipeptidyl peptidase-IV.
  • the compound of the present invention has high inhibitory activity and selectivity to dipeptidyl peptidase-IV, has excellent drug metabolism properties, and has less toxic and side effects, and can be used as a long-acting dipeptidyl peptidase-IV inhibitor.
  • Dipeptidyl peptidase-IV related diseases include diabetes, obesity, insulin resistance or hyperlipidemia.
  • the compound of the present invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, or a combination thereof with other active substances, is used for treatment and A method of peptidyl peptidase-IV related diseases.
  • the amount of the compound according to the invention is from 0.01 to 1000 mg, suitably from 0.5 to 800 mg, preferably from 1 to 400 mg, more preferably from 5 to 200 mg, particularly preferably from 10 to 100 mg, most preferably from 15 to 50 mg, for example It is 20 mg, 25 mg, 30 mg.
  • the pharmaceutical preparation of the present invention or the like may be in a unit dosage form, and the unit dose contains 0.01 to 1000 mg of the compound of the present invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10 to 100 mg, most It is preferably 15-50 mg, for example, 20 mg, 25 mg, 30 mg.
  • the "optionally substituted with a group selected from the substituent group a” means that it may be substituted at any position with one or two or more identical or different substituents selected from the substituent group a.
  • C1-6 alkyl group-substituted means substituted at one position with one or two or more identical or different substituents selected from a C1-6 alkyl group.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the "C1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group and a n-butyl group. a group such as a benzyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-amyl group or the like.
  • the "C2-6 alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a vinyl group, a n-propenyl group, an isopropenyl group, and a n-butenyl group.
  • a group such as isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, tert-pentenyl or the like.
  • the "C2-6 alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, and examples thereof include an ethynyl group, a n-propynyl group, an isopropynyl group, and a n-butyne group. a group such as a benzyl group, an isobutynyl group, a sec-butynyl group, a tert-butynyl group, a n-pentynyl group, an isopentenyl group, a neopentynyl group, a tert-pentynyl group, and the like.
  • the "C3-8 cycloalkyl group” may, for example, be a group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group.
  • the "C1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, and a different form. a group such as propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-amyloxy, and the like group.
  • C1-6 alkylene C2-6 alkenylene
  • C2-6 alkynylene refer to the above “C1-6 alkyl” and “C2-6 alkenyl”, respectively.
  • C2-6 alkynyl group a divalent group of one hydrogen atom is removed.
  • C2-6 alkanoyl group means a linear or branched alkanoyl group having 2 to 6 carbon atoms, and examples thereof include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, and a valeryl group.
  • a group such as isovaleryl or pivaloyl.
  • the "mono C1-6 alkylaminocarbonyl group” means a carbonyl group substituted with an amino group having one of the above-mentioned "C1-6 alkyl group” as a substituent, and examples thereof include a methylaminocarbonyl group and an ethylaminocarbonyl group.
  • N-propylaminocarbonyl isopropylaminocarbonyl, n-butylaminocarbonyl, isobutyl Alkylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, neopentylaminocarbonyl, and the like.
  • the "diC1-6 alkylaminocarbonyl group” means a carbonyl group substituted with two amino groups having the same or different "C1-6 alkyl group” as a substituent, and examples thereof include a dimethylaminocarbonyl group. Diethylaminocarbonyl, di(n-propyl)aminocarbonyl, bis(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, methyl(n-propyl)aminocarbonyl, methyl(isopropyl)aminocarbonyl Wait.
  • the "C6-10 aryl group” means a monocyclic or polycyclic aryl group having 6 to 10 carbon atoms.
  • a partially saturated group is also included.
  • a phenyl group, a naphthyl group, an anthracenyl group, a fluorenyl group, an indanyl group, a tetrahydronaphthyl group, etc. are mentioned.
  • the "C6-10 aryl C1-6 alkyl group” means a group in which the following C6-10 aryl group is bonded to the above C1-6 alkyl group.
  • Examples thereof include a benzyl group, a phenethyl group, a 3-phenyl-n-propyl group, a 4-phenyl-n-butyl group, a 5-phenyl-n-pentyl group, an 8-phenyl-n-hexyl group, a naphthylmethyl group, and the like.
