[go: up one dir, main page]

WO2004048379A1 - Compose de xanthine - Google Patents

Compose de xanthine Download PDF

Info

Publication number
WO2004048379A1
WO2004048379A1 PCT/JP2003/013990 JP0313990W WO2004048379A1 WO 2004048379 A1 WO2004048379 A1 WO 2004048379A1 JP 0313990 W JP0313990 W JP 0313990W WO 2004048379 A1 WO2004048379 A1 WO 2004048379A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
group
xanthine
fluorobenzyl
amino
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.)
Ceased
Application number
PCT/JP2003/013990
Other languages
English (en)
Japanese (ja)
Inventor
Hiroyuki Nakahira
Hitoshi Hochigai
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.)
Sumitomo Pharma Co Ltd
Original Assignee
Sumitomo Pharmaceuticals 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 Sumitomo Pharmaceuticals Co Ltd filed Critical Sumitomo Pharmaceuticals Co Ltd
Priority to AU2003280680A priority Critical patent/AU2003280680A1/en
Publication of WO2004048379A1 publication Critical patent/WO2004048379A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61P3/08—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Definitions

  • the present invention relates to a novel xanthine compound useful as a medicament. More specifically, it relates to a novel xanthine compound effective as a dipeptidyl peptidase-IV (DPP-IV) inhibitor. Furthermore, the present invention relates to a therapeutic agent for diabetes mellitus 1 containing a novel xanthine compound which is effective as a dipeptidyl peptidylase-IV (DPP-IV) inhibitor as an active ingredient.
  • DPP-IV dipeptidyl peptidase-IV
  • DPP-IV is a serine protease that exists widely in the body, is a type of dipeptidylaminopeptidase that hydrolyzes the N-terminal peptide, and a peptide in which the second amino acid from the N-terminal is proline. It is also known as prolyl endopeptidase because it acts particularly strongly on steroids. It is known that DPP-IV uses various biological peptides involved in endocrine system, neuroendocrine system, immune function and the like as substrates.
  • Pancreatic polypeptides such as punk creatic polypeptide (PP) and neuropeptide Y (PY), bathoactive intestinal polypeptide petit K (VIP), glucagon-like peptides— 1 ( GLP-1), glucose-dependent insulin pick-up polypeptide (GIP), glucagon ⁇ -family represented by growth honolemon secretagogue (GRF), etc., and many physiologically active peptides such as the chemokine family are DPP-IV. Is known to be affected by activation / inactivation and promotion of metabolism. S known (edited by J. Langner and S. Ansorge, Cellular Peptidases in Immune Functions and Disease 2 ", Advances in Experimental Medicine and Biology Vo 1. 477).
  • DPP-IV cleaves two amino acids (His-Ala) from the N-terminus of GLP-1. Although the cleaved peptide binds weakly to the GLP-1 receptor, it is known to have no receptor-activating action and to act as an antagoist (LB Knudsen et al., European Journal of P. harraacology, Vol. 318, p429-435, 1996). It is known that the metabolism of GLP-1 in blood by DPP-IV is very rapid, and the inhibition of DPP-IV increases the concentration of active GLP-1 in blood (TJ Kieffer et al., Endocrinology , Vol. 136, p3585- 3596, 1995).
  • GLP-1 is a peptide secreted from the intestinal tract by sugar intake and is a major stimulator of glucose-responsive secretion of insulin in the knee. It is known that GLP-1 has an action of promoting insulin synthesis in knee cells and an action of promoting cell proliferation. Furthermore, it is known that the GLP-1 receptor is expressed in the gastrointestinal tract, liver, muscle, adipose tissue, etc., and GLP-1 is expressed in these tissues by gastrointestinal activity, gastric acid secretion, and glycogen production. It is known to act on synthesis and degradation, insulin-dependent glucose uptake, and the like.
  • DPP-IV inhibitor effective for type 2 diabetes (non-insulin-dependent diabetes) is expected (RA Pederson et al., Diabetes Vol. 47, pl253-1258, 1998).
  • Various DPP-IV inhibitors have been reported.
  • a panflate WQ 02/02560
  • a xanthine compound having a piperazine ring or the like inhibits DPP-IV inhibition. It is reported to be effective as an agent.
  • one of the characteristics of the compound of the present invention is a 3-aminopyridine ring or 1,2-cycloalkanediamine, etc., of xanthine. It is disclosed that the xanthin derivative at position 8 is effective as a DPP-IV inhibitor.
  • Compounds having a benzyl group in which the 5-position on the benzene ring is a fluorine atom and the 2-position is substituted as the 7-benzyl group of the compound disclosed in the literature, such as the compound of the present invention, are as follows: Not listed at all.
  • An object of the present invention is to provide a compound having a high DPP-IV inhibitory activity and having an antidiabetic action.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have a benzyl group having a fluorine atom at the 5-position and a specific substituent at the 2-position at the 7-position of xanthine; and (1) 3_ Aminopiperidine-1-yl, 3-aminopyrrolidine-1-yl or 3-amino-hexahydroazepin-1-yl, or (2) (2-aminocycloalkyl) amino
  • a xanthine derivative characterized by a chemical structure having a group at the 8-position of xanthin is synthesized, and the compound or a prodrug thereof or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as the compound of the present invention as necessary) Has an excellent DPP-IV inhibitory action and further has an antidiabetic action, and completed the present invention. That is, the present invention relates to the following.
