JP2005200427A - Nitrogen-containing five-membered ring compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new aliphatic nitrogen-containing five-membered ring compound having excellent DPPIV (dipeptidyl peptidase IV) inhibitory action. <P>SOLUTION: The aliphatic nitrogen-containing five-membered ring compound is represented by formula [I], [wherein, A is CH<SB>2</SB>or S; B is CH or N; R<SP>1</SP>is H, a lower alkyl or the like; X is a single bond, CO, Alk-CO, COCH<SB>2</SB>, Alk-O, O-CH<SB>2</SB>, SO<SB>2</SB>, S, COO, CON(R<SP>3</SP>), Alk-CON(R<SP>3</SP>), CON(R<SP>3</SP>)CH<SB>2</SB>, NHCH<SB>2</SB>or the like; R<SP>3</SP>is H or a lower alkyl; Alk is a lower alkylene; R<SP>2</SP>is (1) a (substituted) cyclic group, (2) a (substituted) amino group or the like; and, if X is CO, B is N]. And pharmacologically permissible salts thereof and a method for producing the compound are also provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel nitrogen-containing five-membered ring compound having an excellent dipeptidyl peptidase IV (DPPIV) inhibitory activity and useful as a medicament.

  Dipeptidyl peptidase IV (DPPIV) is a kind of serine protease that specifically hydrolyzes Xaa-Pro or Xaa-Ala (Xaa can be any amino acid) dipeptide from the N-terminus of the polypeptide chain. .

  There are various reports regarding the role of DPPIV (also referred to as CD26) in vivo and the relationship with diseases (Non-Patent Documents 1 to 4).

  GLP-1 (glucagon-like peptide 1) is a peptide hormone having a function of amplifying insulin secretion mainly in a glucose-dependent manner, and is secreted mainly from the lower part of the small intestine after meal and acts on the pancreas. There are also reports suggesting that GLP-1 has an antifeedant action. DPPIV hydrolyzes and inactivates GLP-1 to produce a peptide that acts as an antagonist of GLP-1.

  Substances that inhibit the enzyme activity of DPPIV enhance the insulin secretion response to oral glucose load and improve impaired glucose tolerance by enhancing the action of endogenous GLP-1 through its inhibitory action To do.

  For this reason, DPPIV inhibitors are considered useful for the prevention and treatment of diabetes (particularly type 2 diabetes). In addition, other diseases induced or exacerbated by impaired glucose tolerance (hyperglycemia (eg, postprandial hyperglycemia), hyperinsulinemia, diabetic complications (eg, renal disorder, neuropathy), abnormal lipid metabolism, It is expected to be effective in preventing and treating obesity. Furthermore, the effect in prevention and treatment of diseases (overeating, obesity, etc.) that are expected to be improved by enhancing the anti-feeding action of GLP-1 is also expected.

  In addition, DPPIV (CD26) present on the surface of T cells is induced in immune system cells as T cells are activated, and plays an important role in T cell activation and proliferation. It is known that when this DPPIV (CD26) is blocked with an antibody or an inhibitor, T cell activation is suppressed. In addition, there is an interest in the relationship between this enzyme and pathological conditions in disorders of collagen metabolism and immune disorders. For example, DPPIV (CD26) positive rate of peripheral blood T cells is increased in rheumatic patients, and high DPPIV activity is detected in urine of nephritic patients. Furthermore, DPPIV (CD26) is thought to play an important role in HIV entry into lymphocytes.

  Therefore, substances that inhibit DPPIV (CD26) also prevent autoimmune diseases (eg, arthritis, rheumatoid arthritis), osteoporosis, acquired immune deficiency syndrome (AIDS), transplanted organ / tissue rejection, and the like. Or a therapeutic effect is expected.

  On the other hand, as compounds having DPPIV inhibitory action, Patent Documents 1 and 2 describe 2-cyanopyrrolidine derivatives having DPPIV inhibitory action.

Holst et al., Diabetes, 47, 1663-1670, 1998

Augustyns et al., Current Medicinal Chemistry, Vol. 6, pp. 311-327, 1999 Meester et al., Immunol. Today, Vol. 20, pp. 367-375, 1999 Fleicher et al., Immunol. Today, Vol. 15, pp. 180-184, 1994 International Patent Publication WO 98/19998 International Patent Publication WO00 / 34241

  The present invention provides a novel aliphatic nitrogen-containing five-membered ring compound having an excellent DPPIV inhibitory action.

  In order to solve the problem, the present inventors have found a novel nitrogen-containing five-membered ring compound having a DPPIV inhibitory action as a result of intensive studies and completed the present invention.

  That is, the present invention relates to the general formula [I]

[The symbols in the formula have the following meanings.
A: —CH ₂ — or —S—,
B: CH or N,
R ¹ : H, lower alkyl group, hydroxy lower alkyl group or
A lower alkoxy lower alkyl group,
X: a single bond, -CO -, - Alk-CO -, - COCH 2 -,
_{-Alk-O -, - O-} CH 2 -, - SO 2 -, - S -, - COO-,
^{-CON (R 3) -, -} Alk-CON (R 3) -,
_{^{-CON (R 3) CH 2 -}} , - Alk-CON (R 3) CH 2 -,
^{_{-COCH 2 N (R 3) -}} , - SO 2 N (R 3) - or -NHCH ₂ -,
(The bond shown at the right end in each definition of X represents a bond with B)
R ³ : a hydrogen atom or a lower alkyl group,
Alk: lower alkylene group,
R ² : a group selected from the following (1), (2) and (3);
(1) a group which may be substituted and the cyclic group part is (i) a monocyclic or bicyclic hydrocarbon group or (ii) a monocyclic or bicyclic heterocyclic group;
(2) an amino group substituted with one or two identical or different substituents selected from a substituted or unsubstituted lower alkyl group; and (3) a lower alkyl group, a carboxy lower alkyl group, a lower alkoxy group, a lower alkenyl. Group, lower alkoxy-substituted lower alkyl group, phenoxy group, phenoxy-substituted lower alkyl group or phenyl lower alkenyl group.
However, when X is a single bond, R ² is a group selected from the above (1) and (2).
In addition, when X is —CO—, B is N. ]
Or a pharmacologically acceptable salt thereof.

The target compound [I] of the present invention may have optical isomers based on asymmetric carbon, but the present invention includes any of these optical isomers and also includes a mixture thereof. In addition, there may be an isomer (cis isomer or trans isomer) based on the relative position of the substituent with respect to the reference plane of the cyclic group, and the present invention includes any of these isomers, and a mixture thereof. Including.

  In the present invention, the lower alkyl group, the lower alkylthio group, the lower alkylsulfonyl group, the lower alkoxy group, and the lower alkylamino group include linear or branched ones having 1 to 6 carbon atoms. 1-4 are mentioned. Moreover, as a lower alkanoyl group and a lower alkanoylamino group, a C2-C7, especially C2-C5 linear or branched thing is mentioned. Examples of the lower cycloalkyl group and the lower cycloalkenyl group include those having 3 to 8 carbon atoms, particularly 3 to 6 carbon atoms. Examples of the lower alkylene group include straight chain or branched chain groups having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms. Examples of the lower alkenyl group and the lower alkenylene group include those having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms. Furthermore, examples of the halogen atom include fluorine, chlorine, bromine, and iodine.

  The object compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory action on the enzyme activity of DPPIV. In particular, it has an excellent inhibitory action on human DPPIV. It also shows high selectivity for DPPIV (ie, type IV dipeptidyl peptidase) among various serine proteases (eg, plasmin, thrombin, prolyl endopeptidase, trypsin, dipeptidyl peptidase II, etc.). Moreover, the object compound [I] of the present invention or a pharmacologically acceptable salt thereof improves the insulin secretion response to the oral glucose load through its DPPIV inhibitory action.

Specific examples of the “hydrogen atom, lower alkyl group, hydroxy lower alkyl group or lower alkoxy lower alkyl group” represented by R ¹ in the compound [I] of the present invention include, for example, a hydrogen atom, methyl group, hydroxymethyl Group, methoxymethyl group and the like. Among these, a hydrogen atom or a lower alkyl group (such as a methyl group) is preferable.

In the compound [I] of the present invention, as the cyclic group moiety of the “optionally substituted cyclic group” represented by R ² ,
(I) monocyclic or bicyclic hydrocarbon group and (ii) monocyclic or bicyclic heterocyclic group.

Examples of such monocyclic or bicyclic hydrocarbon groups include
The thing of C3-C15 which may be partially or entirely saturated is mentioned.

  As the monocyclic hydrocarbon group, those having 3 to 7 carbon atoms are preferable. Specifically, a phenyl group, a cyclohexyl group, a cyclopentyl group, a cyclobutyl group, a cyclopropyl group, and a part or all of them are included. And a saturated cyclic group.

  As the bicyclic hydrocarbon group, those having 9 to 11 carbon atoms are preferable. Specifically, an indanyl group, an indenyl group, a naphthyl group, a tetrahydronaphthyl group, and a ring in which some or all of them are saturated. Formula group etc. are mentioned.

Examples of monocyclic or bicyclic heterocyclic groups include:
Examples thereof include monocyclic or bicyclic heterocyclic groups containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a part or all of which may be saturated.

The monocyclic heterocyclic group is, for example, a heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, from a saturated or unsaturated 5- to 7-membered ring. A heterocyclic group, specifically,
Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxolanyl, thiolanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl , Thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group , A perhydroazepinyl group, a perhydrothiazepinyl group, and a cyclic group in which some or all of them are saturated.

The bicyclic heterocyclic group is a heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has two saturated or unsaturated 5- to 7-membered rings. A heterocyclic group formed by condensation, specifically,
Indolinyl, isoindolinyl, indolyl, indazolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, benzofuryl, thienopyridyl, thiazolopyridyl, pyrrolopyridyl, dihydro Examples include pyrrolopyridyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, quinazolinyl group, phthalazinyl group, cinnolinyl group, chromanyl group, isochromanyl group, naphthyridinyl group, and cyclic groups in which some or all of them are saturated. .

Of these cyclic groups (monocyclic or bicyclic hydrocarbon groups or monocyclic or bicyclic heterocyclic groups),
"(I) a monocyclic hydrocarbon group having 3 to 7 carbon atoms,
(Ii) a monocyclic heterocyclic group (preferably a monocyclic 5 to 6-membered aliphatic heterocyclic group) containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or
(Iii) “a bicyclic heterocyclic group comprising 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and two condensed 5- to 7-membered rings” is preferred,
Specific examples of such groups include
`` Phenyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxolanyl, thiolanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl Group, triazolyl group, tetrazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, Pyrazinyl group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group, perhydroazepinyl group, perhydrothiazepinyl group, indolinyl group Isoindolinyl group, indolyl group, indazolyl group, isoindolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzodioxolyl group, benzothienyl group, benzofuryl group, thienopyridyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group , A quinolyl group, an isoquinolyl group, a quinoxalinyl group, a quinazolinyl group, a phthalazinyl group, a cinnolinyl group, a chromanyl group, an isochromanyl group, a naphthyridinyl group, and a cyclic group in which some or all of them are saturated.

Among these, “(i) a monocyclic heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (preferably a monocyclic 5 to 6-membered aliphatic heterocyclic group)” Or (ii) a bicyclic heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and is formed by condensing two 5- to 7-membered rings.
Among these, as a more preferable specific example,
`` Phenyl, cyclohexyl, cyclopropyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, piperidyl Group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, isoindolinyl group, indolinyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, benzoxazolyl group, quinolyl group, isoquinolyl group , A quinazolinyl group, an isoindolyl group, an indolyl group, and a cyclic group in which some or all of them are saturated.

