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WO2004113345A1 - Compose de pyrrole condense et son utilisation comme medicament - Google Patents

Compose de pyrrole condense et son utilisation comme medicament Download PDF

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Publication number
WO2004113345A1
WO2004113345A1 PCT/JP2004/008917 JP2004008917W WO2004113345A1 WO 2004113345 A1 WO2004113345 A1 WO 2004113345A1 JP 2004008917 W JP2004008917 W JP 2004008917W WO 2004113345 A1 WO2004113345 A1 WO 2004113345A1
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Prior art keywords
group
hydrogen atom
alkyl
same
alkoxy
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PCT/JP2004/008917
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English (en)
Japanese (ja)
Inventor
Takeshi Nakamura
Masaki Takagi
Toshihiro Kiguchi
Taku Ikenogami
Nobuhisa Ueda
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Japan Tobacco Inc.
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Publication of WO2004113345A1 publication Critical patent/WO2004113345A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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

Definitions

  • the present invention relates to a novel condensed pyrrole compound having HLGPa (Human LiverGlycogenPhosphhory1asea) inhibitory activity and a pharmaceutical use thereof. Furthermore, the present invention relates to a therapeutic agent for diabetes comprising a compound having a condensed pyrrole structure or a pharmaceutically acceptable salt thereof.
  • HLGPa Human LiverGlycogenPhosphhory1asea
  • Diabetes is a chronic disease that results from abnormal sugar, lipid, and amino acid metabolism due to a lack of insulin action. If left untreated, it will show hyperglycemia and urine sugar. Diabetes is divided into insulin-dependent and non-insulin-dependent. Approximately 90% of diabetics have insulin-independent diabetes.
  • Insulin-dependent diabetes mellitus is susceptible to ketemia and acidosis due to the loss of insulin secretion, and if left untreated, falls into diabetic coma. Diet and oral hypoglycemic drugs have no therapeutic effect and can only be treated with insulin.
  • non-insulin dependent diabetes mellitus has a lower than normal insulin action, but has a low tendency to ketemia and acidosis, and does not necessarily require insulin for treatment.
  • hypoglycemic drugs used to correct hyperglycemia include insulin, sulfururea (eg, dalibenclamide, tolptamide), biguanides (eg, metformin), insulin sensitizers (eg, Troglitazone) and a-Darcosidase inhibitors (eg, acarpose) have been used.
  • sulfururea eg, dalibenclamide, tolptamide
  • biguanides eg, metformin
  • insulin sensitizers eg, Troglitazone
  • a-Darcosidase inhibitors eg, acarpose
  • Insulin preparations are used for insulin-dependent diabetes mellitus, and they certainly lower blood glucose, but they must be administered by injection and may cause hypoglycemia.
  • Sulfo-lurea agents stimulate the knee) 3 cells and promote endogenous insulin secretion Force
  • the timing and amount of insulin secretion are determined by the administration timing and dose of the drug, regardless of the blood glucose level. This often results in hypoglycemia as a side effect due to the prolonged action of the drug. In addition, digestive symptoms such as anorexia appear. Contraindicated in patients with severe ketosis or liver or dysfunction.
  • the biguanide drugs do not have i) three-cell stimulation, and do not cause hypoglycemia in healthy individuals and diabetic patients when administered alone.
  • Possible mechanisms of action include increased sugar utilization by anaerobic glycolysis, suppression of gluconeogenesis, and suppression of intestinal absorption of sugar. As a side effect, relatively severe lactic acidosis is likely to occur.
  • Drugs that improve insulin resistance include thiazolidine derivatives, but thiazolidine derivative compounds have no insulin secretion-promoting action, have an increased insulin action, activate insulin receptor kinase, and take up glucose in peripheral tissues. It has a stimulatory effect and an improvement in the state of increased hepatic glucose production, but it is known that gastrointestinal symptoms and edema occur as side effects, and a decrease in red blood cell count, hematocrit, hemoglobin, and an increase in LDH .
  • ⁇ -Darcosidase inhibitors delay the digestion and absorption of carbohydrates in the gastrointestinal tract and suppress the postprandial rise in blood sugar, but have side effects such as bloating, wheezing, and diarrhea. 521-522, see JOSL IN 'SDI ABETES ME LLI TUS 13 Th Edition.
  • NIDDM patients have an increased amount of glucose released from the liver during fasting compared to healthy subjects. This suggests that hepatic sugar release may be a potential target for drug treatment of NI DDM.
  • the source of sugar in the release of sugar from the liver is glucose produced by gluconeogenesis and glycogenolysis.
  • glycogenolysis was significantly involved in the release of glucose from the liver, and that the rate of fasting glycogenolysis was 75% higher than in healthy subjects.
  • glucose output from the liver transiently increased after glucose loading, suggesting that dalicogen degradation is involved in this increase.
  • glycogen disease type IV liver glycogen phosphorylase deficiency
  • glycogenolysis is catalyzed by HLGPa, and by perphosphorylating glycogen (n glucose units), glucose monomonophosphate (G 1-P) and glycogen (EL—one glucose Unit) is known.
  • dihydrhydrazine compounds having a structure similar to that of the present invention are disclosed.
  • the literature does not disclose that the fused ring pyrrole compound as described in the present application has an HLGPa inhibitory activity.
  • the compound is effective as an antidiabetic agent (for example, Ya oxue Xuebao (1984) , 19 (10), 737-7).
  • the following general formula is disclosed as a compound having a darikogen phosphorylase inhibitory activity having the same action as that of the present invention.
  • the structural feature of the invention is an indole hydrazine structure, which is different from the structure having a condensed pyrrole ring and diacyl hydrazine as in our invention. Also there is no disclosure of a compound having the structure as of our invention (e.g., Kokusaioyake Hirakidai 96Z39384 No. Panfuretsuto (Kohyo 10 51 1687 JP) see) 0
  • the invention is characterized by having a dihydryl hydrazine structure and requiring an indole structure.
  • the present application is characterized in that a condensed pyrrole ring is indispensable in addition to the dihydryl hydrazine structure, and the two are different (for example, see WO 03/37864 pamphlet).
  • R 4 and R 5 are independently hydrogen, halo, nitro, cyano, human Doroki death, Furuoromechiru, Jifuruoromechiru, triflate Ruo Russia methyl, Torifuruorome butoxy, Amino, force / Repokishi, mosquito ⁇ Pamoiru, main mercaptopurine, vinegar ⁇ "Famoinore, ⁇ Ray de, 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ji 6 alkoxy, - 6 Arukanoiru, C i-6 alk Noi Ruo alkoxy, N-- 6 alkyl Le) amino, N, N-- 6 alkyl
  • N -— 6 alkyl Carpamoyl, N, N — (Ci- 6 alkyl) 2 carpamoyl, Ci — 6 alkyl S (O) a (where a is 0-2), Ci — 6 alkoxycarpo- Le, Ji 6 alkoxycarbonyl ⁇ Mino, N_ (C - 6 alkyl .) S Rufamoiru, N, N-(C Preparative 6 Anorekiru) 2 sulphamoyl, alkyl Suruhoniruamino Contact Yopi ⁇ - 6 alkyl sulfonyl Lou N-(C i_ 6 alkyl) is selected from ⁇ amino;
  • R 6 is hydrogen or Ci_ 6 alkyl
  • R 1 is hydrogen, halo, nitro, Shiano, human Dorokishi, Amino, carboxy, Cal Pamoiru, mercapto, sulfamoyl, ureido, C 6 alkyl, C 2 - 6 ⁇ alkenyl, C 2 - 6 alkynyl, C ⁇ _ 6 alkoxy , CI- 6 Arukanoiru, C _ 6 alkanoyloxymethyl noisy Ruo alkoxy, N- (C 6 alkyl) amino, N, N-!
  • 6 alkyl S (O) a (In here, a is a 0 to 2), C 6 alkoxycarbonyl, C i_ 6 alkoxy force Ruponiruamino, N-- 6 alkyl) sulphamoyl, N, N- (C ⁇ 6 ⁇ alkyl) 2 sulphamoyl, C i_ 6 alkylsulfonyl ⁇ amino and C i_ 6 Al Kirusuruho two Lou N-(C - 6 alkyl) amino, C 3 _ 8 cycloalkyl, C 3 - 8 Shikuroarukiru Ji 1 - 6 Arukiru, Ariru, Aryl — 6 alkyl, heterocyclic group (heterocyclic group) C — selected from 6 alkyl; where: 1 is substituted on carbon by one or more groups selected from P Often, when the heterocyclic group contains one NH— moiety, the nitrogen may be substituted by a group selected from R; R 2 is
  • E and G are independently a direct bond, One O-, one S-, -SO-, - S0 2 - , -OC (O) primary, one C (O) O-, one C (O) —, — NR a —, one N aC (O) —, -C (O) NR a —, one S0 2 NR a —, one NR a SO 2 —, one NR a C (O) one, one OC (O) NR a -, -NR a C (O) O-, one NR a SO 2 NR b -, -SO 2 NR a C (O) - and single C (O) NR a S0 2 - from Wherein R a and R b are independently selected from hydrogen or alkyl optionally substituted by group V;
  • F is C- 6 alkylene or a direct bond optionally substituted by one or more Q;
  • H is Ariru, is selected from C 3 _ 8 cycloalkyl Contact Yopi heterocyclic group;. Wherein H may be optionally substituted on carbon by one or more selected from S said heterocyclic group If it contains one NH— moiety, the nitrogen atom may be substituted by a group selected from T;
  • R 3 is hydrogen or Ci- 6 alkyl; n is selected from 0-4; wherein the values of R 1 may be the same or different; and the values of R 3 may be the same or different;
  • P, S and Q are independently halo, nitro, Shiano, human Dorokishi, Torifuruo Romechiru, Torifuruorome butoxy, Amino, carboxy, Karupamoiru, Melka script, sulfamoyl, ureido, Ji 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, - 6 alkoxy, C i _ 6 Arukanoiru, 6 Arukanoiruoki Shi, N-(C - 6 alkyl) Amino, N, N- (C ⁇ 6 alkyl) 2 Amino,. C — 6 alkanoylamino, N— (C ⁇ e alkyl) carpamoyl, N, N— (C 1
  • C Bok 6 alkyl) 2 sulphamoyl, C 6 alkylsulfamoyl ⁇ amino, C 6 alkylsulfonyl one N-(C _ 6 alkyl) amino, c 3 _ 8 cycloalkyl, is selected Ariru and to the heterocyclic group;
  • P, S and Q may be independently substituted on carbon by one or more selected from V, and when the heterocycle contains one NH— moiety, a nitrogen atom May be substituted by a group selected from U;
  • V is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carpamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino —Methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-getylcarpamoyl, N-methyl-1-N-ethyl / recarpamoiole, Metinorecio, Echirechio, Methyl / Less / Refinil, Echinoles Luffiel, Mesyl, Echinoresulfur, Methoxycarbonyl, Eth
  • n— is amino, 1-phenyl-1-5-methyl-1 H—1,5 —Venzodiazepine-1,4 (3H, 5H) dione-3-yl, 1-methyl-5-phenyl-2, oxo-1,2,3-dihydro-1H—Venzo (E) ( 1,4) diazepine-1 3-yl, 2- (4-phenyl-1,2,5,6-tetrahydropyridine 1-11) ethinole, 3— (4-phenyleno 1,2,5) , 6-tetrahydropyri'zin-1-yl) propyl, 2- (4-furpiperazine-1-11) ethyl, 2- (N-methylamino) ethyl, 2-morpholinoethyl or 2- (N —Methyl-N-benzylamino) not ethyl;
  • each R a Oyopi scale 15 are independently hydrogen or a C - Ri Cs alkyl der; each R d is independently hydrogen, CI- C 8 alkyl, CI- Cs alkoxy, ⁇
  • X 1 is not NR a , _CH 2 —, O or S).
