WO2007063928A1 - Nouveau derive non cyclique d’amine carboxamide et sel de celui-ci - Google Patents

Nouveau derive non cyclique d’amine carboxamide et sel de celui-ci Download PDF

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WO2007063928A1
WO2007063928A1 PCT/JP2006/323889 JP2006323889W WO2007063928A1 WO 2007063928 A1 WO2007063928 A1 WO 2007063928A1 JP 2006323889 W JP2006323889 W JP 2006323889W WO 2007063928 A1 WO2007063928 A1 WO 2007063928A1
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mmol
methyl
added
stirred
butanamide
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PCT/JP2006/323889
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English (en)
Japanese (ja)
Inventor
Hideaki Fujii
Yutaka Nishimura
Aiko Nitta
Satoshi Sakami
Junko Nakaki
Hideki Kozono
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Toray Industries, Inc.
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Publication of WO2007063928A1 publication Critical patent/WO2007063928A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel orally administrable or preventive agent for diabetes, and an acyclic amine carboxyamide derivative or a pharmaceutically acceptable salt thereof.
  • Diabetes is a group of metabolic diseases mainly characterized by chronic hyperglycemia due to insufficient insulin action, and is often roughly classified into type 1 and type 2.
  • Type 1 diabetes synthesizes and secretes' splenic splenic Langerhans islet ⁇ cell destruction / disappearance power is the main cause of S insulin deficiency
  • type 2 diabetes is a predisposing factor for decreased insulin secretion and insulin resistance It develops with multiple genetic factors, including environmental factors such as overeating (especially high-fat diet), lack of exercise, obesity, and stress, and aging.
  • Currently used therapeutic agents for diabetes include insulin preparations, tolptamide, acetohexamide, chlorpropamide, tolazamide, glycloviramide, daruribole, darifenclamide, daliclazide, glimepiride and other sulfonylureas (nateglinide, (Including fast-acting insulin secretagogues such as mitiglinide and repaglinide), metformin (biguanide), a -darcosidase inhibitors such as voglibose, carbolose and miglitol, and thiazolidinediones such as pioglitazone and rosiglitazone.
  • Insulin preparations have a strong hypoglycemic effect, but often cause severe hypoglycemia. It can also cause weight gain. In addition, many insulin preparations require administration by injection, which places a heavy burden on patients. While sulfonylureas also have a powerful hypoglycemic effect, they often cause severe hypoglycemia. In addition, the effect is low when gaining weight or when administered for a long time. So-called secondary invalidation may occur. Metformin has a hypoglycemic effect, an insulin resistance improving effect, etc., but it often causes gastrointestinal disorders such as diarrhea and bloating. Infrequent but severe lactic acidosis may occur and is contraindicated in patients with renal or liver dysfunction. a-Dalcosidase inhibitor is less effective than sulfonylurea, but has a blood glucose lowering effect, but abdominal pain
  • Non-patent Document 15 May cause gastrointestinal disorders such as diarrhea and bloating.
  • Thiazolidinediones like metformin, have the effect of improving insulin resistance in addition to the hypoglycemic effect, but often cause body weight gain and edema, which may cause heart failure patients and those with a history of heart failure. Not suitable.
  • GLP-1 glucagon-like peptide-1
  • incretin one of the gastrointestinal hormones called incretin, which is useful for improving glucose metabolism in the body, such as insulin secretion promoting action and glucagon secretion inhibiting action, and protection of knee Langernos island ⁇ cells It is said to have an effect.
  • GLP-1 is secreted by dietary intake, that is, it exhibits an insulin secretion promoting action when blood sugar level rises to some extent, so it is generally easy to occur before or during exercise or after exercise, and hypoglycemia is unlikely to occur. It is thought that.
  • GLP-1 is also considered to be unlikely to cause weight gain, which is one of the risk factors for diabetes, due to its gastric motility-inhibiting and appetite-inhibiting effects.
  • GLP-1 is hydrolyzed and inactivated by an enzyme called dipeptidyl peptidase IV (hereinafter abbreviated as DPP-IV), and its half-life is 2 minutes. Because of its very short duration, it was difficult to use GLP-1 itself as a therapeutic drug for diabetes (Non-patent Documents 6-8). Recently, clinical studies of GLP-1 analogues that are not susceptible to enzymatic hydrolysis have been conducted, but none of them can be administered orally (Non-patent Document 8).
  • DPP-IV blocking Pesticides are also expected not to have side effects such as hypoglycemia and weight gain found in conventional oral diabetes drugs.
  • DPP-IV inhibitors including sulfostin derivatives, xanthine derivatives, isoquinolone derivatives and their analogs, isoquinoline derivatives and their analogs, pyridine or pyrimidine derivatives, but most of them.
  • Non-patent Documents 9-11 It is a cyclic amine carboxamide derivative (Non-patent Documents 9-11).
  • DPP-IV inhibitors are cyclic amine carboxamide derivatives, but examples of acyclic amine carboxamide derivatives are also known (Patent Document 1). - Four).
  • Patent Document 3 the DPP-IV inhibitory activity is specifically disclosed only in Example Compounds 1 and 10 of International Publication No. WO05Z40095 (Patent Document 3). Are 0.46 ⁇ and 0.45 ⁇ .
  • Non-Patent Document 1 The Diabetes Society of Japan, Diabetes Treatment Guide 2004— 2005
  • Non-patent document 2 Moller DE, “Nature”, 2001, 414, pp.821-827
  • Non-patent document 3 Skyler JS, “Journal 'Ob' 'Medicine' Chemistry” (Journal of Medicinal Chemistry), 2004, 47th, p. 4113-4117
  • Non-Patent Document 4 Ross S. A. et al., “Chemical Review”, 2004, 104, p. 1225-1282
  • Non-Patent Document 5 Stumvoll M. et al., “Lancet”, 2005, 365, p. 1333-1346
  • Non-Patent Document 6 Vilsboll T. et al., “Diabetologia”, 2004, 47th pp. 357-366
  • Non-Patent Document 7 D'Alessio DA et al., "American Journal of Physiology-Endocrinology and Metabolism", 2004, 286th , P. E882- E890
  • Non-Patent Document 8 Knudse L. B., "Journ of Medicinal Chemistry", 2004, 47th, p. 4128-4134
  • Non-Patent Document 9 Augustyns K. et al., "Current 'Medicine'Chemistry” (Current Me dicinal Chemistry), 1999, VIII, p. 311-327
  • Non-Patent Document 10 Augustyns K. et al., "Expert Opinion on Therapeutic Patens", 2003, 13 pp. 499-510
  • Non-Patent Document 11 Weber AE Author, Journal of Medicinal Chemistry, 2004, 47th, p. 4135-4141
  • Patent Document 1 International Publication No. 04Z37181 Pamphlet
  • Patent Document 2 Pamphlet of International Publication No. 05Z25554
  • Patent Document 3 International Publication No. 05Z40095 Pamphlet
  • Patent Document 4 International Publication No. 05Z95343 Pamphlet
  • An object of the present invention is to provide an orally administrable treatment or prevention agent for diabetes with few side effects and a novel compound useful as the treatment or prevention agent.
  • Ar represents a phenyl optionally substituted with 1 to 5 R 3 ,
  • R 3 represents halogen, hydroxy, alkyl having 1 to 6 carbon atoms, or alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms (wherein alkyl or alkyloxy is 1 to 5 carbon atoms). Substituted with halogen !, may! /,),
  • R 1 represents hydrogen or alkyl having 1 to 6 carbon atoms (wherein alkyl may be substituted with any 1 to 5, preferably 1 to 3, halogen or hydroxy);
  • R 5 represents alkyl having 1 to 6 carbon atoms, aryl or heteroaryl
  • p 0, 1 or 2
  • n each independently represent 1, 2 or 3
  • R 2 represents aryl or heteroaryl optionally substituted with any 1 to 3 substituents for which R 6 or R 7 forces are also selected
  • R 6 is alkyl having 1 to 6 carbon atoms, alkyloxy having 1 to 6 carbon atoms (wherein alkyl or alkyloxy may be substituted with 1 to 5 halogen atoms), cycloalkyl, aryloxy, heteroalkyl. Riloxy, hydroxy, halogen, with shear 0— (CH) q
  • R 9 and R 9 ′ are each independently hydrogen, alkyl having 1 to 6 carbons (wherein alkyl is substituted with 1 alkyl having 1 to 3 carbons or 1 to 5 halogens).
  • R 9 , R 9 ′ and nitrogen together may be pyrrolidine, piperidine (wherein pyrrolidine or piperidine may be substituted with 1 to 5 halogens), Piperazine, N-alkylpiperazine (wherein the alkyl has 1 to 6 carbon atoms), morpholine, thiomorpholine or thiomorpholine 4,4 dioxide,
  • R 1Q and R 1Q ′ each independently represent hydrogen, alkyl having 1 to 6 carbon atoms (which may be substituted with one alkyl group having 1 to 3 carbon atoms or 1 to 5 halogen atoms). Or R 1Q , R 1Q ', combined with nitrogen, pyrrolidine, piperidine (where pyrrolidine or piperidine is 1 May be substituted by 5 halogens), piperidines Rajin, N Arukirupi Bae Rajin (number of carbon atoms in the alkyl here is 1 to 6), morpholine, thiomorpholine or Chiomoruhori Hmm 4, 4 Jiokishido Where pyrrolidine, piperidine, piperazine, N-alkylbiperazine, morpholine, thiomorpholine or thiomorpholine 4,4 dioxide, one methylene may be substituted with oxo,
  • q 0, 1, 2 or 3
  • R 7 represents aryl or heteroaryl (wherein aryl or heteroaryl may be optionally substituted with 1 to 3 R 11 ),
  • R 11 represents alkyl having 1 to 3 carbon atoms, halogen, alkyloxy having 1 to 6 carbon atoms, trifluoromethyl, —SO—R 5 or one NR 9 R 3 ;
  • X represents a valence bond or alkylene having 1 to 6 carbon atoms.
  • the present invention also provides the use of the non-cyclic aminocarboxamide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of diabetes and the production of a hypoglycemic agent. .
  • a method for treating or preventing diabetes and a method for lowering blood glucose comprising administering to a patient an effective amount of the acyclic amine carboxamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of the general formula (I) has one or more asymmetric points. Therefore, the compound of the present invention can be used in which stereoisomers such as enantiomers, racemates or diastereomers may exist. Stereoisomers or mixtures of these isomers are also included.
  • alkyl means a linear or branched saturated hydrocarbon group, specifically, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl. , 2-butyl, 2-methyl-2-propyl, 1,1-dimethylethyl, 1 pentyl, 2-pentyl, 3 pentyl, 1 monohexyl, and the like.
  • Alkyloxy represents a functional group in which the alkyl is bonded to an oxygen atom, and specifically includes methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy and the like. The powers to be listed are not limited to these.
  • Cycloalkyl means a saturated alicyclic hydrocarbon group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Specifically, cyclopropyl, cyclobutyl, cyclohexane Examples include benzyl and cyclohexyl.
  • Alkylene means a straight or branched saturated hydrocarbon chain, specifically,
  • Forces including, but not limited to, methylene, ethylene, trimethylene, tetramethylene and the like.
  • Aryl means an aromatic group having 6 to 10 carbon atoms, and specifically includes forces such as phenyl, naphthyl and the like.
  • the "heteroaryl” includes 1 to 4 heteroatoms arbitrarily selected from S, N, and O.
  • the total number of atoms is 5 to 17, preferably the total number of atoms is 5 to 16.
  • R 8 may be substituted with the same definition as above.
  • the nitrogen atom may be oxidized.
  • chanel (2 chaels, 3 chaels), pyrrolyl (1 pyrrolyl, 2 pyrrolyl, 3 pyrrolyl), 1 methyl pyrrolyl (1 methyl pyrrole, 2 yl, 1-methyl pyrrole, 1 3 -Yl), 1-ethylpyrrolyl (1-ethyl pyrrole 2-yl, 1-ethynole pyrrole 3-yl), furyl (2-furyl, 3-furyl), thiazolyl (thiazole-2-yl, thiazole-4-yl) , Thiazole-5-yl), thiazole-3-oxide 2-yl (ie, thiazole-2-yl N-oxide), thiazole-3-oxide 4-yl, thiazole-3-oxide 5-yl, thiazolyl 3-oxide (ie , Thiazole
  • alkyl substituted with aryl or “alkyl substituted with heteroaryl” is an alkyl having 1 to 3, preferably 1 to 2 carbon atoms substituted with 1 or 2 of the aryl or heteroaryl.