  • R 1 represents a (1) hydrogen atom, or (2) a C w alkyl group optionally substituted with one or more groups independently selected from A r 1 or A 1 Represents
  • a r 1 represents an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted, aliphatic heterocyclic group;
  • n 0, 1, or 2
  • a 1 is a halogen atom (1 to 3 carbon atoms may be substituted on the same carbon atom), hydroxyl group An oxo group, a cyano group, a carboxy group, a carbamoyl group optionally substituted by one or two same or different alkyl groups, an alkoxy group, an amino group,
  • R 2 represents a hydrogen atom, a C 1 H3 alkoxycarbonylmethyl group, or an alkyl group
  • R 3 is a chlorine atom, a bromine atom, an iodine atom, a cyano group, a carboxy group, an optionally substituted amino group, an optionally substituted CH alkyl group, an optionally substituted C w alkylthio group, optionally substituted CH alkylsulfinyl group, optionally substituted CH alkylsulfonyl group, C 2 - 6 Arukeeru group, C 2 -6 alkynyl group, an optionally substituted C w alkylcarboxy - group, Represents an optionally substituted CH alkoxy group or an optionally substituted radical group;
  • One Y—NH 2 has the following formula (A)
  • n 0, 1, or 2
  • R 4 is present one or two times, and independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a carboxy group, an oxo group, or an optionally substituted Represents a mino group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted phenyl group, or an optionally substituted benzyl group, or R 4 is 2 If they are present together, they together represent methylene or ethylene, and can combine with the two carbon atoms of the ring to form a bridged ring.
  • R 5 is one or two and independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a carboxy group, an oxo group, or a substituent.
  • _Y—NH 2 is a group represented by the formula (A), and n is 1 or 2 ⁇ or one Y—NH 2 is a group represented by the formula (B), q [1] or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • —Y—NH 2 is a group represented by the formula (A) and n is 1 or one Y—NH 2 is a group represented by the formula (B) and q is 1 Item 1.
  • R 4 or R 5 is a hydrogen atom, a halogen atom, an optionally substituted 6 Al kill group, or, optionally which may be substituted Ci-6 alkoxy group claim [1] to [4]
  • R 3 is a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a cyano group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, or a difluoromethoxy group [1] to
  • R 1 is a C ⁇ 2 alkyl group substituted with Ar—X—;
  • Ar 1 is an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group;
  • R 1 is an ethyl group substituted at the 2-position with Ar—X—;
  • Ar 1 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted A xanthine compound or a prodrug thereof according to any one of [1] to [6], wherein X is a single bond, or a pharmaceutically acceptable salt thereof. Salt.
  • R 1 is a methyl group substituted by Ar ⁇ X—;
  • a r 1 is section [1] is a phenyl group which may be substituted to [10] noisy deviation or the xanthine compound or a prodrug thereof or their pharmaceutically acceptable salts.
  • a dipeptidyl peptidase-IV inhibitor comprising the xanthine compound according to any one of [1] to [17], a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for diabetes comprising the xanthine compound according to any one of [1] to [17], a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • halogen atom includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • alkyl group examples include methyl, ethyl, propyl, isopropyl, A straight or branched chain with 1 to 6 carbon atoms, such as butinore, isobutinole, sec-butinole, tert-butinole, pentyl, 1-methinolebutyl, 2-methylbutyl, 3-methylinobutynole, 1-ethynolepropynole, hexinole, etc.
  • Examples include a branched alkyl group.
  • Preferred alkyl groups include linear or branched alkyl groups having 1 to 4 carbon atoms. More preferred alkyl groups include methyl or ethyl.
  • Ji 3 alkyl group for example methyl, Echiru, propyl, straight or branched alkyl group having 1 to 3 carbon atoms such as isopropyl.
  • the “rc ⁇ alkyl group” includes methyl or ethyl.
  • the - "c 2 6 alkenyl group” for example Bininore, propenyl, Mechirupuro Bae Interview le, linear or branched carbon atom number 2 6 having at least one double bond such as Puteyuru or Mechirubuteyuru And a branched alkenyl group.
  • Preferred alkenyl groups include linear or branched alkenyl groups having 3 to 4 carbon atoms.
  • C 2 _ 6 alkynyl group for example Echuru, Purobyuru, Mechirupuropie Honoré, Buchuru or Mechirupuchiniru, at least one straight-chain or branched alkynyl group having 2 to 6 carbon atoms having a triple bond such as Is mentioned.
  • Preferred alkynyl groups include linear or branched alkynyl groups having 3 to 4 carbon atoms.
  • the "Ji ⁇ alkoxy group" for example, Cw Arukiruokishi group, C 3 - 6 cycloalk Kiruokishi group.
  • Preferred alkoxy groups include linear or branched alkoxy groups having 1 to 4 carbon atoms.
  • dialkoxy group examples include a C 3 alkyloxy group and a cyclopropyloxy group.
  • a C w alkyl group examples include the aforementioned C M alkyl group.
  • alkoxy in the “C 15 alkoxycarbonyloxy group”, the “C 6 alkoxycarbonylamino group” and the “dialkoxyimino group” include the aforementioned CM alkoxy group.
  • Examples of the alkoxy in the “C 3 alkoxycarbonyl group”, the “C 3 -anolekoxycanolevonyloxy group”, the r C -s alkoxyl propylonylamino group, and the “C 3 alkoxyimino group” include the C ⁇ alkoxy Groups.
  • acyl in the “acylamino group” examples include acetyl, propioel, etc. ⁇
  • aryl group examples include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an indanyl group and the like. Of these, a phenyl group is preferred.