  • the feature of the present invention lies in that it has a fused pyrrole ring and has an amide structure as shown in the title of the present invention.
  • R 2 and R 3 are mentioned a number of exemplified as the substituents of R 3, among them, a hydrogen atom as R 1, and one E- F- G_H (E as R 2 In addition, one NR a C (O) is disclosed), and a hydrogen atom is certainly disclosed as R 3 .
  • R 1 a hydrogen atom
  • E E- F- G_H
  • R 3 a hydrogen atom
  • RR 2 and R 3 there is no disclosure of specific examples of the compound having a diacylhydrazine structure as in the invention of the present application, and further no disclosure of a production method suggesting this.
  • RR 2 and R 3 there is no specific disclosure or suggestion of selecting RR 2 and R 3 to have a structure similar to the present invention among many substituents (for example, WO 02/20530). No. paflet).
  • an object of the present invention is to provide an HLGPa inhibitor which is more active, has no side effects, and is excellent in oral absorption and metabolic stability as compared with conventional drugs for treating diabetes. It is to be.
  • the present invention has been made in view of the above problems, and as a result of intensive studies to search for a therapeutic agent for diabetes having a useful HLGPa inhibitory activity, surprisingly, They have found that they have HLGPa inhibitory activity, and have completed the present invention.
  • R 1 is a hydrogen atom or an acyl group
  • R 2 is a hydrogen atom or an alkyl group
  • R 3 is a hydrogen atom or a C—e alkyl group
  • A is one N (R 8 )-(where R 8 is a hydrogen atom, a Ci-e alkyl group or an aryl group which may have a substituent), one C (R 9 ) (R 10 (Where R 9 and R 10 are the same or different and are independently a hydrogen atom, a hydroxyl group, an amino group,
  • R 12 , 13 , R 14 and R 15 are the same or different and independently represent a hydrogen atom, a halogen atom, an alkyl group, a C- 6 alkoxy group, a nitro group, a hydroxyl group, A cyano group, a haloalkyl group, an aralkyl group, an aryl group which may have a substituent, an aryloxy group, a tetrazolyl group, a triazolyl group,
  • R 19 is an aryl group which may have a substituent, a hydroxyl group, a C- 6 alkoxy group or -N (R 20 )
  • R 21 (where R 20 and R 21 are the same or different and are each independently a hydrogen atom
  • R 22 is a hydrogen atom, a hydroxyl group, C - 6 alkoxy group, an amino group, at C 2 _ 12 dialkylamino group or a C 2 _ 7 alkoxycarbonyl two Ruamino group ), -O- (CH 2 ) r -R 23 (where r is an integer of 1 to 4, R 23 is a hydroxyl group, an amino group, a C 2 _ 7 Alkyl group Ruponioxy group or one CO—R 24 (where R 24 is a hydroxyl group, —6 alkoxy group or one N (R 25 ) ( 26 ) (where R 25 and R 26 are the same or different Or a hydrogen atom, an alkyl group or an aralkyl group, or R 25 and R 26 together with an adjacent nitrogen atom
  • R 27 is - 6 Arukirua an amino group or a C 2 one 12 dialkylamino group
  • R 28 R 29
  • R 28 ⁇ Pi R 29 are the same or different, a hydrogen atom, C -6 alkyl group, aryl group which may have a substituent, acyl group, (CH 2 ) p , — COO— R 3
  • R 3 ° is a hydrogen atom, a substituted or unsubstituted aryl group or —6 alkyl group (the 6 alkyl group is a hydroxyl group, a trifluoromethyl group, Which may be substituted with an aryl group, a morpholino group or a carboxyl group which may have a substituent)) CON (R 31 ) (R 32 ) (where R
  • R 31 and R 32 are the same or different, a hydrogen atom, CI_ 6 have an alkyl group or a substituted group is also good Ariru group), -CO-R 33 (wherein, R 33 is. 6 ⁇ alkyl Or an aryl group which may have a substituent) or one CO— (CH
  • 1 ⁇ 1613 to 1 ⁇ 166 and 1 1715 to 1 ⁇ 178 are the same or different and are each a hydrogen atom, a halogen atom, an alkyl group, an amino group, a hydroxyl group, a —6 alkoxy group, a COOR 35 (here, R 35 They are the same or different, a hydrogen atom or a - 6 alkyl group der Ru) or single CON (R 31 ') (R 32') ( wherein, R 31 'and R 32' are R 31 ⁇ Pi R 3 2 Is synonymous with)
  • Y is one S-, one O- or one N (R 36) i (wherein, R 36 is a hydrogen atom or a 0 E one 6 alkyl group (the - 6 alkyl group, substitution at the carboxyl group or tetrazolyl group May be))
  • n is 0 or an integer from 1 to 4.
  • R 37 ⁇ Pi R 38 are the same or different, a hydrogen atom, a halogen atom, C ⁇ _ 6 alkyl group, - 6 alkoxy group, an amino group, a nitro group, a hydroxyl group, C 2 - 7 ⁇ alkoxy Karuboeru group, carboxyl group, C 2 - 7 haloalkylcarbonyl ⁇ amino group or one O- CO-:. 42 (wherein, R 42 is, CI- 6 alkyl group, DOO 6 alkyl Ruamino group or 0 2 - 12 dialkyl An amino group);
  • R 39 is a hydrogen atom, an aryl group which may have a substituent or a heterocyclic group
  • R 4. ⁇ Pi R 41 are the same or different, a hydrogen atom, CI- 6 alkyl group, CI- 6 ⁇ alkoxy group or a C 2 - 7 alkoxycarbonyl - or a group, or R 4 ° ⁇ Pi R 4 1 is Together with adjacent carbon atoms,
  • Q is one (CH 2 ) t— (where t is 2 or 3 and the methylene group may be substituted with an oxo group), one CO—NH—CH 2 — or one CH 2 — NH— CO—
  • W is one CO—, one CS— or one CH 2 —;
  • V is one CO—, one CS— or one CH 2 —;
  • V 2 is one O—, one CH 2 — or one N (R 46 ) — (where R 46 is a hydrogen atom, a C i-6 alkyl group or an optionally substituted aryl group) ) Is;
  • V 3 is one CH (R 47 ) one or one N (R 47 ′) one (where R 47 and R 47 ′ are A hydrogen atom, an aralkyl group, a heterocyclic group, or an aryl group which may have a substituent), or a condensed pyrrole compound represented by the formula: Pharmaceutically acceptable salts.
  • Y is 1 S—, 1 O— or 1 N (R 36 ) 1 (where R 36 is a hydrogen atom or —6 alkyl group);
  • A shows an N (R 8 ") - (wherein, R 8 '' is a hydrogen atom, an alkyl group or an optionally substituted Ariru group), -C (9") ( R 10 ")
  • R 9 ′ ′ and R 1 () ′′ are the same or different and are independently a hydrogen atom, a hydroxyl group, an amino group, a Ci- 6 alkyl group, a hydroxyalkyl group or a C 2 — 7 alkoxycarbonyl
  • Y is one S— or one N (R 36 ) one (where R 36 is the same as the above [1]), and ⁇ ⁇
  • R 37> and R 38 ′ are the same or different and are a hydrogen atom, a halogen atom, — A 6- alkyl group, a 6- alkoxy group, an amino group, a hydroxyl group or —O—CO—R 42 (where R 42 is as defined in the above [1]);
  • R 39 ′ is a hydrogen atom or an aryl group which may have a substituent
  • R 4G ' ⁇ Pi R 41' are the same or different, a hydrogen atom, CI- 6 alkyl group or a C 2 one 7 alkoxy or a carbonyl group, or together with the carbon atom to ⁇ Pi R 41 'is adjacent Natsu,
  • Q ′ is one (CH 2 ) t-(where t is 2 or 3 and the methylene group may be substituted with an oxo group), one CO—NH—CH 2 — or one CH 2 — NH — CO— is;
  • W is one CO— or one CH 2 —
  • V x 'and V 2 have the same meanings as and V 2 of the above-mentioned [1];
  • V 3 is one CH (R 47 ") one or one N (R 47 “')-(where R 47 "and R 4
  • fused pyrrole compound according to any one of [I] to [5], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a medicament comprising the condensed pyrrole compound according to any of [1] to [13], a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Composition comprising the condensed pyrrole compound according to any of [1] to [13], a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the statin drug is selected from the group consisting of oral pastatin, simpastatin, pravastatin, flupastatin, atorpastatin and seripastatin
  • the antidiabetic drug is selected from the group consisting of an insulin preparation, a sulfururea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an ⁇ - dalcosidase inhibitor and an insulin sensitizer.
  • Pharmaceutical composition wherein the antidiabetic drug is selected from the group consisting of an insulin preparation, a sulfururea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an ⁇ - dalcosidase inhibitor and an insulin sensitizer.