  • benzyl diphenylmethyl, 1-phenylethyl, 2-phenylethyl, pyridine-2-ylmethyl, pyridine 1-oxide 2-ylmethyl, pyridine-3-ylmethyl, pyridine 1-oxide 3-ylmethyl, pyridine 4-methyl methyl, pyridine 1-xoxide 4-phenyl methyl, phenyl (pyridine-2-yl) methyl, phenyl (pyridine-1-oxyd-2-yl) methyl, phenyl (3-yl) pyridine, phenyl (1 pyridine 1 3 yl) methyl, phenol (4 1 pyridine) methyl, phenol (1 pyridine 1 4-methyl) methyl, furan-2-ylmethyl, furan-3-yl.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • diabetes is a disease diagnosed as diabetes according to diagnostic criteria such as WHO (World Health Organization), Japan Diabetes Society, American Diabetes Society or European Diabetes Society. It means state, including type 1 diabetes, type 2 diabetes and gestational diabetes.
  • WHO World Health Organization
  • Therapeutic or prophylactic agent includes not only those used for either treatment or prevention, but also those used simultaneously for both treatment and prevention.
  • “Prophylactic agent” is used for a condition in which diabetes is not diagnosed but shows either glucose tolerance abnormality or fasting blood glucose abnormality, or both glucose tolerance abnormality and fasting blood glucose abnormality Are also included.
  • the “treatment or prevention method” includes not only a method of performing either treatment or prevention, but also a method of performing both treatment and prevention at the same time.
  • diabetes is not diagnosed, but it indicates either glucose tolerance abnormality or fasting blood glucose abnormality, or a state of indicating glucose tolerance abnormality or fasting blood glucose abnormality!
  • the method of carrying out is also included.
  • the “hypoglycemic agent” means a drug having an effect of lowering blood glucose level, and includes effects such as an improvement effect of postprandial hyperglycemia in diabetes and an improvement effect of postprandial blood glucose transition in diabetes.
  • the “blood glucose lowering method” means a method for lowering blood glucose level, and includes a method for improving postprandial hyperglycemia in diabetes, a method for improving postprandial blood glucose transition in diabetes, and the like.
  • the acyclic amine carboxamide derivative of the present invention exhibited a blood glucose lowering action having good oral activity. Furthermore, as a result of intensive studies on the action mechanism of the hypoglycemic action of the acyclic amine carboxamide derivative of the present invention, it has become clear that DPP-IV inhibitory activity is one of the action mechanisms. Surprisingly, the compounds of the present invention showed potent DPP-IV inhibitory activity, as shown in the following examples, despite being acyclic amine carboxamide derivatives. From these facts, it can be said that the compound of the present invention is extremely useful as an agent for treating or preventing diabetes that can be administered orally and can be expected to have no side effects such as hypoglycemia and weight gain.
  • R 3 that can be substituted with Ar is preferably fluorine or chlorine among halogen (fluorine, chlorine, bromine, iodine) or trifluoromethyl.
  • the number of substitution is preferably 1 to 3.
  • R 1 is preferably hydrogen, among hydrogen, methyl or ethyl.
  • R 4 is hydrogen, alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl, 1 propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl, 1 pentyl, 1 monohexyl, etc.
  • Heteroaryl eg, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, virazile, etc.
  • 1 carbon substituted with aryl ⁇ 2 alkyls eg benzyl, phenyl (2-phenyl), etc.
  • m and n are preferably the case where both m and n are 2, even though the sum of m and n is preferably 2, 3, or 4.
  • R 2 is a monocyclic aryl or heteroaryl having 1 to 3, preferably 1 or 2, heteroaryl (where aryl or heteroaryl is selected from R 6 or R 7 forces)
  • aryl or heteroaryl is selected from R 6 or R 7 forces
  • Preferred is an aryl or heteroaryl having the following structure (which may be substituted with any one to three substituents), wherein aryl or heteroaryl is R 6 or R 7 force selection Substituted with any 1 to 3 substituents, which is more preferred).
  • aryl or heteroaryl having the following structure (wherein aryl or heteroaryl may be substituted with any one to three substituents selected as R 6 or R 7 force) is most preferable. .
  • R is preferably hydrogen, methyl, ethyl, 2-methoxyethyl, 2 ethoxyethyl or 2 morpholinoethyl.
  • R 6 represents alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms (which may be substituted with 1 to 5 halogen atoms) (eg, methyl, ethyl, 1 propyl, 2-propyl).
  • R 7 is Hue - Le, pyridine one 2-I le, pyridine one 3-I le, pyridine one 4-I le, pyridine Hmm 1 Okishido 2 I le, pyridine 1 Okishido 3 I le, pyridine 1 Okishi Dough 4-inole, pyrrole 1-yl, pyrrole 2-yl, 1-methylpyrrole 2-yl, pyrrole 3-il, 1 methyl pyrrole 3-yl, furan 2-il, furan 3 yl, thiophene 2 yl, thiophene 3 yl, imidazole 1 yl, imidazole 2 yl, 1 methyl imidazole 2 yl, imidazole 4 yl, 1-methyl imidazole 4 yl, 1 methyl imidazole -5 yl, pyrazole-1 yl, pyrazole-3 yl, 1-methyl pyrazole-3 yl, 2-methylpyrazole-3 yl, 2-methylpyrazo
  • R 11 is alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms (eg, methyl, ethyl, 1 propyl, 2-propyl, etc.), halogen (fluorine, chlorine, bromine, iodine), carbon C 1 -C 3, preferably C 1 -C 3 alkyloxy (for example, methoxy, ethoxy, 1-propoxy, etc.), trifluoromethyl, —SO—R 5 (for example, methylsulfol, ethylsulfo
  • X is preferably a valence bond, among which a valence bond, methylene or ethylene is preferred.
  • an inorganic acid salt such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, Acetate, trifluoroacetate, lactate, citrate, oxalate, dartrate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, etc.
  • Organic carboxylates methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and other organic sulfonates, aspartate, glutamate, and other acidic amino acids Salt, etc., among which hydrochloride, hydrobromide, phosphate, trifluoroacetate, citrate, fumaric acid, tartrate, methanesulfonate, etc. are preferred, but not limited thereto .
  • an acidic substituent such as a phenolic hydroxyl group is present in the general formula (I)
  • a salt with a base is also possible.
  • Alkaline earth metal salts such as salts and magnesium salts, aluminum salts, ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, dicyclohexane
  • Organic base salts such as xyllamine salt, N, N-dibenzylethylenediamine salt, and basic amino acid salts such as arginine salt, lysine salt and orthotin salt, etc., among which sodium salt and potassium salt Ethanolamine salts and the like are preferable, but not limited thereto.
  • Ar is 2-fluorophenyl
  • R 1 is hydrogen
  • Y is NR 4 —
  • R 4 is benzyl
  • m and n are Both are compounds wherein X is a valence bond
  • R 2 is phenol
  • R 7 is phenyl
  • R 11 is methyl sulfone (free base of Example Compound 44)
  • Ar is 2, 4, 5 trifluorophenyl
  • R 1 is hydrogen
  • Y is 0-0
  • m and n are Both compounds are compounds in which X is a valence bond, R 2 is methyl at the 1-position, and benzimidazol-2-yl having a 2-methoxyethoxy group as the substituent at the 5-position (free of Example Compound 141) base):
  • the compounds of the present invention include the following general formulas (II) and (III):
  • Y is as defined above.
  • R & R 6b is the same as the definition of hydrogen or R 6 above.
  • R 3a , R 3b and R 3e are the same as defined above for hydrogen or R 3 .
  • R 6 R 6b is the same as defined for hydrogen or R 6 above.
  • the acyclic amine carboxamide derivative used as an active ingredient of an orally administrable agent for treating or preventing diabetes represented by the general formula (I) is specifically the following scheme.
  • the force that can be produced by the method shown in FIG. The powerful methods not shown by the scheme below have been specifically disclosed in the examples.
  • the compound represented by general formula (I) can be produced by condensing amino acid (IV) and amine (V) to give compound (VI), and removing protecting group P of compound (VI) ( Scheme 1).
  • Amino acid (IV) can be obtained from commercial products, or Cole DC et al., “Tetrahedron”, 1994, 50 ⁇ , p 9517-9582 .; Cardillo G. et al., “Chemical 'Society'” Reviews (Chemical Society Reviews), 1996, 25 ⁇ , ⁇ 117-128 .; Juaristi
  • the removal of the protecting group P can be accomplished by a general deprotection method (Green TW et al., “Protective Groups in Organic Synthesis”, 5th edition, 1999, John '
  • the compound represented by the general formula (I) can be produced by using “Iriichi & And Sons”.
  • Ar in the scheme, Y, m, n, X and R 2 are the same as defined above, and P represents an appropriate protecting group.
  • Acidic agents include peracetic acid, pertrifluoroacetic acid, m-chloroperbenzoic acid (hereinafter abbreviated as mCPBA), t-butyl hydroperoxide, Use organic peroxides such as menhydroperoxide, bis (trimethylsilyl) peroxide, dimethyldioxysilane, and benzoyl peroxide, and inorganic peroxides such as hydrogen peroxide, potassium persulfate, and sodium periodate.
  • mCPBA m-chloroperbenzoic acid
  • Use organic peroxides such as menhydroperoxide, bis (trimethylsilyl) peroxide, dimethyldioxysilane, and benzoyl peroxide
  • inorganic peroxides such as hydrogen peroxide, potassium persulfate, and sodium periodate.
  • TPAP Perruthenium (VII) tetra-n-propylammonium
  • TPAP Perruthenium tetra-n-propylammonium
  • NMO N-methylmorpholine N-oxide
  • it can be carried out at 0.001 mol% to 90 mol%, but 0.1 mol% to 50 mol% is good. Often gives fruit .
  • the amount of co-oxidant can be 1 to 50 equivalents, but usually 1 to 10 equivalents gives good results.
  • halogen solvents such as dichloromethane and chloroform
  • -tolyl solvents such as acetonitrile and propio-tolyl, N, N-dimethylformamide (hereinafter abbreviated as DMF) and a mixture of these solvents
  • DMF N, N-dimethylformamide
  • the reaction temperature can be 0 ° C to 50 ° C, but usually good results are obtained at room temperature.
  • the reaction is often completed in 1 hour to 3 days. If the reaction is slow, better results may be obtained by adding an oxidizing agent and / or a co-acid additive rather than lengthening the reaction time. Addition of molecular sieves (hereinafter abbreviated as MS) is also an effective means.
  • Ar, P, in the scheme m, n, p, X and R 2 are the same as defined above.
  • amino acid (IV) can be obtained from a commercial product, or can be obtained by synthesis by a method described in the literature. Racemic amino acid (IV) and optically active are listed below. A specific method for synthesizing amino acid (IV ′) is shown (Schemes 3 and 4).
  • Amino acid (IV) is obtained by reacting compound (VII), which is commercially available, and ester bromoacetate (VIII) to give compound (IX), and reducing compound (IX). It can be produced by introducing a protecting group P into the amino group of the amino acid ester (X) and hydrolyzing the ester (Scheme 3).
  • Compound (IX) can be prepared according to Enishimino described in Kishi Y. et al., “Journal of Organic Chemistry” (1983, 483-3, p 3833-3835). It can be carried out by the method described in the general synthesis method of esters, etc.
  • the production of I) is a common j8-ketoester described in Kishi Y. et al., “Journal of Organic Chemistry” (1983, 48 ⁇ , p 3833-3835). It can be performed by the method described in the synthesis method and the like. Preparation of ⁇ compounds ( ⁇ ) by hydrolysis of esters is a common method (Green TW et al., “Protective Groups in Organic Synthesis”, 5th edition, 1 999, “John Wiley & Sons” etc.). The asymmetric reduction reaction can be carried out by the method described in Wang Z. et al., “Tetrahedron A symmetry”, 1999, 10 ⁇ , p 225-228.
  • the amidei reaction is a general carboxylic acid amide synthesis method (5th edition, Experimental Chemistry Course 16 Synthesis of Organic Compounds IV, pp. 118-134; Comprehensive 'Organic' Synthesis) by Benz G.
  • the ring-opening reaction of ratatam can be carried out with lithium salt, potassium salt, sodium salt, etc. of alcohol R 13 OH Usually, good results are obtained with sodium salt.
  • Commercially available alcohol salts may be used, and good results are obtained in the case of sodium methoxide and sodium ethoxide as alcohol salts that may be prepared before use.
  • the amount of salt of the alcohol is 1 to: a power that can be carried out with L00 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents.
  • alcohol solvents such as methanol, ethanol and isopropyl alcohol, ether solvents such as tetrahydrofuran (hereinafter abbreviated as THF) and 1,4 dioxane, halogen solvents such as dichloromethane and dichloroethane, DMF and the like can be used.