  • aroyl group examples include arylcarbonyl groups having 11 or less carbon atoms, such as benzoyl and naphthoyl.
  • Examples of the aryl in the "aryloxy group”, the “arylsulfonyl group”, the “arylsulfonyloxy group” and the “arylsulfonylamino group” include the above aryl groups.
  • Examples of the arylsulfonyl group and arylsulfonyloxy group include a toluenesulfonyl group and a toluenesulfonyloxy group.
  • the "aromatic heterocyclic group” includes 0 to 3 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom (the sulfur atom may be oxidized by 1 or 2 oxygen atoms. )
  • the aromatic heterocyclic group in the aromatic heterocyclic group a part of the ring system may be hydrogenated as long as it has aromaticity.
  • the aromatic heterocyclic group In the aromatic hetero ring of the above, one or more carbon atoms on the ring may be substituted with an oxo group as long as a stable structure is obtained.
  • the bonding position of the aromatic ring group is not particularly limited, and the aromatic ring group may be bonded on any nitrogen atom or carbon atom on the bondable ring.
  • aromatic hetero ring in the aromatic hetero ring group examples include furan, thiophene, pyronole, pyridine, indonele, isoindole, purine, phthalazine, 4-oxo-13,4- Dihydrophthalazine, quinoline, 1,2-dihydroquinoline, tetrahydroquinoline, isoquinoline, 2oxo_1,2-dihydroquinoline, tetrahydroisoquinoline, quinazoline, quinoxaline, naphthyridine, virazol, imidazole, triazole, pyrazole, pyrazole, pyrazole Pyrazine, pyridazine, thiazole, oxazole, isoxazole, indolizine, chroman, isochroman, 4-oxo-4H-chromene, indazonole, imidazo pyridine, imidazopyrimidine, benzimidazole 1,2-oxoxo
  • pyridine quinoline, and isoquinoline are preferable, and pyridine is more preferable.
  • Examples of the pyridyl group include a 2-pyridyl group, a 3-pyridyl group, and a 4-pyridyl group.
  • Examples of the aliphatic heterocyclic group include 0 to 3 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom (the sulfur atom may be oxidized by 1 or 2 oxygen atoms). Examples thereof include a 5- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of the following.
  • the aliphatic heterocyclic group may have a partially unsaturated bond. Good.
  • one or more carbon atoms on the ring may be substituted with an oxo group as long as a stable structure is obtained.
  • the bonding position of the aliphatic heterocyclic group is not particularly limited, and it may be bonded on any nitrogen or carbon atom on the bondable ring.
  • aliphatic hetero ring in the aliphatic hetero ring group examples include pyrrolidine, 2-oxopyrrolidine, pyrroline, piperidine, piperazine (the nitrogen atom of the piperazine is substituted with methyl or ethyl. ), 2-oxoimidazolidine, 2,4-dioxoimidazolidine, monoreforin, thiomonoreforin, thiomorpholine-l-oxide, or aliphatic heterocycle such as thiomorpholine-l, l-dioxide. And the like.
  • Optionally substituted C 3 - 6 cycloalkyl group an optionally substituted alkoxy group, an optionally substituted C ⁇ alkyl Cal Poni group, an optionally substituted C w alkylthio group, substituted
  • substituent in the optionally substituted alkylsulfier group, the optionally substituted alkylsulfonyl group, the optionally substituted phenyl group and the optionally substituted benzyl group include the halogeno described above.
  • emissions atoms (which may have 1 to 3 substituent on the same carbon atom), a hydroxyl group, Shiano group, forces Rubokishi group, c 2 _ 6 alkenyl, c 2 _ 6 alkynyl group, c 3 _ 6 cycloalkyl group , ⁇
  • the substituent in the optionally substituted amino group for example, the above optionally substituted alkyl groups, optionally substituted C 3 - 6 cycloalkyl group, C ⁇
  • examples thereof include an alkylcarbonyl group, an aryloyl group, a C w alkoxycarboyl group, a 6- alkylsulfol group, and an arylsulfonyl group.
  • One or two of these substituents may be present.
  • substituted amino group examples include, for example, a methylamino group, an ethylamino group, a dimethylamino group, an acetylamino group, a propionylamino group, a benzoylamino group, a naphthoinoleamino group, a methoxycarbonylamino group, an ethoxycarbonylamino group and a tert-carbonyl group.
  • the substituent in the optionally substituted force Rubamoiru group for example an optionally substituted alkyl group, C 3 _ 6 cycloalkyl group, C 3 - 6 cycloalkyl substituted by a C Bok 3 alkyl group, the alkyl Examples thereof include a carbonyl group and an arylo group, and one or two of these substituents may be present.
  • two substituents of the carbamoyl group are bonded to form pyrrolidine, piperidine, monoreforin, thiomorpholine, thiomonorephorin oxide, thiomonorephorin dioxide, or piperazine (of the piperazine).
  • the nitrogen atom may be substituted with methyl or ethyl), and the like, to form an aliphatic heterocyclic ring which may contain carbon, nitrogen, oxygen or sulfur.
  • substituent rubamoyl group examples include, for example, monomethylcarbamoyl, dimethylenorecanolebamoinole, echinorecanolebamoinole, jetinorecanolebamoinole, N-propinolecanole vamoyl, N-isopropyl rubamoinole, N— Ethyl-N-methylcarbamoyl,
  • N-Methinole-N-propynolecanolebamoinole N-cyclopropinolecanolebamoinole, N-cyclopropinolemethanolebanoinole, acetinole force / rebamoinole, benzoinolecanolebamoyl, pylori Dinocarbonyl, piperidinocarbonyl, morpholinocarbonyl and the like.
  • Examples of the substituent in the aryl group which may be substituted or the aromatic heterocyclic group which may be substituted include a halogen atom, a hydroxyl group, a carboxy group, a cyano group, an amino group, a nitro group and a substituted group.