  • the antidiabetic agent is insulin, dalibenclamide, tolptamide, daliclopyramide, acethexamide, glimepiride, tolazamide, daliclazide, nateglinide, gribuzole, metformin hydrochloride, pformin hydrochloride, poglipoise, acapulose hydrochloride and pioglitazone hydrochloride.
  • the pharmaceutical composition according to the above [20] which is selected from the group consisting of:
  • Halogen atom means chlorine atom, bromine atom, fluorine atom, iodine atom and the like.
  • Alkyl group means an alkyl group having 1 to 6 carbon atoms which may be linear or branched, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group or hexyl group, etc., preferably having 1 to 4 carbon atoms, which may be linear or branched It is an alkyl group.
  • the fC-ealkyl group in R 30 and R 30 ′′ is substituted with a hydroxyl group, a trifluoromethyl group, an aryl group which may have a substituent (synonymous with the “aryl group” below), a morpholino group or a carboxyl group
  • the substitution position is not particularly limited as long as it can be substituted.
  • the number of substituents is not particularly limited.
  • substitution position is not particularly limited as long as substitution is possible.
  • the number of substituents is not particularly limited.
  • R 4 5 ⁇ Pi R 4 5 '' 0 - 6 alkyl group may be substituted with a carboxyl group or a C 2 _ 7 alkoxycarbonyl group (hereinafter synonymous), the substitution position is if possible substitution There is no particular limitation.
  • the number of substituents is not particularly limited.
  • the ". Preparative 6 alkoxy group” represents a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, for example, main butoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, tert- Putokishi Group, pentyloxy group, tert-pentyloxy group or hexyloxy group, preferably a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, for example, methoxy group, ethoxy group, isopropoxy group, Butoxy group and tert-butoxy group.
  • C 2 _ 7 alkoxycarbonyl group refers to an alkoxycarbonyl group in which the alkyl moiety has 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) and is linear or branched. , Methoxycarbonyl group, ethoxycarbonyl group, propoxyl-proponyl group, isopropoxycanoleponyl group, butoxycarbonyl group, isopoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexylol A xycarbol group;
  • C 2 _ 7 alkoxycarbonylamino group refers to an alkoxycarbonylamino group in which the alkyl portion has 1 to 6 carbon atoms (preferably 1 to 4) and is linear or branched.
  • C 3 _ 13 alkoxycarbylalkyl group means that both alkyl portions (alkoxy portion and alkyl portion) have 1 to 6 (preferably 1 to 4) carbon atoms, and Represents an alkoxycarbonylalkyl group which is a branched chain, for example, methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl Tyl group, ethoxycarbonylethyl group, propoxycarbonylmethyl group, isopropoxycarbonyl group, butoxycarbonylmethyl group, isopoxycarbonyl group, tert-butoxy group / leponinolemethinole group, pentinoleoxycanolepol-methyl group And a hexyloxy group.
  • a linear or branched alkyl alkyl group for example, a methylcarboxy group, an ethylcarboxy group, a propylcarboxy group.
  • the - "6 hydroxyalkyl group”, Ri Oh straight-chain or branched-chain alkyl group is substituted with 1 or 2 or more hydroxyl groups group having 1 to 6 carbon atoms (preferably 1-4),
  • the substitution position of the hydroxyl group is not particularly limited. For example, a hydroxymethyl group; 1 or more 2-hydroxyethyl groups; 1-, 2- or 3-hydroxypropyl groups; 1-, 2-, 3- or 4-hydroxybutyl groups; 3-, 4- or 5-hydroxypentynole group; 11, 2-, 3-, 4-, 5- or 6-hydroxyhexynole group; 2-hydroxy-2-methylethyl group; 1,2-dihydroxy And an ethyl group.
  • haloalkyl group is a group in which a straight-chain or branched-chain alkyl group having 1 to 6 (preferably 1 to 4) carbon atoms is substituted with one or more halogen atoms (as defined above). Yes, the substitution position is not particularly limited.
  • trifluoromethyl group 1- or 2-chloroethyl group, 1- or 2-bromoethyl group, 1- or 2-fluoroethyl group, 11, 2- or 3-chloropropyl group, 1 1, 2- or 3-promopropyl tomb, 1, 2- or 3-fluoropropyl, 1, 2-, 3- or 4-chlorobutyl, 1, 2-, 3- or 4-promobutyl A 11, 2-, 31- or 4-fluorobutyl group.
  • the "0 ⁇ 6 alkylamino group” is an amino group monosubstituted by a linear or branched alkyl group having 1 to 6 (preferably 1 to 4) carbon atoms, for example, methylamino And a phenylamino group, a propylamino group, a butylamino group, a pentylamino group or a hexylamino group.
  • C 2 _ 12 dialkylamino group refers to an amino group disubstituted with a straight-chain or branched-chain alkyl group having 1 to 6 (preferably 1 to 4) carbon atoms, wherein the alkyl portions are the same. But they may be different. For example, a dimethylamino group, a acetylamino group, a dipropylamino group, a dibutylamino group, a dipentylamino group, a dihexylamino group, and the like.
  • “. 3 _ 7 cycloalkyl group” means a cycloalkyl group having 3 to 7 (preferably 3 to 6) carbon atoms, and specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, And a cyclohexyl group or a cycloheptyl group.
  • Preferred is a cycloalkyl group having 3 to 6 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • acyl group refers to an alkylcarbyl group such as an acetyl group, a propioyl group, a petyryl group, a piperyl group or the like (the alkyl moiety preferably has 1 to 6, more preferably 1 to 4 carbon atoms.
  • a carbonyl group such as a benzoyl group or a naphthoyl group (preferably the carbon number of the aryl moiety is 6 to 12, more preferably 6 to 10; Group)).
  • the “factory aryl group” preferably has 6 to 12 carbon atoms, more preferably 6 to 10 carbon atoms, such as a fuel group and a naphthyl group.
  • the aryl group includes a phenyl group, a haloalkyl group (similar to the above-mentioned “0 ⁇ 6 haloalkyl group”), a halogen atom (as defined above), an alkyl group (as defined above), and a 6- alkoxy group.
  • a C 2 _ 7 alkoxycarbonyl group (as defined above), a thiol group, a cyano group, a carbonyl group, a hydroxyl group, an amino group, an alkylamino group (as defined above), and a dialkylamino group (as defined above) 1 to 6 identical or different substituents selected from the same as the above-mentioned “0 to 12 dialkylamino group”), and the position of the substituent is arbitrary. There is no restriction.
  • the phenyl group in the above substituents is further substituted at 1 to 6 identical or different substituents selected from the above substituent groups (excluding the phenyl group) at the substitutable position. May be done.
  • the "aryloxy group” preferably has 6 to 12 carbon atoms, more preferably 6 to 10 carbon atoms, and examples thereof include a phenoxy group and a naphthyloxy group.
  • Ariru group in said Ari Ruokishi group, Hue group, a haloalkyl group (the - include those similar to the " ⁇ 6 haloalkyl group"), a halogen atom (as defined above), a C ⁇ 6 alkyl group (the Synonymous), — 6 alkoxy (as defined above), C 2 _ 7 alkoxycarbonyl (as defined above), nitro, cyano, propyloxyl, hydroxyl, amino, amino, 6 alkylamino ( (As defined above) and di-C i -ealkylamino group (as defined above for “C 2 — 12 dialkylamino group”) Force ⁇ Even if substituted with 1 to 6 selected or different substituents Good.
  • the substitution position is not particularly limited as long as it can be substituted.
  • the phenyl group in the above substituents may be further substituted with 1 to 6 identical or different substituents selected from the above substituent groups (excluding the phenyl group).
  • the substitution position is not particularly limited as long as it can be substituted.
  • an “aralkyl group” is a straight- or branched-chain alkyl having an aryl moiety of a phenyl group and an alkyl moiety having 1 to 6 (more preferably 1 to 4) carbon atoms.
  • the phenyl group includes a haloalkyl group (the same as the above-mentioned “ 6- haloalkyl group”), a halogen atom (as defined above), a —6 alkyl group (as defined above). ⁇ alkoxy group (as defined above), C 2 one 7 alkoxycarbonyl group (as defined above), a nitro port group, Shiano group, a carboxyl group, a hydroxyl group, an amino group, C - 6 alkylamino group
  • the “aralkyloxy group” is a straight- or branched-chain alkoxy group in which the aryl part is a fuel group and the alkoxy part preferably has 1 to 6 (more preferably 1 to 4) carbon atoms. And is, for example, a benzyloxy group, a phenylpropoxy group, a phenylbutoxy group or a phenylhexyloxy group.
  • the Hue - le group, a haloalkyl group include those similar to the "0 6 Haroaru kill group", a halogen atom (as defined above), Al Kill group (as defined above), an alkoxy group (as defined above), C 2 7 alkoxy force Ruponiru group (as defined above), a nitro group, Shiano group, forces Rupokishiru group, a hydroxyl group, ⁇ amino group, an alkylamino group (the Synonymous with) dialkylamino group
  • substitution position is not particularly limited as long as it can be substituted.
  • acylamino group has preferably 2 to 13 carbon atoms, more preferably 2 to 11 carbon atoms, for example, alkylcarbonylamino having 2 to 7 carbon atoms (for example, acetylamino, propionyl Amino, petyrylamino, piperoylamino, etc.).
  • Heterocyclic group is a heterocyclic group having one or more, preferably 1 to 3, hetero atoms such as nitrogen atom, sulfur atom, and oxygen atom, and is preferably a 4- to 7-membered ring, It is preferably a 5- to 6-membered ring.
  • the triazolyl group includes both 1,2,3-form and 1,2,4-form. .
  • Examples of the tetrazolyl group include a 1-tetrazolyl group and a 5-tetrazolyl group.
  • the position of the bond of the thiazolyl group, triazolyl group or tetrazolyl group is not particularly limited as long as it is possible.
  • a thiazolyl group in R 5 and R 6 may be replacement by C E _ 6 alkyl group or an Amino group, the number of the substituents, the position of substitution is not particularly limited.
  • Examples of the group represented by “1- (CH 2 ) s—O— (wherein s is an integer of 1 to 3, and the methylene group may be substituted with an oxo group)” include, for example, CH 2 — O—, one CO— CH 2 — O—, one CH 2 — CO— O—, one (CH 2 ) 3 — 0— and the like.
  • the number and position of the oxo groups are not particularly limited.