  • THF tetrahydrofuran
  • halogen solvents such as dichloromethane and dichloroethane, DMF and the like
  • the reaction can be carried out at a temperature from 0 ° C to the reflux temperature of the solvent, but good results are often obtained at room temperature. The reaction is often completed within one day, and usually complete within one hour.
  • Removal of the benzyloxy group can be carried out by a catalytic hydrogenation reaction using a noradium catalyst.
  • the hydrogen pressure is a force that can be carried out at 1 to 10 atmospheres. Usually, good results are obtained at 1 to 3 atmospheres.
  • the amount of palladium can be practiced from 0.001 mol% to 1000 mol%, but is usually from 0.1 mol% to 10 mol%. Good results are obtained at 0 mol%. Satisfactory results are often obtained when an alcohol solvent such as methanol or ethanol is used as the solvent.
  • the reaction temperature can be 0 to 100 ° C, but it is usually carried out at room temperature. The reaction is often completed within one day, and is usually completed within one hour.
  • molybdenum hexacarbox described in Naito T. et al., “Journal of Organic Chemistry”, 2000, 65 ⁇ , p 176-185.
  • This method can also be implemented by using a method.
  • Introduction of the protecting group P to the amino group and hydrolysis of the ester is a common method (Gren TW et al., “Protective Groups in Organic Synthesis”, 5th edition. 1999, John Wiley & Sons etc.).
  • Ar, P and R 13 in the scheme are the same as defined above.
  • Amine (XX) (compound with ammine (V)! /, Where R 1 is hydrogen) can be produced mainly by the methods ⁇ to ⁇ .
  • Amine (XX) is an alcohol (XVIII) obtained by the reaction of a commercially available ketone (XVI) with an organometallic compound (XVII), Krimen LI et al., “Organic Reactions”. ), 1969, 17 ⁇ , p 213-325 .; Bishop R.
  • the compound (XIX) was introduced into the compound (XIX) by the method described in “Comprehensive Organic Synthesis”, 1991, 6300, p.2 61-300, Pergamon Press (Pergamon Press).
  • M represents a metal such as lithium, magnesium, aluminum, zinc, copper, titanium, cerium, etc., and usually good results are obtained with lithium and magnesium.
  • ether solvents such as jetyl ether, THF, and 1,4 dioxane, and aromatic hydrocarbon solvents such as benzene and toluene can be used. Usually, good results are obtained with THF.
  • the reaction can be carried out at a temperature of -100 ° C to 100 ° C, but usually good results are obtained at 78 ° C to 30 ° C.
  • Organometallic compound (XVII) is a force that usually gives good results when used in an equivalent amount of 1 to 2 equivalents to ketone (XVI). It is also possible. The reaction is often completed within one day, and the reaction is usually completed within one hour.
  • the reaction to remove the acyl group by the compound (XIX) force is a general method (Green TW et al., “Protective Groups in Organic Synthesis”, 5th edition, 1999, John Wiley & Sons. Etc.) or WO97 / 32880; Lee GT et al. “Synthetic Communications” (1998) 28 ⁇ , ⁇ 4009-4018. It can be implemented by the method described in 1.
  • R 14 when R 14 is a chloromethyl group, it can be carried out by the method described in Jirgensons A. et al., “Synthesis”, 2000, p. 1709-1711.
  • Y, m, n, X, and R 2 are the same as defined above, and R 14 may be substituted with one halogen and may represent alkyl having 1 to 3 carbon atoms.
  • Amine (XX) is obtained by oximation of ketone (XVI) with benzyloxyamine 'hydrochloride. It can be produced by removing the benzyloxy group of compound ( ⁇ ) by leading to compound (XXII) by reaction of the obtained oxime (XXI) and organometallic compound (XVII).
  • the oximation reaction can be carried out in the presence of a base with a commercially available ketone (XVI) and a commercially available benzyloxyamine 'hydrochloride.
  • Examples of the base that can be used include organic bases such as pyridine and triethylamine (hereinafter abbreviated as TEA), organic sulfonates such as sodium acetate and potassium acetate, and the like.
  • the amount of the base can be used up to 1 equivalent force solvent amount.
  • the amount of benzyloxyamine hydrochloride can be 1 to 10 equivalents, but usually 1 to 3 equivalents gives good results.
  • the solvent alcohol solvents such as methanol and ethanol are usually used, and water can be used as a cosolvent. It is also possible to use a base as a solvent.
  • the reaction can be carried out at a temperature ranging from 0 ° C. to the reflux temperature of the solvent, preferably the reflux temperature of the solvent at room temperature.
  • reaction is often completed within one day, and usually the reaction is completed within 5 hours.
  • M represents a metal such as lithium, magnesium, aluminum, zinc, copper, titanium, cerium, and usually good results are obtained with lithium and magnesium.
  • ether solvents such as jetyl ether, THF, and 1,4 dioxane, and aromatic hydrocarbon solvents such as benzene and toluene can be used. Usually, good results are obtained with jetyl ether. .
  • the reaction temperature is a force that can be carried out at -100 ° C to 100 ° C.
  • the organometallic compound (XVII) is usually used in an amount equivalent to 1 to 2 equivalents of the oxime (XXI). Use more than that amount, or add it sequentially until the reaction is complete. Is also possible.
  • the reaction is often completed within one day, and the reaction is usually completed within one hour.
  • Removal of the benzyloxy group can be carried out by a catalytic hydrogenation reaction using a noradium catalyst.
  • the hydrogen pressure is a force that can be implemented at 1 to 10 atmospheres. Usually, good results are obtained at 1 to 3 atmospheres.
  • the amount of palladium, 0.001 mol% to 1000 mol 0/0 can be carried 1S Usually, good results have been obtained at 0.1 mol% to 100 mol%.
  • reaction temperature is from 0 to: force that can be carried out at L00 ° C Usually carried out at room temperature. The reaction is often completed within a day, and the reaction is usually completed within an hour.
  • Catalytic hydrogenation reaction the molybdenum hexacarbonyl described in Naito T. et al., "Journal 'Ob' Organic 'Chemistry” (Journal of 0 rganic Chemistry), 2000, 65 ⁇ , p 176-185. It can also be implemented by a method. In the scheme, Y, m, n, X and R 2 are the same as defined above.
  • Amin (XX) can be obtained as a commercial product by the method described in Ellman JA et al., “Accounts of Chemical Research”, 2002, 35 ⁇ , p 984-995. It can be produced from a new ketone (XVI) via compound ( ⁇ ) and compound (XXIV).
  • XVI new ketone
  • Y, m, n, M, X, and R 2 are the same as defined above.
  • the organometallic compound (XVII) used in the above-mentioned methods A to C is a commonly used halogen metal exchange reaction or deprotonation reaction (Tomooka K. et al. “Main Group Metals in Organic Synthesis”, 2004, 1 ⁇ , p 1-34. Weilly.; Oshima K. et al. Group Metals in Organic Synthesis), 2004, 1 ⁇ , p 51-154. Weilly.; Katritzky AR et al. “Comprehensive Heterocyclic Chemistry” (1984) 5 ⁇ , p 39-11 0. Pergamon Press, etc.).
  • the compound (XXV) used in the production of the organometallic compound (XVII) is commercially available or, if not commercially available, can be synthesized and obtained by the method shown in Scheme 8-: L1. .
  • X and R 2 are the same as defined above, and Z represents hydrogen or halogen.
  • XXV Compound (XXV ') (compound (XXV) in which R 2 is thiazole- 2- yl, Z is hydrogen, and X is a valence bond) is a commercially available promoketone ( XXVII), or a bromoketone (XXVII) obtained by bromination of a commercially available ketone (XXVI) is cyclized to thiazole (XXVIII) by thiourea or ethyl oxalate, and the thiazole (XXVIII) force is also R 15 (Scheme 8). Bromoketone (XXVII) is produced by Jaeques J.
  • thiourea or thioxamic acid ethyl By using 0.1 to 10 equivalents, preferably 0.5 to 2 equivalents, of thiourea or thioxamic acid ethyl, good results are obtained.
  • the solvent alcohol solvents such as methanol and ethanol, and aprotic polar solvents such as acetone and DMF are preferably used.
  • the reaction can be carried out at a temperature from 0 ° C to the reflux temperature of the solvent, but usually good results are obtained from room temperature to the reflux temperature of the solvent. The reaction is often completed within a day, and usually the reaction is completed within 3 hours.
  • R 15 is an ethoxycarbo group
  • the ethoxycarbo group of thiazole (XXVI ⁇ ) can be synthesized by a general method (Green TW et al., “Protective 'Gnorapes'In'Onoreganic' Synthesis” (Protective Groups). in Organic Synthesis), fifth edition, 1999, John Wiley & Sons, etc.) and then decarboxylated using acids such as hydrochloric acid and hydrobromic acid. It is possible to implement it.
  • an acid used for the reaction may be used as a solvent, or an ether solvent such as THF or 1,4 dioxane may be used as a cosolvent.
  • the reaction temperature can be from room temperature to the reflux temperature of the solvent, but usually favorable results are obtained at the reflux temperature of the solvent.
  • the reaction is often completed within one day, and the reaction is usually completed within one hour.
  • R 7 is the same as defined above, and R 15 represents amino or ethoxycarbonyl.
  • isothiocyanate (XXX) or thiourea (XXXI) is commercially available, it can also be produced from them), and can be produced by cyclization.
  • the isothiocyanate (XXX) can be produced by the reaction of a-line (XXIX) with a thiocarbonylated reagent.
  • a thiocarbonylated reagent Preferable examples of the thiocarbo-Ruyi reagent include thiophosgene, thiocarbodiimidazole (hereinafter abbreviated as TCDI), 1,1, -thiocarbonylji 2 (1H) -pyridinone (hereinafter abbreviated as TCDP), and the like.
  • the amount of the thiocarbonylating reagent can be carried out at 1 to 10 equivalents. Usually, 1 to 3 equivalents gives preferable results.
  • the solvent ether solvents such as THF and 1,4 dioxane, halogen solvents such as dichloromethane and chloroform, and aromatic hydrocarbon solvents such as benzene and toluene are usually used. Satisfactory results are obtained.
  • the reaction can be carried out at a temperature of -100 ° C to 100 ° C, but satisfactory results are often obtained at -20 ° C to room temperature. The reaction is often completed within 1 day, and usually the reaction is completed within 3 hours.
  • Thiourea (XXXI) can be produced by reacting isothiocyanate (XXX) with ammonia.
  • Ammonia may be a gas or an ammonia solution such as ammonia water, methanol, ethanol, 2 propanol, or 1,4 dioxane, but the method using an ammonia solution is simple and has good results. This is the method obtained.
  • the amount of ammonia is not particularly limited, but usually a satisfactory result is obtained with 1 to: LO equivalent.
  • the solvent, THF, 1, 4 ether solvents such Jiokisan, dichloromethane emissions, black hole halogen solvents such Holm, benzene, force normally can be used aromatic hydrocarbon-based Solvent such as toluene, T HF Satisfactory results can be obtained with dichloromethane, etc. Satisfactory results are often obtained at a reaction temperature of ⁇ 100 ° C. to 100 ° C., a force that can be carried out at ⁇ 20 ° C. to room temperature. The reaction is often completed within one day, and usually within 3 hours.
  • Thiourea (XXXI) can also be produced directly by the method described in Meckler H. et al., “Synthesis”, 2000, p 1569-1574. .
  • the compound (XXV) having the substituent R 6 or R 7 can be produced using the compound having these substituents as a raw material as described above, but can also be introduced later.
  • An example of a method to be introduced later is shown in Scheme 11.
  • Other common Suzuki coupling conditions (Suzuk i A. et al. “Chemical Review”, 1995, 95 ⁇ , p 2457-2483; Suz uki A. Cross-Coupling Reactions (Meta ⁇ Catalyzed Cross-Coupling Reactions), 1998, p 49-97.
  • Benzothiazole (XXV,,,) is a copy of Haddock E. et al. "Courtesy ⁇ ⁇ ⁇ Sea” (Journal of Chemical Society C), 1971, p 3994-3999 .; Cadog an JIG. Hemicai Society, Parkin Transaction 1), 1973, p 541-542.; Doyl e MP et al., “Journal of Organic Chemi stry”, 1977, 42 ⁇ , p 3494 -3498;. Chedekel MR et al., ".