  • the substituent here, a halogen atom, an alkyl group, an alkoxycarbonyl group, C 3 alkoxy force Ruponiruokishi group or the like carboxyl group is also an alkyl group, C 2 - 6 Aruke - group, C 2 _ 6 alkynyl, C 3 _ 6 cycloalkyl group, an optionally substituted Cw alkoxy group, C 3 _ 6 cycloalkyl O alkoxy group, an alkylcarbonyl group, C w alkylthio group, an alkyl sulfide El group, Cw alkylsulfonyl El group, 1-2 same or properly are different alkyl groups optionally substituted amino group, CH alkylcarbonyl two Ruamino group, C 6 alkoxycarbonyl ⁇ amino group, CH alkylsulfonyl ⁇ amino group, a force Rubamoiru Group, sulfamoyl group, ureido group
  • the substitution position of the substituent is not particularly limited, and the substituent may be substituted on any nitrogen atom or carbon atom on the bondable ring.
  • the substituent in the aryl group may be the same as the substituent in the aromatic heterocyclic group which may be substituted or may be substituted, and these substituents may be 1 or A plurality may be substituted.
  • Substitution positions on A r 1 substituent, and the bonding position of A r 1 that bind to X is not particularly limited, substituted or bound on any nitrogen atom or carbon atom bondable on the ring May be.
  • the optionally substituted phenyl group preferably has an ortho position or a meta position.
  • the substituent of the optionally substituted phenyl group is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a cyano group, a trifluoromethyl group, a methoxy group.
  • a fluorine atom preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a cyano group, a trifluoromethyl group, a methoxy group.
  • prodrugs those which can be easily hydrolyzed in vivo to regenerate the xanthine compound of the present invention, specifically, for example, the amino group of the xanthine compound: 1 NH 2
  • Q has the following significance.
  • R 17 represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl group or an aryl group such as a naphthyl group.
  • R 18 and R 19 independently represent a hydrogen atom or an alkyl group.
  • R 2 ° represents a hydrogen atom, 6 alkyl, the above-mentioned aryl group or benzyl group.
  • R 21 represents an alkyl group or a benzyl group.
  • Preferred Q includes the group (1) and the group (3).
  • Preferred examples of the group (3) include those in which R 18 is a hydrogen atom, R 19 is a hydrogen atom, methyl or ethyl, and R 20 is a hydrogen atom, methyl or ethyl.
  • prodrugs can be produced under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs, Vol. 7, Molecular Design,” pp. 163 to 198. May be changed.
  • “Pharmaceutically acceptable salts” include, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, propionate, succinate, lactate, Organic acid salts such as malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate are exemplified.
  • the present invention also includes solvates such as hydrates and ethanol solvates of a xanthine compound, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention includes all tautomers of the xanthine compound, all existing stereoisomers, and all forms of crystalline forms.
  • Preferred examples of the xanthine compound of the present invention include the following 3-aminobiperidine compounds.
  • Preferred examples of the xanthine compound of the present invention include the following cycloalkanediamine compounds.
  • a cycloalkanediamine compound having a diamino group having an absolute configuration represented by the following formula (D) or (E) is preferable.
  • a cycloalkylamine compound having a diamino group having an absolute configuration represented by the following formula (D) is more preferable.
  • each substituent in which the amino group of 3-aminobiperidine has the same configuration as the configuration represented by the following formula (C) is more preferable. That is, specifically, each substituent in which the 3-position in D1 to D29 has an R-configuration and the 3-position in D30 and D31 has an S-configuration is more preferable.
  • the method for producing the compound represented by the formula (I) in the present invention will be described with reference to examples, but the present invention is not limited thereto. In this specification, the following abbreviations may be used for the sake of simplicity.
  • the compound represented by the formula (I) can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized by the following method. Manufacturing method 1
  • the compound represented by the formula (I) or a salt thereof is produced by, for example, a method shown below.
  • X 1 and X 2 represent an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or the like.
  • Compound (2) can be produced by reacting compound (1) with bromine in an inert solvent in the presence or absence of an additive (J. Heterocycl. Chem. 37, 1033 (2000) J. Chem. Soc., Perkin Trans. 113, 1833 (1999), J. Med. Chem. 38, 3838 (1995), etc.).
  • an additive include sodium acetate and the like, and the amount of the additive is generally selected from the range of 1 to 5 equivalents relative to compound (1).
  • the amount of bromine to be used is generally selected from the range of 1 to 3 equivalents relative to compound (1).
  • the inert solvent examples include water, alcohols (eg, ethanol, methanol, isopropanol), ether, 4-dioxane, etc.), organic acids (eg, acetic acid, propionic acid), and mixed solvents thereof.
  • the reaction temperature can be selected from the range of about 20 ° C to about 50 ° C.
  • Compound (4) can be produced by reacting compound (2) with compound (3) in an inert solvent in the presence of a base (J. Heterocycl. Chem. 37, 1033 (2000), J. Chem. Soc., Perkin Trans. 113, 1833 (1999), J. Med. Chem. 38, 3838 (1995), etc.).