  • Examples of the group represented by “one (CH 2 ) t — (where t is 2 or 3 and a methylene group may be substituted with an oxo group)” include, for example, one CH 2 —CH 2 — , — CO— CH 2 —, one CH 2 — CO—, one CO—CO—,-(CH 2 ) 3 —, —CO— (CH 2 ) 2 —, one (CH 2 ) 2 — CO— No.
  • the number and position of the oxo group are not particularly limited.
  • “Pharmaceutically acceptable salts” include, for example, salts with inorganic bases [eg, alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium, etc.) Salts), ammonium salts, etc.]; various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate; acetate, propionate, succinate, glycolate, Lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbate Mechanical acid addition salts; salts with various amino acids such as aspartate or glutamate; hydrochloride, methanesulfonate, benzenesulfonate, p- E Nsuruhon salt, sodium salt preferably, particularly preferably
  • the compound (1) of the present invention may be a hydrate or a solvate in some cases, and also includes a prodrug and a metabolite thereof.
  • the “prodrug” in the present invention is a derivative of the compound (1) of the present invention, has a group that can be chemically or metabolically degraded, and is hydrolyzed or solvolyzed, or under physiological conditions.
  • the present invention provides the compound (1) of the present invention that exhibits pharmacological activity when decomposed, and is not particularly limited. For example, (1).
  • For the hydroxyl group of the compound For the hydroxyl group of the compound,
  • the alkyl, alkenyl, aryl, and heterocycle are halogen, alkyl, hydroxyl, alkoxy, ethoxyl, amino, amino acid, .
  • the P0 3 H 2, one S0 3 H, one OPO 3 H 2 may be substituted by one OS0 3 H, etc.
  • single CO- polyethylene glycol residue, mono CO 2 - polyethylene glycol residue, mono CO- polyethylene glycol monoalkyl E one ether residue, mono CO 2 - one polyethylene da recall monoalkyl ether residue or one P0 3 H 2 or the like has been substituted, or
  • an alkoxy group, an aryloxy group (the alkoxy group or the aryloxy group is a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an amino group, an amino acid residue, -PO 3 H 2, one S0 3 H, one OPO 3 H 2, one OS0 may be substituted with 3 H and the like.), or polyethylene glycol residue or a polyethylene da recall monoalkyl ether residue is substituted And others.
  • the compound (1) of the present invention is useful as a medicament, for example, as an HLGPa inhibitor or a therapeutic agent for diabetes mellitus.
  • the present invention When the present invention is used as a therapeutic agent for diabetes, it is administered systemically or locally, orally or parenterally. Dosage varies depending on age, body weight, symptoms, therapeutic effects, etc. 1 Usually, one adult is administered once to several times a day, in the range of 1 mg to lg at a time.
  • the compound (1) of the present invention is a diluent suitable for preparing a composition for oral administration (for example, a solid composition or a liquid composition) or a preparation such as an injection for parenteral administration. , Dispersants, adsorbents, solubilizers and the like can be mixed.
  • the ⁇ pharmaceutically acceptable carrier '' to be added to the pharmaceutical composition, HLGPa inhibitor, antidiabetic agent, etc. of the present invention is not particularly limited as long as it is a pharmaceutically acceptable carrier.
  • the compound (1) of the present invention can be used for the treatment and prevention of diabetes in humans as well as animals other than humans, for example, mammals.
  • the compound (1) of the present invention can be used in combination with one drug or a plurality of other drugs by a general method commonly used in medicine. Although there are various drugs that can be used in combination with the compound (1) of the present invention, drugs for treating hyperlipidemia and drugs for treating diabetes are particularly preferred.
  • Examples of the therapeutic drug for hyperlipidemia that can be used in combination include statins, and specific examples include oral pastatin, simpastatin, prapastatin, funovavastatin, atonorepastatin, and seripastatin.
  • antidiabetic drugs that can be used in combination include insulin preparations, sulfonylureas, insulin secretagogues, sulfonamides, biguanides, a-dalcosidase inhibitors, insulin sensitizers, etc.
  • specific examples of the drug are as follows.
  • insulin is used as an insulin preparation
  • insulin is used as a sulfolurine, dalibenclamide, tolptamide, glicloviramide, acetohexamide, glimepiride, tolazamide, daliclazide, nateglinide, etc.
  • ⁇ -Dalcosidase inhibitors such as metformin hydrochloride and pformin hydrochloride; poglipose and acarbose; and insulin sensitizers such as pioglitazone hydrochloride.
  • the present inventors have demonstrated that the combined use of an HLGPa inhibitor, which has not been used in combination with a diabetes treatment drug, has a synergistic effect on the treatment of diabetes compared with the case of using each drug alone. I found that I can do it. That is, it is useful in terms of effects to use the compound (1) of the present invention together with a therapeutic agent for diabetes.
  • a method for producing the condensed pyrrole compound represented by the compound (1) will be described, but the production method of the present invention is not limited thereto.
  • the functional group other than the site may be protected beforehand as necessary, and may be deprotected at an appropriate stage.
  • the amount of the solvent used in each step is not particularly limited as long as the reaction mixture can be stirred.
  • a reagent used in each step a hydrate or a salt thereof can be used as long as the desired reaction is not inhibited.
  • reaction may be carried out by a usual method, and the isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, column chromatography, and preparative HPLC. Just do it.
  • the method for producing the compound is exemplified below.
  • R 3 ′ is a hydrogen atom, a Ci- 6 alkyl group or an aralkyl group (the aralkyl group may be substituted with a halogen atom).
  • 3 ⁇ is a halogen atom
  • X 2 is a halogen atom or a hydroxyl group
  • ring D is a group selected from the groups represented by formulas (a) to (g).
  • the compound represented by the general formula (3) can be obtained by reacting the compound represented by the general formula (2) with N, N-dimethylformamide (DMF) in a solvent in the presence of a base. .
  • DMF N, N-dimethylformamide
  • Examples of the base used in the reaction include ⁇ -butyl lithium, tert-butyl lithium, and the like. Use as a hexane solution is preferred because of easy handling. Particularly preferred is n-butyllithium (hexane solution).
  • solvent used for the reaction examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane, and diglyme; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. These can be used alone or in combination.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene. These can be used alone or in combination.
  • a preferred solvent in this reaction is THF.
  • the reaction temperature is usually from 100 ° C. (: to 50 ° C., preferably from 80 ° C. to room temperature.
  • the reaction time is usually from 0.1 hour to 10 hours, preferably from 0.5 hour to 5 hours. It is more preferably 1 hour to 2 hours.
  • the compound represented by the general formula (4) can be obtained by reacting the compound represented by the general formula (3) with ethyl azidoacetate in a solvent in the presence of a base.
  • the solvent used in the reaction include getyl ether, THF, dioxane,
  • ether solvents such as 1,2-dimethoxetane and diglyme
  • alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol. These may be used alone or in combination.
  • a preferred solvent in this reaction is ethanol.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide, sodium methoxide, potassium hydride Alkali metal alkoxides such as tert-butoxide; lithium metal amides such as lithium diisopropylamide, sodium amide, and lithium bistrimethylsilyl amide; and sodium methoxide is preferable.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • sodium ethoxide, sodium methoxide, potassium hydride Alkali metal alkoxides such as tert-butoxide
  • lithium metal amides such as lithium diisopropylamide, sodium amide, and lithium bistrimethylsilyl amide
  • sodium methoxide is preferable.
  • the reaction temperature is usually from ⁇ 20 ° C. to 50 ° C., preferably from 0 ° C. to room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • the compound represented by the general formula (5) can be obtained by reacting the compound represented by the general formula (4) in a solvent.
  • Examples of the solvent used for the reaction include hydrocarbon solvents such as benzene, toluene, hexane, and xylene, and these can be used alone or in combination.
  • a preferred solvent in this reaction is xylene.
  • the reaction temperature is usually from 110 ° C to 200 ° C, preferably from room temperature to 150 ° C.
  • the reaction time is generally 10 minutes or more, preferably 30 minutes to 24 hours, and more preferably 30 minutes to 2 hours.
  • the compound represented by the general formula (6) can be obtained by hydrolyzing the compound represented by the general formula (5) in a solvent in the presence of a base.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; polar solvents such as acetate, DMF, dimethyl sulfoxide, and water. These can be used alone or in combination.
  • a preferred solvent in this reaction is methanol.
  • Examples of the base used in the reaction include lithium hydroxide, sodium hydroxide, and alkali metal hydroxides such as hydroxide hydroxide, and sodium hydroxide is preferable.
  • the reaction temperature is usually from ⁇ 30 ° C. to 100 ° C., preferably from 0 ° C. to 50 ° C.
  • the reaction time is generally 0.1 hour to 48 hours, preferably 0.5 hour to 12 hours.
  • the compound represented by the general formula (8) By reacting the compound represented by the general formula (5) with the compound represented by the general formula (7) in a solvent in the presence of a base, the compound represented by the general formula (8) can be obtained. .
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium ethoxide, sodium methoxide, potassium tert-butoxide; n-butyllithium; Alkyl lithium such as butyl lithium; alkali metal amides such as lithium disopropylamide, sodium amide and lithium bistrimethylsilyl amide; alkali metal carbonates such as sodium carbonate and carbon dioxide; sodium hydrogen carbonate, potassium hydrogen carbonate Alkali metal bicarbonates; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxylated lime; Alkali metal carboxylate salts such as sodium acetate and acetic acid; Sodium phosphate, potassium phosphate, etc.
  • the phosphoric acid Organic metal bases such as triethylamine, pyridine, N-methylmorpholine and the like, preferably sodium hydride; .
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate A polar solvent such as acetone, DMF, dimethyl sulfoxide and the like, which can be used alone or in combination. A preferred solvent in this reaction is DMF.
  • ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme
  • hydrocarbon solvents such
  • the reaction temperature is usually from 150 ° C to 50 ° C, preferably from 120 ° C to room temperature.
  • the reaction time is generally 0.1 hour to 10 hours, preferably 0.5 hour to 5 hours, more preferably 1 hour to 2 hours.
  • Process 1-6 The compound represented by the general formula (9) is obtained by reacting the compound represented by the general formula (6) with the compound represented by the general formula (7) in the same manner as in step 115. Can be.
  • the compound represented by the general formula (11) can be obtained by reacting the compound represented by the general formula (8) with the compound represented by the general formula (10) in a solvent.