  • Compound (XXV '''') is a general phenolic hydroxyl group alkylation condition (Protective Groups in Organic Synthesis, Green TW et al., Protective Groups in Organic Synthesis), 5th edition, 1999, John Wiley & Sons etc.) or general Mitsunobu reaction conditions (Mitsunobu 0. “Synthesis”, 1981, p 1- 28 ; Benzothiazole (XXV,,, ') force can be produced by Hughes DL, “Organic Reactions”, 1992, 42 ⁇ , ⁇ 335-656.
  • R 17 represents alkyl having 1 to 6 carbon atoms or (CH 3) q—R 8 (q and R 8 are as defined above).
  • Amine (XX,) (a compound in which R 2 is benzimidazol-2-yl and X is a valence bond in Amine (XX)) is a commercially available ketone (XVI).
  • Strecker Reaction, followed by hydrolysis of the cyano group (Steiger RE, “Organic Synthesis”, 1942, 22 ⁇ , p 13-15, etc.) leads to the amino acid (XXXIV) and amino acid It can be produced by introducing an Fmoc group into the (XXXIV) amino group, then subjecting it to a phenylenediamine (XXX VI), followed by an amide reaction followed by a cyclization reaction, and then removing the Fmoc group It is.
  • Fmoc group Introduction of the Fmoc group can be carried out by the method described in McLaughlm M. et al., “Tetrahedron Letters”, 1997, 3813, p 4013-4016.
  • the amidation reaction of amino acid (XXXIV) and phenylenediamine (XXXVI) is carried out using a general carboxylic acid amide synthesis method (5th edition, Laboratory Chemistry Course 16 Synthesis of Organic Compounds IV, pp. 118-134 .; Benz G. “Comprehensive Organic Synthesis”, 1991, 6 ⁇ , p.381-417, Pergamon Press .; Bailey PD et al.
  • acids include organic carboxylic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid, inorganic acids such as hydrochloric acid and hydrobromic acid, methanesulfonic acid, and P-toluenesulfonic acid.
  • organic carboxylic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid
  • inorganic acids such as hydrochloric acid and hydrobromic acid, methanesulfonic acid, and P-toluenesulfonic acid.
  • the ability to use sulfonic acids such as polyphosphoric acid etc.
  • the acid is preferably used in a solvent amount.
  • the reaction temperature can be carried out at room temperature or the reflux temperature of the solvent, and is preferably from 50 ° C to the reflux temperature of the solvent.
  • the reaction is often completed within 3 days, and the reaction is usually completed within 1 day.
  • Phenylenediamine may be available as a commercial product. If it is not available, it can be obtained by synthesis.
  • An example of a process for producing phenylenediamine (XXXVI) is shown in Scheme 13.
  • Phenol-Diamine (XXXVI) is commercially available-Toro-Rin (XXXVII) amino group Voskresens S. et al. "Synthetic Communications" (Synthetic Communications), 2000, 30 ⁇ , p .
  • Amine (XX ,,) (a compound in which R 2 is thiazole-4-yl and X is a valence bond in Amine (XX)) is a commercially available amino acid ester (XXXIX) by Chen P. et al. Tetrahedron Letters, 1997, 38 ⁇ , ⁇ 3175-3178.
  • the compound (XL) can be prepared by the method described in the above, and the compound (XL) and thioamide (XLI) can be reacted and cyclized, and then the Boc group can be removed.
  • Thioamide (XLI) may be available as a commercial product, or if it is not available as a commercial product, Taylor EC et al.
  • the anti-diabetic effect and the hypoglycemic effect of the compounds of the present invention are described in, for example, glucose tolerance using experimental animals described in Takeni Hironi et al. Although it can be confirmed by a test (Oral Glucose Tolerance Test, hereinafter abbreviated as OGTT test), it is not limited to this method.
  • OGTT test Oral Glucose Tolerance Test
  • experimental animals Normal animals such as mice, rats, dogs, monkeys, etc. or diabetic model animals (for example, the obesity diabetes model described in Winzell MS et al. Induced Obesity Model (hereinafter abbreviated as DIO model), etc.
  • DIO model Induced Obesity Model
  • the drug when the compound of the present invention is clinically used as a drug such as a therapeutic drug for diabetes, the drug may be a free form or a salt thereof itself, or an excipient, a stabilizer, a preservative, a buffer, a dissolution agent.
  • Additives such as auxiliary agents, emulsifiers, diluents, tonicity agents and the like may be appropriately mixed.
  • the dosage form includes tablets' capsules, granules, powders, syrups and other oral preparations, as well as parenterals such as injections, suppositories, etc., or ointments, creams, and patches. Topical administration is also possible. These preparations can be made by generally known manufacturing methods.
  • the therapeutic or prophylactic agent for diabetes of the present invention preferably contains 0.00001 to 90% by weight, more preferably 0.0001 to 70% by weight of the active ingredient.
  • the amount to be used is appropriately selected according to the symptom, age, body weight, administration method, etc. For adults, the amount of active ingredient is 1 ⁇ g to 10 g per day for oral preparations. Or it can be administered in several divided doses.
  • the compound represented by the general formula (I) and a salt thereof of the present invention can be used as a therapeutic or preventive agent for diabetes and a hypoglycemic agent.
  • the compound represented by the general formula (I) and the salt thereof of the present invention can be used in combination with other antidiabetic agents (hereinafter abbreviated as concomitant drugs).
  • concomitant drugs antidiabetic agents
  • the administration time of the compound represented by the general formula (I) of the present invention and the salt thereof and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or with a time difference. It may be administered.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound represented by the general formula (I) of the present invention and a salt thereof and the concomitant drug can be appropriately selected depending on the administration subject, administration route, symptom, combination and the like.
  • Concomitant drugs include insulin preparations (super fast-acting insulin preparations, fast-acting insulin preparations, mixed insulin preparations, intermediate-type insulin preparations, continuous-type insulin preparations, long-acting dissolved insulin preparations, transpulmonary insulin preparations, oral insulin preparations) ), Insulin sensitizers (Pioglitazone, Rosiglitazone, Netoglitazon, Farglitazar, Ribo) Gritazone (Rivoglitazone), Oxeglitazar, Naveg Litazar, Balaglitazone, ONO-5129, AVE-0847, LBM-642, CKD-501, AVE-5376, etc., oc— Darcosidase inhibitors (Acarbose, Voglibose, Mi
  • Fructose 1, 6 bisphosphatase inhibitor (MB-6322, MB-07803, etc.), SGLT (somum-dependent renal glucose transporter) inhibitor: ⁇ (J — 033, KGA—2727, SAR—7226, etc., 11 ⁇ — HSD1 (11 ⁇ -hydroxysteroid dehydrogenase 1) inhibitors (BVT-3498, AMG-221, INCB-13739, etc.), PTP-1B (protein tyrosine phosphatase- IB) inhibitors (ISIS-113715, JTT-551, etc.), GSK3 ⁇ (glycogen synthase kinase 3 ⁇ ) inhibitors (SAR-502250, etc.), glucagon antagonists (BAY-27-9955, NN-2501, etc.), glycogen Phosphorylase inhibitors (such as Isofagomine, PSN-357), CPT1 (Cartin 0—palmitoyltransferase 1) inhibitors (such
  • FIG. 1 is a graph showing the blood glucose elevation inhibitory effect of Example Compound 8.
  • FIG. 2 is a graph showing the blood glucose increase inhibitory effect of Example Compound 60.
  • FIG. 3 is a graph showing the blood glucose increase inhibitory effect of Example Compound 73.
  • FIG. 4 is a graph showing the blood glucose increase inhibitory effect of Example Compound 75.
  • FIG. 5 is a graph showing the blood glucose increase inhibitory effect of Example Compound 121.
  • FIG. 6 is a graph showing the blood glucose increase inhibitory effect of Example Compound 122.
  • FIG. 7 is a graph showing the blood glucose increase inhibitory effect of Example Compound 125.
  • FIG. 8 is a graph showing the blood glucose elevation inhibitory effect of Comparative Compounds 1 and 2.
  • FIG. 9 is a graph showing the blood glucose elevation inhibitory effect of Example Compound 60 in a diabetes model mouse.
  • Step 1 Synthesis of benzyl 4 ferrobiperidine 4 ol (reference compound 1)
  • Step 3 1 Synthesis of Benjirou 4 ferrobiperidine 4-amamine (Reference compound 3)
  • N— (1-benzyl-4-phenolbiperidine-4-yl) acetamide (lOlmg, 0.33 mmol) was suspended in THF (0.2 mL) and titanium tetraisopropoxide (96 ⁇ L, 0.32 mmol) and diphenylsilane (0.15 mL, 0.81 mmol) were added, and the mixture was stirred at room temperature. After 12 hours, the mixture was diluted with ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution was added and stirred vigorously. The resulting white solid was filtered off, and the filtrate was separated and extracted with ethyl acetate.
  • Step 4 (3R) —N— (1—Benzyl—4-phenolbiperidine—4-yl) —4— (2 fluorophenol) -3— (2-methyl-2-propoxycarbolamamino) butanamide (Reference Compound 4) Synthesis
  • EDCI 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide
  • EDCI 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide
  • Step 5 Synthesis of 3-amino-1-N- (l-benzyl-1-4-biruberidine-1-4-yl) 4- (2-fluorophenyl) butanamide dihydrochloride (compound 1)
  • Step 1 Synthesis of methyl 4 ferrobiperidine 4 ol (Reference compound 5)
  • ferrous lithium Z cyclohexane-jetyl ether solution (1.05M, 7.7 mL, 8. lmmol) was added to THF (5 mL).
  • THF 5 mL
  • a solution of peridone (0.5 mL, 4. 1 mmol) in THF (3 mL) was added dropwise. After completion of the dropwise addition, the ice bath was removed and the mixture was stirred at room temperature. 1.5 hours later, a saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried and concentrated.
  • the obtained crude product was purified by silica gel column chromatography to obtain the title compound (877 mg, 97%).
  • Step 3 (3R) — 4— (2 Fluorophenol) — N— (l-Methyl—4-Ferruberidine-4-yl) -3— (2-Methyl-2-propoxycarbolamamino) butanamide (Reference Compound 7) Synthesis
  • N— (1-methyl-4-phenol-biperidine-4-yl) acetamide (58 mg, 0.25 mmol) was suspended in THF (0.1 mL) and titanium tetraisopropoxide (75 ⁇ L , 0.25 mmol) and diphenylsilane (0.12 mL, 0.65 mmol) were added and stirred at room temperature. After 12 hours, the mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was vigorously stirred. The resulting white solid was filtered off, and the filtrate was separated and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried and concentrated.
  • Step 4 (3R) — 3 Amino 4— (2 Funoleo mouth Hue-Nole) 1 N— (l—Methinore 1— Synthesis of phthalbiperidine 4-yl) butanamide dihydrochloride (compound 2) Under argon atmosphere, (3R) —4— (2 fluorophenyl) N— (1-methyl-4 ferrobiperidine 4-yl) 3- (2-Methyl-2-propoxycarbo-lumino) butanamide (49 mg, 0.1 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (3 mL), stirred at room temperature for 3 hours, concentrated and concentrated. 31 mg (67%) of product was obtained.
  • N— (1-methyl-4-phenol-biperidine-4-yl) acetamide (Reference compound 6) (HOmg, 0.47 mmol) was suspended in THF (0.1 mL), and titanium tetrisopropoxide (0.15 mL, 0.51 mmol) and diphenylsilane (0.22 mL, 1.2 mmol) were added and stirred at room temperature. After 12 hours, the reaction mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was vigorously stirred. The resulting white solid was separated by filtration, and the filtrate was separated and extracted with ethyl acetate.
  • Step 2 (3R) —3 amino 4- (2, 4, 5 trifluorophenol) 1 N— (l-methyl 4-phenylbiperidine 4-yl) butanamide dihydrochloride (compound 3 )
  • Propoxy ball Amino) butanamide (81 mg, 0.16 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (3 mL), stirred at room temperature for 3 hours and concentrated to give 59 mg (77%) of the title compound.
  • Step 1 4 Synthesis of 2H-tetrahydropyran 4ol (Reference Compound 9)
  • N— (4-Ferro 2H-tetrahydropyran-4-yl) acetamide 63 mg, 0.29 mmol
  • THF 0. ImL
  • titanium tetraisopropoxide 80 0
  • diphenylsilane 0.13 mL, 0.70 mmol
  • the resulting white solid was filtered off, and the filtrate was separated and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried and concentrated.
  • Step 4 (3R) — 3 Amino 4— (2 Funoreux mouth-nore) 1 N— (4 Hue-Nole 1 H-tetrahydropyran 4 yl) butanamide hydrochloride (Compound 4)
  • N— (4 Fethiane-4-yl) acetamide 60 mg, 0.25 mmol was suspended in THF (0.1 mL) and titanium tetraisopropoxide (76 L, 0.26 mmol).