  • the amount of compound (3) to be used is generally selected from the range of 1 equivalent to 3 equivalents relative to the compound of formula (2).
  • the base include, for example, aluminum carbonate (carbonate, sodium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, etc.) and aluminum hydroxide (potassium hydroxide, sodium hydroxide, etc.). Examples include potassium carbonate and the like.
  • the amount of the base to be used is generally selected from the range of 1 to 5 equivalents relative to compound (2).
  • inert solvents include aprotic solvents (dimethylformamide, dimethylsulfoxide, etc.), ethers (getyl ether, tetrahydrofuran, 1,4-dioxane, etc.), ketones (acetone, etc.), mixed solvents of these, etc. And preferably dimethylformamide, dimethylsulfoxide and the like.
  • the reaction temperature can be selected from the range of about 10 ° C to about 50 ° C. 3) Process 3
  • Compound (6) can be produced by reacting compound (4) with compound (5) in an inert solvent in the presence of a base.
  • the amount of compound (5) to be used is generally selected from the range of 1 to 3 equivalents based on compound (4).
  • the base include aluminum carbonate (lithium carbonate, sodium carbonate, hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali hydroxide (hydroxide, sodium hydroxide, etc.), hydrogen hydride Power (sodium hydride, hydrogenation power, etc.), alkoxyal power (tert-butoxy power, etc.) and the like, and preferably, lithium carbonate, sodium hydride and the like.
  • the amount of the base to be used is generally selected from the range of 1 to 5 equivalents based on compound (4).
  • the inert solvent for example, aprotic solvents (dimethylformamide, dimethinoresnoleoxide, etc.), ethenore (jetizoleatenole, tetrahydrofuran, 1,4-dioxane, etc.), ketone (acetone) And the like, and a mixed solvent thereof, and more preferably, dimethylformamide and the like.
  • the reaction temperature can be selected from the range of about 10 ° C. to about 10 ° C.
  • Compound (8) can be produced by reacting compound (6) with compound (7) in an inert solvent in the presence or absence of a base.
  • a base for example Min, triethylamine, pyridine, 4- (dimethylamino) pyridine, N-methylmorpholine and the like, preferably diisopropylpropylethylamine and triethylamine.
  • the amount of the base to be used is generally selected from the range of 1 to 5 equivalents based on compound (6).
  • the inert solvent include alcohols (eg, ethanol, methanol, isopropanol), ethers (eg, 1,4-dioxane), and mixed solvents thereof.
  • the reaction temperature can be selected from the range of about 50 ° C to about 150 ° C.
  • the reaction can also be carried out in a closed reaction vessel such as an autoclave. Manufacturing method 2
  • the compound represented by the formula (I) or a salt thereof is produced by, for example, a method shown below.
  • Compound (10) can be produced from compound (6) by the same method as in step 4 of production method 1.
  • Compound (8) can be produced by optically resolving compound (10).
  • the compound (10) is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as getyl ether, an ester solvent such as ethyl ester, etc.).
  • an inert solvent for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as getyl ether, an ester solvent such as ethyl ester, etc.
  • a hydrocarbon-based solvent such as toluene, or acetonitrile, etc., and a mixed solvent thereof
  • an optically active acid eg, a monocarboxylic acid such as mandelic acid, N-benzyloxyalanan, or lactic acid, tartaric acid, o -Dicarboxylic acid such as diisopropylidene tartaric acid or malic acid, or sulfonic acid such as camphors / lefonic acid or bromocamphorsnolephonic acid.
  • the temperature at which the salt is formed include a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent.
  • the salt Before the precipitated salt is collected by filtration, the salt can be cooled if necessary to improve the yield.
  • the amount of the optically active acid or amine used is in the range of about 0.5 equivalent to about 2.0 equivalent, preferably about 1 equivalent, relative to the substrate. The surroundings are appropriate. If necessary, the crystals are placed in an inert solvent (eg, methanol, ethanol,
  • the compound represented by the formula (10) or a salt thereof is produced, for example, by the method shown below.
  • Compound (12) can be produced from compound (6) by a method similar to that in step 4 of production method 1.
  • Process 2 Compound (10) can be produced by deprotecting the Boc group of compound (12) in an inert solvent in the presence of an acid.
  • the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, and preferably trifluoroacetic acid and the like.
  • the amount of the acid to be used is generally selected from the range of 1 equivalent to 5 equivalents relative to compound (12).
  • the inert solvent include halogenated hydrocarbon solvents (dichloromethane, dichloroethane, chloroform, etc.), ethers, 4-dioxane, etc., and mixed solvents thereof.
  • the reaction temperature can be selected from the range of about -20 ° C to about 30 ° C. Manufacturing method 4
  • compound (11) can be produced from compound (13) according to the method described in, for example, J. Org. Chera. 58, 879 (1993).
  • R 4 and n are as defined above.
  • R 4 and n are as defined above.
  • Compounds (7-1) to (7_9) include pharmaceutically acceptable salts.
  • Compound (7) can be synthesized from substituted D-ortin by a known method. Specific examples include the method described in V. Comprehensive Organic transformation, RC Flock, VCH publisher Inc., 1989.