  • the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Pi-based solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; esters such as ethyl acetate, methyl acetate, and butyl acetate System solvents; polar solvents such as acetone, DMF, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination.
  • the reaction temperature is usually from 20 ° C to 100 ° C, preferably from room temperature to 50 ° C.
  • the reaction time is generally 0.1 hour to 24 hours, preferably 0.5 hour to 2 hours.
  • the compound represented by the general formula (11) is obtained by reacting the compound represented by the general formula (9) with the compound represented by the general formula (10) in a solvent in the presence of a condensing agent. be able to.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and ethyl acetate; acetone, DMF, and dimethyl Examples thereof include polar solvents such as sulfoxide, and these can be used alone or in combination.
  • ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme
  • hydrocarbon solvents such as benzene, toluene,
  • the preferred solvent in this reaction is DMF.
  • the condensing agent used in the reaction may be any condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent), and among them, 1-hydroxy Preferred is a combination of benzotriazo monohydrate (HOB t ⁇ H 2 O) and 11- (3- (dimethylamino) propyl) -13-ethylcarposimid hydrochloride (EDC).
  • a usual peptide condensation method for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent
  • 1-hydroxy Preferred is a combination of benzotriazo monohydrate (HOB t ⁇ H 2 O) and 11- (3- (dimethylamino) propyl) -13-ethylcarposimid hydrochloride (EDC).
  • the reaction temperature is usually from 20 ° C to 50 ° C, preferably from 0 ° C to room temperature.
  • the reaction time is generally 1 hour to 48 hours, preferably 2 hours to 24 hours.
  • the compound represented by the general formula (111) By reacting a compound represented by the general formula (11) with a compound represented by the general formula (12) using a condensing agent in a solvent, the compound represented by the general formula (111) ) Can be obtained.
  • a base can be used to make this reaction proceed smoothly.
  • X 2 when X 2 is a hydroxyl group, a condensing agent is used, but a base may be used for smoothly proceeding the reaction.
  • X 2 is a halogen atom
  • the reaction can proceed smoothly by using a base without using a condensing agent.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane and chloroform.
  • ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • dichloromethane and chloroform examples of the solvent used in the reaction.
  • Halogen solvents such as oral form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and ethyl acetate; acetone, DMF, Examples thereof include polar solvents such as dimethyl sulfoxide, and these can be used alone or in combination. Preferred solvents in this reaction are DMF and THF.
  • the condensing agent used in the reaction may be any condensing agent used in a conventional peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent), and among them, 1-hydroxy Preferred is a combination of benzotriazole monohydrate and 11- (3- (dimethylamino) propyl) -13-ethylcarbodiimide hydrochloride.
  • Bases used in the reaction include, for example, triethylamine, N-methylmorpholine. And organic bases such as sodium bicarbonate; and inorganic bases such as sodium bicarbonate. Triethylamine is preferable.
  • the reaction temperature is usually from 10 to 60 ° C, preferably from 0 ° C to room temperature.
  • the reaction time is generally 10 minutes or more, preferably 1 hour to 48 hours, more preferably 3 hours to 24 hours, and further preferably 3 hours to 15 hours.
  • the target compound By reacting the compound represented by the general formula (11) with a compound represented by the general formula (13) or a reagent equivalent thereto (eg, methylbenzimidate hydrochloride) in a solvent, the target compound is obtained.
  • a compound represented by the general formula (13) or a reagent equivalent thereto eg, methylbenzimidate hydrochloride
  • the compound represented by the general formula (1-2) can be obtained.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide and the like, and these can be used alone or in combination.
  • a preferred solvent in this reaction is methanol. '
  • the reaction temperature is usually in the range of 30 ° C to 50 ° C, preferably 0 ° C to room temperature.
  • the reaction time is generally 0.5 hour to 48 hours, preferably 1 hour to 12 hours.
  • the compound represented by the general formula (12) is subjected to a condensation reaction with the compound represented by the general formula (12) using a condensing agent in a solvent using a condensing agent. You can get things.
  • Examples of the solvent used in the reaction include getyl ether, THF, dioxane,
  • Ether solvents such as 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, chloroform, tetrachloride carbon, and 1,2-dichloroethane Alcoholic solvents such as isopropyl alcohol and tert-butanol; ethyl acetate, methyl acetate, and butyl acetate Ester solvents such as tyl; polar solvents such as acetone, DMF, and dimethyl sulfoxide; and the like, and these can be used alone or in combination.
  • the preferred solvent in this reaction is DMF.
  • the condensing agent used in the reaction may be any condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent), and among them, 1-hydroxy Preferred is a combination of benzotriazole monohydrate and 11- (3- (dimethylamino) propyl) -13-ethylcarbodiimide hydrochloride.
  • the reaction temperature is usually from 130 ° C to 50 ° C, preferably from 120 ° C to room temperature.
  • the reaction time is generally 1 hour to 48 hours, preferably 2 hours to 6 hours.
  • the compound represented by the general formula (1 2 ′) is subjected to a condensation reaction with a compound represented by the general formula (9) using a condensing agent in a solvent to obtain a compound represented by the general formula (1) -The compound represented by 1) can be obtained.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, DMF, and dimethyl Examples thereof include polar solvents such as sulfoxide, and these can be used alone or in combination. A preferred solvent in this reaction is DMF.
  • ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme
  • hydrocarbon solvents such as benzene
  • the condensing agent used in the reaction may be a condensing agent used in a usual peptide condensing method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent, etc.).
  • a condensing agent used in a usual peptide condensing method for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent, etc.
  • Preferred is a combination of hydroxybenzotriazole monohydrate and 1- (3- (dimethylamino) propyl) -13-ethylcarbodiimide hydrochloride.
  • the reaction temperature is usually from 130 ° C. to 50 ° C., preferably from ⁇ 20 ° C. to room temperature.
  • the reaction time is generally 1 hour to 48 hours, preferably 1 hour to 24 hours.
  • the method for producing the compound is exemplified below.
  • Examples of the reducing agent used in the reaction include lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydride and the like, preferably lithium aluminum hydride.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane and diglyme.
  • ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane and diglyme.
  • the preferred solvent in this reaction is THF.
  • the reaction temperature is usually ⁇ 20 ° C. to 50 ° C., preferably 110 ° C. to room temperature.
  • the reaction time is generally 1 hour to 12 hours, preferably 2 hours to 8 hours.
  • the compound represented by the general formula (16) can be obtained by reacting the compound represented by the general formula (15) in a solvent using an oxidizing agent.
  • the oxidizing agent used in the reaction includes, for example, manganese dioxide, pyridi-dimethylchromate and the like, and is preferably manganese dioxide.
  • Solvents used for the reaction include, for example, halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and the like.
  • Ether solvents such as diglyme; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. These can be used alone or in combination.
  • a preferred solvent in this reaction is chloroform.
  • the reaction temperature is usually from 20 ° C to 100 ° C, preferably from 0 ° C to 60 ° C.
  • the reaction time is generally 1 hour to 10 hours, preferably 1 hour to 5 hours.
  • the compound represented by the general formula (18) can be obtained from the compound represented by the general formula (17) in the same manner as in Steps 1-3 of Production Method 1.
  • the compound represented by the general formula (19) can be obtained from the compound represented by the general formula (18) in the same manner as in Steps 1-4 of Production Method 1.
  • the compound represented by the general formula (20) is reacted with the compound represented by the general formula (18) and the compound represented by the general formula (7) in the same manner as in Steps 1 to 5 of the production method 1. A compound can be obtained.
  • the compound represented by the general formula (22) is reacted with the compound represented by the general formula (20) and the compound represented by the general formula (10) in the same manner as in the step 117 of the production method 1.
  • a compound can be obtained.
  • the compound represented by the general formula (22) is obtained by reacting the compound represented by the general formula (21) with the compound represented by the general formula (10) in the same manner as in Steps 18 of Production Method 1. A compound can be obtained.
  • the compound represented by the general formula (22) was obtained in the same manner as in Steps 1 to 10 of Production Method 1.
  • a compound represented by the general formula (13) or a reagent equivalent thereto for example, methylbenzimidate hydrochloride, etc.
  • the compound represented by (1-4) can be obtained.
  • R 1 R 2 , R 3 ′, G x , G 2 , G 3 , R 48 and ring D are the same as described above, and R 37 ′′ and R 38 ′′ are a hydrogen atom, a halogen atom.
  • Process 3-1 The general formula (1,) obtained in Steps 1-9, 1-10, 2-9 or 2-10 (where the general formula (1,) is the general formula (1-1), (1-2) , (1-3) or (1-4) is the same), the ring D is
  • R 12 ′ and R 13 ′ are the same or different and are each a hydrogen atom, a halogen atom, a C- 6 alkyl group, an alkoxy group or a hydroxyl group (R 12 ′ and R 13 ′ are R 37 is synonymous with R 38 ), and R 48 is synonymous with R 45 ) in a solvent, a phosgene equivalent (eg, carbopimidazole, diphosgene, triphosgene, etc.)
  • triphosgene a compound represented by the general formula (1-5), which is one of the target compounds, can be obtained.
  • the reagent besides the above-mentioned phosgene equivalent, ethyl methyl carbonate and the like can be used.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate
  • a polar solvent such as acetone, DMF, dimethyl sulfoxide, water and the like, and these can be used alone or in combination.
  • a preferred solvent in this reaction is a mixture of DMF, THF and water.
  • a base In this reaction, it is preferable to use a base.
  • examples of usable bases include inorganic bases such as sodium hydroxide, sodium bicarbonate, and potassium carbonate; and organic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] indene-7-ene. And preferably sodium bicarbonate.
  • the reaction temperature is usually from 110 ° C to 60 ° C, preferably from 0 ° C to room temperature.
  • the reaction time is generally 1 hour or longer, preferably 1 hour to 24 hours, more preferably 3 hours to 24 hours, and preferably 6 hours to 12 hours.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide, polar solvents such as water, and the like, and these can be used alone or in combination.
  • a preferred solvent in this reaction is THF.
  • thiocarbonyl compound used in the reaction examples include thiocarbonyldiimidazole, carbon disulfide, thiophosgene, and the like. It's Midazo.
  • a base may be desired.
  • examples of the base to be used include inorganic bases such as sodium hydroxide, sodium hydrogencarbonate and carbonated carbonate; triethylamine, 1,8-diazabicyclo [5.4.0]
  • the reaction temperature is usually from 110 ° C to 60 ° C, preferably from 0 to room temperature.
  • the reaction time is generally 1 hour to 12 hours, preferably 2 hours to 6 hours.
  • Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide, formic acid and the like, and these can be used alone or in combination.
  • the preferred solvent in this reaction is DMF.
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and preferably methanesulfonic acid. is there.
  • methyl orthoacetate is preferred.
  • Formic acid and its derivatives include, for example, formic acid and ethyl formate. Among them, formic acid is preferred.
  • the reaction temperature is usually from 10 ° C to 100 ° C, preferably from 0 ° C to room temperature.
  • the reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 6 hours, and more preferably 1 hour to 6 hours.
  • the reaction temperature is usually 80 ° C to 300. C, preferably between 100 ° C and 200 ° C.
  • the reaction time is generally 4 hours to 24 hours, preferably 5 hours to 12 hours.
  • R 12> and R 13 ′ are the same as above
  • a solvent in the presence of an organic base (for example, pyridine, triethylamine, sodium hydrogen carbonate, etc.), a haloacetyl halide compound (Eg, chloroacetyl chloride, bromoacetyl bromide, etc.).
  • an organic base for example, pyridine, triethylamine, sodium hydrogen carbonate, etc.
  • a haloacetyl halide compound Eg, chloroacetyl chloride, bromoacetyl bromide, etc.
  • Examples of the solvent in (1) and (2) include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. ; Dichloromethane, chloropho Halogen solvents such as lume, carbon tetrachloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, D
  • ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Examples thereof include polar solvents such as MF and dimethyl sulfoxide, and these can be used alone or in combination.
  • a preferred solvent in this reaction is a solvent that is THF, ethyl acetate or DMF, or a mixed solvent thereof.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; n-butyllithium Alkyl lithium such as butyllithium, sec-butyllithium, etc .; Alkali metal amides such as lithium diisopropylamide, sodium amide, lithium bistrimethylsilyl azide; Alkali metal carbonates such as sodium carbonate, carbonated lime; sodium hydrogen carbonate, hydrogen carbonate Alkali metal bicarbonates such as potassium; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal salts of carboxylic acids such as sodium acetate and potassium acetate; sodium phosphate and potassium phosphate Phosphoric acid Alkali metal salts; Toryechiruamin, pyridine, N- methylmorpholine, 1, 8-Jiazabis
  • the reaction temperature is usually from 130 ° C to 100 ° C.
  • the temperature is preferably 0 ° C. to 80 ° C., and more preferably 0 ° C. to room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 1 hour to 15 hours, and preferably 2 hours to 12 hours.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate A polar solvent such as acetone, DMF, dimethyl sulfoxide and the like, and these can be used alone or in combination.
  • the preferred solvent in this reaction is DMF.
  • the condensing agent used in the reaction may be any condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent), and among them, 1-hydroxy Preferred is a combination of benzotriazole monohydrate and 1- (3- (dimethylamino) propyl) -13-ethylcarbodiimide hydrochloride.
  • the reaction temperature is usually from 30 ° C to 60 ° C, preferably from 0 ° C to room temperature.
  • reaction time is generally 5 hours to 24 hours, preferably 10 hours to 20 hours.
  • X 3 is a halogen atom or one OSO 2 - alkyl, or is one o S 0 2 7 Lil, R 1 2 ' ⁇ Pi R 1 3' is the same as) a compound represented by The compound is dissolved in a solvent and cyclized with a base and, if necessary, an alkali metal halide such as sodium iodide, to give one of the target compounds represented by the general formula (1-116) Can be obtained.
  • X 3 is preferably a bromine atom.
  • solvent used in the reaction examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ethyl acetate, methyl acetate, butyl acetate, etc. And a polar solvent such as acetone, N, N-dimethylformamide (DMF), dimethylsulfoxide, and formate. These can be used alone or in combination. A preferred solvent in this reaction is DMF.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium ethoxide, sodium methoxide, potassium tert-butoxide; n-butyllithium; Alkyl lithium such as sec-butyl lithium; Alkali metal amide such as lithium diisopropylamide, sodium amide, lithium bistrimethylsilyl amide; Alkali metal carbonate such as sodium carbonate, carbon dioxide lime; sodium hydrogencarbonate, carbonate Alkali metal bicarbonates such as potassium hydrogen; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxide hydroxide; alkali metal salts of carboxylic acids such as sodium acetate and potassium acetate; sodium phosphate, phosphorus Phosphoric acid such as potassium acid Alkali metal salts; Toryechiruamin, pyridine, N- methylmorpholine, Organic bases such as 1,8-diazabic
  • the reaction temperature is usually from 20 ° C to 300 ° C, preferably from 60 ° C to 200 ° C.
  • the reaction time is generally 1 hour to 48 hours, preferably 2 hours to 24 hours.
  • the compound (23) synthesized according to WO 03/068743 is dissolved in a polar solvent such as acetone, an ether solvent, or a halogen solvent such as chloroform, and the reaction is carried out by adding an acid chloride such as acetyl chloride and then reacting.
  • a polar solvent such as acetone, an ether solvent, or a halogen solvent such as chloroform
  • Compound (24) can be obtained by the above operation.
  • the compound (24) is dissolved in an acid such as acetic acid or polyphosphoric acid alone or in a solvent containing an acid, and then the compound (25) is added and reacted to obtain a compound represented by the general formula (1-1)
  • the compound represented by 7) can be obtained.
  • Examples of the acid used for the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; Organic acids such as oral acetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, and acetic acid is preferred.
  • inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid
  • Organic acids such as oral acetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, and acetic acid is preferred.
  • Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, DMF, dimethyl sulfoxide, and formate.
  • ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • dichloromethane Halogen solvents such as form, carbon tetrach
  • the reaction temperature is usually from 40 ° C to 300 ° C, preferably from 60 ° C to 200 ° C.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • Compound represented by the general formula (1) is, R 3 and: R 4 together with the adjacent nitrogen atom,
  • G 1 G 2 , G 3 , RR 2 , R 3 ′, R 39 , R 40 and R 41 are as defined above, and boc is a tert-butoxycarbonyl group).
  • Step 17 The compound represented by the general formula (31) and the compound represented by the general formula (32) obtained in the same manner as in step 7 or 1-8 are subjected to the same condensation reaction as in step 1-9. By adding the compound, a compound represented by the general formula (33) can be obtained.
  • the tert-butoxycarbonyl group of the compound represented by the general formula (33) is removed with an acid (for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, etc.).
  • an acid for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, etc.
  • the obtained amino compound is cyclized with a phosgene equivalent (for example, carbonyldiimidazole, triphosgene, etc.) in the presence of a base to obtain a compound represented by the general formula (1-1-2) which is one of the target compounds. ) Can be obtained.
  • a phosgene equivalent for example, carbonyldiimidazole, triphosgene, etc.
  • Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, diglyme, and diphenyl ether; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. ; Jikurorome Tan, black hole Holm, carbon tetrachloride, black hole benzene, 1, 2-halogen-based solvents such as Jikuroroetan; methanol, ethanol, isopropyl alcohol, t e alcohol solvents rt over butanol; DM F, dimethyl sulfoxide, Examples thereof include polar solvents such as water. These can be used alone or in combination, or the reaction can be carried out without a solvent.
  • a preferred solvent used in this reaction is THF.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; n-butyllithium, sec.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide
  • n-butyllithium sec.
  • Alkyl lithium such as monobutyllithium; alkali metal amides such as lithium disopropylamide, sodium amide and lithium bistrimethylsilyl amide; alkali metal carbonates such as sodium carbonate and carbon dioxide rim; sodium hydrogencarbonate, hydrogencarbonate Alkali metal bicarbonates such as potassium; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydrating hydroxide; Alkali metal carboxylate such as sodium acetate and potassium acetate; Sodium phosphate, phosphoric acid Phosphoric acid such as potassium Alkali metal salts; organic bases such as triethylamine, pyridine, N-methylmorpholine, and 1,8-diazabicyclo [5.4.0] indene-7-ene; and the like, with preference given to triethylamine.
  • alkali metal amides such as lithium disopropylamide, sodium amide and lithium bistrimethylsilyl amide
  • alkali metal carbonates such as sodium carbon
  • the reaction temperature is usually 0 ° C to 100 ° C, preferably room temperature to 60 ° C.
  • the reaction time is generally 1 hour to 48 hours, preferably 1 hour to 25 hours, more preferably 2 hours to 24 hours.
  • the tert-butyrate of the compound represented by the general formula (33) Deprotection of the xycarpoxyl group with an acid (eg, trifluoroacetic acid, hydrochloric acid, etc.), and then cyclization with a thiocarbonylation reagent (eg, thiocarbonyl diimidazole, carbon disulfide, thiophosgene, etc.) in the presence of a base.
  • a thiocarbonylation reagent eg, thiocarbonyl diimidazole, carbon disulfide, thiophosgene, etc.
  • the compound represented by the general formula (36) can be obtained by reacting the compound represented by the general formula (34) with the compound represented by the general formula (35) in acetonitrile.
  • the reaction temperature is usually 50 ° C to 200 ° C, preferably 80: to 100 ° C.
  • the reaction time is generally 1 hour to 10 hours, preferably 2 hours to 5 hours.
  • Solvents used in the reaction include, for example, ether / solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, diglyme, diphene / leate / le; benzene, toluene, hexane, xylene, etc.
  • Hydrocarbon solvents dichloromethane, chloroform, formaldehyde, carbon benzene, carbon tetrachloride, 1,2-dichloroethane, etc .; halogen solvents; methanol, ethanol, isopropyl alcohol, tert-butanol, etc .; DMF, dimethyl
  • polar solvents such as sulfoxide and water, and dimethylfurin. These can be used alone or in combination, or the reaction can be carried out without a solvent.
  • a preferred solvent used in the present reaction is THF.
  • Examples of the base used in the reaction include, for example, sodium hydride, potassium hydride, and the like.
  • the reaction temperature is usually 0 ° C to 100 ° C, preferably 0 ° C to room temperature.
  • reaction time is generally 1 hour to 24 hours, preferably 4 hours to 10 hours.
  • Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, diglyme, and diphenyl ether; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • a halogen-based solvent such as dichloromethane, chloroform-form, carbon tetrachloride, carbon-benzene, and 1,2-dichloroethane
  • an alcohol-based solvent such as methanol, ethanol, isopropyl alcohol, tert-butanol
  • DMF dimethyl sulfoxide, water, etc.
  • polar solvents dimethylaniline and the like.
  • This reaction is preferably performed in the presence of an acid or a base.
  • the reaction temperature is usually 0 ° C to 100 ° C, preferably 0 ° C to room temperature.
  • the reaction time is generally 1 hour to 10 days, preferably 1 day to 10 days, more preferably 1 day to 3 days.
  • the compound represented by the general formula (1-15) (where R 39 is a hydrogen atom) can be produced not only by the method of the above step 417 but also by the following method. :
  • the reduction can be carried out by a conventional method.
  • the desired compound can be produced by reacting the compound represented by (1-15) with a reducing agent such as sodium cyanoborohydride.
  • R 3 and R 4 are combined with an adjacent nitrogen atom
  • R 47 ′ has the same meaning as described above.
  • the compound represented by the general formula (50) is reacted in a solvent using a phosgene equivalent (eg, lipodidiimidazole, triphosgene, diphosgene, or the like, preferably triphosgene) to obtain an intermediate of the target compound.
  • a phosgene equivalent eg, lipodidiimidazole, triphosgene, diphosgene, or the like, preferably triphosgene
  • reagent besides the above-mentioned phosgene equivalent, ethyl ethyl carbonate and the like can be used.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide, polar solvents such as water and the like, and these can be used alone or in combination.
  • a preferred solvent in this reaction is dioxane.
  • the reaction temperature is usually from 10 ° C to 60 ° C, preferably from 0 ° C to room temperature.
  • the reaction time is generally 1 hour or more, preferably 1 hour to 12 hours.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as n-tan; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, DMF, dimethyl sulfoxide, water, etc. These can be used alone or in combination.
  • the preferred solvent in this reaction is toluene.
  • the reaction temperature is usually from 120 ° C to 150 ° C, preferably from 5 ° C to 70 ° C.
  • the reaction time is generally 1 hour or more, preferably 1 hour to 3 hours.
  • the reaction After reacting the compound represented by the general formula (51) in a solvent in the presence of a base, the reaction is carried out using the compound represented by the general formula (53), thereby obtaining one of the target compounds.
  • the compound represented by the formula (54) can be obtained.
  • Examples of the solvent used in the reaction include getyl ether, THF, dioxane,
  • Ether solvents such as 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; halogen solvents such as dichloromethane, chloroform, tetrachlorocarbon and 1,2-dichloroethane Ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, DMF, dimethyl sulfoxide, and water; and the like, which can be used alone or in combination.
  • the preferred solvent in this reaction is DMF.
  • Examples of the base used in the reaction include, for example, sodium hydride, potassium hydride, and the like.
  • the reaction temperature is generally 0 ° C. to 300 ° C., preferably room temperature to 100 ° C.
  • the reaction time is usually 30 minutes or more, preferably 1 hour to 12 hours.
  • a compound represented by the general formula (55) can be obtained by reacting the compound represented by the general formula (54) in a solvent in the presence of an acid.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide and the like, and these can be used alone or in combination.
  • a preferred solvent in this reaction is ethanol.
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid. is there.
  • the reaction temperature is usually 0 ° C to 300 ° C N, preferably 50 ° C to 200 ° C.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • G 2 , G 3 , R 1 and R 2 are as defined above, and Ra is a hydrogen atom, a 6- alkyl group, an aralkyl group or an aryl group which may have a substituent, Rb is an alkyl group, an aralkyl group or a substituted or unsubstituted aryl group.
  • solvent used in the reaction examples include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, DMF, and dimethyl sulfoxide; Or they can be used in combination.
  • a preferred solvent is black form.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; lithium disopropylamide Alkali metal amides such as sodium amide, sodium amide and lithium bistrimethylsilyl amide; Al metal hydrides such as sodium bicarbonate; Organic compounds such as 2,6-lutidine and pyridine Bases and the like are preferred, and 2,6-lutidine or pyridine is preferred.
  • the reaction of the second step can be performed by dissolving the compound represented by the general formula (62) in a solvent and treating with a base.
  • Solvents that can be used in the reaction include, for example, alcohol solvents such as methanol and ethanol, ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; benzene, toluene, hexane, xylene, and the like.
  • Hydrocarbon solvents Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, N, N-dimethylform Polar solvents such as amide (DMF) and dimethyl sulfoxide.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; lithium disodium Alkali metal amides such as propyl amide, sodium amide, and lithium pistrimethylsilyl amide; Al metal hydrides such as sodium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide; pyridine, DBU, etc. And the like. Preferred is sodium hydroxide.
  • the free compound of the present invention (1) obtained by the above Production Methods 1 to 6 can be converted into a salt according to a conventional method.
  • the title compound 32 (154 mg 82%) was obtained from compound 25 (123 mg) and anthralic acid in the same manner as in Example 1 d) (obtained in the same manner as in Example 1-2 b). Obtained as yellow morphus.
  • the title compound 22 was synthesized by hydrolyzing the compound 20 obtained in a) of Example 16 with sodium hydroxide.
  • the title compound 35 (154 mg , 82%) was obtained by reacting the compound 20 obtained in Example 16-b) with benzoic acid hydrazide in the same manner as in Example 1 c). Obtained as Amorphous.
  • Example 2 could also be produced by the following method.
  • the title compound 19 was synthesized from thiophene-3-carboxyaldehyde in the same manner as in Example 1 b).
  • the title compound 21 was synthesized by hydrolyzing the compound 19 obtained in a) of Example 2-2 with sodium hydroxide.
  • the title compound was obtained by a method similar to the method disclosed in Jouran alofOrganic Chemistry, 1991, 56, Vol. 6, page 2260, and WO 03Z037864. .
  • Example 3 37 (75 mg, 83%) of the title compound was obtained from compound 33 (86 mg) (obtained in the same manner as in Example 2-2).
  • Methyl 2- (2-bromoethoxy) benzoate (1.15 g) was dissolved in a mixed solvent of methanol (8.80 ml) and tetrahydrofuran (8.80 ml), and 4N aqueous solution was added. Add lithium oxide (L i OH) (2.20 ml) and add at room temperature Stirred overnight. After concentrating the reaction mixture, the mixture was acidified by adding INHC1 under ice-cooling. The precipitated solid was collected by filtration to give the title compound (590 mg, yield 55%) as a white solid.
  • Example 3 The title compound was obtained in the same manner as in Example 3-2 (or Example 3).
  • Example 3-13 The compound obtained in Example 3-13 was suspended in methanol (3 ml). To this mixture was added a 4N aqueous sodium hydroxide solution (0.43 ml), and the mixture was stirred at room temperature for 30 minutes. The mixture was ice-cooled, and 6N hydrochloric acid aqueous solution (0.33 ml) was added. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give 274 mg of the title compound as a pale yellow solid.
  • a salt was prepared in the same manner as in Example 4 to give the title compound.
  • Example 2-7 The compound of Example 2-7 was converted to a sodium salt according to an ordinary method to obtain the title compound.
  • HH H 2 N 2.33 (3H, s), 5.60 (2H, m), 6.69 (lH, m),-2 6.84 (lH, m), 7.08-7.16 (5H, m), 7.46 (2H, m),
  • Examples 5-25-5 can be obtained in the same manner as in Examples 1-17-1 and 2-27 and Example 5, or a method analogous thereto. The obtained compounds are shown in Table 3. Table-3
  • the compounds of Examples 7 to 76 can be obtained by a method similar to or a method analogous to Examples 1 to 7 and 2-2-7.
  • the compounds obtained are shown in Table 5.
  • Test Example (1) Method for measuring liver glycogen phosphorylase activity
  • glycogen phosphorylase activity was performed by measuring the concentration of phosphoric acid generated during the reverse reaction, ie, the reaction of glycogen phosphorylase to synthesize G1-P into glycogen.
  • a cell lysate of Sf9 cells in which recombinant human liver glycogen phosphorylase was forcibly expressed was imM imidazole-hydrochloride buffer ( ⁇ 7.0, 0.2 mM PMS F , 25 OmM NaC 1, containing 0.025% BSA) to a protein amount of 80 g gZniL.
  • imM imidazole-hydrochloride buffer ⁇ 7.0, 0.2 mM PMS F , 25 OmM NaC 1, containing 0.025% BSA
  • substrate solution 25mM T ris- H 1 buffer (1) 117. 2, 25 OmM KC 1, 6. 25 mM Mg C 1 2, 6.
  • the test drug was dissolved in 0.5% dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the enzyme reaction was started by adding 20 ⁇ l of the enzyme solution to a mixture of the test drug 101 and 20 ⁇ l of the substrate solution. As a control, 0.5% DMSO was added instead of the test drug. A sample without addition of the enzyme was used as a blank. After allowing the reaction to proceed at room temperature for 60 minutes, adding 500 l of malachite green solution, and further reacting at room temperature for 20 minutes, the absorbance at 650 ⁇ m was measured.
  • the enzyme solution was added to the blank at the same time as the malachite green solution, and the measurement was performed in the same manner.
  • the inhibition rate (%) of the test drug was calculated by ((control value ⁇ test drug value) / (control value ⁇ blank value)) XI 00 (%).
  • Table 6 shows the test results of the above test examples.
  • the enzyme inhibitory activity against HLGPa is +, when IC 50 (nM) is 100 nM or more and less than 1000 nM, Indicated by ++.
  • Glucose-1-phosphate which is produced from glycogen by glycogen phosphorylase, is used to convert glucose-1-: hosphate to phospho-hognogolecomtase (h. Glucose 6-phosphate dehydrogenase (G6 PDH)] to conduct a transphosphorylation reaction and dehydrogenation reaction, and to obtain a Darconau ⁇ -lactone 6-phosphate (g 1 uc ⁇ ⁇ ⁇
  • a mixture of 8 UZmL phosphoglucomutase 60 15 / m LG 6 PDH was prepared in BES buffer.
  • Reaction buffer (1. 4 mm ol ZL NAD P , 3 0 mm o 1 / L Mg C 1 2, 8 / imol / L glucose one 1, 6 Jihosufue Ichito (G lucose- 1, 6- diphosphate) , 8 mg / mL glycogen, 40 mmol ZL BES, containing 0.8 mmo1 / L EDTA, and glucose solution (TS mmol ZL gnorecose, 100 mmo1 / LBES, 2 mmo) 1 / L EDTA).
  • the test substance was dissolved in an aqueous solution containing 1% DMSO.
  • a mixture of 20 ⁇ L of glucose solution, 20 L of substrate solution, 100 L of reaction buffer, and 20 ⁇ L of test substance, combined with 20 ⁇ L of recombinant human liver glycogen phosphorylase solution and phosphognorecomtase (Phosphoglcomutase) and 20 L of a mixed solution of G6PDH were added to start the enzyme reaction.
  • an aqueous solution containing l% DMS O was added instead of the test substance.
  • the one without the substrate was used as a blank.
  • the absorbance at 340 nm was measured. After reacting at room temperature for 75 minutes, the absorbance at 340 nm was measured again.
  • the value obtained by subtracting Planck from the absorbance change for 75 minutes was defined as the enzyme activity.
  • the inhibition rate (%) of the test substance was calculated from “(11 (enzyme activity of test substance) / (enzyme activity of control)) XI 00”.
  • IC 5 The value was calculated from the concentration obtained from the intersection with the 50% inhibition rate by calculating a linear equation from the concentration points before and after the 50% inhibition rate.
  • Table 7 shows the test results of the above test examples.
  • the enzyme inhibitory activity against HLGPa is indicated by ++ when the IC 50 (nM) is not less than ⁇ ⁇ ⁇ and less than 100 OnM, and is indicated by ++ when the IC 50 (nM) is less than 100 OnM.
  • the effect of the compound (1) of the present invention on plasma glucose concentration was examined using db / db mice, which are obese diabetes models.
  • the plasma glucose concentration of dbZdb mice (10 to 15 weeks of age) was measured, and the mice were divided into groups of 5 animals so that there was no difference in the average value of the plasma glucose concentration of each group.
  • dbZdb mice were orally administered an example compound or a solvent (0.5% methylcellulose), and plasma glucose levels were measured 1 and 3 hours after administration. Evaluation of the hypoglycemic action of the example compound was performed by performing a significant difference test between the solvent administration group and the example compound administration group at each time interval (Dunnett test).
  • hypoglycemic effect was indicated by 10 when the minimum effective dose was 100 mg Zkg or less, and by ++ when the minimum effective dose was 1 Omg / kg or less.
  • the novel compound of the present invention and its pharmaceutically acceptable salt strongly inhibited human liver glycogen phosphorylase. Having such an action mechanism, the compound (1) of the present invention is useful as a therapeutic drug for diabetes. In addition, the compound of the present invention is useful in combination with another drug for treating diabetes or a drug for treating hyperlipidemia.
  • This application is based on a patent application No. 2003-1777213 filed in Japan, the contents of which are incorporated in full herein.

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

Abstract

L'invention concerne un composé de pyrrole condensé, représenté par la formule générale (1), dans laquelle les symboles ont la signification indiquée dans la description. L'invention concerne également un promédicament à base dudit composé, ou un sel pharmaceutiquement acceptable dudit composé ou dudit promédicament. Ce composé (1), ce promédicament et ce sel sont utiles comme agent thérapeutique, présentant un effet inhibiteur de la HLGPa, pour lutter contre le diabète.
PCT/JP2004/008917 2003-06-20 2004-06-18 Compose de pyrrole condense et son utilisation comme medicament WO2004113345A1 (fr)

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JP2003-177213 2003-06-20
JP2003177213 2003-06-20

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115648B2 (en) 2002-03-06 2006-10-03 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7122567B2 (en) 2002-03-06 2006-10-17 Astrazeneca Ab Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity
US7129249B2 (en) 2002-03-06 2006-10-31 Astrazeneca Ab Heterocyclic amide derivatives as inhibitors of glycogen phoshorylase
US7138415B2 (en) 2002-03-06 2006-11-21 Astrazeneca Ab Indolamid derivatives which possess glycogenphosphorylase inhibitory activity
US7166636B2 (en) 2002-03-06 2007-01-23 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7169927B2 (en) 2002-03-06 2007-01-30 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
US7307174B2 (en) 2002-10-03 2007-12-11 Astrazeneca Ab Process and intermediates for the preparation of thienopyrrole derivatives
WO2008047821A1 (fr) * 2006-10-18 2008-04-24 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné
US7411074B2 (en) 2002-10-03 2008-08-12 Astrazeneca Ab Process and intermediates for the preparation of the thienopyrrole derivatives
US7884124B2 (en) 2006-06-30 2011-02-08 Sepracor Inc. Fluoro-substituted inhibitors of D-amino acid oxidase
US7884112B2 (en) 2004-03-08 2011-02-08 Stuart Edward Bradley Pyrrolopyridine-2-carboxylic acid hydrazides
US7893098B2 (en) 2003-12-29 2011-02-22 Sepracor Inc. Pyrrole and pyrazole DAAO inhibitors
US7902252B2 (en) 2007-01-18 2011-03-08 Sepracor, Inc. Inhibitors of D-amino acid oxidase
US8053603B2 (en) 2006-01-06 2011-11-08 Sunovion Pharmaceuticals Inc. Tetralone-based monoamine reuptake inhibitors
US8093265B2 (en) 2007-03-09 2012-01-10 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US8097760B2 (en) 2006-03-31 2012-01-17 Sunovion Pharmacuticals Inc. Preparation of chiral amides and amines
US8669291B2 (en) 2007-05-31 2014-03-11 Sunovion Pharmaceuticals Inc. Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors
US8877975B2 (en) 2006-01-06 2014-11-04 Sunovion Pharmaceuticals Inc. Cycloalkylamines as monoamine reuptake inhibitors

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JP2001131181A (ja) * 1999-09-30 2001-05-15 Pfizer Prod Inc グリコーゲンホスホリラーゼ阻害物質としての二環式ピロリルアミド類
JP2001302546A (ja) * 2000-03-22 2001-10-31 Pfizer Prod Inc Ｉｉ型糖尿病を発症する危険性の高い個体を予防的に処置する方法
WO2002020530A1 (fr) * 2000-09-06 2002-03-14 Astrazeneca Ab Amides de pyrrolyle bicycliques servant d'inhibiteurs de glycogene phosphorylase
WO2003037864A1 (fr) * 2001-10-29 2003-05-08 Japan Tobacco Inc. Compose indolique, et utilisation a des fins therapeutiques

Patent Citations (4)

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JP2001131181A (ja) * 1999-09-30 2001-05-15 Pfizer Prod Inc グリコーゲンホスホリラーゼ阻害物質としての二環式ピロリルアミド類
JP2001302546A (ja) * 2000-03-22 2001-10-31 Pfizer Prod Inc Ｉｉ型糖尿病を発症する危険性の高い個体を予防的に処置する方法
WO2002020530A1 (fr) * 2000-09-06 2002-03-14 Astrazeneca Ab Amides de pyrrolyle bicycliques servant d'inhibiteurs de glycogene phosphorylase
WO2003037864A1 (fr) * 2001-10-29 2003-05-08 Japan Tobacco Inc. Compose indolique, et utilisation a des fins therapeutiques

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7332515B2 (en) 2002-03-06 2008-02-19 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7115648B2 (en) 2002-03-06 2006-10-03 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7129249B2 (en) 2002-03-06 2006-10-31 Astrazeneca Ab Heterocyclic amide derivatives as inhibitors of glycogen phoshorylase
US7138415B2 (en) 2002-03-06 2006-11-21 Astrazeneca Ab Indolamid derivatives which possess glycogenphosphorylase inhibitory activity
US7166636B2 (en) 2002-03-06 2007-01-23 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7169927B2 (en) 2002-03-06 2007-01-30 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7122567B2 (en) 2002-03-06 2006-10-17 Astrazeneca Ab Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity
US7411074B2 (en) 2002-10-03 2008-08-12 Astrazeneca Ab Process and intermediates for the preparation of the thienopyrrole derivatives
US7307174B2 (en) 2002-10-03 2007-12-11 Astrazeneca Ab Process and intermediates for the preparation of thienopyrrole derivatives
US7893098B2 (en) 2003-12-29 2011-02-22 Sepracor Inc. Pyrrole and pyrazole DAAO inhibitors
US7884112B2 (en) 2004-03-08 2011-02-08 Stuart Edward Bradley Pyrrolopyridine-2-carboxylic acid hydrazides
US8053603B2 (en) 2006-01-06 2011-11-08 Sunovion Pharmaceuticals Inc. Tetralone-based monoamine reuptake inhibitors
US10562878B2 (en) 2006-01-06 2020-02-18 Sunovion Pharamceuticals Inc. Cycloalkylamines as monoamine reuptake inhibitors
US9868718B2 (en) 2006-01-06 2018-01-16 Sunovion Pharmaceuticals Inc. Cycloalkylamines as monoamine reuptake inhibitors
US8877975B2 (en) 2006-01-06 2014-11-04 Sunovion Pharmaceuticals Inc. Cycloalkylamines as monoamine reuptake inhibitors
US8097760B2 (en) 2006-03-31 2012-01-17 Sunovion Pharmacuticals Inc. Preparation of chiral amides and amines
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
EP2351568A2 (fr) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Utilisations d'inhibiteurs de l'enzyme dpp iv
US7884124B2 (en) 2006-06-30 2011-02-08 Sepracor Inc. Fluoro-substituted inhibitors of D-amino acid oxidase
EP2298772A1 (fr) * 2006-10-18 2011-03-23 Takeda Pharmaceutical Company Limited Composés hétérocycliques condenseé
US8492405B2 (en) 2006-10-18 2013-07-23 Takeda Pharmaceutical Company Limited Glucokinase-activating fused heterocyclic compounds and methods of treating diabetes and obesity
JP5306818B2 (ja) * 2006-10-18 2013-10-02 武田薬品工業株式会社 縮合複素環化合物
WO2008047821A1 (fr) * 2006-10-18 2008-04-24 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné
US7902252B2 (en) 2007-01-18 2011-03-08 Sepracor, Inc. Inhibitors of D-amino acid oxidase
US8093265B2 (en) 2007-03-09 2012-01-10 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US8669291B2 (en) 2007-05-31 2014-03-11 Sunovion Pharmaceuticals Inc. Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors
US9586888B2 (en) 2007-05-31 2017-03-07 Sunovion Pharmaceuticals Inc. Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors

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