  • diphenylsilane (0.12 mL, 0.65 mmol) were added and stirred at room temperature. After 13 hours, the mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was vigorously stirred. The resulting white solid was filtered off, and the filtrate was separated and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried and concentrated.
  • Step 4 (3R) —3-amino 4- (2-fluorophenol) -one N— (4-phenol cyan 4-yl) butanamide hydrochloride (Compound 5)
  • Step 2 (3R) — 3 Amino 4— (2 Funeo-Leo Fue-Nole) 1 N— (4 F-Nole 1, 1 Dioxothian 4 yl) butanamide hydrochloride (Compound 6)
  • N— (4 ferrothane-4-yl) acetamide (Reference compound 13) (181 mg, 0.77 mmol) was suspended in THF (0.3 mL), and titanium tetraisopropoxide (0.23 mL, 0 77 mmol) and diphenylsilane (0.36 mL, 1.94 mmol) were added at room temperature. And stirred. After 20 hours, the mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was vigorously stirred. The resulting white solid was separated by filtration, and the filtrate was separated and extracted with ethyl acetate.
  • Step 2 (3R) — 3 amino 1- 4 — (2, 4, 5 trifluorophenol) 1 N— (4 phenyl 2- 1 4-yl) butanamide 'hydrochloride (compound 7 )
  • Step 2 (3R) — 3 amino 1- 4 — (2, 4, 5 trifluorophenol) 1 N— (4 phenol 2 1, 1 dioxothian 4 yl) butanamide hydrochloride (compound 8)
  • Step 1 Synthesis of 4- (3-fluorophenyl) thiane-4-1ol (Reference Compound 18) Under argon atmosphere, 1-bromo-3fluorobenzene (753 mg, 4.30 mmol) in T HF (15 mL) was cooled to -78 ° C, n-Butyllithium Z-hexane solution (1.39M, 3.4mL, 4.73mmol) was added. After 10 minutes, a solution of 4-oxothiane (500 mg, 4.30 mmol) in THF (10 mL) was added and stirred at 78 ° C. for 2.5 hours, and then the mixture was further warmed to room temperature and stirred.
  • Step 3 Synthesis of 4— (4 fluorophenyl) thian-4-amamine (Reference compound 25)
  • a solution of N- (4- (4 fluorophenyl) thian-4-yl) acetamide (530 mg, 2. O5 mmol) in THF (1 mL) was added to titanium tetraisopropoxide (0.53 mL, 1.93 mmol), Diphenylsilane (0.90 mL, 2.50 mmol) was added and stirred at room temperature. After 12 hours, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the resulting insoluble material was removed by Celite filtration. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain 220 mg (51%) of the title compound.
  • Step 4 (3R) —4— (2 Funoleo Mouth Hue-Nole) One N— (4 One (4-Fonoleo Mouth Hue-Nole)) ) Synthesis of butanamide (reference compound 26)
  • Step 5 (3R) —4— (2 Funoleo Mouth Hue-Nole) N— (4 One (4 Funoleo Mouth Hue-Nole)
  • Step 6 (3R) — 3 amino 4— (2 fluorophenol) 1 N— (4— (4 fluoro 1) 1-Dioxothian 4 4-yl) butanamide 'hydrochloride (Compound 10) Synthesis under argon atmosphere (3R) —4 1 (2 Fluoro-F) N— (4 1 (4 Fluorophenyl) 1, 1, 1-Dioxothian 1 4-yl) 3— (2-Methyl 2-propoxyl-amino) butanamide (33 mg, 0.06 mmol) in 10% hydrogen chloride Z methanol solution (3 mL The mixture was stirred at room temperature for 12 hours and concentrated to give 30 mg (quantitative) of the title compound.
  • Step 3 Synthesis of 4— (2,3 difluorophenol) thian-4-amamine (Reference compound 30) Under argon atmosphere, titanium tetraisopropoxide (0.3 mL , 1. lOmmol) and diphenylsilane (0.51mL, 2.70mmol) were added and stirred at room temperature. After 17 hours, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the resulting insoluble material was removed by Celite filtration. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain 100 mg (40%) of the title compound.
  • Step 5 (3R) — 4— (2 Fluorophenol) 1 N— (4— (2, 3 Difluorophenol) —1, 1-Dioxothian 4 yl) -3— ( Synthesis of 2-methyl-2-propoxycarbo-lamino) butanamide (Reference compound 32)
  • Step 6 (3R) —3 amino 1- 4— (2 fluorophenol) 1 N— (4— (2, 3 diph Fluorophylol) -1,1,1-Dioxothiane-4yl) butanamide 'hydrochloride (compound 11) synthesis
  • Step 3 4 (2,4 Difluorophenol) thiane 4-amamine (Reference compound 35) Composition
  • Step 5 (3R) — 4— (2 Fluorophenol) 1 N— (4— (2, 6 Difluorophenol) —1, 1-Dioxothian-4 yl) -3— ( Synthesis of 2-methyl-2-propoxycarbo-lamino) butanamide (Reference compound 47)
  • Step 3 4 Synthesis of (3,5 difluorophenol) thian-4-amamine (Reference compound 50)
  • Step 3 4 Synthesis of (m-Tolyl) thian-4-amamine (Reference Compound 55)
  • Step 5 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force Rubonylamino) N— (4— (m—Tolyl) — 1, 1—Dioxothian— 4— B) Synthesis of butanamide (Reference compound 57)
  • Step 6 (3R) — 3 amino 1 4 — (2 fluorophenol) 1 N— (4 — (m-tolyl) — 1, 1 dioxothian 4 yl) butanamide hydrochloride (compound 16) Under an argon atmosphere, (3R) —4— (2 fluorophenyl) —3— (2—methyl—2, double-carboxylamino) N— (4— (m—tolyl) — 1, 1—dioxanthian—4— Yl) butanamide (72 mg, 0.08 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (4 mL), stirred at room temperature for 12 hours and concentrated to obtain 66 mg (quantitative) of the title compound. .
  • Step 3 Synthesis of 4— (p-Tolyl) thian-4-amamine (Reference Compound 60) Under argon atmosphere, titanium tetraisopropoxide (0.47mL, 1.57mmol) in THF (lmL) solution of N— (4- (p-tolyl) thian-4-yl) acetamide (391mg, 1.57mmol), Diphenylsilane (0.73 mL, 3.93 mmol) was added and stirred at room temperature. After 17 hours, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the resulting insoluble material was removed by Celite filtration. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain 215 mg (94%) of the title compound.
  • Step 4 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 propoxy force, Rolamino) N— (4— (p-tolyl) thian—4-yl) butanamide ( Synthesis of Reference Compound 61)
  • Step 5 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Rolamino) N— (4— (p Tolyl) — 1, 1—Dioxothian— 4— Yl) butanamide (Reference compound 62)
  • Step 6 (3R) —3 amino 1 4 -— (2 Fluorophenol) 1 N— (4— (p-Tolyl) 1 1, 1 Dioxothian 4yl) butanamide hydrochloride (Compound 17) synthesis (3R) —4— (2 fluorophenol) —3— (2-methyl-2-polyoxyboramino) N under argon atmosphere — (4- (p-tolyl)-1,1-dioxothian-4-yl) butanamide (89 mg, 0.17 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (4 mL) and stirred at room temperature for 12 hours. After concentrating, 80 mg (quantitative) of the title compound was obtained.
  • Step 2 Synthesis of N-methyl-4-phenol-4-amine (Reference compound 64)
  • N-methyl-N- (4-phenol-4-yl) acetamide 530 mg, 2. 13 mmol
  • Titanium tetraisopropoxide (0.63 mL, 2.13 mmol
  • diphenylsilane (0.99 mL, 5.31 mmol) were added and stirred at room temperature.
  • ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the resulting insoluble material was removed by celite filtration.
  • the filtrate was extracted with ethyl acetate, washed with saturated brine, dried and concentrated.
  • the resulting crude product was purified by silica gel column chromatography to obtain 324 mg (73%) of the title compound.
  • Step 3 (3R) — 4— (2 Fluorophenol) — N—Methyl—3— (2—Methyl—2—propoxycarbolamino) N— (4-Feltian-4-yl) butanamide ( Reference Synthesis of Compound 65) Under an argon atmosphere, add (3R) —4 ((2-fluorophenyl) 3- (2 methyl —2 propoxycarbo) to a DMF (2 mL) solution of N-methyl-4 phenthian—4 amine (59 mg, 0.28 mmol).
  • Step 4 (3R) — 4— (2 Fluorophenol) — N—Methyl—3— (2—Methyl—2—propoxycarbolumino) N— (4-Fue-Lu 1, 1—Dioxothian— 4-yl) butanamide (reference compound 66)
  • Step 5 (3R) — 3 Amino 4— (2 Funoleo Mouth Hue-Nole) 1 N—Methinore 1 N— (4—Fel—1, 1 Dioxothian— 4 -yl) butanamide hydrochloride ( Synthesis of Compound 18) Under an argon atmosphere, (3R) —4— (2 fluorophenyl) N-methyl 3— (2-methyl-2-propoxycarbolamino) N— (4 phenyl-1,1, 1-dioxothiane 4 Yl) butanamide (90 mg, 0.17 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (4 mL), stirred at room temperature for 12 hours and concentrated to obtain 70 mg (quantitative) of the title compound. .
  • Step 1 Synthesis of 4- (2-fluorophenyl) thiane-4-1ol (reference compound 67) Under an argon atmosphere, a solution of 2 fluorob-mouthed mobenzene (3.91 mL, 36. Ommol) in THF (50 mL) was cooled to -78 ° C, and n-butyllithium Z-hexane solution (1.59 M, 21.6 mL, 34 4 mmol) was added dropwise. After 20 minutes, a solution of 4-oxothiane (4. OOg, 34.4 mmol) in THF (25 mL) was added dropwise.
  • Step 3 Synthesis of (2 fluorophenyl) thian-4 amine 'hydrochloride (Reference Compound 69)
  • N— (4- (2 fluorophenyl) thian-4-yl) acetamide (5.OOg, 19.7 mmol) was suspended in THF (3 mL), and titanium tetraisopropoxide (5.85 mL, 19.7 mmol) and diphenylsilane (5.50 mL, 29.6 mmol) were added and stirred for 15 hours. After diluting the reaction solution by adding ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was further stirred for 30 minutes. After filtration through Celite, distilled water was added to the filtrate, and the mixture was extracted with ethyl acetate.
  • Step 4 (R) — 4— (3 Black Mole) 1 N— (4— (2 Fluorophenyl) Thiane-4-yl) 3-— (2-Methyl-2-propoxycarbolamamino) butanamide (reference Synthesis of compound 70)
  • Step 5 (3R) —4 (3 black mouth-nore) N— (4— (2 funoreo mouth-nore) 1, 1-Dioxochian 4 ill) -3— (2— Synthesis of methyl-2-propoxycarbonylamino) butanamide (Reference compound 71)
  • Step 6 (3R) — 3 Amino 4— (3 Black Mole) 1 N— (4— (2 Fluorophenol) 1, 1—Dioxothian 1 4-yl) Butanamide Hydrochloride ( Synthesis of compound 19) Under argon atmosphere, (3R) -4- (3 black mouth ring) N— (4- (2 fluorophenol) —1, 1-dioxothiane 4 yl) 3— (2 —Methyl-2-propoxycarbonylaminoamino) butanamide (148 mg, 0.28 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (3 mL) and black mouthform (3 mL), stirred at room temperature for 14 hours and concentrated to give the title compound 1 29 mg (98%) were obtained.
  • Step 1 (3R) —4— (2 Black Mole) N— (4— (2 Fluorophenyl) Thiane-4-yl) 3 -— (2-Methyl-2-propoxycarbolamino) butanamide (Reference Compound 74) )
  • Step 2 (3R) —4— (2 black mouth-nore) N— (4— (2 funoreo mouth-nore)-1, 1-Dioxochian 4 il) -3— ( Synthesis of 2-methyl-2-propoxycarbonylamino) butanamide (Reference Compound 75)
  • Step 3 (3R) — 3 Amino 4— (2 Black Mole) 1 N— (4— (2 Fluorophenol) 1, 1—Dioxothian 1 4-yl) Butanamide Hydrochloride ( Synthesis of compound 21) Under argon atmosphere, (3R) -4- (2 black-mouthed) N— (4- (2 fluorophenol) -1, 1, 1-dioxothiane 4) 3— (2 —Methyl-2-propoxycarbonylaminoamino) butanamide (l lOmg, 0.20mmol) in 10% hydrogen chloride Z methanol solution (3m L), dissolved in black mouth form (3 mL), stirred at room temperature for 14 hours and then concentrated to obtain 9 lmg (94%) of the title compound.