Landscapes

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

Abstract

L'invention concerne un composé de xanthine représenté par la formule suivante (I), lequel composé possède une forte activité inhibitrice de la DPP IV ou est amélioré en matière de sécurité, de non toxicité, etc. Cette invention concerne également un promédicament de ce composé ou un sel pharmaceutiquement acceptable dudit composé ou promédicament.
PCT/JP2003/013990 2002-11-01 2003-10-31 Compose de xanthine Ceased WO2004048379A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003280680A AU2003280680A1 (en) 2002-11-01 2003-10-31 Xanthine compound

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
JP2002320216 2002-11-01
JP2002-320216 2002-11-01
JP2002362953 2002-12-13
JP2002-362953 2002-12-13
JP2002364885 2002-12-17
JP2002-364885 2002-12-17
JP2002-367260 2002-12-18
JP2002367260 2002-12-18
JP2002381161 2002-12-27
JP2002-381161 2002-12-27

Publications (1)

Publication Number Publication Date
WO2004048379A1 true WO2004048379A1 (fr) 2004-06-10

Family

ID=32398335

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2003/013990 Ceased WO2004048379A1 (fr) 2002-11-01 2003-10-31 Compose de xanthine

Country Status (2)

Country Link
AU (1) AU2003280680A1 (fr)
WO (1) WO2004048379A1 (fr)

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006018117A1 (fr) * 2004-08-14 2006-02-23 Sanofi-Aventis Deutschland Gmbh 8-aminoalcoxi-xanthines substituees, leur procede de production, et leur utilisation en tant que medicaments
US7074923B2 (en) * 2002-05-31 2006-07-11 Schering Corporation Process for preparing xanthine phosphodiesterase V inhibitors and precursors thereof
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
US7393847B2 (en) 2004-03-13 2008-07-01 Boehringer Ingleheim International Gmbh Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7439370B2 (en) 2004-05-10 2008-10-21 Boehringer Ingelheim International Gmbh Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides
US7470716B2 (en) 2004-06-24 2008-12-30 Boehringer Ingelheim International Gmbh Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
US7482337B2 (en) 2002-11-08 2009-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7495003B2 (en) 2004-09-11 2009-02-24 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7495002B2 (en) 2004-09-14 2009-02-24 Boehringer Ingelheim International Gmbh 3-methyl-7-butinyl-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7495005B2 (en) 2002-08-22 2009-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
WO2009024542A3 (fr) * 2007-08-17 2009-05-22 Boehringer Ingelheim Int Utilisation de dérivés de la purine
US7550455B2 (en) 2003-11-27 2009-06-23 Boehringer Ingelheim International Gmbh 8-(piperazin-1yl)- and 8-([1,4]diazepan-1yl)-xanthines, the preparation thereof and their use as pharmaceutical composition
US7560450B2 (en) 2002-11-21 2009-07-14 Boehringer Ingelheim Pharma Gmbh & Co., Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7566707B2 (en) 2003-06-18 2009-07-28 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
US7569574B2 (en) 2002-08-22 2009-08-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Purine derivatives, the preparation thereof and their use as pharmaceutical compositions
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
EP2119717A1 (fr) 2004-02-18 2009-11-18 Boehringer Ingelheim International GmbH 8-[3-amino-pipéridine-1-yl]-xanthine, leur fabrication et leur utilisation en tant que complexe DDP IV
US7645763B2 (en) 2004-02-23 2010-01-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical composition
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
JP4797021B2 (ja) * 2004-10-01 2011-10-19 メルク・シャープ・エンド・ドーム・コーポレイション 糖尿病の治療または予防用のジペプチジルペプチダ−ゼ−ｉｖ阻害剤としてのアミノピペリジン
US8071583B2 (en) 2006-08-08 2011-12-06 Boehringer Ingelheim International Gmbh Pyrrolo[3,2-D] pyrimidines as DPP-IV inhibitors for the treatment of diabetes mellitus
US8106060B2 (en) 2005-07-30 2012-01-31 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
US8232281B2 (en) 2006-05-04 2012-07-31 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US8236810B2 (en) 2004-08-03 2012-08-07 Sanofi-Aventis Deutschland Gmbh Substituted 8-aminoalkylthioxanthines, and their use as inhibitors of dipeptidyl peptidase IV
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
US8846695B2 (en) 2009-01-07 2014-09-30 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US9149478B2 (en) 2010-06-24 2015-10-06 Boehringer Ingelheim International Gmbh Diabetes therapy
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9186392B2 (en) 2010-05-05 2015-11-17 Boehringer Ingelheim International Gmbh Combination therapy
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US9457029B2 (en) 2009-11-27 2016-10-04 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug
US12312352B2 (en) 2012-05-14 2025-05-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in SIRS and/or sepsis

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002560A2 (fr) * 2000-07-04 2002-01-10 Novo Nordisk A/S Composes heterocycliques inhibiteurs de l'enzyme dpp-iv
WO2002068420A1 (fr) * 2001-02-24 2002-09-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives xanthine, fabrication et utilisations en tant qu'agents pharmaceutiques
WO2003004496A1 (fr) * 2001-07-03 2003-01-16 Novo Nordisk A/S Derives de purine inhibiteurs de dpp-iv pour le traitement du diabete

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002560A2 (fr) * 2000-07-04 2002-01-10 Novo Nordisk A/S Composes heterocycliques inhibiteurs de l'enzyme dpp-iv
WO2002068420A1 (fr) * 2001-02-24 2002-09-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives xanthine, fabrication et utilisations en tant qu'agents pharmaceutiques
WO2003004496A1 (fr) * 2001-07-03 2003-01-16 Novo Nordisk A/S Derives de purine inhibiteurs de dpp-iv pour le traitement du diabete