  • the "5-11 membered heterocyclic group” means 5 to 7 which is an atom constituting the ring and contains, in addition to the carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • a heteroaromatic heterocyclic ring, a saturated heterocyclic ring, an unsaturated heterocyclic ring or a fused heterocyclic ring obtained by condensing these heterocyclic rings with a benzene ring.
  • the "C6-10 aryl C1-6 alkoxy group” means a group in which the above “C6-10 aryl C1-6 alkyl group” is bonded to an oxygen atom.
  • a benzyloxy group, a phenethyloxy group, a naphthylmethyloxy group, etc. are mentioned.
  • the "C1-6 alkylthio group” may, for example, be a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, an isobutylthio group, a sec-butylthio group or a tertiary group.
  • the "C1-6 alkylsulfinyl group” may, for example, be a methylsulfinyl group, an ethylsulfinyl group, a n-propylsulfinyl group, an isopropylsulfinyl group or a n-butylsulfinic acid.
  • Preferred embodiments of the present invention include the following.
  • R 3 is preferably a C1-6 alkyl group such as a methyl group, an ethyl group or an isopropyl group, or a cyclopropyl group.
  • R 5 is preferably a single bond.
  • R 5 is preferably a single bond
  • R 6 is preferably a C1-6 alkyl group, more preferably a methyl group.
  • R 7 and R 8 are each independently preferably a C1-6 alkyl group, more preferably a methyl group or a different group. Propyl.
  • R 9 is preferably a single bond.
  • a 3 is N
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is C
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is N
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C
  • the ring A is preferably an unsaturated ring, and the ring B is a saturated ring; preferably, the ring A is an unsaturated ring, and the ring B is an unsaturated ring.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is N
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is N.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is N
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is N.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • Ar is preferably a phenyl group optionally substituted by 1 to 5 halogen atoms, and more preferably a phenyl group substituted by 2 fluorine atoms.
  • the "pharmaceutically acceptable salt” in the present specification includes a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid, or with acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, and fumaric acid.
  • an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid
  • acetic acid such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, and fumaric acid.
  • a salt of a metal ion a salt with an amine such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like. It is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the conversion of the free base of the compound of the present invention to the salt can be carried out by a conventional method.
  • the compound of the present invention may also exist as various solvates.
  • the compounds of the present invention may contain one or more asymmetric centers, thereby being capable of racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers, and the like.
  • the term "crystalline" includes various crystals of the compounds of the invention, such as single crystals, polymorphs, and the like.
  • the compounds of the invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical formulation.
  • pharmaceutically acceptable carriers, excipients and diluents refer to inactive ingredients in pharmaceutical compositions which do not cause significant irritation to the organism and which do not interfere with the biological activity of the administered compound.
  • excipient and diluent comprising water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate , calcium phosphate, cellulose, aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil Various oils, etc.
  • excipient or diluent in the above carrier, excipient or diluent, it may be mixed as needed.
  • Additives such as extenders, binders, disintegrants, pH adjusters, solubilizers, etc., can be used as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions by conventional formulation techniques.
  • Oral or parenteral drugs such as agents, ointments, injections, and skin patches are prepared.
  • the compounds of the invention may be administered orally or parenterally to an adult patient.
  • the composition or compound of the present invention is generally administered once every 3-12 days, preferably once every 5-10 days, more preferably once a week, and the total amount of administration is 0.01 to 1000 mg/time.
  • the dose of the compound of the present invention can be appropriately increased or decreased depending on the type of the disease to be treated, the age, body weight, symptoms, and the like of the patient.
  • the compound of the present invention further contains a compound in which one or more hydrogen atoms, fluorine atoms, carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms are replaced by a radioisotope or a stable isotope.
  • a radioisotope or a stable isotope can be used for metabolic or pharmacokinetic studies, ligands as receptors, and the like for biological analysis and the like.
  • the compounds of the invention may be used in combination with one or more other drugs (e.g., metformin) to treat, prevent, inhibit or ameliorate a disease or condition, wherein the combined use of the drug is safer or more secure than the separate use of any of the drugs. effective.
  • other drugs may be administered simultaneously or sequentially with the compounds of the present invention in the routes and amounts conventionally used for this purpose.
  • a pharmaceutical composition comprising the other agent and a compound of the invention in a unit dosage form is preferred, especially in combination with a pharmaceutically acceptable carrier.
  • combination therapy can also include treatment of a compound of the invention and one or more other drugs in different overlapping schedules.
  • the compounds of the invention and the other active ingredients may be employed in lower doses than when each is used alone.
  • the pharmaceutical compositions of the invention also include those compositions containing one or more additional active ingredients.
  • the compound of the present invention can be produced, for example, by the method shown below.
  • the compound of the present invention represented by the formula (1) can be produced by the synthesis method shown in Scheme 1.
  • the ketone represented by the formula (2) and the amine represented by the formula (3) are subjected to reductive amination at a temperature of 0 to 50 ° C, preferably 10 to 40 ° C for 0.5 to 30 hours, preferably 1 to 12 hours.
  • a reductive amination product as shown, and the obtained product is further subjected to an amino-protecting group under acidic conditions of pH 2 to 6, to obtain a compound of the formula (1).
  • an oxidation product in the case where the B ring is a saturated ring in the compound represented by the formula (4), an oxidation product can be obtained by an oxidation reaction of DDQ at 10 to 40 ° C for 4 to 10 hours, followed by a halogenated carboxylic acid, preferably trifluoromethane. Under the action of acetic acid at 10-40 ° C, the reaction was removed for 10-16 hours to remove Boc protection, and the corresponding compound having two double bonds in the B ring was obtained.
  • the reaction scheme is as follows:
  • the amine compound represented by the formula (3) in the above ⁇ Scheme 1> is In time, it can be produced by the synthesis method shown in Scheme 2.
  • 3-N-Boc-pyrrolidone is reacted with DMF-DMA at 0-50 ° C, preferably 10-40 ° C for 1-24 hours, preferably 2-12 hours, to give 1-tert-butoxycarbonyl-3-((2) Methylamino)methenyl)-4-pyrrolidone.
  • an alkali metal alkoxide preferably sodium ethoxide, methylthiocyanate and 1-tert-butoxycarbonyl-3-((dimethylamino)methenyl)-4-pyrrolidone are at 10-100 ° C, It is preferably refluxed at 30 to 50 ° C for 0.5 to 48 hours, preferably 2 to 24 hours, to give 2-(methylthio)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester.
  • the amine compound represented by the formula (3) in the above ⁇ Scheme 1> is In time, it can be produced by the synthesis method shown in Scheme 3.
  • the thiourea and 1-tert-butoxycarbonyl-3-((dimethylamino)methenyl)-4-pyrrolidone are subjected to 10-100 ° C, preferably 30-50, under the action of an alkali metal alkoxide, preferably sodium ethoxide.
  • the mixture is refluxed at ° C for 0.5-48 hours, preferably 2-24 hours, to give the desired product 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester.
  • 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is reacted with a halogenated hydrocarbon at a concentration of 5-45 ° C, preferably 10-40 ° C in the presence of a base 0.5-24
  • the alkylation product is obtained in hours, preferably from 1 to 12 hours.
  • the resulting alkylated product and m-chloroperoxybenzophenone The oxidizing agent such as an acid is reacted at 10 to 40 ° C, preferably at room temperature to obtain an oxidation product, and then the Boc protecting group is removed by a halogenated carboxylic acid, preferably trifluoroacetic acid, to obtain an amino compound of the desired product.
  • the amine compound represented by the formula (3) in the above ⁇ Scheme 1> is In time, it can be produced by the synthesis method shown in Scheme 4.
  • R 1 and R 2 are each independently hydrogen or any group selected from the aforementioned substituent group a.
  • the 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is oxidized with chlorine gas for 1 to 20 hours, preferably 2 to 6 hours, and then quenched with an amine compound to obtain a sulfonate. Amide product.
  • the Boc protecting group is then removed by the action of a halogenated carboxylic acid, preferably trifluoroacetic acid, to give the amino compound.
  • the nuclear magnetic resonance ( 1 H NMR) measuring instrument uses a JEOL Eclipse 400 nuclear magnetic instrument; the measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexamethylene dimethyl sulfoxide (DMSO-d6); The internal standard substance is tetramethylsilane (TMS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometer
  • ESI Agilent 6120B
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
  • the compound n' represents a salt form of the compound n.
  • Example 1-1 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine (Compound 1-1) and its ditrifluoroacetic acid Preparation of salt (compound 1-1')
  • Step 3 Synthesis of 2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
  • Step 7 Free compound (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidine-6 (Preparation of 7H)-yl)tetrahydro-2H-pyran-3-amine (Compound 1-1)
  • (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl) Tetrahydro-2H-pyran-3-amine ditrifluoroacetate is sonicated with 2M sodium carbonate aqueous solution, and then filtered to obtain the free compound (2R, 3S, 5R)-2-(2,5-difluoro Phenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine.
  • Example 1-2 (2R,3S,5S)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3,4-d]pyrimidine-6 ( 7H) - yl) tetrahydro -2H-pyran-3-amine (compound 1-2) and its dihydrochloride (compound 1-2 ') of
  • reaction solution was concentrated to dryness to give a semi-solid crude product, which was purified to crude (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-6H-pyrrole [3,4-d]Pyridin-6-yl)tetrahydro-2H-pyran-3-amine trifluoroacetate (38 mg, yellow solid), yield: 75%.
  • Boc-5H-pyrrole [3,4-d]pyrimidin-6(7H)-2-carboxamide instead of (2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidine-6 (7H - tert-butyl carboxylate
  • the Boc-5H-pyrrole[3,4-d]pyrimidin-6(7H)-2-carboxamide was charged in an amount of 200 mg, and the same operation as in the fourth step of Example 1.
  • the title product was obtained in 190 mg in a yield of 90%.
  • the second step synthesis of 2-ethylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
  • Example 12 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 6,7-7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-sulfonylisopropylamine ditrifluoroacetate (combination Preparation of substance 12')
  • Example 10 The same as Example 10 except that isopropylamine was used instead of dimethylamine, and the amount of 2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate was 1 g. The same procedure was carried out in one step to give 720 mg of title product.
  • Step 4 (2R, 3S, 5R)-5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine Synthesis of tert-butyl-6-(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-carbamate
  • Step 5 ((2R,3S,5R)-5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-( Synthesis of 2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate
  • Step 5 ((2R,3S,5R)-5-(2-(Isobutylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-( Synthesis of 2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate
  • the title product was obtained in the same manner as in the first step of Example 10 except that tetrahydropyrrole was used instead of dimethylamine, and the amount of the tetrahydropyrrole was 1 g.
  • the title product was obtained in the same manner as in the first step of Example 10, except that dimethyl hydrazine was used instead of dimethylamine, and the amount of dimethyl hydrazine was 1 g.
  • the feed was 110 mg, and 32 mg of the product was obtained, and the yield was 25%.
  • the third step ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-sulfamoyl-5H-pyrrole [3,4-d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester
  • Step 3 2-(N-(propylformamide)sulfamoyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
  • the reaction liquid of the second step was heated to 45 ° C, and then 1.1 mL of n-propylamine was added. After reacting for 2 hours, the reaction system was concentrated and purified by column chromatography to obtain 2-(N-(propylformamide)sulfamoyl)- 5H-Pyrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (0.39 g, yellow solid, yield, 76.1%).
  • Step 5 ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(N-(propylformamide)sulfamoyl)-5H-pyrrolo[ 3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester
  • Step 6 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyranyl-N-propylformamide-5H-pyrrole And [3,4-d]pyrimidin-6(7H)-2-sulfonamide ditrifluoroacetate
  • the fourth step 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-(N-A Base group)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate
  • Step 3 tert-Butyl ((2R,3S,5R)-5-(2-(N-decylsulfamoyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine- 6-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate
  • the third step ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(6-(methylsulfonyl)-1H-pyrrolo[3,4-c]pyridine-2 (3H)-yl)tetrahydro-2H-pyran-3-yl)amino-tert-butylformate
  • Glycinamide hydrochloride (107 g, 0.968 mol), methanol (500 ml) was added to the reaction flask.
  • the reaction was maintained at -35 ° C for 2 h and then allowed to rise to room temperature overnight. The TLC was monitored until the starting material was completely reacted.
  • the third step synthesis of 2,3-dimethyl-5-(methylsulfonyl)pyrazine
  • 2,3-Dibromomethyl-5-(methylsulfonyl)pyrazine (6 g, 17.4 mmol), triphenylmethylamine (4.5 g, 17.4 mmol), N,N-diisopropylethylamine (6.75 g, 52.3 mmol), N,N-dimethylformamide (60 ml) was added to the reaction flask.
  • the reaction solution was heated to 60 ° C under nitrogen atmosphere, stirred for 1 h, and monitored by TLC until the reaction of the starting material was completed. Water was added to the reaction mixture, and the mixture was evaporated.
  • Step 7 ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-5H-pyrrolo[3,4-b]pyrazine Synthesis of -6(7H)-yl)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester
  • Step 8 (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-5H-pyrrolo[3,4-b]pyrazine- Synthesis of 6(7H)-yl)tetrahydro-2H-pyran-3-amine, ditrifluoroacetate
  • reaction mixture was concentrated and purified ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2- (N-(propylformamide)sulfamoyl)-6H-pyrrolo[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (38 mg, Yellow solid, yield 64%).
  • the fourth step isoporphyrin-5-sulfonamide
  • Step 5 ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-sulfonamideisoindoline-2-yl)tetrahydropyran-3-yl ) tert-butyl formate.
  • Step 6 2-((2R,3S,5R)-5-Amino-6-(2,5-difluorophenyl)-tetrahydropyran-3-yl)isoindoline-5-sulfonamide
  • EtOAc EtOAc
  • tert-Butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (0.7 g, 2.203 mmol) was added dropwise to dimethylamine hydrochloride (1.79 g, 22.03 mmol) and triethylamine. (2.23 g, 22.03 mmol), the reaction was carried out for three hours at room temperature. A 56 um solid of yellow solid was filtered and taken directly to the next.
  • the third step is tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(N,N-dimethylsulfamoyl)isoindoline- 2-yl)tetrahydro-2H-pyran-3-yl)carbamate
  • Step 2 Synthesis of 5-(chlorosulfonyl)isoindoline-2-carbonate tert-butyl ester
  • Step 3 Synthesis of 5-(N-methylaminesulfonyl)isoindoline-2-carbonate tert-butyl ester
  • Step 2 Synthesis of 5-(isopropylaminosulfonyl)isoindoline-2-carbonate tert-butyl ester
  • 5-sulfonamide isoindole-2-carboxylic acid tert-butyl ester (0.584 g, 1.96 mmol) was dissolved in 10 mL of acetonitrile under ice-cooling, then 0.57 mL of triethylamine was added, (0.367 g, 2.35 mmol) of chlorine
  • the phenyl formate was dissolved in 2 mL of acetonitrile and slowly added dropwise to the reaction system. After the reaction was completed, the reaction solution was directly used for the next reaction.
  • the reaction liquid of the second step was heated to 45 ° C, and then 1.5 mL of n-propylamine was added. After reacting for 2 hours, the reaction system was concentrated and purified by column chromatography to obtain 5-(N-(propylformamide)sulfamoyl) Tert-butyl phthalate-2-carboxylate (0.375 g, 50% yield in two steps).
  • the third step product and ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (0.382 g, 1.17 mmol) was dissolved in THF/DMA (8 mL / 4 mL), and reacted at 60 ° C for 1 h under argon. After cooling, sodium cyanoborohydride (0.307 g, 4.9 mmol) was added and the reaction was continued for 25 min. The reaction was quenched and extracted with ethyl acetate and brine. Purification by column chromatography gave 325 mg of crude material.
  • Step 2 Synthesis of 5-(decylsulfonyl)isoindoline-2-carbonate tert-butyl ester
  • tert-Butyl 5-(methylsulfonamido)isoindoline-2-carbonate (420 mg, 1.35 mmol) was added to a solution of 15 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (260 mg, 78%). MS m/z (ESI): 21:21.
  • tert-Butyl 5-(sec-butylsulfonyl)isoindoline-2-carbonate 500 mg, 1.47 mmol was added to a solution of 15 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated to give crystall MS m/z (ESI): 242.
  • Test Example 1 Detection of inhibition of DPP-2/4/8/9 enzyme activity by compound
  • Enzyme DPP-2/4/8/9 Recombinant Human DPP-4/CD26; manufacturer: R&D Company;
  • DPP-4/8/9 substrate H-Gly-Pro-AMC ⁇ HBr
  • DPP-2 substrate Lys-Pro-AMC
  • manufacturer Bachem
  • test compound was dissolved in assay buffer (25 mM Tris-HCl, 140 mM NaCl, 10 mM KCl, 0.1% BSA, pH 7.4) at various concentrations.
  • DPP-4 and the test compound were added to a 384-well plate, and the mixture was incubated at 37 ° C for 15 minutes.
  • the reaction was initiated by the addition of a substrate (H-Gly-Pro-AMC.HBr).
  • the well plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence value.
  • the slope of the change in fluorescence value of each experimental group was calculated during the linear reaction period, and the half-inhibitory concentration IC 50 value of the compound was fitted using SigmaPlot or GraphPad Prism 5 software.
  • Detection method for inhibition of DPP-2 enzyme activity The test compound is dissolved in the detection buffer at different concentrations. Add DPP-2 and the test compound to the multi-well plate, mix and add the substrate (Lys-Pro-AMC) and test under the microplate reader. Calculate the slope of the fluorescence value of each experimental group during the linear reaction period, using SigmaPlot or fitting software GraphPad Prism 5 50 value of the compound IC.
  • Detection method for inhibition of DPP-8/9 enzyme activity The test compound was dissolved in a detection buffer (25 mM Tris-HCl, 140 mM NaCl, 10 mM KCl, 0.1% BSA, pH 7.4) at various concentrations. DPP-8/9 and the test compound were added to a 384-well plate, and the mixture was incubated at 37 ° C for 15 minutes. The reaction was initiated by the addition of a substrate (H-Gly-Pro-AMC.HBr). The well plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence value. The slope of the change in fluorescence value of each experimental group was calculated during the linear reaction period, and the IC 50 value of the compound was fitted using SigmaPlot or GraphPad Prism 5 software.
  • Compound DPP-4IC 50 1-1 0.45 111’ 0.50 5’ 1.24 7’ 0.46 8' 1.00 twenty two 0.52 10’ 0.36 11’ 0.65 12’ 0.82 26’ 0.95 29’ 0.45 30’ 0.67 28 1.10 28’ 1.38 20’ 0.69 31’ 0.43 19 0.85 19’ 0.90 14’ 0.47 16’ 1.20 17’ 0.97 twenty one' 0.33 twenty two' 0.52 twenty three' 0.56 36 0.81 37 0.43 38’ 0.35 39’ 0.83 41’ 0.65 42’ 1.37 46’ 1.02 47’ 1.16 48’ 0.67
  • the compounds of the present invention showed substantially no inhibitory effect on DPP-2, DPP-8, and DPP-9.
  • the compounds of the present application differ in selectivity for different DPPs, and the compounds of the present invention have a significant inhibitory effect on DPP-4 relative to DPP-2, DPP-8 and DPP-9.
  • the compound of the present invention has a similar inhibitory effect as the above compound, and the inhibitory effect on DPP-4 is significantly higher than that on DPP-2, DPP-8, and DPP-9, indicating that the compound of the present invention has excellent DPP subtype selectivity. .
  • the free base of the compound of the present invention or a salt thereof has a similar inhibitory effect as the above compound, and the inhibitory effect on DPP-4 is significantly higher than that on DPP-2, DPP-8, and DPP-9, indicating that the compound of the present invention is excellent.
  • DPP subtype selectivity DPP subtype selectivity.
  • DPP-4 substrate H-Gly-Pro-AMC ⁇ HBr; manufacturer: Bachem.
  • In vivo DPP-4 enzyme activity inhibition detection method a plasma sample and a detection buffer are mixed in a multi-well plate, and then a DPP-4 substrate is added to initiate the reaction. The well plate was placed in a microplate reader for detection. The slope of the fluorescence value of each experimental group was calculated during the linear reaction period, and the inhibition rate of the enzyme activity was calculated.
  • This experiment primarily investigates the long-acting effects of the compounds of the invention, such as DPP-4 inhibition over 48 hours (e.g., 2-4 days).
  • Table 7 shows the inhibition rate of plasma DPP-4 after compound 19' and Ogedetine intravenous (iv) administration
  • the compound 39' of the present invention was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.5 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg.
  • the inhibition rate at high doses and the 87.5% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
  • the compound 19' of the present invention was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.73 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg.
  • the inhibition rate at high doses and the 81.6% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
  • the compound of the present invention 19 was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.73 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg.
  • the inhibition rate at the dose and still had an inhibition rate of 85.4% at 96 hours, indicating that the compound has an excellent inhibitory effect.
  • the compound 39' of the present invention was administered by intragastric administration (po) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 1 mg/kg was significantly higher than that of the positive control alogliptin 2 mg/kg.
  • the inhibition rate at high doses and the 91.7% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
  • the compound 19' of the present invention was administered by intragastric administration (po) in dogs, and at a low dose of 1.25 mg/kg, there was still 86.8% inhibition rate of plasma DPP-4 at 96 hours, which was significantly higher than that.
  • the inhibition rate of the positive control alogliptin at a high dose of 2 mg/kg indicates that the compound has an excellent inhibitory effect.
  • the compound 19 of the present invention was administered by intragastric administration (PO) in dogs, and at a low dose of 1.25 mg/kg, there was still 86.5% inhibition of plasma DPP-4 at 96 hours, which was significantly higher than that of the positive one.
  • the inhibition rate of the high dose of the control of alogliptin at 2 mg/kg, indicates that the compound has an excellent inhibitory effect.
  • the compound of the present invention has a similar inhibitory effect on plasma DPP-4 and a longer potency when administered intravenously (iv) or intragastrically (po) in dogs.
  • the free base of the compound of the present invention or a salt thereof has a plasma DPP-4 inhibitory effect and a longer pharmacodynamic time similar to those of the above compounds when administered intravenously (iv) or intragastrically (po) in dogs.
  • the male compounds of the present invention were administered intravenously and intragastrically, respectively, to examine the pharmacokinetic characteristics.
  • the respective doses of iv and po were 5% DMSO: 5% solutol: 90% Saline.
  • Blood was collected at different time points after iv administration and po administration for PK/PD studies. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS. The results are shown in the table below.
  • the compound of the present invention has similar pharmacokinetic effects as the above compounds.
  • the free base of the compound of the present invention or a salt thereof is administered by intravenous (IV) administration or intragastric administration (po), it exhibits a similar pharmacological parameter exposure to the above-mentioned compound than the body, and exhibits excellent bioavailability.
  • the potassium channel encoded by the human Ether-a-go-go Related Gene mediates a delayed rectifier potassium current (IKr). IKr inhibition is the most important mechanism for drug-induced QT interval prolongation.
  • the manual patch clamp method was judged to be that if the compound IC 50 > 30 ⁇ M, it was judged that the compound had no inhibitory effect on hERG.
  • test cells were CHO cell lines transfected with hERG cDNA and stably expressing hERG channels. The cells were placed in an electrophysiological recording cell under an inverted microscope. The extracellular fluid was continuously perfused in the recording tank. The experimental procedure uses conventional whole-cell patch clamp current recording techniques. The test results are shown in Table 15:
  • the compounds of the invention have similar safety to the compounds described above.
  • the free base of the compound of the present invention or a salt thereof has similar safety to the above compounds.
  • liver microsome solution (the final concentration of liver microsomes in the reaction system was 0.2 mg/mL) was added to a 1.1 mL centrifuge tube. No positive inhibitor and test compound were added to the blank sample, 2 ⁇ L of DMSO was added, 200 ⁇ L of internal standard methanol solution was added, vortexed for 1 min (ie, minutes), and finally 20 ⁇ L of NADPH solution was added. For non-blank samples, add 2 ⁇ L of inhibitor or stock solution of the test compound (10 ⁇ M) to a 1.1 mL centrifuge tube, vortex and mix for 5 min at 37 °C, and add 20 ⁇ L of NADPH solution to start the reaction (NADPH in the reaction system).
  • the final concentration was 1 mM) and incubated for 20 min at 37 ° C with shaking. After the incubation, the reaction was terminated by adding an internal standard methanol solution, and the sample was centrifuged at 4000 rpm for 5 min, and the supernatant was taken to LC/MS/MS for analysis.
  • the compounds of the present invention have similar safety to the above-mentioned compounds, and the risk of drug interactions in clinical combination is small.
  • the free base or a salt thereof of the compound of the present invention has similar safety to the above-mentioned compound, and the clinical combination drug has a lower risk of drug interaction.
  • a 100 mg titer tablet consisting of the following ingredients was produced.
  • the active substance, microcrystalline cellulose and croscarmellose are mixed, and then the mixture is lubricated with magnesium stearate and compressed into tablets.
  • a granule for capsule filling containing the following components was produced.
  • the compound represented by the formula (1) and lactose were passed through a sieve of 60 mesh.
  • the corn flour was passed through a 120 mesh sieve. These were mixed, and the HPC-L solution was added to the mixed powder, kneaded, granulated, and dried. After the obtained dried granules were sized, 150 mg of the obtained dried granules were filled in a No. 4 hard gelatin capsule.
  • the compound of formula (1) and lactose were passed through a 60 mesh sieve.
  • the corn flour was passed through a sieve of 120 mesh. They were mixed using a V-type mixer.
  • An HPC-L (low viscosity hydroxypropylcellulose) aqueous solution is added to the mixed powder, and kneading, granulation (extrusion granulation pore diameter: 0.5 to 1 mm), and drying are carried out.
  • the obtained dried granules were sieved with a shaking sieve (12/60 mesh) to obtain granules.
  • a compound which is a dipeptidyl peptidase-IV inhibitor which has high inhibitory activity against dipeptidyl peptidase-IV and has excellent drug metabolism properties can be used for treatment and prevention including treatment of diabetes, Especially DPP-4 related diseases of type II diabetes.

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  • Chemical & Material Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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Abstract

La présente invention concerne un inhibiteur de dipeptidyl-peptidase-IV à action prolongée, ses applications, et un procédé de préparation d'un intermédiaire de celui-ci. Spécifiquement, la présente invention concerne un composé de formule générale (1) et son procédé de préparation, des applications du composé dans le traitement et la prévention de maladies comprenant le diabète sucré et les maladies associées à la DPP-4 du diabète de type 2, ainsi qu'une composition pharmaceutique et une préparation pharmaceutique comprenant le composé de formule générale (1), les définitions des symboles dans la formule générale étant identiques à celles figurant dans la description.
PCT/CN2016/000478 2015-08-24 2016-08-23 Inhibiteur de dipeptidyl-peptidase-iv à action prolongée, ses applications, et un procédé de préparation d'un intermédiaire de celui-ci WO2017031918A1 (fr)

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WO2018169252A1 (fr) * 2017-03-16 2018-09-20 경희대학교 산학협력단 Dérivé de n-benzyl-n-phénoxyl-carbonyl-phénylsulfonamide et composition pharmaceutique comprenant celui-ci
WO2022003610A1 (fr) 2020-07-02 2022-01-06 Pi Industries Ltd. Dérivés de 2-(4,5-dihydroisoxazol-3-yl) isoindoline-5-carboxamide et composés similaires utilisés comme pesticides pour la protection des cultures
WO2023037253A1 (fr) 2021-09-08 2023-03-16 Pi Industries Ltd Composés d'isoxazoline et leur utilisation en tant qu'agents de lutte contre les nuisibles
WO2024081775A1 (fr) * 2022-10-14 2024-04-18 Eli Lilly And Company Synthèse de composés 6-fluoro-2-méthylbenzo[d] thiazol-5-yle

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WO2018028666A1 (fr) * 2016-08-12 2018-02-15 正大天晴药业集团股份有限公司 Cristal d'inhibiteur de dpp-iv à action prolongée et son sel
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CN109874304B (zh) * 2016-08-12 2021-06-25 正大天晴药业集团股份有限公司 Dpp-iv长效抑制剂的结晶及其盐
WO2018169252A1 (fr) * 2017-03-16 2018-09-20 경희대학교 산학협력단 Dérivé de n-benzyl-n-phénoxyl-carbonyl-phénylsulfonamide et composition pharmaceutique comprenant celui-ci
KR20180105987A (ko) * 2017-03-16 2018-10-01 경희대학교 산학협력단 N-벤질-n-페녹시카르보닐-페닐설폰아마이드 유도체 및 그를 포함하는 약제학적 조성물
KR102294129B1 (ko) * 2017-03-16 2021-08-27 국제약품 주식회사 N-벤질-n-페녹시카르보닐-페닐설폰아마이드 유도체 및 그를 포함하는 약제학적 조성물
WO2022003610A1 (fr) 2020-07-02 2022-01-06 Pi Industries Ltd. Dérivés de 2-(4,5-dihydroisoxazol-3-yl) isoindoline-5-carboxamide et composés similaires utilisés comme pesticides pour la protection des cultures
WO2023037253A1 (fr) 2021-09-08 2023-03-16 Pi Industries Ltd Composés d'isoxazoline et leur utilisation en tant qu'agents de lutte contre les nuisibles
WO2024081775A1 (fr) * 2022-10-14 2024-04-18 Eli Lilly And Company Synthèse de composés 6-fluoro-2-méthylbenzo[d] thiazol-5-yle

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