  • Step 2 (3R) -4- (4 Black-headed Hue-Nole) N— (4— (2 Funoleo-mouthed Hue-Nole) 1, 1-Dioxothiane 4 Fil) -3 (2 —Synthesis of methyl-2-propoxycarbonylamino) butanamide (Reference Compound 77)
  • Step 2 (3R) — 4— (2, 4 Dichlorophenol-Nole) One N— (4— (2 Funoleo-Fue-Nole) —1, 1-Dioxothiane 4-yl) -3— Synthesis of (2-Methyl-2-propoxycarbolamamino) butanamide (Reference Compound 79)
  • Step 2 (3R) — 4— (3, 4 Dichlorophenol-NO) 1 N— (4— (2 Funeo Leo-Fue-Nole) —1, 1-Dioxothiane 4) 3— Synthesis of (2-Methyl-2-propoxycarbolamamino) butanamide (Reference Compound 81)
  • Step 1 Synthesis of 4- (3-chlorophenyl) thian-4-ol (reference compound 82) 1—Cro-neck 3 1-benzene (1 lmL, 8.7 mmol) in THF (20 mL) was cooled to —78 ° C under argon atmosphere. N-Butyllithium Z-hexane solution (1.59M, 5.4 mL, 8.6 mmol) was added dropwise. After 20 minutes, a solution of 4-oxothiane (1. Og, 8.6 mmol) in THF (10 mL) was added dropwise. 30 minutes after completion of the dropwise addition, the temperature was slowly raised to room temperature, and 30 minutes later, an aqueous salt ammonium solution was added.
  • Step 3 4 Synthesis of (3 Chlorophenyl) thian-4-amamine (Reference Compound 84)
  • N— (4- (3 chlorophenyl) thian-4-yl) acetamide (62 Omg, 2.30 mmol) was suspended in THF (2 mL), and titanium tetraisopropoxide (678 L, 2.30 mmol) was suspended.
  • diphenylsilane (640 / z L, 3.54 mmol) were added, and the mixture was stirred at room temperature for 15 hours. After diluting with ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was further stirred for 30 minutes. After filtration through celite, the filtrate was poured into distilled water and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 320 mg (61%) of the title compound.
  • Step 5 (313 ⁇ 4 —? ⁇ -(4- (3-chlorophenol) -1,1,1-dioxanthane-4-yl) 4 (2-fluorophenol) 3- (2-methyl-2-propoxy) Carbo-Lamino) Butanamide (Reference Compound 86)
  • Step 6 (3R) — 3 Amino N— (4— (3 Closing Fell) 1 1, 1-Dioxothian 4 yl) 4 1 (2 Fluorophenyl) Butanamide Hydrochloride Synthesis of Compound 25) Under an argon atmosphere, ( 3 R) — N— (4— (3 black mouth file) — 1, 1-Dioxothian 4 yl) -4 one (2 Fluorophenol) -3— (2-Methyl-2-propoxycarbonylamino) butanamide (180 mg, 0.33 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (4 mL) and chloroform (2 mL), stirred at room temperature for 15 hours, concentrated. The title compound 1 52 mg (96%) was obtained.
  • Step 1 4-—Synthesis of (4 trifluoromethylphenol) thian—4-ol (reference compound 87)
  • N— (4 trifluoromethylphenol) thian-4-yl) acetamide (1.20 g, 3.96 mmol) was suspended in THF (3 mL), and titanium tetraisopropoxide ( 1. 17 mL, 3.96 mmol) and diphenol-noresilane (1.10 mL, 5.94 mmol) were added and stirred for 15 hours. After diluting with ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was further stirred for 30 minutes.
  • Step 4 (3R) —N— (4— (4 trifluoromethylphenol) thiane — 4—yl) —4 1 (2, 4, 5 trifluorotation) -3— ( Synthesis of 2-Methyl-2-propoxycarbolamino) butanamide (Reference Compound 90)
  • Step 5 (3R) —N— (4— (4 trifluoromethyl filed) 1, 1, 1-dioxothione 4 yl) 4 1 ( 2 , 4) 5 trifluorophenol) Synthesis of 3- (2-Methyl-2-propoxycarbonylamino) butanamide (Reference Compound 91)
  • Step 3 Synthesis of (3 Trifluoromethyl Phenol) thian — 4 Amine (Reference Compound 94)
  • N— (4- (3-trifluoromethylphenol) thian-4-yl) acetamide (1.20 g, 3.96 mmol) was suspended in THF (3 mL), and titanium tetra Isopropoxide (1.17 mL, 3.96 mmol) and diphenol-noresisilane (1.10 mL, 5.94 mmol) were added and stirred for 15 hours. After diluting with ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was further stirred for 30 minutes.
  • Step 4 (3R) —N— (4— (3 trifluoromethylphenol) thiane — 4—yl) —4 1 (2, 4, 5 trifluorotation) -3— ( Synthesis of 2-Methyl-2-propoxycarbolamino) butanamide (Reference Compound 95)
  • Step 2 4 Synthesis of 2- (2-Black 6-Funoleo-Fue-Nore) 1 3-— (2-Methinore 2 Propoxycarbonylamino) Butyrate Ethyl (Reference Compound 98)
  • Step 3 4 Synthesis of 2- (2 Black Mouth 6 Funoleo Mouth Hue-Nole) 1 3-— (2-Methinore 1 Propoxycarbonylamino) Butyric Acid
  • Step 4 (2 Black mouth 6 Funoleo mouth fuel) One N— (4— (2 Funore mouth mouth) Thiane 4 ill) -3— (2-Methyl-2-propoxycarbolamamino) ) Synthesis of butanamide (Reference compound 100)
  • Step 5 (2 Black mouth 6 Funoleo mouth fue-nore) 1 N— (4— (2 Funoleo mouth feel) —1, 1-Dioxochian 4 il) -3— Synthesis of (2-Methyl-2-propoxycarbo-lamino) butanamide (Reference Compound 101)
  • Step 2 4 (2 Black mouth— 4 Fluorophenol) —3— Synthesis of (2-Methyl-2 propoxycarbonylamino) butyrate (Reference compound 103)
  • Step 3 4 Synthesis of 2- (2-chlorotetrafluoro) -3- (2-methyl-2-propoxycarbonylamino) butyric acid (Reference Compound 104)
  • Step 4 (2 Black mouth 4 Funoleo mouth fuel) One N— (4— (2 Funore mouth mouth) Thiane 4 ill) -3— (2-Methyl-2-propoxycarbolamamino) ) Butanamide Synthesis of Reference Compound 105
  • Step 5 (2 Black mouth 4 Funoleo mouth fuel) 1 N— (4— (2 Funore mouth mouth) —1, 1-Dioxochian 4 ill) -3— Synthesis of (2-Methyl-2-propoxycarbo-lamino) butanamide (Reference Compound 106)
  • reaction solution was allowed to cool, THF (30 mL) and an aqueous potassium carbonate solution were added, and the mixture was further stirred for 20 minutes. After decanting the supernatant of the reaction solution in two layers, the aqueous layer was washed with THF.
  • the crude product obtained by drying and concentrating the organic layer was roughly purified by silica gel column chromatography. Under an argon atmosphere, sodium borohydride (918 mg, 24.3 mmol) was slowly added to acetic acid (15 ml) at room temperature, and then the acetic acid (5 mL) solution of the crude product was added to the reaction mixture stirred for 30 minutes at room temperature. Stir for 7 hours.
  • Step 2 4 Synthesis of 2- (2 Black Mouth 3, 6 Difunoleo Mouth Hue-Nole) 1 3-— (2-Methinore 2 Propoxycarbolamino) Ethyl Butyrate (Reference Compound 108)
  • Step 3 4 Synthesis of 2- (2 Black Mouth 3, 6 Difunoleo Mouth Hue-Nole) 1 3-— (2-Methinore 2 Propoxycarbonylamino) Butyric Acid (Reference Compound 109)
  • To the solution was added IN sodium hydroxide aqueous solution (6 mL) and stirred for 14 hours.
  • 1N Hydrochloric acid was added to weakly acidify, and the mixture was further stirred for 3 hr.
  • the precipitated white solid was collected by filtration and dried to obtain 1.17 g (90%) of the title compound.
  • Step 4 (2 Black mouth 3,3 Diphnoreo mouth Fu-Nole) One N— (4— (2 Funoleolophane) Cyan-4 Fil) -3— (2-Methyl-2-propoxycarbo- Synthesis of Ruamino) butanamide (Reference Compound 110)
  • Step 5 4 (2 Black-and-white 3, 6 Diphnoreo-mouthed Fu-Nore) One N— (4— (2 Funoleolophenyl) 1, 1-Dioxothian— 4-yl) —3— (2-Methyl —2 Synthesis of Propoxybonylamino) butanamide (Reference Compound 111)
  • Step 6 3 Amino 4— (2 Black mouth 3, 6 Difluorophenol) 1 N— (4— (2 Fluorophenol) —1, 1-Dioxothian 4 yl) Butanamide hydrochloride Synthesis of compound 30) 4 (2 chloro-3, 6 difluorophenol) N— (4— (2—fluorophenol) —1, 1—dioxothian— 4—yl) —3— (2-methyl-2 pro Poxycarbolamino) butanamide (135 mg, 0.25 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (3 mL) and black mouth form (4 mL), stirred at room temperature for 15 hours and concentrated to give the title compound 116 mg ( 97%).
  • Step 2 4 (3 Trifluoromethylphenol) — 3— (2-Methyl-2 propoxycarbonylamino) butyric acid (Reference compound 113)
  • Step 3 4 (3 trifluoromethyl phenol) —N— (4— (2 Fluorophenyl) tian-4 yl) -3— (2-Methyl-2-propoxycarbolamamino) butanamide (see Synthesis of compound 114)
  • Step 4 4 (3 trifluoromethyl phenol) —N— (4— (2 fluorophenol)
  • Step 2 4 (3 Black mouth 6 Funoreo mouth Hue-nore) 1 3— (2—Metinore 1 Propoxy Synthesis of Cycarbonylamino) Ethyl Butyrate (Reference Compound 117)
  • Step 3 4 (3 Black mouth 6 Funoleo mouth Hue-Nole) 1 3— (2-Methinore 2 Propoxycarbonylamino) Butyric acid (Reference compound 118) Synthesis
  • Step 4 (3 Black mouth 6 Funoleo mouth Fuerole) One N— (4— (2 Funoleo mouth Fuer) Thiane 4 ill) -3 (2-Methyl-2-propoxycarbolamamino) ) Synthesis of butanamide (Reference compound 119)
  • Step 5 (3 Black mouth 6 Funoleo mouth Hue-Nole) 1 N— (4— (2 Funoleo mouth Huel) —1, 1-Dioxochian 4 Fil) -3— Synthesis of (2-Methyl-2-propoxycarbo-lamino) butanamide (Reference Compound 120) 4— (3 Black mouth 6 Fluorophenol) -N- (4— (2 Fluorophenol) thian 4 yl) -3— (2-Methyl-2-propoxycarbolamamino) butanamide (115 mg, 0.22 mmol) was dissolved in dichloromethane (10 mL), and mCPBA (> 65%) (95 mg,> 0.36 mmol) was added under ice cooling.
  • Step 6 Amino-4 (3 Chloro-6 Funoleo Oral Fenol) N— (4 1 (2 Orenol Orophol) —1, 1-Dioxothian-4-yl) butanamide Hydrochloride ( Synthesis of compound 32)
  • reaction solution was poured into distilled water and extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid, distilled water and saturated brine. The organic layer was dried and concentrated, and the resulting crude product was purified by silica gel column chromatography to obtain 493 mg (20%) of the title compound.
  • Step 2 4 (3 Black-headed 1, 6 Diphnoreo-mouthed Fu-Nore) One N— (4— (2 Funoleolophane) Thiane 4 ill) -3— (2-Methyl-2-propoxycarbo- Synthesis of Ruamino) butanamide (Reference Compound 122)
  • Step 3 4 (3 Black-and-white 2, 6 Diphnoreo-mouth Fue-Nole) One N— (4— (2 Funoleolophenyl) 1, 1-Dioxothiane — 4-yl) —3— (2-Methyl —2 Synthesis of propoxybonylamino) butanamide (reference compound 123)
  • Step 1 (3R) —4— (2 Fluorophenol) —3— (2—Methyl-2 propoxyl force Rupolumino) N— (4 Phenylbiperidine 4 yl) butanamide (Reference compound 12 4)
  • Step 2 Synthesis of 3 amino 1- 4 — (2 fluorophenol) 1 N— (4 vinylbiperidine-4-yl) butanamide dihydrochloride (compound 34) Under an argon atmosphere, (3R) —4— (2 fluorophenyl) —3— (2-methyl-2-propylcarboxylamino) N— (4-phenylbiperidine-4-yl) butanamide (50 mg, (0.1 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (2 mL), stirred at room temperature for 3 hours and concentrated to obtain 42 mg (89%) of the title compound.
  • Step 2 Synthesis of 3-amino 4- (2 Fluoro-Fe) -N- (l-methylsulfo di-ru 4 4-biruberidine 4 yl) butanamide 'hydrochloride (Compound 35) Under argon atmosphere, (3R) —4— (2 fluorophenyl) —3— (2—Methyl-2 propoxycarbolamino) N— (1-methylsulfolulu 4-phenolbiperidine—4 yl) butanamide (55 mg, 0.1 mmol) was dissolved in 10% hydrogen chloride Z methanol solution (3 mL), stirred at room temperature for 9 hours and concentrated to give 51 mg (quantitative) of the title compound.
  • Step 2 4 (2-Methyl-2 propoxycarbolamino) — Synthesis of 4-phenolbiperidine (Reference compound 127)
  • Step 3 4 (2-Methyl-2 propoxycarbolamino) — Synthesis of 4-ferro- 1- (pyrimidine 2-yl) piperidine (reference compound 128)
  • Step 4 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Rolamino) N— (1— (Pyrimidine 1—2) 4-Ferbiperidine 1 4-yl) butanamide (reference compound 129)
  • Step 2 1 Synthesis of Acetyl-4 ferrobiperidine-4-amamine (Reference Compound 131)
  • Step 3 (3R) — N— (1-acetyl- 4-phenolbiperidine — 4-yl) —4— (2 fluorophenol) -3— (2-methyl-2-propoxycarbolamamino) butanamide (Reference Compound 132) Synthesis
  • Step 4 (3R) — N— (1—Acetyl— 4—Ferbiperidine — 4—yl) 3 Amino— 4— (2 Fluorophenyl) butanamide hydrochloride (Compound 37)
  • Step 2 Synthesis of Phenacyl-4 Phenolbiperidine-4-amamine (Reference Compound 134)
  • Step 4 (3R) — 3 amino 1 4 — (2 fluorophenol) 1 N— (l phenacyl 1 4 phenylbiperidine 4 yl) butanamide hydrochloride (compound 38)
  • Step 3 (3R) — N— (1—Benzyl 1- 4- (2 Fluoro-Phenol) Piperidine 4-4-yl) -4 (2-Fluoro-Phenol) -3— (2-Methyl-2 Synthesis of propoxycarboamino) butanamide (Reference compound 138)
  • N— (1—benzyl—4- (2 fluorophenyl) piperidine—4 yl) acetamide (880 mg, 2.7 mmol) was suspended in THF (0. 1 mL) and titanium tetrisoproboxide (800 / z L, 2.7 mmol) and diphenylsilane (750 / z L, 4. Ommol) were added and stirred at room temperature. After 18 hours, the reaction mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was vigorously stirred. The produced white solid was separated by filtration, and the filtrate was separated and extracted with ethyl acetate.
  • N— (1-benzyl-4- (3-phenol) piperidine-4-yl) acetamide 200 mg, 0.46 mmol was dissolved in 1,4 dioxane (3 mL).
  • copper (I) iodide (4 mg, 0.023 mmol)
  • trans-N, N, -dimethyl 1,2 cyclohexanediamine 13 mg, 0.092 mmol
  • potassium phosphate 258 mg, 0.997 mmol
  • Step 5 (3R) — N— (1—Benzyl 1- 4— (3— (Pyrrol 1-yl) -Fel) Piperidine 4-4-1) 2-4 (2-Fluoro-Fel) Synthesis of 3- (2-Methyl-2-propoxycarbonylamino) butanamide (Reference Compound 143)
  • N— (1-benzyl-4- (3-phenol) piperidine-4-yl) acetamide (reference compound 140) 400 mg, 0.92 mmol was added to 1,4 dioxane (4 mL).
  • Imidazolene (62mg, 0.92mmol) Yowi copper (I) (9mg, 0.047mmol), 1, 10 phenanthr phosphorus (166mg, 0.092mmol), cesium carbonate (600mg, 1.8) mmol) was added, and the mixture was stirred at 110 ° C for 15 hours. After allowing to cool, the solid was filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 217 mg (63%) of the title compound.
  • Step 2 Synthesis of benzyl-4- (3- (imidazole-1-yl) phenol) piperidine-4-amine (reference compound 145)
  • Step 3 (3R) —N— (1—Benjirou 4— (3— (Imidazol-1 Fil) Fel) piperidine—4—yl) —4— (2 Fluorophenol) —3— ( Synthesis of 2-Methyl-2-propoxycarbonylamino) butanamide (Reference Compound 146)
  • N— (1—benzyl— 4— (3 pseudophenol) piperidine — 4— Yl) acetamide (reference compound 140) 200 mg, 0.46 mmol) dissolved in 1,4 dioxane (3 mL), pyrazonole (31 mg, 0.46 mmol), yowi copper (I) (4 mg, 0.023 mmol) ), Trans-N, N, monodimethyl 1,2 cyclohexanediamine (13 mg, 0.092 mmol) and potassium phosphate (258 mg, 0.97 mmol) were added and stirred at 110 ° C. for 15 hours. After allowing to cool, the solid was filtered, and the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography to obtain 165 mg (96%) of the title compound.
  • Step 2 1 Synthesis of benzyl-4- (3- (pyrazole-1-yl) phenol) piperidine-4-amine (reference compound 148)
  • the resulting crude product was purified by silica gel column chromatography to obtain 1.9 mg (8%) of the title compound (free base).
  • the title compound (free base) was made into a methanol solution, salted with 10% salt-hydrogen Z methanol solution, and concentrated to obtain the title compound (trihydrochloride).
  • Step 2 (3R) — 4— (2, 4, 5 trifluorophenyl) — N— (4— (2 Fluorophenyl) 1, 1—Dioxothian— 4—yl) —3— (2 —Methyl—2 (propoxycarbonylamino) butanamide (Reference Compound 151)
  • N— (1-benzyl-4- (3-phenol) piperidine-4-yl) acetamide (reference compound 140) 400 mg, 0.92 mmol was added to 1,4 dioxane (6 mL).
  • 4- (methylthio) furboronic acid 155mg, 0.92mmol
  • tetrakis (triphenylphosphine) palladium 106mg, 0.092mmol
  • potassium phosphate 7.36mg, 2.8mmol
  • Step 2 N (l Benzyl— 4— (3— (4-Methylsulfurylphenol) phenol) Synthesis of piperidine-4-yl) acetamide (reference compound 153)
  • N— (1-Benzylru 4-1- (3- (4-methylsulfururfel) phenol) piperidine-4-yl) acetamide (242 mg, 0.52 mmol) was dissolved in THF ( The suspension was suspended in 0.05 mL), and titanium tetraisopropoxide (154 L, 0.52 mmol) and diphenylsilane (146 0.78 mmol) were added and stirred at room temperature. After 16 hours, the mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was vigorously stirred. The resulting white solid was separated by filtration, and the filtrate was separated and extracted with ethyl acetate. The combined organic layers were dried and concentrated, and the resulting crude product was purified by silica gel column chromatography to obtain 146 mg (66%) of the title compound.
  • Step 4 (3R) —N— (1—Benzylue 4— (3— (4-Methylsulfurylphenol) tiv) piperidine—4—yl) —4— (2 —Fluorophenol) —3— (2-Methyl-2-propoxycarbonylamino) butanamide (Reference Compound 155)
  • Step 1 4 i (3 Yodofueniru) Chian 4 Under argon atmosphere blanket ol (Reference Compound 156), 1, 3 over the jaw de benzene (5. 7 g, 17 mmol) and THF (50 mL) dissolved solution was cooled to 78 ° C N-Butyllithium Z-hexane solution (2.55 M, 6.8 mL, 17 mmol) was added dropwise. After 10 minutes, a solution of 4-oxothiane (2 g, 17 mmol) in THF (30 mL) was added dropwise. After completion of the dropwise addition, the temperature was slowly raised to room temperature. After 2 hours, distilled water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 4.7 g (85%) of the title compound.
  • the obtained crude product (5.8 g) was dissolved in ethanol (90 mL) and acetic acid (18 mL), and thiourea (1.3 g, 18 mmol) was added and heated to reflux. After 12 hours, the mixture was allowed to cool, an aqueous solution of potassium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated.
  • the obtained crude product was purified by silica gel column chromatography, Compound 1.8g (38%) was obtained.
  • Step 2 (313 ⁇ 4—4— (2-Fluorofer)-? ⁇ -(4— (3--Fodefer) —1, 1—Dioxothian-4 Fil) —3— (2 —Synthesis of methyl-2-propoxycarbonylamino) butanamide (Reference Compound 161)
  • Step 4 (3R) — 3 amino 1 4— (2 Fluoro-Fel) 1 N— (4— (3— (Pyridine 4 Fil) file) —1, 1-Dioxothian 4yl) butanamide dihydrochloride (Compound 46)
  • Step 1 Synthesis of 2 (Tributyl Star) thiazole (Reference Compound 163) 78.
  • n-butyllithium Z-hexane solution (2.55M, 2.5mL, 6.5mmol)
  • THF 24mL
  • a THF solution (15 mL) of thiazole (500 mg, 5.9 mmol) was added dropwise over 20 minutes and stirred for 1 hour.
  • a solution of tryptyl chloride (1.8 mL, 6.5 mmol) in THF (9 mL) was added dropwise over 15 minutes, stirred for 1 hour, saturated aqueous sodium hydrogen carbonate solution and jetyl ether were added, and the mixture was stirred at room temperature for 2 hours. did. After separation, the organic layer was dried and concentrated to give 2.4 g of the title compound as a crude product.
  • Step 2 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Rolamino) -N- (4— (3- (Thiazol-2-yl) phenol -L) — 1, 1—Dioxosothian 4 yl) butanamide (Reference Compound 164)
  • Step 4 (3R) —3 Amino— 4— (2 Fluorophenol) — N— (4— (3— (Thiazo One-Loop 5-Fil)) — 1, 1—Dioxothian— 4 —Yil) Butanamide 'Synthesis of hydrochloride (I compound 48)
  • Step 2 Synthesis of tributyl star 1 Tritylpyrazole (Reference Compound 169) Under an argon atmosphere, THF (30 mL) was added with n-butyllithium Z-hexane solution (2.55 M, 1. OmL, 2.5 mmol). Cooled to -78 ° C. 4 A THF solution (6 mL) of 1-tritylpyrazole (1. Og, about 2.3 mmol) was added dropwise over 20 minutes and stirred for 1 hour. A THF solution (6 mL) of tributyltin chloride (0.62 mL, 2.3 mmol) was added dropwise over 10 minutes, stirred for 30 minutes, warmed to room temperature, and stirred for 2 hours. An aqueous sodium chloride solution was added, and the mixture was extracted with jetyl ether. The organic layer was dried and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 1.2 g (84%) of the title compound.
  • Step 3 (R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Rolamino) N— (4— (3— (1—Tritylpyrazole—4-yl) ) Fuel) — 1, 1 Dioxothian 4 yl) Butanamide (Reference Compound 170)
  • Step 4 (3R) — 3 Amino 1 4— (2 Fluoro-Fel) 1 N— (4— (3— (Virazo 1-Lu 4-Fil) Fail) — 1, 1—Dioxothian— 4 —Yl) butanamide 'hydrochloride (I compound 49) synthesis
  • Step 2 (3R) — 4— (2 Fluorophenol) — N— (4— (3— (1—Methylimidazo One-Loop 5-Fil) Fuel) — 1, 1—Dioxothian— 4 —Yl) —3— (2-Methyl-2 propoxycarbonylamino) butanamide (Reference Compound 172)
  • Step 2 (3R) — 4— (2, 4, 5 trifluorofeles) 1 N— (4— (3 pseudofeles) —1, 1-Dioxothian 4 ills) 3— (2—Methyl 2 Propoxycarbo-Luamino) butanamide (Reference Compound 174)
  • Step 3 (3R) — 4— (2, 4, 5 trifluorophenol) —3— (2—Methyl-2 propoxycarbolamino) —N— (4— (3 (thiazole-5 yl) ) Fuel) -1,1,1-Dioxothian 4 yl) butanamide (Reference compound 175)
  • Step 1 Synthesis of 4- (4-phenyl) thiane-4-1ol (Reference Compound 176) 1,4-Jodobenzene (5.7 g, 17 mmol) in THF (50 mL) was cooled to 78 ° C under an argon atmosphere. Then, n-butyllithium Z-hexane solution (2.55 M, 6.8 mL, 17 mmol) was added dropwise. After 30 minutes, a solution of 4-oxothiane (2. Og, 17 mmol) in THF (30 mL) was added dropwise.
  • Step 2 Synthesis of (4 odophenol) thiane 4-amamine (reference compound 177)
  • Step 4 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Rolamino) N— (4— (4— (Thiazol-5-yl) phenol Lu) thian-4-yl) butanamide (reference compound 179) synthesis
  • Step 5 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Rolamino) N— (4— (4— (Thiazol-5-yl) Fe- ) — 1, 1—Dioxosothian — 4-yl) butanamide (Reference Compound 180)
  • Step 6 (3R) — 3 Amino 1 4 — (2 Fluoro-Fel) 1 N— (4— (4— (Thiazo 1-Lu 5-F))) 1, 1, 1-Dioxothian 4 —Yl) butanamide 'hydrochloride (compound 52) synthesis
  • Step 2 (3R) —4— (2,4 Diclonal Fuenole) —3— (2-Methanole 2 Propoxy carbolumino) N— (4— (3— (Thiazole 5-yl) Hue -L) Synthesis of 1, 1-dioxothiane 4-yl) butanamide (Reference compound 185)
  • Step 1 5 Synthesis of tributylstar-2-methylthiazole (reference compound 186) Under an argon atmosphere, add n-butyllithium Z-hexane solution (2.55M, 4.4mL, llmmol) to THF (40mL), 78. Cooled to C. A THF solution (15 mL) of 2-methylthiazole (1. Og, 10 mmol) was added dropwise over 50 minutes and stirred for 1 hour. A THF solution (15 mL) of sodium chloride triptylutin (2.7 mL, lOmmol) was added dropwise over 20 minutes, and the mixture was stirred for 1 hour.
  • Step 4 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Rolamino) -N- (4- (3- (2-Methylthiazole-5 yl) ) Fuel) -1,1,1-Dioxothian-4 yl) butanamide (Reference compound 189)
  • n-butyllithium Z-hexane solution (2.55 M, 0.81 mL, 2. 1 mmol) was added to THF (8 mL), and the mixture was cooled to 78 ° C. 2
  • a THF solution (3 mL) of piperidinothiazole (316 mg, 1.9 mmol) was added dropwise over 20 minutes, and the mixture was stirred for 1 hour.
  • a THF solution (3 mL) of tributyltin chloride (0.51 mL, 1.9 mmol) was added dropwise over 20 minutes and stirred for 1 hour.
  • Step 4 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Lolamino) N— (4— (3— (2 Piperidinothiazole—5-—) L) Fer) thian — 4yl) butanamide (Reference Compound 193)
  • Step 5 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, L-amino) —N— (4— (3— (2 Piperidinothiazole-5 L) Ferl) 1, 1 Dioxothian 4 yl) butanamide (Reference compound 194)
  • Step 3 Synthesis of 4 (thiazole-2-yl) thian-4-amamine (Reference Compound 197) Under argon atmosphere, N— (4 (thiazol-2-yl) thian-4-yl) acetamide (70 mg, 0.29 mmol) Suspended in THF (0.2 mL), titanium tetraisopropoxide (86 / z L, 0.29 mmol) and diphenylsilane (0.15 mL, 0.76 mmol) were added and stirred at room temperature. After 15 hours, the reaction mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was vigorously stirred.
  • Step 4 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Lolamino) N— (4— (Thiazol-2-yl) thian — 4— B) Synthesis of butanamide (reference compound 198)
  • Step 5 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 propoxy force rubonylamino) —N— (4— (thiazole 2-yl) 1, 1—Dioxothian 1 — Synthesis of butanamide (Reference Compound 199)
  • Step 1 Synthesis of 4-oxothiane O benzyloxime (reference compound 200)
  • 4-benzothiane 500 mg, 4.30 mmol
  • 16% aqueous methanol 60 mL
  • O-bendyrocyanine hydrochloride 1.37 g, 8. 60 mmol
  • sodium acetate 1.76 g, 21.5 mmol
  • the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried and concentrated.
  • the resulting crude product was purified by silica gel column chromatography to obtain 1.95 g (quantitative) of the title compound.
  • Step 3 Synthesis of 4- (Pyridine-2-yl) thian-4-amamine (Reference Compound 202) N-Benzyloxy 4- (Pyridine-2-yl) thian-4amine (300 mg, 1. OOmmol) under argon atmosphere ) was added to a solution of acetonitrile (17 mL) with distilled water (1 mL) and molybdenum hexacarbonyl (264 mg, 1.OOmmol) and heated to reflux. After 3 hours, the mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 60 mg (31%) of the title compound.
  • Step 5 (3R) — 4— (2 Fluorophenol) —3— (2—Methyl—2 Propoxy force, Rolamino) N— (4— (Pyridine 2-yl) 1, 1—Dioxothian Synthesis of 4-anil) butanamide (Reference compound 204)
  • Step 3 (3R) —N— (4— (Benzothiazole-2-yl) thiane — 4-yl) —4 1 (2 fluorophenol) -3— (2-methyl-2-propoxycarbo- Synthesis of Ruamino) butanamide (Reference Compound 207)
  • Step 2 (3R) — N— (4— (Benzothiazole 2-yl) 1, 1-Dioxothian —4—yl) —4— (2, 4, 5 Trifluorophenol) —3 — Synthesis of (2-Methyl-2 propoxycarbonylamino) butanamide (Reference Compound 210)
  • Step 3 (3R) — 4— (2 Fluorophenol) 1 N— (4— (6—Methoxybenzothiazo 1 lou 2 yl) thian 4 yl) 3— (2—Methyl-2-propoxycarbo) -Luamino) butanamide (Reference Compound 213)
  • Step 4 (3R) — 4— (2 Fluorophenyl) 1 N— (4— (6—Methoxybenzothiazo 1 Lu 2 yl) 1, 1—Dioxothian— 4—yl) —3— (2-Methyl-2-Provo Synthesis of (xycarbonylamino) butanamide (Reference compound 214)
  • Step 5 (3R) — 3 Amino 4— (2 Fluorophenol) 1 N— (4— (6-Methoxybenzothiazol 2 yl) 1, 1-dioxothian 4 yl) butanamide 'hydrochloride (compound 61)
  • the reaction mixture was diluted with chloroform, and saturated aqueous sodium hydrogen carbonate solution was slowly added under ice-cooling. After liquid separation, the mixture was extracted with black mouth form, dried and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 27 mg (71%) of the title compound (free base).
  • the title compound (free base) was dissolved in methanol, and 10% salt-hydrogen Z methanol solution was added dropwise for chlorination. By concentrating this solution, 21 mg of the title compound (hydrochloride) was obtained.
  • Step 2 (3R) — 4— (2, 4, 5 trifluorophenol) 1 N— (4— (6-Methoxybenzothiazole-2-yl) —1, 1-dioxothiane 4-yl) 3 Synthesis of — (2-Methyl-2-propoxycarbonylamino) butanamide (Reference Compound 216)
  • Step 3 3-amino 4- (2, 4, 5 trifluorophenol) 1 N— (4- (6-methoxybenzothiazol-2-yl) 1, 1-dio Synthesis of xotian-4yl) butanamide 'hydrochloride (compound 63)
  • Step 2 (3R) —N— (4— (6 Black Mouth Benzothiazole-2-yl) thiane-4-yl) — 4— (2 Fluorophenol) —3— (2-Methyl- 2 Synthesis of propoxycarboamino) butanamide (Reference compound 218) Under an argon atmosphere, a solution of 6-clobenzothiazole (95 mg, 0.56 mmol) in THF (5 mL) was cooled to ⁇ 78 ° C., and n-butyllithium Z-hexane solution (1.57 M, 0.31 mL, 0 49 mmol) was added dropwise.
  • the obtained crude product was dissolved in methanol (2 mL) under an argon atmosphere, and 10% hydrochloric acid-hydrogen Z-methanol (4 mL) was added thereto, followed by stirring at room temperature for 19 hours.
  • the crude product obtained by concentration in an argon atmosphere was dissolved in DMF (3 mL) and dissolved in (3R) —4— (2-Fluorophthalate) -3— (2-Methyl-2-propoxycarbo- Luamino) butyric acid (22 mg, 0.08 mmol), ⁇ (32 ⁇ ⁇ , 0.25 mmol), and HATU (31 mg, 0.08 mmol) were added, and the mixture was stirred at room temperature.
  • Step 3 (3R) —N— (4— (6 Black mouth benzothiazole 2-yl) 1, 1-dioxothiane 4-yl) —4— (2 Fluorophenol) —3— (2 Synthesis of —methyl-2-propoxycarbonylamino) butanamide (Reference Compound 219)
  • Step 2 (3R) —4 (2 Fluorophenyl) —N— (4— (4 Methylbenzothiazo 1 Ru 2 yl) 1, 1—Dioxothian— 4—yl) —3— (2 Synthesis of —Methyl-2-propoxycarbonylamino) butanamide (Reference Compound 221)
  • Step 3 (3R) —4 (2 Fluorophenyl) —N— (4— (6 Methylbenzothiazo 1 Lu 2 yl) 1, 1—Dioxothian — 4—yl) —3— (2 Synthesis of —Methyl-2-propoxycarbonylamino) butanamide (Reference Compound 224)
  • Step 4 (3R) —3 amino 1- 4— (2 fluorophenol) 1 N— (4 -— (6-methylbenzothiazole-2-yl) 1,1-dioxothiane 4-yl) butanamide 'hydrochloride (compound 67 )

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Abstract

La présente invention concerne un agent thérapeutique ou préventif pour le diabète à administrer par voie orale et présentant peu d’effets indésirables. L’invention concerne également un nouveau composé utile pour cet agent thérapeutique ou préventif pour le diabète. L’invention concerne plus particulièrement un excellent agent thérapeutique ou préventif pour le diabète qui contient, en tant que principe actif, un dérivé non cyclique d’amine carboxamide (I) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2006/323889 2005-11-30 2006-11-30 Nouveau derive non cyclique d’amine carboxamide et sel de celui-ci WO2007063928A1 (fr)

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WO2010114291A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2010114292A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
US20110059970A1 (en) * 2007-09-13 2011-03-10 Ipsen Pharma S.A.S. 4-phenyl-1,3-thiazoles and 4-phenyl-1,3-oxazoles derivatives as cannabinoid receptor ligands
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
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WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
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WO2012035549A2 (fr) 2010-09-13 2012-03-22 Panacea Biotec Ltd Procédé amélioré pour la synthèse de dérivés d'acides bêta-aminés
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
JP2015044845A (ja) * 2008-01-17 2015-03-12 田辺三菱製薬株式会社 Ｓｇｌｔ阻害剤及びｄｐｐ４阻害剤からなる併用療法
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

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JP2004535445A (ja) * 2001-06-27 2004-11-25 スミスクライン ビーチャム コーポレーション ジペプチジルペプチダーゼ阻害剤としてのフルオロピロリジン類
JP2004168772A (ja) * 2002-11-06 2004-06-17 Takeda Chem Ind Ltd 受容体調節剤
WO2005040095A1 (fr) * 2003-10-16 2005-05-06 Astrazeneca Ab Inhibiteurs de la dipeptidyl-peptidase iv
WO2005095343A1 (fr) * 2004-03-05 2005-10-13 Santhera Pharmaceuticals (Schweiz) Gmbh Inhibiteurs de la dpp-iv

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
US20110059970A1 (en) * 2007-09-13 2011-03-10 Ipsen Pharma S.A.S. 4-phenyl-1,3-thiazoles and 4-phenyl-1,3-oxazoles derivatives as cannabinoid receptor ligands
JP2015044845A (ja) * 2008-01-17 2015-03-12 田辺三菱製薬株式会社 Ｓｇｌｔ阻害剤及びｄｐｐ４阻害剤からなる併用療法
EP2669266A1 (fr) 2009-03-30 2013-12-04 Dong-A Pharmaceutical Co., Ltd. Procédé amélioré de préparation d'inhibiteur de dipeptidyl peptidase-IV et d'intermédiaire
WO2010114291A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2010114292A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012035549A2 (fr) 2010-09-13 2012-03-22 Panacea Biotec Ltd Procédé amélioré pour la synthèse de dérivés d'acides bêta-aminés
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

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