Cited By (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7786301B2 (en) * 2002-05-31 2010-08-31 Schering Corporation Process for preparing xanthine phosphodiesterase V inhibitors and precursors thereof
US7074923B2 (en) * 2002-05-31 2006-07-11 Schering Corporation Process for preparing xanthine phosphodiesterase V inhibitors and precursors thereof
US8178541B2 (en) 2002-08-21 2012-05-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9108964B2 (en) 2002-08-21 2015-08-18 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US10023574B2 (en) 2002-08-21 2018-07-17 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US10202383B2 (en) 2002-08-21 2019-02-12 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9321791B2 (en) 2002-08-21 2016-04-26 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9556175B2 (en) 2002-08-21 2017-01-31 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions
US8664232B2 (en) 2002-08-21 2014-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8119648B2 (en) 2002-08-21 2012-02-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7495005B2 (en) 2002-08-22 2009-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
US7569574B2 (en) 2002-08-22 2009-08-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Purine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7838529B2 (en) 2002-08-22 2010-11-23 Boehringer Ingelheim International Gmbh Xanthine derivates, their preparation and their use in pharmaceutical compositions
US7696212B2 (en) 2002-11-08 2010-04-13 Boehringer Ingelheim Pharma Gmbh And Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7482337B2 (en) 2002-11-08 2009-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7560450B2 (en) 2002-11-21 2009-07-14 Boehringer Ingelheim Pharma Gmbh & Co., Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US8034941B2 (en) 2003-06-18 2011-10-11 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
US7566707B2 (en) 2003-06-18 2009-07-28 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
US7550455B2 (en) 2003-11-27 2009-06-23 Boehringer Ingelheim International Gmbh 8-(piperazin-1yl)- and 8-([1,4]diazepan-1yl)-xanthines, the preparation thereof and their use as pharmaceutical composition
US8697868B2 (en) 2004-02-18 2014-04-15 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
EP2119717A1 (fr) 2004-02-18 2009-11-18 Boehringer Ingelheim International GmbH 8-[3-amino-pipéridine-1-yl]-xanthine, leur fabrication et leur utilisation en tant que complexe DDP IV
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US7645763B2 (en) 2004-02-23 2010-01-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical composition
US7393847B2 (en) 2004-03-13 2008-07-01 Boehringer Ingleheim International Gmbh Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
US7432262B2 (en) 2004-03-13 2008-10-07 Boehringer Ingelheim International Gmbh Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
US7667035B2 (en) 2004-05-10 2010-02-23 Boehringer Ingelheim International Gmbh Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides
US7439370B2 (en) 2004-05-10 2008-10-21 Boehringer Ingelheim International Gmbh Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides
US7906539B2 (en) 2004-06-24 2011-03-15 Boehringer Ingelheim International Gmbh Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
US7470716B2 (en) 2004-06-24 2008-12-30 Boehringer Ingelheim International Gmbh Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
US8236810B2 (en) 2004-08-03 2012-08-07 Sanofi-Aventis Deutschland Gmbh Substituted 8-aminoalkylthioxanthines, and their use as inhibitors of dipeptidyl peptidase IV
WO2006018117A1 (fr) * 2004-08-14 2006-02-23 Sanofi-Aventis Deutschland Gmbh 8-aminoalcoxi-xanthines substituees, leur procede de production, et leur utilisation en tant que medicaments
US7879864B2 (en) 2004-08-14 2011-02-01 Sanofi-Aventis Deutschland Gmbh Substituted 8-aminoalkoxy-xanthine compounds and compositions useful in the treatment of hyperlipidemia and diabetes
US7495003B2 (en) 2004-09-11 2009-02-24 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7495002B2 (en) 2004-09-14 2009-02-24 Boehringer Ingelheim International Gmbh 3-methyl-7-butinyl-xanthines, the preparation thereof and their use as pharmaceutical compositions
JP4797021B2 (ja) * 2004-10-01 2011-10-19 メルク・シャープ・エンド・ドーム・コーポレイション 糖尿病の治療または予防用のジペプチジルペプチダ−ゼ−ｉｖ阻害剤としてのアミノピペリジン
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
US8541450B2 (en) 2004-11-05 2013-09-24 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines
US9751855B2 (en) 2004-11-05 2017-09-05 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US8883805B2 (en) 2004-11-05 2014-11-11 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US9499546B2 (en) 2004-11-05 2016-11-22 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
US8106060B2 (en) 2005-07-30 2012-01-31 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
EP2540724A1 (fr) 2005-07-30 2013-01-02 Boehringer Ingelheim International GmbH Chlorhydrate et hydrates de 1-[(3-cyano-pyridine-2-yl) méthyl]-3-méthyl-7-(2-butine-1-yl)-8-(3-amino-pipéridine-1-yl)-xanthine, leur fabrication et leur utilisation comme médicament
US8637530B2 (en) 2005-07-30 2014-01-28 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
EP2253311A2 (fr) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Utilisation d'agonistes du récepteur de GPR119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose, et thérapie de combinaison associée
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
US11084819B2 (en) 2006-05-04 2021-08-10 Boehringer Ingelheim International Gmbh Polymorphs
US9173859B2 (en) 2006-05-04 2015-11-03 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US10301313B2 (en) 2006-05-04 2019-05-28 Boehringer Ingelheim International Gmbh Polymorphs
US9493462B2 (en) 2006-05-04 2016-11-15 Boehringer Ingelheim International Gmbh Polymorphs
US8673927B2 (en) 2006-05-04 2014-03-18 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11291668B2 (en) 2006-05-04 2022-04-05 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US10080754B2 (en) 2006-05-04 2018-09-25 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US8232281B2 (en) 2006-05-04 2012-07-31 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US11919903B2 (en) 2006-05-04 2024-03-05 Boehringer Ingelheim International Gmbh Polymorphs
US12171767B2 (en) 2006-05-04 2024-12-24 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US12178819B2 (en) 2006-05-04 2024-12-31 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US9815837B2 (en) 2006-05-04 2017-11-14 Boehringer Ingelheim International Gmbh Polymorphs
US8071583B2 (en) 2006-08-08 2011-12-06 Boehringer Ingelheim International Gmbh Pyrrolo[3,2-D] pyrimidines as DPP-IV inhibitors for the treatment of diabetes mellitus
EP2190434B1 (fr) 2007-08-17 2019-04-17 Boehringer Ingelheim International GmbH Utilisation de derives de la purine pour leur utilisation dans le traitement des maladies liees a fap
EP3542801A1 (fr) * 2007-08-17 2019-09-25 Boehringer Ingelheim International GmbH Dérivés de la purine destinés à être utilisés dans le traitement de maladies associées à fab
WO2009024542A3 (fr) * 2007-08-17 2009-05-22 Boehringer Ingelheim Int Utilisation de dérivés de la purine
US10022379B2 (en) 2008-04-03 2018-07-17 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US10973827B2 (en) 2008-04-03 2021-04-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9415016B2 (en) 2008-04-03 2016-08-16 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US10034877B2 (en) 2008-08-06 2018-07-31 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug
US9212183B2 (en) 2008-12-23 2015-12-15 Boehringer Ingelheim International Gmbh Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US8846695B2 (en) 2009-01-07 2014-09-30 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
US9457029B2 (en) 2009-11-27 2016-10-04 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US10092571B2 (en) 2009-11-27 2018-10-09 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
US9603851B2 (en) 2010-05-05 2017-03-28 Boehringer Ingelheim International Gmbh Combination therapy
US10004747B2 (en) 2010-05-05 2018-06-26 Boehringer Ingelheim International Gmbh Combination therapy
US9186392B2 (en) 2010-05-05 2015-11-17 Boehringer Ingelheim International Gmbh Combination therapy
US9149478B2 (en) 2010-06-24 2015-10-06 Boehringer Ingelheim International Gmbh Diabetes therapy
EP3323818A1 (fr) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US11911387B2 (en) 2010-11-15 2024-02-27 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US8962636B2 (en) 2011-07-15 2015-02-24 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9199998B2 (en) 2011-07-15 2015-12-01 Boehringer Ingelheim Internatioal Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US10195203B2 (en) 2012-05-14 2019-02-05 Boehringr Ingelheim International GmbH Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US12312352B2 (en) 2012-05-14 2025-05-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in SIRS and/or sepsis
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US12364700B2 (en) 2016-06-10 2025-07-22 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy

Also Published As

Publication number Publication date
AU2003280680A1 (en) 2004-06-18

Similar Documents

Publication Publication Date Title
WO2004048379A1 (fr) Compose de xanthine
AU2020341681B2 (en) RIP1 inhibitory compounds and methods for making and using the same
CN102918034B (zh) 多取代芳族化合物作为凝血酶的抑制剂
RU2285693C2 (ru) Производные пиридина и хинолина, способ их получения, фармацевтическая композиция, применение соединений для лечения заболеваний, ассоциированных с dpp-iv
EP1067123B1 (fr) Composes heterocycliques azotes
KR101444489B1 (ko) 심혈관 질환을 예방 및 치료하기 위한 화합물
RS62987B1 (sr) Novi heterociklični derivati korisni kao shp2 inhibitori
CN106068265B (zh) 用于治疗代谢病症的二氢吡啶酮mgat2抑制剂
JP2000264877A (ja) 含窒素複素環化合物
CN106061968B (zh) 四唑酮-取代的二氢吡啶酮mgat2抑制剂
CN105209467A (zh) 咪唑并吡咯烷酮衍生物及其在治疗疾病中的用途
CA2966250C (fr) Derives benzo a cycle a six chainons en tant qu'inhibiteur de la dpp-4 et son utilisation
CN105324117A (zh) 作为丝氨酸蛋白酶抑制剂的多取代芳族化合物
JPWO2006001318A1 (ja) スルホンアミド化合物
CN111183140B (zh) 制备和使用pde9抑制剂的方法
AU2016218693A1 (en) Substituted amino six-membered saturated heterocyclic fat used as long-acting DPP-IV inhibitor
EP2733144B1 (fr) Nouveau composé ayant une activité d'inhibition de parp
JP7394140B2 (ja) 標的ユビキチン化分解ｂｒｄ４タンパク質化合物、その調製方法および応用
WO2016034137A1 (fr) Dérivés de pyrazolo[3,4-c]pyridine
CN101124223A (zh) 吡啶并-嘧啶衍生物，它们的制备方法与其治疗用途
JP3853389B2 (ja) 新規の３−フェニルスルホニル−３，７−ジアザビシクロ［３，３，１］ノナン−化合物、その製法及び抗不整脈剤
WO1999003858A9 (fr) Derives purine et leur application medicinale
JP2002536365A (ja) 貧血と闘うのに使用される置換ピラゾールカルボン酸
KR101082227B1 (ko) 피라졸로피리미딘 화합물의 메탄술폰산염, 그 결정 및 그제조 방법
CN111662239A (zh) 1,2,4-三唑类化合物及其制法和药物用途

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP