WO2004007446A1 - Novel azetidine derivative or salt thereof - Google Patents

Novel azetidine derivative or salt thereof Download PDF

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Publication number
WO2004007446A1
WO2004007446A1 PCT/JP2003/008727 JP0308727W WO2004007446A1 WO 2004007446 A1 WO2004007446 A1 WO 2004007446A1 JP 0308727 W JP0308727 W JP 0308727W WO 2004007446 A1 WO2004007446 A1 WO 2004007446A1
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substituted
range
optionally substituted
compound
amino
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PCT/JP2003/008727
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French (fr)
Japanese (ja)
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Masahiko Hayakawa
Kenji Negoro
Takayuki Suzuki
Tatsuya Maruyama
Ryosuke Nakano
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Yamanouchi Pharmaceutical Co., Ltd.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D205/00Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04Heterocyclic compounds containing four-membered rings with one nitrogen 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

Abstract

A compound represented by the following formula (I), which has excellent dipeptidyl peptidase IV inhibitory activity; and a therapeutic agent which, based on the activity, is highly effective against insulin dependent diabetes (type 1 diabetes), especially noninsulin-dependent diabetes (type 2 diabetes), insulin-resistant diseases, and obesity. (I) (The substituents are as defined in claim 1.)

Description

Specification

Novel Azechijin derivative or a salt thereof art

The present invention relates to pharmaceutical, Tokunijipe Puchijiru peptidase IV (hereinafter to as "DPP-IV".) Useful as inhibitors, novel Azechijin derivatives or salts thereof, and pharmaceutical comprising as an active ingredient the compound. BACKGROUND

DPP-IV is a proline at the second position from the N-terminal sequence containing a hydroxycarboxylic proline or Aranin (H-Xaa-Pro, H-Xaa-Hyp, or H-Xaa-Ala [Xaa represents any amino] ) is recognized and cut serine protease. Distribution of in vivo DPP-IV is over a wide range, kidney, liver, other organizations, such as the salivary glands, serum, urine, has been known to be present in body fluids such as saliva. Its physiological role has not been completely elucidated, it is believed to be involved in regulatory biological function by cutting various physiological activities base peptide (Non-Patent Document 1). Very particular, the child controls the activity of the hormone, called Inkurechin involved in blood glucose increase inhibition after meals has attracted attention.

Incretins are secreted from the intestinal tract after the nutrient is ingested orally, Ru hormones der to adjust the blood glucose by enhancing insulin secretion by acting on Teng] 3 cells. In patients with type 2 diabetes it has been known that the incretin effect is attenuated

(Non-Patent Document 2), this effect attenuation is considered one of the development factors of diabetes. Therefore, it is believed that it would be capable of improving postprandial hyperglycemia in diabetic patients by enhancing the incretin effect.

Currently, as a compound exhibiting the strongest incretin effect in vivo, Gurukago down like peptide (hereinafter, referred to as "GLP-1".) Is known. Thereafter GLP-1 is secreted into the blood, but is rapidly inactivated, the inactivation is mainly known to be due by that cut DPP-IV (Non-Patent Document 3). Further, when the inactive form was cleaved by DPP-IV GLP-1 binds to GLP-1 receptor, for the inhibition of binding of active GLP-1, further incretin effect of GLP-1 is attenuated considered are (non-patent document 4).

These things force ゝ al, by preventing inactivation of active GLP-1 by DPP-IV inhibitor can enhance incretin effect, correct postprandial hyperglycemia seen in such diabetics as a result would be able to. Further, Inkurechi down forces et enhance the sugar concentration dependent Insurin secretion of biological, DPP-IV inhibitors to be a safe therapeutic agents free of side effects such as hypoglycemia found in existing Insurin secretion drugs Be expected.

Indeed, DPP-IV inhibitor administration, reducing the blood glucose level in type 2 diabetic patients and diabetic animals has been reported (Non-Patent Document 5, 6). However, as described above, and the fact that DPP-IV is involved in the control of various physiological phenomena in vivo, when diabetics which generally has a disease other than diabetes sagging, since , by diseases that are comorbid each patient, than long to inhibit DPP-IV, before and after meals, Les and to inhibit short DPP-IV desirable for the treatment of diabetes, cormorants case there (non-Patent Document 7).

On the other hand, as a compound having a DPP-IV inhibitory activity, some 2-Shianopiroriji down derivative is known (Patent Document 1 to 7).

Particularly WO Among the WO 02/30890 Patent Panfuretsuto (Patent Document 5), a compound represented by the general formula (A) are disclosed, diabetes prevention and treatment of, induced or exacerbated by impaired glucose tolerance that was impaired other diseases, hyperinsulinemia, effective in the prevention and treatment of diabetes complications are described that are expected.

R

R and X- B -NH-CH CO NA (A)

NC

(Symbols in the formula, refer to this publication)

Further, in the WO 02/38541 Patent pamphlet (Patent Document 6), a compound represented by the general formula (B) is disclosed, possible to suppress an increase significantly the blood glucose level in oral glucose tolerance test in Zucker Fatty rats There has been described.

(Symbols in the formula, refer to this publication)

Further, in the WO 03/002553 Patent pamphlet (Patent Document 7), Formula (C), (D), (E), (F), (G), is disclosed a compound represented by (H) , diabetes, have been described to be useful in the treatment of diseases such as obesity.

(Symbols in the formula, refer to this publication)

However, DPP-IV report on inhibitor releasing 'Under such circumstances, development of drugs having more excellent DPP-IV inhibitory action has been desired concerning Azechijin derivatives.

Non-Patent Document 1] Mentlein R. al., "Regiyurei tree. Bae Putai do" (Regulatory Peptide), 1999 years, the first 85 Certificates, ρ · 9-24

[Non-Patent Document 2] Nauck MA al., "Daiabetorojia" (Diabetologia), 1986 years, the first 29 Certificates, p.46-52

Non-Patent Document 3] Drucker DJ al., "Daiabetsu" (Diabetes), 1998 years, the first 47 Certificates, p.159-169

[Non-Patent Document 4] Knudsen LB al., "® bite Lesbian 'journal O Breakfast' fur Makoroji one" (European Journal of Pharmacology), 1996 years, the 318 Certificates, p.429-435

[Non-Patent Document 5] Ahren B. al., "Daiabetsu care" (Diabetes Care), 2002 years, the first 25 Certificates, p.869-875

Non-Patent Document 6] Balkan B. et al al., "Daiabetorojia" (Diabetologia), 1999 years, the first 42 Certificates, p.1324-1331

[Non-Patent Document 7] Holst JJ al., "Daiabetsu" (Diabetes), 1998 years, the first 47 Certificates, p.1663-1670

[Patent Document 1] International Publication No. WO 98/19998 No. Panfuretsuto

[Patent Document 2] International Publication No. WO 01/96295 pamphlet

[Patent Document 3] International Publication No. WO 00/34241 No. Panfuretsuto

[Patent Document 4] International Publication No. WO 01/55105 No. Panfuretsu door

[Patent Document 5] International Publication No. WO 02/30890 pamphlet

[Patent Document 6] International Publication No. WO 02/38541 pamphlet

[Patent Document Ί] disclosure of International Publication No. WO 03/002553 pamphlet invention

The present inventors found that insulin-dependent diabetes mellitus (type 1 diabetes), non-insulin dependent diabetes mellitus (type 2 diabetes), insulin resistance diseases, and the compound having a DPP-IV inhibitory action effectiveness can be expected for obesity further was intensively studied, novel Azechijin derivative or a salt thereof of the present invention has an excellent inhibitory effect on DPP-IV, and completed the present invention.

That is, according to the present invention, useful as DPP-IV inhibitors, Azechijin derivative or a pharmaceutically acceptable salt thereof is shown is provided by the following general formula (I).

[Symbols in the formula have the following meanings.

R 1: optionally substituted bridged hydrocarbon rings, optionally substituted bridged non-aromatic heterocyclic, optionally substituted non-aromatic heterocyclic, substituted Yoi cycloalkyl, or optionally substituted lower alkyl.

R 2: -H, lower alkyl which may be substituted with -OH, or - Yoi cycloalkyl optionally substituted with OH.

However, R 1 and R 2 are both - are not representative of the H.

Further, R 1 R 2 are taken together with the adjacent nitrogen atom and carbon atom, also exhibit cyclic amino which may be substituted good les.

R 3, R 4: the same or different, -H, halogen, Shiano or Echeru. ] As R 1 in the general formula (I), preferably, each optionally substituted bridged hydrocarbon ring, and the heterocyclic ring bridged non-aromatic, heterocyclic non-aromatic, or lower alkyl There; more preferably, optionally substituted Adama pentane - 1_ I le; halogen, triflate Ruo Russia methyl, optionally aromatic substituted with one or more groups selected from the group consisting of Shiano and nitro Echiru substituted with Amino substituted by hetero ring group; an optionally substituted piperidine - 4-I le; Broiler properly may be substituted 8- Azabishikuro [3.2.1] octane - 3-I Lumpur. Further, as R 2 in the general formula (I), preferably it is - H.

Further, as R 3 in the general formula (I), preferably it is - H.

Further, as R 4 in the general formula (I), preferably - H, Furuoro, Wakashi Ku is an Shiano; - is H and more preferably.

Incidentally, Azechijin derivative of the present invention has the amino acid derivative to the 1-position of Azechijin ring, characterized in chemical structure to a point having a Shiano group at the 2-position of the Azechijin ring, having DPP-IV inhibitory action having the features of pharmacological point. The compounds of the present invention relative to have a Azechijin ring is 4-membered heterocyclic, compound described in Patent Document 1 to 7 are those differing in structure at the point or the like having a 5-membered heterocyclic ring (thiazolidine or pyrrolidine) , and the addition, as shown in the following test examples, while the present invention compounds which have good oral activity in comparison with compounds having a conventional DPP-IV inhibitory action, as soon as the activity is lost in the body It has a feature.

Among the compounds represented by formula (I), preferably, R 1 is optionally substituted bridged hydrocarbon rings, optionally substituted bridged non-aromatic heterocyclic, substituted heterocycles good non-aromatic, or also lower alkyl substituted, R 2 is - a compound which is H;

More preferably, te R 'is an optionally substituted bridged hydrocarbon ring, it may also be substituted les, terrorist ring to crosslinkable aromatic, Yo Le substituted, non-aromatic a mouth ring, or lower alkyl which may be substituted, R 2 is - is H, R 3 is - is H der Ru compound;

More preferably, te R 1 is optionally substituted bridged hydrocarbon rings, optionally substituted Itemoyore, terrorist ring to crosslinkable aromatic, Yo Le substituted, non-aromatic a mouth ring, or lower alkyl which may be substituted, R 2 is - is H, R 3 is - H der Ri, R 4 is - H, a compound which is Furuoro, or Shiano;

Particularly preferably, R 1 is optionally substituted bridged hydrocarbon ring, it may also be substituted les, terrorist ring to crosslinkable aromatic, Yo Le substituted, Te nonaromatic a mouth ring, or an optionally substituted lower alkyl, R 2 is - is H, R 3 is - H der Ri, R 4 is - a compound which is H.

Further, among the compounds represented by formula (I), as another preferred embodiment, R 1 forces optionally substituted bridged hydrocarbon ring, preferably an optionally substituted Adamantan - 1- I le ; optionally substituted lower alkyl, preferably c androgenic, triflumizole Ruo Russia methyl, Yo Le optionally substituted with one or more groups selected from the group consisting of Shiano and nitro, terrorist ring aromatic Echiru substituted with in substituted Amino; optionally substituted non-aromatic heterocyclic, preferably piperidine substituted - 4 I le; or, optionally substituted crosslinked type non Kaoru aromatic heterocycle, preferably optionally substituted 8- Azabishikuro [3.2.1] Okutan 3 I le, R 2 is - H, and R 3 is - H, and R 4 is - H, and compounds is Furuoro or shea § Bruno be able to.

As another preferred embodiment, R 1 is - a H, R 2 is - lower alkyl or optionally substituted by OH - a cycloalkyl which may be substituted with OH, R 3 is - is H, R 4 is - compound is H; preferably, R 1 is - is H, R 2 is lower alkyl, R 3 is - is H, R 4 is - include H, compound be able to.

Among these compounds, in particular,

(S) -l - {[(3- hydroxycarboxylic § Dammann Tan - 1 Inore) amino] Asechiru} Azechijin - 2 Cal Bonitoriru,

(S) -l- [(Adamantan - 1 Iruamino) Asechinore] Azechijin - 2-carbomethoxy nitrile, 6 - {[2 - ({2 - [(2S) -2- Shianoazechijin - Rail] -2- Okisoechiru} amino) Echiru] amino} Nikochino nitrile,

(2S) -l - [(2S) -2- Amino-2-cycloheteroalkyl Kishiruetanoiru] Azechijin - 2-carbomethoxy two tri le,

(2S) -l - [(2S, 3S) -2- amino-3-methyl-penta Neu Honoré] Azechijin - 2-carbomethoxy - tolyl, or,

(2S) -l - [(2S) -2- amino-3,3-dimethyl-pig Noi Honoré] Azechijin - 2-carbomethoxy two Torinore, or acceptable salts in a pharmaceutically are preferred, among them,

(S) -l - {[(3- hydroxycarboxylic § Dammann Tan - 1-I le) Amino] Asechiru} Azechijin -2 Chikararu Bonitoriru,

(S) -l- [(Adamantan - 1 Iruamino) Asechiru] Azechijin - 2-carbomethoxy two Torinore, young details,

6 - {[2 - ({2 - [(2S) -2- Shianoazechijin - 1 I] -2- Okisoechiru} amino) Echiru] § Mi Roh} Nikochino nitrile, or a pharmaceutically acceptable salts are preferred.

Further, according to the present invention, a pharmaceutical composition as an active ingredient any one of the above-mentioned compounds; in particular, insulin-dependent diabetes mellitus (type 1 diabetes), non-insulin dependent diabetes mellitus (type 2 diabetes), insulin resistance diseases, or a therapeutic and / or prophylactic agent for obesity, the Le, the pharmaceutical composition as an active ingredient a compound of Zureka; a DPP-IV inhibitor, the Le, pharmaceutical compositions and compounds of active ingredient Zureka object is provided.

The following will explain the present invention compounds more.

In the present specification, the "lower alkyl" means a straight or branched alkyl of C 1-6, specifically, for example, methyl, Echiru, propyl, Isopuropiru, heptyl, tert- butyl, pentyl , neopentyl, hexyl and the like to, preferably, Mechinore a C M alkyl, Echiru, propyl, isopropyl, butyl, Isobuchi Le, sec- butyl, tert- butyl. "Cycloalkyl" means a monovalent group of a carbon ring of C 3-8, these rings may have an unsaturated bond in a part. Specifically, for example, a cyclopropyl, consequent opening Penchinore, cyclopent two Honoré, Kishinore cyclohexane, Kiseninore cyclohexane, cyclo Okuchiru, cycloalkyl O click Tangier chloride.

By "bridged hydrocarbon ring" means a monovalent group of the crosslinked hydrocarbon ring, specifically, for example, Adamanchiru, bornyl, norbornyl, bicyclo [2.2.2] Okuchi Le, bicyclo [3.2.1 ] Okuchiru, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] to be able to include Petit Le, preferably Adamanchiru, bicyclo [2.2.2] Okuchiru der is, particularly preferably Adamanchiru.

The "hetero ring non-aromatic" means nitrogen, monovalent non-aromatic hetero ring containing oxygen and one or more heteroatoms selected from the group consisting of sulfur in at least one ring , Specifically, for example, there may be mentioned Azechijuru, pyrrolidinyl, Piberijieru, § Zepiniru, Tetorahi Dorofuriru, Tetorahi Dorobiraniru, Tetorahi Dorochiofu Lil, tetrahydropyran Chio tetrahydropyranyl, Imidazorijiniru, pyrazolidinyl, moles digging, a thiomorpholyl, preferably Piberijieru, Tet a Rahi Doropiraeru, particularly preferably piperidinyl.

"Cyclic Amino" refers to one of heterocyclic non-aromatic, means a monovalent group of ring containing at least one nitrogen atom in the ring, these rings but it may also be condensed with a benzene ring. Specifically, for example, Azechijuru, pyrrolidinyl, piperidinyl, Azepi alkenyl, imidazolidinyl, pyrazolidinyl, morpholyl, thiomorpholyl, di arsenide Doroindoriru, dihydric Doroindazoriru, Tetorahi Dorokinoriru, Tetorahi Doroisokinoriru, can be mentioned Benzookisajin, preferably pylori Jiniru, Tetorahi Doroisokinoriru it is.

The "heterocycle bridged non-aromatic", non-aromatic cross-linked means the monovalent group of heterocycles, specifically, for example, quinuclidinyl, 7-Azabishikuro [2.2.1] heptyl, 8- Azabishikuro [3.2.1] Okuchiru, 8 Okisabishikuro [3.2.1] Okuchiru, mention may be made of 8-Chiabishiku port [3.2.1] Okuchiru, preferably quinuclidinyl, 8-Azabishi click port [3.2.1] at Otachiru There, particularly preferably 8 Azabishiku port [3.2.1] Ru Okuchiru der.

The "halogen", Funoreo port, black hole, bromo, Yodo can be mentioned, Furuoro, black port Shi favored.

In this specification, the term permissible substituents of "optionally substituted", rather good be any substituent which is usually used as a substituent for each group, one for each of the groups it may have a more substituents. In the general formula (I) to your Keru R 1, including the carbon atoms of R 1 directly bonded to NH groups may have a substituent on a carbon atom and / or nitrogen atoms.

"Optionally substituted bridged hydrocarbon ring" in R 1, "substituted hetero to also be cross-linked non-aromatic optionally ring", "optionally substituted non-aromatic hetero ring", " replacement is cycloalkyl which may have "," optionally substituted lower alkyl "," optionally substituted Adamanchiru small I le "," optionally substituted 8- § the bicyclo [3.2. 1] Okutan 3 Inore "," good substituted I-piperidin - the permissible substituents on the carbon atom at the 4-I le "substituent group X, -OH, -0- substituent group X, halogen, -CO- substituent group X, -COO- substituent group X, -S0 2 - substituted with a substituent selected from substituent group X, 1 or 2 substituents group X cited yo I Amino be substituted with a which may Karubamo I le, 1 or 2 substituents selected from substituent group X Bets can be; preferably - OH, methyl, human Dorokishimechiru, phenylene Honoré, a phenoxy.

Herein, the substituent group X, -OH, -0- lower alkyl, Fuwenokishi, halogen, triflate Ruo Russia methyl, optionally substituted respectively with one or more groups selected from the group consisting of Shiano and nitro lower alkyl, showing a heterocyclic ring Ariru or aromatic. Here, "Ariru" means a monovalent group of monocyclic to tricyclic aromatic ring of C 6. 14 of carbon atoms, specifically, for example, phenyl, naphthyl, preferably phenyl is there. Further, "aromatic hetero ring" means a monovalent aromatic monocyclic or tricyclic ring having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, specifically furanyl in, thienyl, pyrrolyl, pyridyl, Okisazoriru, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, Te Torazoriru, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, I Seo Okisazorinore, Toriazorinore, Benzofura - / Les, Benzocheniru, Benzochia Jiazoriru, benzothiazolyl, Okisazoriru, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, quinazolyl, quinolyl, isoquinolyl, quinoxalyl, imidazopyridinyl, imidazopyrimidinyl, and the like, preferably pyridyl A.

"Optionally substituted bridged hydrocarbon ring" in R 1, "substituted hetero to also be cross-linked non-aromatic optionally ring", "optionally substituted non-aromatic hetero ring", " cycloalkyl which may optionally be substitution "," optionally substituted lower alkyl "," optionally substituted Adamanchiru 1-I le "," optionally substituted 8- § the Bishiku port [3.2.1] octane - 3-I le "," optionally substituted piperidine - the permissible substituents on the nitrogen atom at 4-I le "substituent group X, -CO- substituent group X, -COO- substituent group X, -S0 2 - substituent group X, -C0 2 H, -CHO can be mentioned; preferred details, methanesulfonyl, 2-arsenide de Loki Chez Tan sulfonyl, 2- Furuoroetan sulfonyl, human Dorokishiasechiru, Asechiru, -CHO, benzyl.

The permissible substituents in "optionally cyclic Amino be substituted" in R 1 and R 2, substituent group X, -OH, -0- substituent group X, halogen, -CO- substituent group X , -COO- substituent group X, -S0 2 - substituent group X, one or two optionally substituted with a substituent selected from substituent group X force Rubamoiru, one or two substituents substituted with a substituent selected from the group X can also be mentioned an amino; is good Mashiku - OH, 1 or 2 optionally substituted with a substituent selected from substituent group X is Yoi Amino.

Further, the present invention compounds, tautomers, include those mixtures and isolated various stereoisomers such as optical isomers.

The present invention compounds may form acid addition salts. In some cases, they form salts with bases Te cowpea on the type of substituent. Such salts, specifically, hydrochloric acid, hydrobromic acid, ® © hydrogen acid, sulfuric acid, nitric acid, mineral acids such as phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid , fumaric acid, maleic acid, lactic acid, Li Ngosan, tartaric, Kuen acid, methanesulfonic acid, ethanesulfonic acid, organic acids such as P- toluenesulfonic acid, Asuparagin acid, acid addition salts with acidic amino acids glutamic acid, sodium, potassium, magnesium, calcium, aluminum and the like inorganic bases, Mechiruamin, Echiruamin, organic bases such Etanoruamin, lysine, ol - salts and ammonium with basic amino acids such as Chin - © beam salts, and Ru the like.

Further, in the present compound, hydrates, pharmaceutically acceptable various solvates and binding Akirao shapes and the like are also included. As a matter of course, not limited to the compounds described in Examples below to the present invention, it encompasses all of the general formula (I) derivatives and pharmaceutically acceptable salts thereof represented by it is intended to.

Further, in the present compound, converted the compound to the general formula is metabolized (I) in vivo, or compounds which are converted into their salts, those containing Te base that is also advised so-called prodrugs. As a group forming a prodrug of the compound of the present invention, Prog Med 5:.. 2157-2161 (1985) and groups described in "Development of Pharmaceuticals" Hirokawa Shoten 1990 annual Volume 7 Molecular Design 163-198 They include groups described in pages. (Production Method)

Salts present invention is compounds and acceptable their pharmaceutically lies its basic skeleton Le, can be prepared by utilizing the characteristics based on the kind of the substituent, by applying various known synthetic methods. At that time, depending on the type of functional group, the functional group stage with a suitable protecting group of raw material or intermediate, i.e. easily the functional groups replaced with a convertible group Okuko and manufacturing technical effective there is a case. After accordingly, the protective group is removed if necessary, it is possible to obtain the desired compound. Such functional groups as for example hydroxyl or Cal Bokishiru group, an amino group can be exemplified, as their protecting groups, such as grayed Li Ichin (Greene) and U'tsu (Wuts) al, "Protective Groups in Organic SynthesisJ the third can be exemplified protecting group as described Edition, Re appropriately for Rere according to these reaction conditions Bayoi.

The following illustrates a typical production method.

The first method

(Wherein, the definitions of R 1 R 2, RR 4 is above, X is a leaving group such as halogen, Suruhoniruokishi group. Forth.)

This reaction is a reaction to obtain the present compound by reacting the Amin compound represented relative to compound (II) in the general formula Ι ^ ΝΗ 2. This reaction can be carried out the reaction using a non-solvent or Solvent As the solvent used, toluene, aromatic hydrocarbons such as xylene, methyl E chill ketone, ketones such as acetone, Jiokisan, Tetorahi Dorofuran, ethers such as diglyme, methanol, ethanol, alcohols such as isopropanol, black hole Holm, salts methylene, Asetonitoriru, dimethylformamidine de, dimethyl sulfoxide, water, or include a mixture of these solvents, type of reaction substrate is appropriately selected depending on the reaction conditions.

In this reaction, addition of a base are useful for the smooth progress of the reaction. As completely as examples of the base include sodium carbonate, alkali carbonate such as potassium carbonate, sodium carbonate Hydrogen, alkali metal bicarbonate such as potassium bicarbonate, Toryechiruami down, diisopropyl E chill § Min, organic amines such as pyridine the recited Ru.

The second method

(III) (I)

(Wherein, P is meant tert- butoxy carboxymethyl Interview group, benzyl O alkoxycarbonyl group, 0 nit port benzene sulphates We sulfonyl protecting groups such as)

This reaction is carried out for the removal of the protective group the compound (III) without solvent or in a solvent, a reaction for obtaining the compound of the present invention. Protecting group used, and "Protective Groups in Organic Synthesis Third Edition supra As removal methods include a method described in Maruzen publishing" experiments the basis for Peptide Synthesis ", or the like.

Of the Intermediate Production Method 1

(Wherein, X 1 is meant halogen, a leaving group such as a hydroxyl group. Forth.)

After obtaining the intermediate (VI) with a compound to the reaction of the compound (IV) to Ashiru reaction to act (V) line Ukoto, whereby a compound (II) by subjecting the dehydration reaction. Ashiru reaction can be carried out by a conventional method, if X 1 is a hydroxyl group New, Nyu'- dicyclo hexyl Cal positive imide, 1-Echiru 3- (3, - dimethylcarbamoyl Ruaminopuropiru) Karubojiimi de , 1, 1, - carbonitrile El diimidazole, it can be carried out in the presence reactions Jifue two Le phosphoryl condensing agent such as azide. When X 1 is a halogen atom may solvent, a method for the presence of a base reactions apply. Specific examples of the base include sodium carbonate, alkali carbonate such as potassium carbonate, sodium hydrogen carbonate acid, bicarbonate Al force Li such as bicarbonate force potassium, Toryechiru Amin, diisopropyl E chill § Min, organic such as pyridine amine, and the like.

Examples of the dehydrating agent dehydration reaction can also be carried out according to a conventional method of dehydration of amino de group to intermediates (VI), mention may be made Torifuruoro acetic anhydride, Okishi salt Ihirin, chloride Chioniru like. Further, there is a case where the dehydration reaction proceeds rapidly by there use a base as an additive or a solvent, base used may be used bases exemplified above Ashiru reaction.

Of the Intermediate Production Method 2

(VII) (VIII)

This synthesis after obtaining (VIII) by performing the Ashiru reduction reaction the action of compound (VII) to the compound (IV), a method of obtaining a compound (III) by subjecting the dehydration reaction, and compound a method of the compound (III) is prepared by carrying out the Ashiru reaction of (IX) with the compound (VII). For more information about Ashiru reaction and dehydration reaction can be used the same method as that described in Production Method 1 of the intermediate.

Furthermore, some of the compounds contained in the present compound, more compound thus obtained (I) from the known alkylation, Ashiru, oxidation, reduction, pressurized water solution or the like, those skilled in the art usually employ can also be prepared by combining may process arbitrarily.

Thus the present invention compound produced is still free, or subjected to salt formation treatment by a known method are isolated and purified as its salt. Isolation and purification are extracted, enrichment, distillation, crystallization, filtration, recrystallization, and dividing by employing general chemical operations of various kinds of chromatography and the like.

Further, the present invention compound is an optical isomer is present in the case of having an asymmetric carbon. These optical isomers can be resolved by conventional methods fractional crystallization or column chromatography Dara Fi Chief of suitable salt and recrystallization. Moreover, optically active compounds can also be prepared by using a suitable equivalent optically active starting. Industrial Applicability

The present invention compound has a DPP-IV inhibitory action. That is, the knee] hormones that regulate blood glucose by 3 acts on cells to enhance insulin secretion, has the effect of harming particularly inhibitory degradation of GLP-1.

Therefore, the compounds of the present invention based on these effects, insulin-dependent diabetes mellitus (type 1 diabetes), especially Insurin-dependent diabetes mellitus (type 2 diabetes), insulin resistance diseases, and useful for the treatment and Roh or prevention of obesity, such as it is. Note that the "treatment" Te herein odor, is a concept also includes prevention.

Excellent DPP-IV inhibitory action of the compounds of the present invention was confirmed by test methods described below.

(1) DPP-IV inhibitory activity Measurement Test

Procedure of DPP-IV activity measurement is as follows. The reaction was performed using a 96 © El plate. 25 mM Tris-HCl, 140 mM chloride Natoriumu, 10 mM chloride force Riumu, 1% © shea serum albumin, the reaction solution was added a test compound in various concentrations in an aqueous solution consisting of 0.01 mM Gly-Pro-AMC (BACHEM) ( to 95 .mu.1 / Ueru) and incubated 20 min plasma collected from healthy adult volunteers 5 Mi added at room temperature. After the reaction, fluorescence intensity of each Ueru (Exitation 355 nm I Emission 460 nm) measured (ARVO, PerkinElmer). The measurement results were calculated by averaging the values ​​of 3 Ueru the same conditions. Calculating percent inhibition relative to solvent addition group, determined meth IC 50 values by logistic analysis. The results are shown in Table 1.

(table 1 )

As indicated above, the compounds of the present invention exhibited a DPP-IV inhibitory action.

(2) DPP-IV inhibitory action sustained evaluation test in mice

For each group 5 cases of male ICR mice (Japan SLC), a test compound dissolved in distilled water was orally administered at a dose of 10 mg / kg, in control group only distilled water was orally administered. Spoon compound administered after 0.5 were bled from the orbital venous plexus after 2 and 4 hours. Collected blood was centrifuged immediately, was collected plasma was measured in plasma DPP-IV activity.

Procedure in DPP-IV activity assay plasma is as follows. Incidentally reactions were performed using a 96 © E Le plate. 25 mM Tris-HCl, 140 mM sodium chloride, 10 mM Shioi匕 potassium, 1% © shea serum albumin, plasma 5 was taken 0.01 mM Gly-Pro-AMC (BACHEM) force Ranaru solution (95 μΐ / Weru) μΐ added to incubator Beshiyon 20 minutes at room temperature, the fluorescence intensity (Exitation 355 nm I Emission 460 nm) was measured (ARVO, PerkinElmer).

The fluorescence intensity of Ueru plus plasma collected from the control group to calculate the DPP-IV activity in a subject compound administration mice in plasma as 100%, the difference in activity between the control group and percent inhibition by the test compound . The results are shown in Table 2.

(Table 2) DPP-IV inhibitory action sustained evaluation test in mice

In the table, the comparative compound 1, a compound of Example 3 6 of Patent Document 6, and Comparative Compound 2 is a compound of Example 3 3 of Patent Document 6, comparison of compound 3 is a compound of example 1 of Patent Document 3, the comparative compound 4 is a compound of No.18 of WO WO 95/15309 described, the comparative compound 5, International Publication No. WO 02/14271 is the compound of example 5 according. The structure of comparative compound 1-5 are shown below. Comparative Compound 3 Comparative Compound 4

Comparative Compound 5

As shown in Table 2, especially in 0.5 hours after administration, the compounds of the present invention had good oral activity. Moreover, compared with comparative compound is maintaining high activity even 4 hours after administration, the compounds of the present invention that either et al showed the disappearance of rapid activity, and the present invention compounds known DPP-IV inhibitor It revealed to have a completely different DPP-IV inhibitory activity of profiles. As described above, DPP-IV has been implicated in the control of various physiological phenomena in vivo, also diabetics many cases generally have a disease other than diabetes. Therefore, since some it is concurrent each patient disease than long to inhibit DPP-IV, before and after meals, inhibiting short time DPP-IV is also considered desirable for treatment of diabetes, DPP-IV inhibitors showing a rapid disappearance of the DPP-IV inhibitory activity as the compounds of the present invention are useful Te ​​fit poles.

And the compound of the present invention, a pharmaceutical composition containing as an their pharmaceutically active ingredient one or more acceptable salts are used carriers Ya excipients for the formulation generally used, other additives Te, tablets, powders, fine granules, granules, capsules, pills, solutions, Note Ysaye, suppositories, ointments, are prepared in plasters are administered orally or parenterally. Symptoms of patients clinical dose applied for human of the compound of the present invention, body weight, but is appropriately determined in consideration of age, gender, etc., 0.1 to 500 mg in an adult per day orally, parenterally 0.01 to 100 mg preferably administered in divided manner once or several times. The doses to be used varies depending on various conditions, there is a case that sufficient in an amount less than the above dosage ranges.

As the solid composition for oral administration of the compounds of the invention, tablets, powders, granules and the like are used. In such a solid composition, one or more active compounds, at least one inert diluent such as lactose, mannitol, glucose, hydroxycarboxylic cellulose, microcrystalline cellulose, starch, poly Byurupiro Li pyrrolidone, It is mixed with magnesium aluminometasilicate. The composition is therefore a conventional method, additives other than the inert diluent, such as disintegrants, lactose yo una stabilizers such as good Una lubricant or calcium cellulose glycolate magnesium stearate, glutamic acid or yo les, also contain a solubilizing or dissolving auxiliary agent such as Asuparagin acid. The tablets or pills sucrose, gelatin, hydro hydroxypropyl cellulose, it may also be coated with a film of hydroxycarboxylic propyl methyl Se Honoré roast sugar or a gastric or enteric compound such phthalate les.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, inert diluents commonly used in, for example, purified water , including the ethyl alcohol. The composition solubilizers other than inert diluents, solubilizing agents, wetting agents, adjuvants such as suspending agents, sweetening agents, flavoring agents, Fang pastilles and may contain a preservative.

The injections for parenteral administration includes aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and diluents suspending agents include, for example, injection distilled water and saline. Non-aqueous solutions and as a diluent for suspending agents, such as propylene glycol, polyethylene glycol, vegetable oils such as Oribu oil, alcohols such as ethyl alcohol, polysorbate 80 (trade name).

Such composition may further contain tonicity agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilization agents (e.g., rata toast), but contain additives such as solubilizing agents or dissolving aids by Les,. These filtration through a bacteria retaining filter, are sterilized by Blend of a germicide or irradiation. They also making into sterile solid compositions may be used by dissolving in sterile water or a sterile solvent for injection before use. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, a detailed explanation of the present invention through examples, the present invention is in no way limited by these examples. Incidentally, the raw material for compounds used in the Examples also includes a novel material is described manufacturing method from a known compound of such starting compounds as reference examples.

Reference Example 1

Black hole Asechirukurori de under ice-cooling 1.60 ml of black hole Holm 20 ml solution, the literature SL mounting methods (Chem. Pharm. Bull. (1998), 46 (5), 787-796, J. Heterocycl. Chem. ( 1973), 10 (5), 795-9; was synthesized according to Japanese Patent application Publication Sho 61-85358 discloses) (S) - Azechijin - 2 Karubokisami de monohydrochloride 2.50 g and New, Nyu- diisopropyl was added dropwise black port Holm 20 ml suspension of Echirua min 6.70 ml, and the reaction mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was concentrated under reduced pressure, under ice-cooling to black port Holm 20 ml solution of the resulting residue, was added dropwise Torifuruoro acetic anhydride 5.24 ml. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture saturated aqueous solution of sodium hydrogen carbonate was added and extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. Removing the desiccant, by distilling off the solvent under reduced pressure (S)-l-(chloroacetyl) § Zechijin - 2-carbonitrile was obtained nitrile 0.95 g. This was used in the subsequent reaction without further purification.

Reference Example 2

(S) -2 -... [(N-tert- butoxycarbonyl) Amino] -3, 3-dimethyl butanoic acid (463 mg), the method of literature described (Chem Pharm Bull (1998), 46 (5), .. 787-796, J. Heterocycl Chem (1973), 10 (5), 795-9; was synthesized according to Japanese Patent application Publication Sho 61-85358 discloses) (S) - Azechijin - 2- Karubokisami de to a solution of DMF 6 ml of monohydrochloride 300 mg 及 Pi 1- arsenide Dorokishiben Zotoriazoru 405 mg, added Toryechiruamin 0.31 ml and 1-Echiru 3- (3-dimethylaminopropyl § amino propyl) Karubojiimi de monohydrochloride 575 mg the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was added water and extracted with acetic acid Echiru, The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Except for desiccant, tert- butyl by distilling off the solvent under reduced pressure the [(S) -l - - (1- carbonyl (S) -2- Karubamo Iruazechijin) -2,2-dimethylpropyl] force Rubamato as a crude product was obtained 0.87 g. Under ice-cooling to THF 10 ml solution of the resulting crude product was added sequentially dropwise Toryechiru Amin 1.12 ml and Torifuruoro acetic anhydride 0.57 ml, and the reaction mixture was stirred under ice-cooling for 15 minutes. The reaction mixture was added water and extracted with acetic acid Echiru, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Except as desiccant, by distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel flash column chromatography (chloroform: methanol = 200: 1-100: 1) to give the, tert- butyl [( S) -l - ((S) -2- Shianoazechijin - 1- carbonyl) -2,2-dimethylpropyl] force Rubamato give 0.51 g as a light yellow solid.

In the same manner as in Reference Example 2, Reference Example 3-6 shown in Table 3 were prepared by using the respective corresponding starting materials.

Symbols in the tables have the following meanings (the same applies hereinafter). Rf: Reference Example number,

Structure: structural formula,

Data: Physicochemical data (NMR: (CH 3) was 4 Si as an internal standard, the DMSO- was measured Solvent, peaks in 1H-NMR δ [ppm], FAB-MS: FAB mass analysis, EI -MS: EI mass analysis, mp: melting point),

Boc: tert-butyl O butoxycarbonyl, Me: methyl.

Salt: salt (HC1: hydrochloride, 2HC1: dihydrochloride, none described: flip integral).

Example 1

The method of Patent literature (WO WO 02/20495 No. Panfuretsuto, the WO 99/65897 Patent brochures, pamphlets same. WO 98/03485) was synthesized according to the 6 - [(2-Aminoechinore) Amino] Nikochino two Torinore 1.53 g of chloroform - Asetonito Lil (1: 1; v / v, 15 ml) under ice-cooling to a suspension, obtained in reference example 1 (S) -l- (Kuroroasechi Le) Azechijin - 2-carbomethoxy two tolyl 0.50 g of black port Holm 5 ml solution was added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 days. Silica gel 5 g is added and the reaction mixture was concentrated under reduced pressure. The resulting supported material by silica gel flash column click port Matogurafi - (black port Holm: methanol: 28% aqueous ammonia = 100: 1: 0.1-20: 1: 0.1) to give a, 0.17 g to give a yellow oily compound It was. THF in in 10 ml of the obtained yellow oily compound was while handling 1,4 Jiokisan solution 1 ml of 4M hydrochloric acid. Under reduced pressure, the solvent was removed by distillation, and the residue methanol - as tetrahydrofuran - was recrystallized from acetic acid Echiru, 6- {2- [2 - ((S) -2- Shianoazechijin - 1-I) -2- It was obtained 0.11 g as Okisoechi Ruamino] Echiruamino} Nikochino two Torinore 'dihydrochloride pale brown solid.

As in Example 1, Example 2 and 3 shown in Table 4, it was prepared using the respective corresponding starting materials.

Example 4

tert- Butyl obtained in Reference Example 2 [(S) -l - ((S) -2- Shianoazechijin - 1 carbonylation Honoré) -2,2-dimethylpropyl] force Rubamato 0.47 g of acetic acid Echiru 3 ml solution the added acetate Echiru solution 4 ml of 4M hydrochloric acid and the reaction mixture was stirred at room temperature for 2 hours. It added Jefferies chill ether 50 ml counterclockwise 応混 compounds, and the precipitated solid was collected by filtration and washed dried under vacuum over Jechiruete Le, (S) -l - ((S) -2- Amino - 3, 3 Jimechirubutano Inore) Azechijin -. 2 carbonylation Torinore give 0.32 g of the monohydrochloride salt as a colorless solid. As in Example 4, the Examples 5-8 shown in Table 4 were prepared by using the respective corresponding starting materials. (Table 4)

Hereinafter, the NMR data of several Example compounds in Table 5.

9 Mine) to

LZL800 / £ 00ZdT / 13d 9 00 請 OAV

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Claims

The scope of the claims
Azechijin derivative or a pharmaceutically acceptable Ru salt represented by the general formula (I).
[Symbols in the formula have the following meanings.
R 1: -H, optionally substituted bridged hydrocarbon ring, a substituted terrorism to be cross-linking-type non-aromatic optionally ring, optionally substituted non-aromatic heterocyclic, substituted which may be cycloalkyl, or optionally substituted lower alk kill.
R 2: -H, lower alkyl which may be substituted with -OH, or - cycloalkyl which may be substituted with OH.
However, R 1 and R 2 are both - are not representative of the H.
Further, R 1 R 2 are taken together with the adjacent nitrogen atom and carbon atom may indicate a cyclic amino which may optionally be substitution.
RR 4: the same or different, -H, halogen, Shiano or Echuru. ]. R 1 is optionally substituted bridged hydrocarbon rings, optionally substituted cross-linking type also have a non-aromatic heterocyclic, optionally substituted non-aromatic heterocyclic, or optionally substituted and it is also lower alkyl, R 2 is - H, and the range 1 compound according claims. . R 3 is - H, and the compound of according to claim 2, wherein. . R 4 is - H, Furuoro, or a Shiano, range 3 A compound according to claim. R 4 is - range 4 A compound according to claim is H. R 1 is is also be cross-linked have hydrocarbon ring substituted, range 4 A compound according to claim. Optionally R 1 is substituted Adamantan - 1-I is Le, 6 Symbol mounting compound claims. Optionally R 1 is an optionally substituted lower alkyl, range 4 compounds of the description of claims. There is a Echiru substituted with halogen, triflate Ruo Russia methyl, Amino substituted with Shiano and one or more hetero ring to aromatic substituted by a group selected from the group consisting of nitro, range 8 a compound according to claim. 1 is a heterocyclic ring non-aromatic may be substituted, the compound in the range 4 according claims. R 1 is an optionally substituted piperidine - 4-I a Le, range 1 0 SL placement of the compounds of the claims. R 1 is a hetero ring to be crosslinked non-aromatic substituted, range 4 A compound according to claim. R 1 may be substituted 8 Azabishikuro [3.2.1] octane - 3 I is Le, range 1 2 A compound according to claim. 1 - is H, R 2 is - a cycloalkyl which may be substituted by optionally substituted lower alkyl or -OH with OH, R 3 is - is H, R 4 is - in H there, range 1 compound according claims. R 2 is lower alkyl, range 1 4 compound according to claim.
(S) -l - {[(3- hydroxycarboxylic § Dammann Tan - 1 Inore) Amino] Asechiru} Azechijin - 2-carbomethoxy nitriles,
(S) -l- [(Adamantan - 1 Iruamino) Asechiru] Azechijin - 2-carbomethoxy two birds Honoré,
6 - {[2 - ({2 - [(2S) -2- Shianoazechijin - I] -2- Okisoechiru} Amino) E Ji Honoré] Amino) Nikochino - tolyl,
(2S) -l - [(2S) -2- amino-2-cyclohexyl-ethanone Noi Honoré] Azechijin - 2-carbomethoxy nitriles,
(2S) -l - [(2S, 3S) -2- Amino-3-methyl-penta Noi le] Azechijin - 2-carbomethoxy two preparative drill, or,
(2S) -l - [(2S) -2- Amino - 3,3-dimethyl-pig Noi le] Azechijin - 2-carbonitrile two preparative drill, or a pharmaceutically acceptable salt thereof, the scope of the claims 1 compounds of the described. Range 1-1 6 any of the compounds of a pharmaceutical composition comprising, as an active ingredient according to the claims. Insulin-dependent diabetes mellitus (type 1 diabetes), non-insulin dependent diabetes mellitus (type 2 diabetes), is a therapeutic agent for insulin resistance diseases, or obesity, range 1 7 The pharmaceutical composition according to claim. Di peptidyl peptidase IV inhibitor, range 1 7 The pharmaceutical composition according to claim.
PCT/JP2003/008727 2002-07-10 2003-07-09 Novel azetidine derivative or salt thereof WO2004007446A1 (en)

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WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
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US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
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