As a more preferable specific example,
“Piperidyl group (1-piperidyl group etc.), piperazinyl group (1-piperazinyl group etc.), morpholinyl group (4-morpholinyl group etc.), indolinyl group (1-indolinyl group etc.), isoindolinyl group (2-isoindolinyl group etc.) And thiazolopyridyl group (thiazolo [5,4-b] pyridin-2-yl group and the like).

Among these, as a particularly preferred specific example,
“1-piperidyl group, 1-piperazinyl group, 4-morpholinyl group, 1-indolinyl group, 2-isoindolinyl group, thiazolo [5,4-b] pyridin-2-yl group, etc.”.

The “optionally substituted cyclic group (monocyclic or bicyclic hydrocarbon group or monocyclic or bicyclic heterocyclic group)” represented by R ² may be unsubstituted. May have 1 to 3 substituents which are the same or different. The substituent in the cyclic group is not particularly limited, and specific examples include substituents selected from the following “Group A substituents”, and among these, “A ′ group substituents” are particularly preferable.

In the object compound [I] of the present invention, the substituent in the “amino group substituted with 1 or 2 substituents selected from a substituted or unsubstituted lower alkyl group” represented by R ² is not particularly limited. More specifically, for example, “cyano group, lower alkoxy group (methoxy group etc.), monocyclic aryl group (phenyl group etc.), nitrogen-containing monocyclic 6-membered aromatic heterocyclic group (pyridyl group etc.), etc. And a lower alkyl group substituted with a group selected from:

---- Group A substituent: -------------------------
Group A substituents include the following:
Halogen atom (Cl, F, Br, etc.), cyano group, nitro group, amino group, oxo group, lower alkyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower cycloalkanoyl group Halo-lower alkyl group, halo-lower alkylcarbonyl group, nitrogen-containing monocyclic 5-6 membered aliphatic heterocyclic group substituted carbonyl group, nitrogen-containing monocyclic 6-membered aromatic heterocyclic group, monocyclic aryl group, single Cyclic aryl group-substituted aryl lower alkylcarbonylamino group, lower alkylthio group, aminosulfonyl group and the like.
[Specific examples of the “nitrogen-containing monocyclic 5 to 6-membered aliphatic heterocyclic group-substituted carbonyl group” include “pyrrolidinyl group, piperidinyl group” Group, piperazinyl group, etc. ".
Specific examples of the “nitrogen-containing monocyclic 6-membered aromatic heterocyclic group” include “pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyranyl group and the like”.
Specific examples of the “monocyclic aryl group” in “monocyclic aryl group” and “monocyclic aryl group-substituted aryl lower alkylcarbonylamino group” include a phenyl group and the like. ]
-------------------------------------------------- -----------
--- A 'group substituent (especially preferred group A substituent): -------------
More preferred Group A substituents include the following:
An oxo group, a lower alkanoyl group, a lower cycloalkanoyl group, a lower alkoxycarbonyl group, and a nitrogen-containing monocyclic 5- to 6-membered aliphatic heterocyclic group-substituted carbonyl group (pyrrolidinyl group, piperidinyl group, etc.).
-------------------------------------------------- ------------

In the compound of the present invention [I] wherein B is CH, R ² when X is a single bond is represented by the formula

(1) an optionally substituted monocyclic or bicyclic nitrogen-containing heterocyclic group, or (2) substituted with 1 to 2 substituents selected from a substituted or unsubstituted lower alkyl group A preferred example is an amino group.

  Among the target compounds [I] of the present invention, in which B is CH, among the two cis-trans isomers having the cyclohexyl ring in the structure of [I] as a reference plane, the trans isomer compound is , More preferable in that higher DPPIV inhibitory activity can be obtained. That is, in the compound of the present invention [I] wherein B is CH, the following partial structure

Or a pharmacologically acceptable salt thereof.

As one compound group of the compounds of the present invention, among the compounds [I],
X is a single bond, -Alk-CO -, - COCH 2 -,
_{-Alk-O -, - O-} CH 2 -, - SO 2 -, - S -, - COO-,
^{-CON (R 3) -, -} Alk-CON (R 3) -,
_{^{-CON (R 3) CH 2 -}} , - Alk-CON (R 3) CH 2 -,
^{_{-COCH 2 N (R 3) -}} , - SO 2 N (R 3) - or -NHCH ₂ - and is,
R ² is (1) an optionally substituted cyclic group, and the cyclic group moiety is (i) a monocyclic or bicyclic hydrocarbon group or (ii) a monocyclic or bicyclic heterocyclic group A group;
Or (2) a compound group which is an amino group substituted with one or two identical or different substituents selected from a substituted or unsubstituted lower alkyl group.
(Compound Group 1, Compound Ie)

In addition, as another compound group, among the compound [I] or the compound group 1, R ² is
(1) a cyclic group which may have the same or different 1 to 3 substituents selected from group A substituents, wherein the cyclic group moiety is (i) monocyclic or bicyclic carbonization A group which is a hydrogen group or (ii) a monocyclic or bicyclic heterocyclic group;
(2) The same or different 1 selected from “a lower alkyl group optionally substituted with a group selected from a cyano group, a lower alkoxy group, a phenyl group and a nitrogen-containing monocyclic 6-membered aromatic heterocyclic group” An amino group substituted with 2 substituents; and (3) a lower alkyl group, a carboxy lower alkyl group, a lower alkoxy group, a lower alkenyl group, a lower alkoxy substituted lower alkyl group, a phenoxy group, a phenoxy substituted lower alkyl group or A phenyl lower alkenyl group;
And a group of compounds that are groups selected from: (Compound group 2)

As another compound group, compound [I] or the compound group 1 or 2,
R ² is an optionally substituted cyclic group, and the cyclic group moiety is
(I) a monocyclic hydrocarbon group having 3 to 7 carbon atoms,
(Ii) a monocyclic heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and
(Iii) A bicyclic heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and two 5- to 7-membered rings are condensed.
And a group of compounds that are groups selected from: (Compound group 3)

Further, as another more preferable compound group, among the compound [I] or the compound group 1, 2, or 3,
R ² is a cyclic group which may have the same or different 1 to 3 substituents selected from the A ′ group substituent, and the cyclic group is a piperidyl group, a piperazinyl group, a morpholinyl group, Examples include a group of compounds that are groups selected from an indolinyl group, an isoindolinyl group, and a thiazolopyridyl group. (Compound group 4)

As another preferred compound group, among the compound [I] or the compound groups 1, 2, 3 or 4, B is CH, X is a single bond, and R ² is a formula

(1) an optionally substituted monocyclic or bicyclic nitrogen-containing heterocyclic group, or (2) substituted with 1 to 2 substituents selected from a substituted or unsubstituted lower alkyl group And a group of compounds that are amino groups. (Compound group 5)

Moreover, as a more preferable compound group among compound [I] or the said compound groups 1, 2, 3, 4 or 5,
A group of compounds in which B is CH, X is a single bond, and A is —CH ₂ —;
A group of compounds in which B is CH, X is a single bond, A is —CH ₂ —, and R ¹ is a hydrogen atom or a lower alkyl group;
A group of compounds in which B is CH, X is a single bond, and A is -S-;
A group of compounds in which B is CH, X is a single bond, A is -S-, and R ¹ is a hydrogen atom or a lower alkyl group;
Etc.

Furthermore, in each of the above compound groups, as a more preferable compound group,
B is CH and the following partial structure

A group of compounds having

Moreover, the following compounds are mentioned as a preferable specific compound.
(S) -2-cyano-1- [t-4- (4-acetyl-1-piperazinyl) -1-methyl-r-1-cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (1,3-dioxo-2-isoindolinyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- (trans-4-morpholinocyclohexylamino) acetylpyrrolidine; and (S) -2-cyano-1- [trans-4- (thiazolo [5,4-b] pyridine-2. -Yl) cyclohexylamino] acetylpyrrolidine and the like.

  The object compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory action on the enzyme activity of DPPIV. In particular, it has an excellent inhibitory action on human DPPIV. It also shows high selectivity for DPPIV (ie, type IV dipeptidyl peptidase) among various serine proteases (eg, plasmin, thrombin, prolyl endopeptidase, trypsin, dipeptidyl peptidase II, etc.). Moreover, the object compound [I] of the present invention or a pharmacologically acceptable salt thereof improves the insulin secretion response to the oral glucose load through its DPPIV inhibitory action.

  Therefore, the object compound [I] of the present invention or a pharmacologically acceptable salt thereof can improve the disease state by inhibiting DPPIV-related diseases (diseases mediated by DPPIV), that is, inhibiting the enzyme activity of DPPIV. It is useful as a preventive or therapeutic agent for possible diseases.

  Examples of such diseases include diabetes (for example, type 1 diabetes, type 2 diabetes), hyperglycemia (for example, postprandial hyperglycemia), hyperinsulinemia, diabetic complications (for example, renal disorder, neurological disorder, etc.) ), Obesity, overeating, dyslipidemia (eg, hyperlipidemia such as hypertriglyceridemia), autoimmune disease (eg, arthritis, rheumatoid arthritis, etc.), osteoporosis, acquired immune deficiency syndrome (AIDS), Examples include rejection of transplanted organs and tissues. The object compound [I] of the present invention or a pharmacologically acceptable salt thereof is particularly useful as a preventive or therapeutic agent for diabetes (especially type 2 diabetes).

  Further, the compound of the present invention has low toxicity and has high safety when used as a pharmaceutical compound. It also exhibits excellent pharmacokinetic properties (bioavailability, in vitro metabolic stability (stability in human liver homogenate), P450 inhibitory activity, protein binding, etc.).

The DPPIV inhibitory action of the compound of the present invention and the drug efficacy based thereon (antiglycemic effect, insulin secretion response improving effect on glucose load, etc.) are known methods or equivalent methods (WO 98/19998; WO 00/34241; Holst et al., Diabetes). 47, 1663-1670, 1998; Augustyns et al., Current Medicinal Chemistry, 6, 311-327, 1999; Meester et al., Immunol. Today, 20, 367-375. 1999; Fleicher et al., Immunol. Today, Vol. 15, pp. 180-184, 1994).

  The object compound [I] of the present invention can be used for pharmaceutical use in a free form or a pharmacologically acceptable salt form. Examples of the pharmacologically acceptable salt of compound [I] include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate and citric acid. Examples thereof include organic salts such as salts, methanesulfonate, benzenesulfonate, tosylate or maleate. In addition, when it has a substituent such as a carboxyl group, a salt with a base (for example, an alkali metal salt such as sodium salt or potassium salt or an alkaline earth metal salt such as calcium salt) can be used.

  The object compound [I] or a salt thereof of the present invention includes any of its intramolecular salts and adducts, solvates or hydrates thereof.

  The object compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, such as tablets, granules, capsules, powders, injections, inhalants, etc. It can be used as a conventional pharmaceutical preparation. For example, the compound of the present invention is used in combination with an activator or diluent such as a binder, a disintegrant, a filler, a filler, a lubricant, and the like, which are acceptable in general pharmaceuticals, and formulated by a conventional method. be able to.

The dose of the object compound [I] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight and condition, but is usually about 0.01 to 300 mg / kg per day. In particular, it is preferably about 0.1 to 30 mg / kg.

  According to the present invention, the target compound [I] can be produced by the following [Method A] to [Method D], but is not limited thereto.

[Method A]
The object compound [I] of the present invention is represented by the general formula [II].

(In the formula, Z ¹ represents a reactive residue, and other symbols have the same meaning as described above.)
And a compound of the general formula [III]

(In the formula, the symbols have the same meaning as described above.)
Can be produced by reacting the compound represented by the formula (I) or a salt thereof with the pharmacologically acceptable salt if desired.

  As the salt of compound [III], for example, an inorganic acid such as hydrochloride and sulfate, or a salt with an inorganic base such as alkali metal salt and alkaline earth metal salt can be used.

As the reactive residue for Z ¹ , a conventional reactive residue such as a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyloxy group and the like can be preferably used, and a halogen atom is particularly preferable.

  The reaction of compound [II] with compound [III] or a salt thereof can be carried out in a suitable solvent or without solvent in the presence or absence of a deoxidizing agent.

  The solvent may be any solvent that does not adversely affect the reaction, such as acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride. , Dichloroethane, chloroform, or a mixed solvent thereof can be appropriately used.

  This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.

  Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metals such as sodium, sodium hydroxide , Alkali metal hydroxides such as potassium hydroxide, etc.) or organic bases (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) can be suitably used.

[Method B]
Further, in the compound [I], R ² is a monocyclic or bicyclic nitrogen-containing heterocyclic group which may be substituted, and the general formula [Ia] in which X is —COO—.

(In the formula, R ²¹ represents an optionally substituted monocyclic or bicyclic nitrogen-containing heterocyclic group, and other symbols have the same meaning as described above.)
The compound represented by general formula [IV]

(In the formula, R represents an amino-protecting group, and other symbols have the same meaning as described above.)
The compound represented by general formula (I) or a salt thereof is reacted with phosgene or an equivalent thereof, and then further represented by the general formula [V].
R ²¹ H [V]
(In the formula, the symbols have the same meaning as described above.)
Is reacted with a compound represented by the general formula [VI]

(In the formula, the symbols have the same meaning as described above.)
Or a salt thereof, and the amino group protecting group (R) of the product can be removed to produce the compound.

  After reacting compound [IV] with phosgene or its equivalent, further reaction with the compound represented by compound [V] is carried out in a suitable solvent or in the presence of phosgene or its equivalent and a deoxidizing agent. It can be carried out without solvent.

  As “phosgenes or equivalents thereof”, triphosgene, diphosgene, carbonyldiimidazole, 4-nitrophenyl chloroformate and the like can be suitably used.

  Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal amides such as sodium amide and lithium amide, and alkali metals such as sodium methoxide). Alkoxide, alkali metal such as sodium, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc.) or organic base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) Can be suitably used.

  The solvent may be any solvent that does not adversely affect the reaction. For example, methylene chloride, dichloroethane, chloroform, ether, tetrahydrofuran, ethyl acetate, toluene, or a mixed solvent thereof can be used as appropriate. This reaction suitably proceeds at −78 to 110 ° C., particularly 0 ° C. to room temperature.

Subsequent removal of the amino-protecting group (R) of the compound [VI] can be carried out by a conventional method, for example, it can be carried out by acid treatment, base treatment or catalytic reduction in a suitable solvent or without solvent. .

  As the acid, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid can be preferably used.

  Examples of the base include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali carbonates such as sodium carbonate and potassium carbonate, alkali metal amides such as sodium amide and lithium amide, alkali metal alkoxides such as sodium methoxide, Alkali metal such as sodium, alkali metal hydroxide such as sodium hydroxide and potassium hydroxide) or organic base (for example, triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, piperidine, dimethylaniline, dimethylaminopyridine, etc.) Etc.) can be preferably used.

  The catalytic reduction reaction can be carried out by suitably using palladium carbon, palladium hydroxide carbon, platinum oxide, Raney nickel or the like in a hydrogen atmosphere.

The solvent may be any solvent that does not adversely affect the reaction.For example, methanol, ethanol, isopropyl alcohol, propyl alcohol, dioxane, methylene chloride, chloroform, dichloroethane, ether, tetrahydrofuran, ethyl acetate, toluene or a mixed solvent thereof can be used. It can be used as appropriate. This reaction suitably proceeds at −78 to 80 ° C., particularly 0 ° C. to room temperature.

[Method C]
Among compounds [I], B is N and X is —CO—, —Alk—CO— or
—SO ₂ — is the general formula [Ib]

(In the formula, X ¹ represents —CO—, —Alk—CO— or —SO ₂ —, and the other symbols have the same meaning as described above.)
The compound represented by general formula [VII]

(In the formula, n represents 0, 1, 2, or 3, P represents a resin residue, and other symbols have the same meaning as described above.)
And a compound of the general formula [VIII]
R ² -V ¹ [VIII]
(In the formula, V ¹ represents —COOH, —Alk—COOH or a chlorosulfonyl group, and other symbols have the same meaning as described above.)
Is reacted with a compound represented by the formula:

(In the formula, the symbols have the same meaning as described above.)
It can be produced by removing the linker and the resin residue part represented by

Alternatively, in the compound [Ib], a compound in which X ¹ is —CO— and R ² is a carboxy lower alkylene group may be represented by the general formula [X] instead of the general formula [VIII] or a salt thereof.

(However, Alk1 represents a lower alkylene group.)
The compound represented by formula (IX) can be used for the reaction with compound [VII], and then the linker represented by the general formula [IX] and the resin residue can be removed from the reaction product.

[Method D]
Moreover, among compounds [I], B is CH, X is —CON (R ³ ) —,
—Alk—CON (R ³ ) — or —SO ₂ N (R ³ ) —

[Wherein, X ² represents -CON (R ³ )-, -Alk-CON (R ³ )-or -SO ₂ N (R ³ )-, and other symbols have the same meaning as described above. ]
The compound represented by the general formula [XI]

(In the formula, the symbols have the same meaning as described above.)
And a compound of the general formula [XII]
R ² —V ² [XII]
^{(Wherein, V} 2 is, -COOH, represents -Alk-COOH or chlorosulfonyl group and the other symbols are the same as defined above.)
Can be produced by reacting the compound represented by the formula (1) or a salt thereof, and then removing the linker and the resin residue moiety represented by the above general formula [IX] from the reaction product.

Alternatively, in the compound [Ic], a compound in which X ² is —CON (R ³ ) — and R ² is a carboxy lower alkyl group is
Reaction with compound [XI] is carried out using compound [X] instead of compound [XII] or a salt thereof, and then the linker and the resin residue represented by the general formula [IX] are removed from the reaction product. Can be manufactured.

Further, in compound [I], B is CH, and X is
The general formula [Id] which is —CON (R ³ ) CH ₂ — or —Alk-CON (R ³ ) CH ₂ —.

(In the formula, X ³ represents —CON (R ³ ) CH ₂ — or —Alk-CON (R ³ ) CH ₂ —, and other symbols have the same meanings as described above.)
The compound represented by general formula [XIII]

(In the formula, the symbols have the same meaning as described above.)
By reacting the compound represented by the general formula [XII] or a salt thereof, and then removing the linker and the resin residue part represented by the general formula [IX] from the reaction product. can do.

Alternatively, in the compound [Id], a compound in which X ³ is —CON (R ³ ) CH ₂ — and R ² is a carboxy lower alkyl group is obtained by replacing the compound [XII] or a salt thereof with the compound [X ] Is then used for the reaction with compound [XIII], and then the linker and the resin residue represented by the general formula [IX] are removed from the reaction product.

[Reactions in Method C and Method D]
Reaction in Method C (reaction between Compound [VII] and Compound [VIII] or a salt thereof (or Compound [X])); and Reaction in Method D (Compound [XI] or [XIII] and Compound [XII] Or a salt thereof (or reaction with compound [X]) is carried out in the presence of a condensing agent and / or a deoxidizing agent in an appropriate solvent or without solvent, if necessary, and the linker and the resin residue part are further removed. It can be carried out by removing by a conventional method and purifying by, for example, extraction, distribution, reprecipitation, crystallization, recrystallization, various chromatographies, high-speed chromatography and the like, if necessary.

  Examples of the linker include groups obtained by removing the resin residue (P) moiety from those represented by the general formula [IX].

  As the resin residue represented by P, resins used in ordinary solid phase synthesis can be used, for example, Merrifield resin (such as 4-chloromethylpolystyrene resin), Wangresin (such as 4-benzyloxybenzyl alcohol resin), Resin residues such as hydroxymethyl polystyrene resin (such as 4-hydroxymethyl polystyrene resin) can be used. The type of resin is not particularly limited as long as it does not adversely influence the reaction, and can be appropriately selected according to the type of target compound. In general, the particle size is preferably 70 to 200 μm, The loading capacity is preferably 0.1 to 2 mmol / g.

  As the condensing agent, O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate, DCC (dicyclohexylcarbodiimide), EDC (1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide), chloroformates (for example, ethyl chloroformate, isobutyl chloroformate), carbonyldiimidazole and the like can be suitably used. In order to accelerate the reaction, a base (sodium carbonate, sodium hydrogen carbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, etc.) Additives such as 1-hydroxybenzotriazole and 1-hydroxysuccinimide can also be added to the condensing agent.

  Examples of deoxidizers include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, organic bases (triethylamine, Pyridine and the like can be preferably used.

  Subsequent removal of the linker and resin residue is treated with trifluoroacetic acid, trifluoromethanesulfonic acid, hydrogen fluoride, hydrogen bromide, hydrogen chloride, or a mixture thereof in a suitable solvent or without solvent. It can implement suitably.

  The solvent in the reaction may be any solvent that does not adversely influence the reaction. For example, methylene chloride, N-methylmorpholine, dimethylformamide, tetrahydrofuran, dimethylacetamide, or a mixed solvent thereof can be used as appropriate.

  The reaction in Method C suitably proceeds at 0 to 120 ° C, particularly 20 to 50 ° C. In addition, the reaction in Method D suitably proceeds at 0 to 50 ° C, particularly 0 to 30 ° C.

The solvent in the subsequent linker and resin residue removal reaction may be any solvent that does not adversely affect the reaction. For example, methylene chloride, acetic acid, trifluoroacetic acid, or a mixed solvent thereof can be appropriately used. This reaction suitably proceeds at 0 to 50 ° C, particularly 0 to 30 ° C.

[Raw compound of Method A]
The raw material compound [II] of the present invention can be produced, for example, according to the method described in International Patent Publications WO98 / 19998, WO00 / 34241, Reference Examples (Reference Example 1 or 2) described later, and the like.

  For example, compound [II] is represented by the general formula [20].

(In the formula, the symbols have the same meaning as described above.)
And a compound of the general formula [21]
_{^{Z 2 -CH 2 CO-Z 3}} [21]
(In the formula, Z ² and Z ³ are the same or different and represent reactive residues.)
And a compound represented by general formula [22] in the presence of a deoxidizing agent (for example, triethylamine).

(In the formula, the symbols have the same meaning as described above.)
And the product can be obtained by treating the product with a dehydrating agent (for example, phosphorus oxychloride, trifluoroacetic anhydride, etc.) by a conventional method.

As the reactive residue of Z ² or Z ³ , a conventional reactive residue similar to Z ¹ can be preferably used.

  Specifically, the raw material compound [III] can be produced, for example, in the same manner as described in Reference Examples (Reference Examples 7 to 10) described later.

For example, the compound [III] in which X is —O—CH ₂ — or —NHCH ₂ — is represented by the general formula [23].

(In the formula, V ³ represents a hydroxy group or an amino group, and other symbols have the same meaning as described above.)
A compound having the amino group protected therein or a salt thereof, and the general formula [24]
R ² -Z ⁴ [24]
(In the formula, Z ⁴ represents a reactive residue, and other symbols have the same meaning as described above.)
And a compound represented by
The reaction is carried out in the presence or absence of a deoxidizing agent (for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydride or potassium carbonate). It can be manufactured by deprotection.

  As the amino-protecting group, any conventional protective group similar to R can be suitably used.

As the reactive residue of Z ⁴ , a conventional reactive residue similar to Z ¹ can be preferably used.

In addition, the compound [III] in which X is —Alk—O— or —S— is
Formula [25]

(In the formula, V ⁴ represents a hydroxy group or a mercapto group, and other symbols have the same meaning as described above.)
A compound represented by the following, a protected amino group thereof or a salt thereof;
General formula [26a] or General formula [26b]
R ² —Z ⁵¹ [26a] or R ² —Alk—Z ⁵² [26b]
(In the formula, Z ⁵¹ and Z ⁵² represent a reactive residue, and other symbols have the same meaning as described above.)
Is reacted in the presence or absence of a deoxidizing agent (for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydride or potassium carbonate), and if necessary, an amino group Can be produced by deprotecting the protecting group according to a conventional method. As the amino-protecting group, any conventional protecting group similar to R 1 can be preferably used.

As the reactive residues of Z ⁵¹ and Z ⁵² , conventional reactive residues similar to Z ¹ can be preferably used.

In addition, compound [III] wherein X is —COCH ₂ N (R ³ ) — or —SO ₂ N (R ³ ) — is represented by the general formula [27]

(In the formula, V ⁵ represents —N (R ₃ ) H, and other symbols have the same meaning as described above.)
A compound represented by the following, a protected amino group thereof or a salt thereof;
General formula [28a] or General formula [28b]
R ² —COCH ₂ —Z ⁶¹ [28a] or
R ² —SO ₂ —Z ⁶² [28b]
(In the formula, Z ⁶¹ and Z ⁶² represent reactive residues, and other symbols have the same meaning as described above.)
Is reacted in the presence or absence of a deoxidizing agent (for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydride or potassium carbonate), and if necessary, an amino group Can be produced by deprotecting the protecting group according to a conventional method. As the amino-protecting group, any conventional protecting group similar to R 1 can be preferably used.

As the reactive residue of Z ⁶¹ and Z ⁶² , a conventional reactive residue similar to Z ¹ can be preferably used.

In addition, the compound [III] in which X is —CON (R ³ ) —, —Alk—CON (R ³ ) —, or —SO ₂ N (R ³ ) — is represented by the general formula [27]
A compound represented by the following formula, a protected amino group thereof or a salt thereof; and a general formula [29]
R ² -V ⁶ [29]
[However, ^{V 6} represents -COOH, an -Alk-COOH or -SO ₃ H, and the other symbols are the same meaning. ]
Or a salt thereof in the presence of a condensing agent (such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), and if necessary, the amino-protecting group is removed by a conventional method. It can be manufactured by protecting. As the amino-protecting group, any conventional protective group similar to R can be suitably used.

In addition, the compound [III] in which X is —CON (R ³ ) CH ₂ — or —Alk-CON (R ³ ) CH ₂ — is represented by the general formula [30].

(However, ^{V 7} represents -N ^(R 3) H, and the other symbols are the same meaning.)
A compound represented by the following formula, a protected amino group thereof or a salt thereof; and a general formula [31]
R ² -V ⁸ [31]
[However, ^{V 8} represents -COOH or -Alk-COOH, and the other symbols are the same meaning. ]
Or a salt thereof in the presence of a condensing agent (such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), and if necessary, the amino-protecting group is removed by a conventional method. It can be manufactured by protecting. As the amino-protecting group, any conventional protecting group similar to R 1 can be preferably used.

B is CH, X is -Alk-CO-, and R ² is a formula

(1) an optionally substituted monocyclic or bicyclic nitrogen-containing heterocyclic group, or (2) substituted with 1 to 2 substituents selected from a substituted or unsubstituted lower alkyl group Compound [III], which is an amino group,
General formula [32]

(In the formula, V ⁹ represents —COOH, and other symbols have the same meaning as described above.)
A compound represented by the following, a protected amino group thereof or a salt thereof;
Formula [33a]
R ²² -Alk-H [33a]
(Wherein R ²² is a formula

(1) an optionally substituted monocyclic or bicyclic nitrogen-containing heterocyclic group, or (2) substituted with 1 to 2 substituents selected from a substituted or unsubstituted lower alkyl group And other symbols have the same meaning as described above. )
Or a salt thereof in the presence of a condensing agent (such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), and if necessary, the amino-protecting group is removed by a conventional method. It can be manufactured by protecting. As the amino-protecting group, any conventional protective group similar to R can be suitably used.

B is N, X is —CO— or —Alk—CO—, and R ² is a compound represented by the formula

(1) an optionally substituted monocyclic or bicyclic nitrogen-containing heterocyclic group, or (2) substituted with 1 to 2 substituents selected from a substituted or unsubstituted lower alkyl group Compound [III], which is an amino group,
Formula [330]

[Wherein, R ¹ has the same meaning as described above. ]
A compound represented by the following, a protected amino group thereof or a salt thereof;
General formula [331] or [332]
R ²² —CO—Z ⁷ [331]
R ²² -Alk-COOH [332]
[Wherein R ²² represents the formula

(1) an optionally substituted monocyclic or bicyclic nitrogen-containing heterocyclic group, or (2) substituted with 1 to 2 substituents selected from a substituted or unsubstituted lower alkyl group Z ⁷ represents a reactive residue. ]
Or a salt thereof in the presence or absence of a deoxidizing agent (for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydride or potassium carbonate) and the like. It can be produced by deprotecting an amino-protecting group by a conventional method. As the amino-protecting group, any conventional protective group similar to R can be suitably used. As the reactive residue of Z ⁷ , a conventional reactive residue similar to Z ¹ can be preferably used.

Also, B is CH, X is a single bond, and R ² is a formula

(1) an optionally substituted monocyclic or bicyclic nitrogen-containing heterocyclic group, or (2) substituted with 1 to 2 substituents selected from a substituted or unsubstituted lower alkyl group Compound [III], which is an amino group,
General formula [34]

(In the formula, the symbols have the same meaning as described above.)
A compound having the amino group protected therein or a salt thereof, and the general formula [33b]
R ²² -H [33b]
[Wherein R ²² has the same meaning as described above. ]
Can be produced by reacting in the presence of a reducing agent (such as sodium triacetoxyborohydride) and deprotecting the amino-protecting group by a conventional method, if necessary. As the amino-protecting group, any conventional protective group similar to R can be suitably used.

Also, B is CH, X is a single bond, and R ² is a formula

Compound [III], which is a group represented by general formula [35]

(In the formula, the symbols have the same meaning as described above.)
A compound represented by the following formula, a protected amino group thereof or a salt thereof, and a general formula [36]

[Wherein, the cyclic group Ar represents an arylene (such as phenylene) which may have a substituent. ]
Is reacted in the presence or absence of a deoxidizing agent (for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydride or potassium carbonate), and if necessary, an amino group Can be produced by deprotecting the protecting group according to a conventional method. As the amino-protecting group, any conventional protective group similar to R can be suitably used.

Also, B is CH, X is a single bond, and R ² is a formula

Compound [III], which is a nitrogen-containing heterocyclic group which may be substituted, represented by general formula [35] is a compound represented by the above general formula [35], its protected amino group or a salt thereof, and general formula [37]

(In the formula, Z ⁸¹ and Z ⁸² represent reactive residues.)
Or a salt thereof,
The reaction is carried out in the presence or absence of a deoxidizing agent (for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydride or potassium carbonate). It can be manufactured by deprotection. As the amino-protecting group, any conventional protecting group similar to R 1 can be preferably used.

As the reactive residues for Z ⁸¹ and Z ^82, the same conventional reactive residues as for Z ¹ can be preferably used.

  In addition, the compound [III] in which B is N and X is a single bond is represented by the general formula [38].

(In the formula, the symbols have the same meaning as described above.)
A compound having the amino group protected therein or a salt thereof, and the general formula [24]
R ² -Z ⁴ [24]
Is reacted in the presence or absence of a deoxidizing agent (for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydride or potassium carbonate), and if necessary, an amino group Can be produced by deprotecting the protecting group according to a conventional method. As the amino-protecting group, any conventional protective group similar to R can be suitably used.

  The compound [III] wherein X is —COO— is represented by the general formula [39].

(In the formula, the symbols have the same meaning as described above.)
A protected amino group or a salt thereof of the compound represented by formula [40]
R ² —COCl [40]
(In the formula, the symbols have the same meaning as described above.)
Can be produced by reacting in the presence of a deoxidizing agent (such as dimethylaminopyridine) and deprotecting the amino-protecting group by a conventional method. As the amino-protecting group, any conventional protective group similar to R can be suitably used.

The raw material compounds [20] to [40] can be produced in the same manner as in the known method or the method described in Reference Examples below. In the raw material compound [III] in which B is CH, there are cis / trans isomers having a cyclohexane ring as a reference plane. The isomer raw material compound [III] can be obtained. Alternatively, after obtaining the raw material compound [III] as a mixture of cis and trans isomers, the target isomer can be separated by chromatography or the like.

  [Raw compound of Method B]

General formula [IV] (wherein the symbols have the same meaning as described above)
Or a salt thereof represented by the above general formula [II]
(In the formula, the symbols have the same meaning as described above.)
And a compound of the general formula [41] (wherein the symbols have the same meaning as described above).
Is reacted with a compound represented by the formula:
A compound represented by the general formula [42] or a salt thereof is obtained, which is further represented by the general formula [43] or the general formula [44] (wherein R represents an amino-protecting group).
It is obtained by reacting with a compound represented by

  The reaction of compound [II] with compound [41] or a salt thereof can be carried out in a suitable solvent or without solvent in the presence or absence of a deoxidizing agent. The solvent may be any solvent that does not adversely affect the reaction, such as acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride. , Dichloroethane, chloroform, or a mixed solvent thereof can be appropriately used. This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.

  Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metals such as sodium, sodium hydroxide , Alkali metal hydroxides such as potassium hydroxide, etc.) or organic bases (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) can be suitably used.

  The reaction of compound [42] or a salt thereof and compound [43] or [44] can be carried out in a suitable solvent or without solvent in the presence of a deoxidizing agent.

  The solvent may be any solvent that does not adversely affect the reaction. For example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride, dichloroethane, chloroform, water Or these mixed solvents can be used suitably. This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.

Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metals such as sodium, sodium hydroxide , Alkali metal hydroxides such as potassium hydroxide, etc.) or organic bases (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) can be suitably used.

[Raw compound of Method C and Method D]
Compound [VII], Compound [XI] or Compound [XIII]
Each of the general formula [50], the general formula [51], or the general formula [52]

(Wherein V ¹⁰ , V ¹¹ and V ¹² represent an amino-protecting group, and other symbols have the same meaning as described above.)
And a compound of the general formula [53]

(In the formula, the symbols have the same meaning as described above.)
Is reacted in the presence of a reducing agent (such as sodium triacetoxyborohydride) by a conventional method, and then the product is converted into a compound [II] and a deoxidizing agent (such as diisopropylethylamine). After the reaction in the presence, the amino-protecting group can be removed by a conventional method. As the amino-protecting group, a conventional protecting group similar to R can be preferably used.

  The compound [I] of the present invention or its starting compound produced as described above is isolated and purified as it is or as a salt thereof. The salt can be produced by subjecting it to a commonly used salt formation treatment. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.

In the compound of the present invention or the starting compound thereof, optical isomers such as racemates, optically active substances, diastereomers and the like may exist alone or as a mixture. Stereochemically pure isomers can be derived by using stereochemically pure raw material compounds or by separating optical isomers by a general racemic resolution method. A mixture of diastereomers can be separated by a conventional method such as fractional crystallization or chromatography.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, these Examples do not restrict | limit this invention.

Example 1-1
(S) -1-bromoacetyl-2-cyanopyrrolidine (Reference Example 1 described later) 100 mg
4-Amino-1- (2-pyrimidinyl) piperidine (Reference Example 7-1) 247 mg of acetonitrile-methanol solution is stirred at room temperature for 15 hours. Add water to the reaction mixture and extract with chloroform. The extract is dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by diol column chromatography [solvent: 0-10% methanol-chloroform], dissolved in ethyl acetate 0.5 ml-chloroform 0.5 ml, 2N hydrochloric acid-ether 1.0 ml, and then ether 2 ml were added. Taken and washed with ether to give (S) -2-cyano-1- [1- (2-pyrimidinyl) piperidin-4-ylamino] acetylpyrrolidine dihydrochloride (Table 1 Example 1-1).

Examples 1-2 to 1-90, 1-92 to 1-109
(S) -1-Bromoacetyl-2-cyanopyrrolidine and the corresponding starting material compound were treated in the same manner as in Example 1-1 to give Table 1 below (Examples 1-2 to 1-90 and 1-92). To 1-109).
(However, the compound of Example 1-33 is obtained as a by-product of Example 1-33.)
(Corresponding raw material compounds are obtained by a method similar to that described in Reference Examples below, a known method, or a combination thereof.)

Example 1-91
To a solution of 300 mg of trans-1,4-cyclohexanediamine and 457 μL of N, N-diisopropylethylamine in 5 ml of acetonitrile is added 570 mg of (S) -1-bromoacetyl-2-cyanopyrrolidine, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with saturated brine and extracted with chloroform. The extract is dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [solvent: chloroform-methanol (100: 0-95: 5)] to give an oil. This was dissolved in 0.5 ml of chloroform, 0.5 ml of 1N hydrochloric acid-ether and then 4 ml of ether were added, and the deposited precipitate was washed with ether, and (S) -2-cyano-1- {trans-4-[(S)-( 2-Cyano-1-pyrrolidinyl) carbonylmethylamino] cyclohexylamino} acetylpyrrolidine dihydrochloride (Table 1 Example 1-91) 307 mg is obtained.

Examples 2-1 to 2-9
(1) A mixture of 600 mg of 4-tert-butoxycarbonylamino-4-methylcyclohexanone (compound of Reference Example 6-1 (3)), 783 mg of sodium triacetoxyborohydride, 252 mg of morpholine, 159 mg of acetic acid, and 6 ml of dichloroethane Stir at room temperature for 16 hours. Dilute with saturated aqueous sodium bicarbonate and extract with chloroform. The extract is dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [solvent: chloroform-methanol (20: 1) → chloroform-methanol (10: 1) + 1% aqueous ammonia] to give N-tert-butoxycarbonyl-1-methyl-c- 600 mg of a mixture of 4-morpholino-r-1-cyclohexylamine and N-tert-butoxycarbonyl-1-methyl-t-4-morpholino-r-1-cyclohexylamine (Reference Example 8-54; compound before deprotection) Get. 220 mg of this compound is stirred in a mixed solution of 4N hydrochloric acid / dioxane (2 ml) and ethanol (2 ml) at room temperature for 15 hours to deprotect the N-tert-butoxycarbonyl group, and then the reaction solution is concentrated to obtain a residue.

  (2) To the compound obtained in the above (1), 320 mg of (S) -1-bromoacetyl-2-cyanopyrrolidine, 0.6 ml of triethylamine, 3.5 ml of acetonitryl, and 1 ml of methanol are added and stirred at room temperature for 15 hours. Dilute with saturated aqueous sodium bicarbonate and extract with chloroform. The extract is dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [solvent: chloroform-hexane (1: 1) → chloroform] to obtain two types of oils.

The compound on the low polarity side was treated with hydrochloric acid to give (S) -2-cyano-1- [1-methyl-c-4-morpholino-r-1-cyclohexylamino] acetylpyrrolidine dihydrochloride (Table 2 Examples) 2-1) 33 mg is obtained. In addition, the highly polar compound was treated with hydrochloric acid to give (S) -2-cyano-1- [1-methyl-t-4-morpholino-r-1-cyclohexylamino] acetylpyrrolidine dihydrochloride (Table 2 Example 2-2) 82 mg is obtained.
Moreover, it carries out similarly to the above, and the compound of Table 2 Examples 2-3-2-9 is obtained.

Example 3
(1) To 40 ml of trans-4-aminocyclohexanol 4.78 g of acetonitrile / methanol mixture (3/1), 3.00 g of (S) -1-bromoacetyl-2-cyanopyrrolidine was added under ice-cooling. Stir for hours. 1.93 ml of triethylamine and then 16 ml of acetonitrile solution of di-tert-butyl dicarbonate are added to the reaction solution at room temperature, and the mixture is stirred for 3 hours. The solvent is concentrated under reduced pressure, water is added to the residue, neutralized with aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried and concentrated. The resulting residue is purified by silica gel column chromatography to obtain 4.72 g of (S) -1- (N-tert-butoxycarbonyl-trans-4-hydroxy-1-cyclohexylamino) acetyl-2-cyanopyrrolidine. .

  (2) To a solution of 150 mg of the compound obtained in the above (1) and 121 μL of pyridine in 2 mL of methylene chloride, 84 mg of triphosgene is added at room temperature, and the mixture is stirred for 1 hour. Next, add 1 mL of 186 μL of morpholine in methylene chloride, stir at room temperature for 1 hour, and dilute with aqueous citric acid. After extraction with ethyl acetate, drying, concentration, and purification by silica gel column chromatography, (S) -1- [N-tert-butoxycarbonyl-trans-4- (morpholinocarbonyloxy) cyclohexylamino] acetyl- 174 mg of 2-cyanopyrrolidine is obtained.

(3) 157 mg of the compound obtained in (2) above is dissolved in 1.5 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the residue is made alkaline by adding aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried and concentrated. Then, the residue is purified by column chromatography [solvent: 0-5% methanol-chloroform] to obtain an oily substance. This was dissolved in 1 mL of ethyl acetate, 0.5 mL of 1N hydrochloric acid-ether and then 2 mL of ether were added, and the deposited precipitate was washed with ether, and (S) -2-cyano-1- [trans-4- (morpholinocarbonyloxy). ) Cyclohexylamino] acetylpyrrolidine hydrochloride (Table 3 Example 3) 97 mg is obtained.

Example 4-1
(1) A mixture of 500 mg of the resin compound obtained in paragraph (2) of Reference Example 3 and 0.5M methanesulfonic acid-dioxane / methylene chloride (1/9) is stirred at room temperature for 18 hours. The resin is filtered and washed with dimethylformamide, 10% triethylamine-methylene chloride, dimethylformamide-water (1: 1), methanol, tetrahydrofuran, methanol, and methylene chloride. A mixture of the resulting resin, 277 μl of benzyl isocyanate, and 4 ml of methylene chloride is stirred at room temperature for 18 hours. The resin is collected by filtration, washed with dimethylformamide, dimethylformamide-water (1: 1), methanol, tetrahydrofuran, methanol, and methylene chloride, and then dried under reduced pressure to obtain a resin.

(2) A mixture of the resin obtained in (1) and 4 ml of trifluoroacetic acid is stirred at room temperature for 18 hours. The resin is filtered off and washed with methylene chloride, and the filtrate and washings are combined and concentrated. To the residue is added an aqueous sodium hydrogen carbonate solution to make it alkaline, and the mixture is extracted with chloroform, dried and concentrated. The resulting residue is purified by diol column chromatography [solvent: 0-5% methanol-chloroform] to obtain an oil. This was dissolved in 0.5 ml of ethyl acetate, 0.5 ml of 1N hydrochloric acid-ether and then 2 ml of ether were added, and the deposited precipitate was washed with ether, and (S) -2-cyano-1- [1- (benzylaminocarbonyl) piperidine. -4-ylamino] acetylpyrrolidine hydrochloride (Table 4 Example 4-1) is obtained.

Examples 4-2 to 4-5
Using the corresponding starting material compound (isocyanate compound), the compounds of Table 4 Examples 4-2 to 4-3 are obtained in the same manner as in Example 4-1. Further, in place of the isocyanate compound, an intramolecular cyclic anhydride of carboxylic acid (succinic anhydride and glutaric anhydride) was used as a raw material compound, and in the same manner as in Example 4-1, Table 4 Examples 4-4 to 4-4 The compound of 4-5 is obtained.

Examples 4-6 to 4-10
Table 4 Example 4-6 in the same manner as in Example 4-1 except that methyl chloroformate was used as a starting compound in place of benzyl isocyanate and the reaction of item (1) was performed in the presence of triethylamine. The compound is obtained. Moreover, the corresponding raw material compound (chloride) is used in the same manner as described above to obtain the compounds of Table 4 Examples 4-7 to 4-10.

Example 4-11
A mixture of 500 mg of the resin compound obtained in item (2) of Reference Example 3 and 0.5 M methanesulfonic acid-dioxane / methylene chloride (1/9) is stirred at room temperature for 18 hours. The resin is filtered and washed with dimethylformamide, 10% triethylamine-methylene chloride, dimethylformamide-water (1: 1), methanol, tetrahydrofuran, methanol, and methylene chloride. Obtained resin and 2-quinolinecarboxylic acid 177 mg, 1-hydroxybenzotriazole 138 mg, O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate 387 mg, N -A mixture of 224 ml of methylmorpholine and 4 ml of dimethylformamide is stirred at room temperature for 18 hours. The resin is collected by filtration, washed with dimethylformamide, dimethylformamide-water (1: 1), methanol, tetrahydrofuran, methanol, and methylene chloride, and then dried under reduced pressure to obtain a resin. This resin was treated with trifluoroacetic acid in the same manner as in section (2) of Example 4-1, to give (S) -2-cyano-1- [1- (2-quinolylcarbonyl) piperidine-4- Ilamino] acetylpyrrolidine dihydrochloride (Table 4 Example 4-11) 136 mg is obtained.

Examples 4-12 to 4-19
The corresponding starting material compound (carboxylic acid compound) is used in the same manner as in Example 4-11 to obtain the compounds of Table 4 Examples 4-12 to 4-19.

Examples 5-1 to 5-12
In place of the resin compound described in Reference Example 3 (2), the resin compound obtained in Reference Example 4 was used, and the same procedure as in Examples 4-1 to 4-10 was performed. To obtain a compound of

Examples 5-13 to 5-36
Using the resin compound obtained in Reference Example 4 instead of the resin compound in Reference Example 3 (2), the compounds of Table 5 Examples 5-13 to 5-30 are obtained in the same manner as in Example 4-11. . Moreover, the compound of Table 5- Examples 5-31-5-36 is obtained similarly using the resin compound obtained by the reference example 5 (5) term.

Examples 5-37 to 5-39
A mixture of 500 mg of the resin compound (1.01 mmol / g) obtained in Reference Example 5 (5) and 0.5 M methanesulfonic acid-dioxane / methylene chloride (1/9) is shaken at room temperature for 30 minutes. The resin is filtered and washed with methylene chloride, 10% triethylamine-methylene chloride, methylene chloride, dimethylformamide, dimethylformamide-water (1: 1), tetrahydrofuran, methanol, tetrahydrofuran, methanol and dimethylacetamide. A mixture of the obtained resin, 293 mg of 2-chloro-5-bromopyrimidine and 211 μl of triethylamine is shaken at 55 ° C. for 16 hours. The resin is filtered and washed with dimethylformamide, methylene chloride, 10% triethylamine-methylene chloride, methylene chloride, dimethylformamide, dimethylformamide-water (1: 1), tetrahydrofuran, methanol, tetrahydrofuran, methanol and methylene chloride. The total amount of the resulting resin was treated with trifluoroacetic acid to give (S) -1- [trans-4- (5-bromopyrimidin-2-ylaminomethyl) cyclohexylamino] acetyl-2-cyanopyrrolidine hydrochloride (Table 5 Example 5-37) 61 mg is obtained.

Moreover, the corresponding raw material compounds are used in the same manner to obtain the compounds of Table 5 Examples 5-38 to 5-39.

  Example 6-1

(1) trans-4- (tert-Butoxycarbonylaminomethyl) cyclohexylamine (item (3) in Reference Example 5 described later) 519 mg, 2,4,6-trimethoxybenzaldehyde 446 mg, sodium triacetoxyborohydride 608 A mixture of mg and 11 mL of methylene chloride is stirred at room temperature for 14 hours. The reaction mixture is diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by diol column chromatography [solvent: 0-20% methanol-chloroform]. A mixture of the obtained compound (969 mg), (S) -1-bromoacetyl-2-cyanopyrrolidine 641 mg, diisopropylethylamine 791 μL, and dimethylacetamide 8 mL is stirred at 50 ° C. for 1 hour. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by diol column chromatography [solvent: 50-0% hexane-chloroform] to give (S) -2-cyano-1- [N- (2,4,6-trimethoxyphenylmethyl) -trans There are obtained 834 mg of -4- (tert-butoxycarbonylaminomethyl) cyclohexylamino] acetylpyrrolidine.

  (2) A mixture of 818 mg of the compound obtained in (1) above and 20 mL of 0.5M methanesulfonic acid-dioxane / methylene chloride (1/9) is stirred at room temperature for 2 hours. The reaction mixture is diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give (S) -2-cyano-1- [N- (2,4,6-trimethoxyphenylmethyl) -trans -4- mg of (4- (aminomethyl) cyclohexylamino] acetylpyrrolidine.

  (3) A mixture of the compound obtained in the above (2) 155 mg, 2,5-dichloropyrimidine 104 mg, triethylamine 146 μL, tetrahydrofuran 1 mL, and dimethylformamide 1 mL is stirred at 60 ° C. for 14 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by diol column chromatography [solvent: 0-20% methanol- (33% hexane-chloroform)] to give (S) -2-cyano-1- [N- (2,4,6-tri 104 mg of methoxyphenylmethyl) -trans-4- (5-chloropyrimidin-2-ylaminomethyl) cyclohexylamino] acetylpyrrolidine are obtained.

(4) A mixture of 90 mg of the compound obtained in (3) above and 4 mL of trifluoroacetic acid is stirred at room temperature for 18 hours. After distilling off trifluoroacetic acid under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with chloroform. The extract is dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by diol column chromatography [solvent: 40-0% hexane-chloroform]. The obtained compound is dissolved in chloroform (0.5 mL), 1N hydrochloric acid-ether (0.5 mL) and then ether (2 mL) are added. The precipitated precipitate is washed with ether, and (S) -1- [trans-4- (5-chloropyrimidine-2 -Ilaminomethyl) cyclohexylamino] acetyl-2-cyanopyrrolidine dihydrochloride (Table 6 Example 6-1) 22 mg is obtained.

Examples 6-2 to 6-4
Using the compound obtained in Example 6-1 (2) and the corresponding starting compound, in the same manner as in (3) to (4) of Example 6-1, Table 6 Examples 6-2 to 6- 4 compounds are obtained.

Examples 7-1 to 7-10
Instead of (S) -1-bromoacetyl-2-cyanopyrrolidine, (R) -3-chloroacetyl-4-cyanothiazolidine (a compound of Reference Example 2 described later) is used and treated in the same manner as in Example 1. Thus, the compounds of Table 7 Examples 7-1 to 7-10 are obtained.

Examples 8-1 to 8-8
Except for using (R) -3-chloroacetyl-4-cyanothiazolidine instead of (S) -1-bromoacetyl-2-cyanopyrrolidine, the same as in Example 6-1 (1) to (2). Thus, (R) -4-cyano-3- [N- (2,4,6-trimethoxyphenylmethyl) -trans-4-aminomethylcyclohexylamino] acetylthiazolidine is obtained. Using this compound and the corresponding starting material compound, the compounds of Table 8 Examples 8-1 to 8-8 are obtained in the same manner as in Example 6-1 (3) to (4).
(However, in Examples 8-7 and 8-8, a carboxylic acid compound was used as a starting compound in the step corresponding to Example 6-1 (3), and 1-hydroxybenzotriazole and 1-ethyl-3 were used. The reaction is carried out in the presence of-(3-dimethylaminopropyl) -carbodiimide.)

Reference example 1
(S) -1-bromoacetyl-2-cyanopyrrolidine is obtained by reacting L-prolinamide (commercially available product) and bromoacetyl bromide, followed by dehydration according to the method described in the literature (WO98 / 19998).

Reference example 2
L-thioprolinamide hydrochloride is synthesized according to the method described in the literature (Ashworth et al., Bioorg. Med. Chem. Lett., 6, 2745-2748, 1996). 2.36 ml of chloroacetyl chloride is added to a solution of 5.00 g of L-thioprolinamide hydrochloride and 8.67 ml of triethylamine in 150 ml of dichloromethane under ice cooling, and the mixture is stirred at the same temperature for 1 hour. Add 4.8 ml of pyridine and 8.4 ml of trifluoroacetic anhydride to the reaction mixture, and further stir at room temperature for 1 hour. The reaction solution was washed with 10% aqueous HCl and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was crystallized from ether to obtain 4.82 g of (R) -3-chloroacetyl-4-cyanothiazolidine. Obtained as tan crystals.

  Reference example 3

(1) Resin ((4-formyl-3,5-dimethoxyphenyloxy) methylpolystyrene) [synthesized by the method of Cecile Pegurier et al. (Bioorg. Med. Chem., Vol. 8, pp. 163-171, 2000) A mixture of 14.5 g (1.40 mmol / g), 7.85 g of 4-amino-1-tert-butoxycarbonylpiperidine, 10.71 g of sodium triacetoxyborohydride, and 180 ml of methylene chloride is stirred at room temperature for 18 hours. The resin is collected by filtration, washed with methylene chloride, dimethylformamide-water (1: 1), 10% triethylamine-methylene chloride, dimethylformamide-water (1: 1), methanol, tetrahydrofuran, and methanol, and then dried under reduced pressure. As a result, 16.83 g (1.17 mmol / g) of the resin compound (1) shown in the above figure is obtained.

(2) A mixture of 16.73 g of the resin compound obtained in (1) above, 8.50 g of (S) -1-bromoacetyl-2-cyanopyrrolidine, 6.82 mL of diisopropylethylamine, and 80 ml of dimethylformamide was stirred at 50 ° C. for 18 hours. To do. The resin compound shown in the above figure is obtained by filtering the resin, washing with dimethylformamide, 10% triethylamine-methylene chloride, dimethylformamide-water (1: 1), methanol, tetrahydrofuran, and methanol and then drying under reduced pressure. (2) 19.14 g (1.02 mmol / g) is obtained.

  Reference example 4

To a solution of 30.00 g of 1,4-trans-cyclohexanediamine and 131 ml of 2N hydrochloric acid in 250 ml of ethanol, a solution of 52.13 g of di-tert-butyl dicarbonate in 150 ml of ethanol is added dropwise over 4 hours. The reaction mixture is stirred for 20 hours, concentrated, diluted with aqueous citric acid solution, washed with chloroform, and made alkaline with aqueous sodium hydroxide solution. Extraction with chloroform, drying and concentration yields 22.33 g of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine.
Using this compound and resin ((4-formyl-3,5-dimethoxyphenyloxy) methylpolystyrene), the resin shown in the above figure is treated in the same manner as in the above-mentioned Reference Example 3 (1) to (2). A compound is obtained.

  Reference Example 5

(1) A solution of 10.0 g of trans-4-aminomethylcyclohexanecarboxylic acid, 14.6 g of di-tert-butyl dicarbonate and 11.2 g of sodium bicarbonate in 200 ml of dioxane-water (1: 1) is stirred at room temperature for 72 hours. After adding 50 ml of 10% NaOH aqueous solution and 300 ml of ether to the reaction mixture and separating the organic phase, the aqueous phase is acidified with 10% HCl aqueous solution and extracted with ethyl acetate. The extract is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is washed with isopropyl ether to obtain 15.3 g of trans-4- (tert-butoxycarbonylaminomethyl) cyclohexanecarboxylic acid.

  (2) A solution of the compound obtained in the above (1) (5.15 g), diphenylphosphoryl azide (6.05 g) and triethylamine (3.1 ml) in 100 ml of toluene is heated to reflux for 3 hours, then benzyl alcohol (2.3 ml) is added and the mixture is further heated to reflux overnight. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography [solvent: ethyl acetate-chloroform (1:20)], crystallized from hexane, and N-benzyloxycarbonyl-trans-4- 5.32 g of (tert-butoxycarbonylaminomethyl) cyclohexylamine are obtained.

  (3) A solution of 5.19 g of the compound obtained in the above item (2) and 200 ml of 10% palladium on carbon in ethanol is stirred for 6 hours under a hydrogen atmosphere of 1 atm. The catalyst is filtered off and washed with ethanol, and the filtrate and washings are combined. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography [solvent: chloroform-methanol-concentrated aqueous ammonia (50: 10: 1)] and crystallized from a mixed solvent of isopropyl ether and hexane, trans- 2.55 g of 4- (tert-butoxycarbonylaminomethyl) cyclohexylamine is obtained.

  (4) Compound (2.54 g) obtained in the above (3), resin ((4-formyl-3,5-dimethoxyphenyloxy) methylpolystyrene) (1.43 mmol / g) 4.15 g, sodium triacetoxyborohydride 3.24 A mixture of g and 80 ml of methylene chloride is stirred at room temperature for 20 hours. The resin was filtered off and methylene chloride, dimethylformamide, methylene chloride, 10% triethylamine-methylene chloride, methylene chloride, dimethylformamide, dimethylformamide-water (1: 1), dimethylformamide, methanol, tetrahydrofuran, methanol, tetrahydrofuran, and The resin compound (4) 5.19 g (1.14 mmol / g) shown by the said figure is obtained by drying under reduced pressure after washing | cleaning with methanol.

(5) A mixture of the resin obtained in (4) (1.14 mmol / g) 5.12 g, (S) -1-bromoacetyl-2-cyanopyrrolidine 2.53 g, diisopropylethylamine 2.03 ml, and dimethylformamide 50 ml Stir at ℃ 18 hours. The resin was collected by filtration, washed with dimethylformamide, dimethylformamide-water (1: 1), dimethylformamide, methanol, tetrahydrofuran, methanol, tetrahydrofuran, and methanol, and then dried under reduced pressure to give the resin compound shown in the above figure ( 5) 5.78 g (1.01 mmol / g) are obtained.

  Reference Example 6-1

(1) According to the method described in the literature (JP83-118577), methyl 1,4-dioxaspiro [4.5] decane-8-carboxylate is reacted with methyl iodide in the presence of LDA (lithium diisopropylamide) to give 8-methyl-1, Methyl 4-dioxaspiro [4.5] decane-8-carboxylate (compound (1) in the above figure) is obtained.
[The raw material compound was synthesized according to the methods described in Rosemmund et al. (Chem. Ber., 1975, 108, 1871-1895) and Black et al. (Synthesis, 1981, 829). Use. ]
(2) A mixture of the compound obtained in the above (1) 3.80 g, sodium hydroxide 3.55 g, methanol 16 mL, and water 25 mL is heated to reflux for 2 hours. The reaction mixture is ice-cooled, adjusted to pH 5 with 2N hydrochloric acid and 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure to give 8-methyl-1,4-dioxaspiro [4.5] decane-8-carboxylic acid (compound shown above). (2)) 3.46 g is obtained.

  (3) A mixture of 16.19 g of the compound obtained in (2), 24.51 g of diphenylphosphoryl azide, 9.00 g of triethylamine, and 160 mL of toluene is heated to reflux for 2.5 hours. The reaction mixture is ice-cooled, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. To a solution of the obtained compound in 100 mL of dimethylacetamide, 9.55 g of potassium tert-butoxy is gradually added under ice-cooling, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice water, and the precipitated crystals are collected by filtration, washed with water and dried. 100 mL of an aqueous solution of 30.87 g of p-toluenesulfonic acid hydrate is added to a 100 mL solution of the obtained compound in tetrahydrofuran, and the mixture is stirred at room temperature for 16 hours. Dilute with saturated aqueous sodium bicarbonate and extract with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 10.41 g of 4-tert-butoxycarbonylamino-4-methylcyclohexanone (compound (3) in the above figure). obtain.

  (4) A mixture of 10.41 g of the compound obtained in the above (3), 11.01 g of sodium triacetoxyborohydride, 5.10 mL of benzylamine, and 150 mL of methylene chloride is stirred at room temperature for 16 hours. Dilute with saturated aqueous sodium bicarbonate and extract with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. Add 3.32 g of p-toluenesulfonic acid hydrate and then 160 mL of ether to a 15 mL solution of the compound obtained in methanol. The precipitate was collected by filtration, washed with ether and dried, and N-benzyl-t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine / p-toluenesulfonate (compound (4 in the above figure)) )) Obtain 7.49 g.

(5) A mixture of the compound obtained in (4) (16.63 g), 10% palladium carbon (5.0 g), and methanol (400 mL) is stirred under a hydrogen atmosphere (1 atm) for 24 hours. 10% palladium on carbon is filtered off and the filtrate is concentrated. The obtained residue was dissolved in a mixture of 50 mL of 10% aqueous sodium hydroxide and 300 mL of ether, the ether layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
6.87 g of t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound (5) in the above figure) is obtained.

(6) The filtrate of the step (4) is treated with an aqueous sodium hydroxide solution and extracted with chloroform. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to NH-silica gel column chromatography (solvent: hexane-ethyl acetate (30: 1 → 3: 1)) to give N-benzyl-c-4-tert-butoxycarbonylamino-4-methyl-r- 1-cyclohexylamine is obtained. Then, this is treated in the same manner as in the above section (5) to obtain c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound (6) in the above figure).

Reference Example 6-2
Except for using benzyloxymethyl chloride in place of methyl iodide in the step (1) of Reference Example 6-1 in the same manner as in (1) to (5) or (6) of Reference Example 6-1, t-4-tert-butoxycarbonylamino-4-hydroxylmethyl-r-1-cyclohexylamine or c-4-tert-butoxycarbonylamino-4-hydroxylmethyl-r-1-cyclohexylamine is obtained.

Further, in the step (1) of Reference Example 6-1 except that methoxymethyl chloride is used instead of methyl iodide, the same as (1) to (5) or (6) of Reference Example 6-1 T-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine or c-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine.

Reference Example 6-3
(1) N-tert-butoxycarbonyl-4-ethoxycarbonylpiperidine (synthesized according to the method described in Gilligan et al. (J. Med. Chem., 37, 364-370, 1994)) and N-tert-butoxycarbonyl-4-carboxyl was treated with methoxymethyl chloride in the same manner as in item (1) of Reference Example 6-1 and then in the same manner as in item (2) of Reference Example 6-1. -4-Methoxymethylpiperidine is obtained. N-tert-butoxycarbonyl-4-benzyloxycarbonylamino-4 was treated in the same manner as in Reference Example 6-1 (3) except that this compound was used and benzyl alcohol was used instead of tert-butoxypotassium. -Obtain methoxymethylpiperidine.

(2) A mixture of 9.4 g of the compound obtained in (1) above, 1.9 g of 10% palladium carbon, and 190 mL of methanol is stirred under a hydrogen atmosphere (1 atm) for 2 hours. 10% Palladium carbon is removed by filtration, and the filtrate is concentrated to obtain 6.02 g of 4-amino-N-tert-butoxycarbonyl-4-methoxymethylpiperidine.
Subsequently, the protecting group (tert-butoxycarbonyl group) is removed by treating the compound with an acid to obtain 4-amino-4-methoxymethylpiperidine.

Reference Example 6-4
N-tert-butoxycarbonyl-4-benzyloxycarbonylamino-4-methoxymethylpiperidine [compound obtained in paragraph (1) of Reference Example 6-3] A mixture of 3.78 g and 38 ml of concentrated hydrochloric acid is refluxed for 3 days. After concentrating the reaction mixture, the residue is washed with tetrahydrofuran to obtain 2.8 g of 4-amino-4-hydroxymethylpiperidine dihydrochloride.

Reference Examples 7-1 to 7-7
(1) To a 200 ml tetrahydrofuran solution of 16 g of 4-amino-1-tert-butoxycarbonylpiperidine and 17.5 g of N-carboethoxyphthalimide, add 16.7 ml of triethylamine under ice cooling, and stir at room temperature for 4 hours. Add water to the reaction mixture and extract with ethyl acetate. The extract is washed with a saturated aqueous sodium bicarbonate solution, water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is suspended in ether-hexane, and the crystals are collected by filtration to obtain 25.7 g of 2- (1-tert-butoxycarbonyl-4-piperidyl) isoindoline-1,3-dione.
A suspension of 25.5 g of this compound in 170 ml of 15% hydrochloric acid-ethanol is stirred at room temperature for 5 hours. The precipitate is filtered to obtain 16.0 g of 2- (4-piperidyl) isoindoline-1,3-dione hydrochloride.

(2) Add 3.13 ml of triethylamine to a solution of 1.57 g of the compound obtained in (1) above and 644 mg of 2-chloropyrimidine in 3 ml of tetrahydrofuran in 15 ml-N, N-dimethylacetamide, and stir at 50 ° C. for 12 hours. After cooling, a saturated aqueous sodium bicarbonate solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is suspended in ether-hexane, and the crystals are collected by filtration to obtain 1.50 g of 2- [1- (2-pyrimidinyl) -4-piperidyl] isoindoline-1,3-dione. (Yield: 87%)
Subsequently, 0.25 ml of hydrazine monohydrate is added to a suspension of 800 mg of this compound in 15 ml of ethanol and refluxed for 2 hours. After cooling, the insoluble material is filtered off and the solvent is distilled off under reduced pressure. The residue was purified by NH silica gel flash column chromatography [solvent: chloroform-methanol (500: 1)] to obtain 417 mg of 4-amino-1- (2-pyrimidinyl) piperidine (Table 9 Reference Example 7-1). obtain.
Moreover, the compound of Table 9 reference examples 7-2 to 7-7 is obtained in the same manner as described above using the corresponding starting material compound.

Reference examples 8-1 to 8-7
A suspension of 260 mg of 4-amino-4-methylpiperidine [synthesized by the method described in US.5821240], 237 mg of 2-chloropyrimidine, and 858 mg of potassium carbonate in 2 ml of ethanol is stirred at 50 ° C. for 12 hours. The reaction mixture is poured into water and extracted with chloroform. The extract is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography [solvent: chloroform-methanol-aqueous ammonia (300: 10: 1)] to give 4-amino-4-methyl-N- (2-pyrimidinyl) piperidine (see Table 9). Example 8-1) 259 mg is obtained.
In addition, using the corresponding starting material compounds, the compounds of Table 9 Reference Examples 8-2 to 8-7 are obtained in the same manner as described above.

Reference examples 8-8 to 8-21
4-amino-4-methoxymethylpiperidine (Reference Example 6-3 (2)) and the corresponding starting material compound were treated in the same manner as in Reference Example 8-1, and Table 9 Reference Examples 8-8 to 8- 15 compounds are obtained.
Further, 4-amino-4-hydroxymethylpiperidine dihydrochloride (Reference Example 6-4) and the corresponding starting material compound were treated in the same manner to obtain the compounds of Table 9 Reference Examples 8-16 to 8-21. .

Reference Examples 8-22 to 8-23
Triethylamine was added to a suspension of 1.00 g of t-4-tert-butoxycarbonylamino-4-hydroxymethyl-r-1-cyclohexylamine (Reference Example 6-2) and 897 mg of N-carboethoxyphthalimide in 15 ml of terahydrofuran. Add 0.86 ml and heat at 50 ° C. for 5 hours. Add water to the reaction mixture and extract with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-tert-butoxycarbonyl-1-hydroxymethyl-t-4-phthalimide- 1.47 g of r-1-cyclohexylamine are obtained. To a solution of 1.44 g of this compound in 10 ml of dioxane, 10 ml of 4N hydrochloric acid / dioxane is added and stirred at room temperature for 3 hours. The reaction mixture is diluted with diethyl ether and the crystals are collected by filtration. The obtained crystals are washed with diethyl ether to obtain 1.03 g of 1-hydroxymethyl-t-4-phthalimido-r-1-cyclohexylamine (Table 9 Reference Example 8-22).

Moreover, it carries out similarly to the above, and the compound of Table 9 reference examples 8-23 is obtained.

Reference Example 8-24
(1) N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine
A solution of 500 mg, 2-bromomethylbenzoic acid ethyl ester 623 mg, triethylamine 354 mg in toluene 15 ml-chloroform 1.5 ml is heated at 100 ° C. for 5 hours. After cooling, add water and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel flash column chromatography to give 400 mg of N-tert-butoxycarbonyl-trans-4- (1-oxo-2-isoindolinyl) cyclohexylamine.

(2) To a solution of 380 mg of the compound obtained in (1) above in 10 ml of dioxane, 10 ml of 4 N HCl / dioxane is added and stirred at room temperature for 5 hours. After concentrating the reaction solution, the residue was triturated with diethyl ether to obtain 298 mg of trans-4- (1-oxo-2-isoindolinyl) cyclohexylamine hydrochloride (Table 9 Reference Example 8-24). .

Reference examples 8-25 to 8-31
A solution of 500 mg of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine and 540 mg of 3-nitrophthalic anhydride in 15 ml of chloroform is refluxed for 1 hour. After cooling, add 756 mg of carbonyldiimidazole and stir at room temperature for 15 hours. Add water to the reaction mixture and extract with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel flash column chromatography to give 900 mg of N-tert-butoxycarbonyl-trans-4- (1,3-dioxo-4-nitro-2-isoindolinyl) cyclohexylamine.
To a suspension of 885 mg of this compound in 10 ml of dioxane, 10 ml of 4 N HCl in dioxane is added and stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was triturated with diethyl ether to give trans-4- (1,3-dioxo-4-nitro-2-isoindolinyl) cyclohexylamine hydrochloride (Table 9 Reference Example 8-25). ) Obtain 700 mg.
Moreover, the corresponding raw material compounds are used in the same manner to obtain the compounds of Table 9 Reference Examples 8-26 to 8-31.

Reference Example 8-32
To a solution of 1.5 g of trimellitic chloride anhydride and 0.303 ml of methanol in 20 ml of methylene chloride is added 1.49 ml of triethylamine under ice cooling, and the mixture is stirred at room temperature for 3 hours. Add water to the reaction mixture and extract with chloroform. The organic layer is dried over sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.81 g of 4-methoxycarbonylphthalic anhydride. Using this compound as a raw material instead of 3-nitrophthalic anhydride, trans-4- (1,3-dioxo-5-methoxycarbonyl-2-isoindolinyl) cyclohexylamine hydrochloride was prepared in the same manner as in Reference Example 8-25. (Table 9 Reference Example 8-32) is obtained.

Reference examples 8-33 to 8-34
Add 354 mg of pyrrolidine and 577 mg of triethylamine to a solution of 1.0 g of trimellitic chloride anhydride in 10 ml of methylene chloride, and stir at room temperature for 2 hours. Add water to the reaction mixture and extract with chloroform. The organic layer is dried over sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.09 g of 4- (1-pyrrolidinyl) carbonylphthalic anhydride. This compound was used as a raw material instead of 3-nitrophthalic anhydride and treated in the same manner as in Reference Example 8-25 to give trans-4- [1,3-dioxo-5- (1-pyrrolidinyl) carbonyl-2-isoindolinyl. ] Cyclohexylamine hydrochloride (Table 9 Reference Example 8-33) is obtained.
Moreover, the compound of Table 9 Reference Example 8-34 is obtained like the above.

Reference Example 8-35
(1) Add 5.92 ml of thionyl chloride to a suspension of 15.00 g of trans- (4-benzyloxycarbonylamino) cyclohexane-1-carboxylic acid in 150 ml of methylene chloride, and heat to reflux for 4 hours. The reaction solution is concentrated under reduced pressure, and methylene chloride is added and concentrated under reduced pressure twice to obtain trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid chloride.

  (2) The compound obtained in (1) is made into a solution of 70 ml of methylene chloride, and an aqueous solution of concentrated aqueous ammonia 60 ml-water 120 ml is added dropwise under ice cooling. After stirring at room temperature for 30 minutes, the deposited precipitate was collected by filtration and washed with water, 2-propanol, and isopropyl ether to obtain 14.17 g of trans-4- (benzyloxycarbonylamino) -1-cyclohexanecarboxamide. obtain.

  (3) Thionyl chloride (5.54 ml) is added to a suspension of 7.00 g of the compound obtained in (2) above in 140 ml of acetonitrile, and the mixture is heated to reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, then acetonitrile was added, and further concentrated under reduced pressure, diisopropyl ether was added to the resulting solid, and filtered to obtain trans-4- (benzyloxycarbonylamino) -1-cyclohexanecarbonitrile 6.14 g Get.

  (4) Compound obtained in the above item (3) 1. Into a suspension of 1.20 g of ethanol in 24 ml of ethanol, hydrogen chloride gas is added under ice-salt cooling until the starting compound dissolves once and precipitates again. . The reaction is stirred at room temperature for 14 hours and concentrated in vacuo. Saturated aqueous sodium hydrogen carbonate solution is added to the resulting residue, and the mixture is extracted twice with chloroform. The extract is dried over sodium sulfate and concentrated under reduced pressure to obtain 0.93 g of trans-4- (benzyloxycarbonylamino) cyclohexane-1-imidic acid ethyl ester.

(5) 163 mg of the compound obtained in the above (4) in a solution of 929 mg of ethanol 6 ml-water 1 ml is added with ammonium chloride 163 mg and stirred at room temperature for 9 hours. The reaction solution is concentrated under reduced pressure, and toluene is added and concentrated under reduced pressure twice. By adding ethanol 0.3 ml-ether 20 ml to the resulting solid residue and filtering it,
Trans-4- (benzyloxycarbonylamino) -1-cyclohexanecarboxamidine hydrochloride 859 mg is obtained.

  (6) According to the method of Schmidt. Et al. (Schmidt. HW et al., J. Hetrocycl Chem., 24, 1305, 1987) using the compound (500 mg) obtained in the above (5) as a starting material. Reaction with ethoxyethylenemalononitrile yields trans-1- (benzyloxycarbonylamino) -4- (4-amino-5-cyanopyrimidin-2-yl) cyclohexane (186 mg).

(7) To a suspension of 174 mg of the compound obtained in (6) above in 7 ml of acetonitrile, add 282 μL of trimethylsilyl iodide under ice-cooling and stir at room temperature for 1 hour. Ice water is added to the reaction mixture, washed with chloroform, saturated with potassium carbonate in the aqueous layer, and extracted three times with chloroform. The extract is dried over sodium sulfate and concentrated under reduced pressure to obtain 105 mg of trans-4- (4-amino-5-cyanopyrimidin-2-yl) cyclohexylamine (Table 9 Reference Example 8-35).

Reference Example 8-36
trans-4- (benzyloxycarbonylamino) -1-cyclohexanecarboxamidine hydrochloride (compound of Reference Example 8-35 (5)) (348 mg) was used as a starting material, and the method of Libman et al. (J. Chem Soc., 2305, 1952) to give trans-1-benzyloxycarbonylamino-4- (4,6-dimethylpyrimidin-2-yl) cyclohexane (220 mg).
This compound (205 mg) was treated with trimethylsilyl iodide in the same manner as in (7) of Reference Example 8-35 to give trans-4- (4,6-dimethylpyrimidin-2-yl) cyclohexylamine (Table 9 Reference Example 8-36) (129 mg) is obtained.

Reference examples 8-37 to 8-39
N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine 500 mg, 1,4-dichlorobutane 326 mg, potassium carbonate 805 mg, sodium iodide 70 mg, and ethanol-water (8 ml-2 ml) The mixture is stirred at 90 ° C. for 12 days. Add water to the reaction mixture and extract with chloroform. The extract is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol-aqueous ammonia = 100/5 / 0.5 to 100/10 / 0.5) to give N-tert-butoxycarbonyl-trans-4- ( 453 mg of 1-pyrrolidinyl) cyclohexylamine is obtained.
This compound is deprotected under acidic conditions to obtain trans-4- (1-pyrrolidinyl) cyclohexylamine (Table 9 Reference Example 8-37).
Moreover, it carries out similarly to the above, and the compound of Table 9 referential examples 8-38 to 8-39 is obtained.

Reference Example 8-40
trans-4- (tert-Butoxycarbonylamino) cyclohexanecarboxylic acid 10g and 2-chloro-3-aminopyridine 7.93g, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 10.2g, 4-dimethylamino A mixture of 6.5 g of pyridine and 180 mL of N, N-dimethylformamide is stirred at room temperature for 15 hours. The reaction mixture is made alkaline by adding aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain trans-4-tert-butoxycarbonylamino-N- (2-chloro-3-pyridyl) cyclohexanecarboxamide. Get.

Reference Example 8-41
trans-4-tert-Butoxycarbonylamino-N- (2-chloro-3-pyridyl) cyclohexanecarboxamide (Reference Example 8-40) 500 mg, 2,4-bis (4-methoxyphenyl) -1,3-dithio A mixture of 858 mg of 2,4-diphosphetane-2,4-disulfide and 10 mL of tetrahydrofuran is stirred at 60 degrees for 18 hours. The insoluble material is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography [solvent: chloroform-methanol 50: 1].
Suspend the resulting crude crystals in 5 mL of ethanol, add 10 mL of 4N-hydrochloric ethanol solution, and heat to reflux for 1.5 hours. After distilling off ethanol under reduced pressure, the residue is dissolved in water and washed with ether. The aqueous layer is made alkaline by adding potassium carbonate, and then extracted with chloroform. The extract was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain trans-4- (thiazolo [5,4-b] pyridin-2-yl) cyclohexylamine (Table 9 Reference Example 8-41) 195 mg is obtained.

Reference Example 8-42
trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid,
2-Aminophenol is treated in the same manner as in Reference Example 8-40 to obtain trans-4-benzyloxycarbonylamino-N- (2-hydroxyphenyl) cyclohexanecarboxamide.
A mixture of 300 mg of this compound, 286 mg of pyridinium-p-toluenesulfonate, 6 mL of methanol, and 6 mL of 1,2-dichloromethane is heated to reflux for 48 hours. Water and ethyl acetate are added to the reaction solution, and the organic layer is separated. The extract is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel flash column chromatography [solvent: chloroform].
A mixture of 150 mg of this compound, 30 mg of 10% palladium on carbon, and 7.5 mL of methanol is stirred at room temperature for 2 hours under a hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated to obtain 63 mg of trans-4- (benzo [d] [1,3] oxazol-2-yl) cyclohexylamine (Table 9, Reference Example 8-42).

Reference Example 8-43
(1) 0.74 g of sodium borohydride is suspended in 35 ml of tetrahydrofuran, and boron trifluoride diethyl complex is added thereto under ice cooling. After stirring for 30 minutes under ice cooling, 90 ml of tetrahydrofuran solution containing 3.60 g of trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid is added under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture is poured into ice water and extracted with chloroform. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is suspended in diisopropyl ether and collected by filtration to give N-benzyloxycarbonyl-trans-4- (hydroxymethyl) cyclohexylamine.

  (2) Add 0.81 ml of oxalyl chloride to a solution of 1.95 g of the compound obtained in (1) above and 1.45 g of dimethyl sulfoxide in 35 ml of dichloromethane at -78 ° C. Stir at -45 ° C for 2 hours, cool to -78 ° C, add 562 g of triethylamine in 5 ml of dichloromethane, warm to room temperature, and stir for 2 hours. The reaction mixture is washed with water, aqueous hydrochloric acid and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography (solvent: hexane-ethyl acetate = 4: 1) to obtain trans-4- (benzyloxycarbonylamino) cyclohexanecarbaldehyde.

(3) To a 4 mL solution of thionyl chloride in 512 mL of dichloromethane is added dropwise 568 μL of pyridine in 4 mL of dichloromethane under ice-cooling, and then 1.53 g of the compound obtained in the above (2) is added. The reaction mixture is stirred at room temperature for 1 hour, then 715 mg 2-aminobenzylamine and then 961 mg sodium acetate in 15 mL water are added. After stirring the reaction mixture at room temperature for 1 hour, dichloromethane is distilled off under reduced pressure. The residual mixture is made alkaline with 10% aqueous sodium hydroxide solution, stirred at room temperature for 30 minutes, and extracted with chloroform. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. A mixture of the obtained residue and 2.66 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 75 mL of toluene is stirred at room temperature for 14 hours. The reaction mixture is diluted with chloroform, washed successively with 10% aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel flash column chromatography [solvent: chloroform], the obtained residue is suspended in a mixed solvent of isopropyl ether-hexane, and the deposited precipitate is collected by filtration.
362 mg of this compound is dissolved in 7 mL of acetonitrile. Under ice-cooling, 427 μL of trimethylsilyl iodide is added dropwise and stirred at room temperature for 15 minutes. Methanol and water are added to the reaction mixture, followed by washing with chloroform. The aqueous layer is made alkaline by adding potassium carbonate, and then extracted with chloroform. The extract was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain trans-4- (quinazolin-2-yl) cyclohexylamine (Table 9 Reference Example 8-43) 220. Get mg.

Reference Example 8-44
trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid,
3- (aminomethylcarbonyl) pyridine was treated in the same manner as in Reference Example 8-40,
trans-4-Benzyloxycarbonylamino-N- (3-pyridylcarbonylmethyl) cyclohexanecarboxamide is obtained.
A mixture of 600 mg of this compound, 283 μL of phosphorus oxychloride, and 9 mL of N, N-dimethylformamide is stirred at room temperature for 1 hour. The reaction mixture is poured into water, made alkaline with sodium bicarbonate water, and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is suspended in diethyl ether, and the deposited precipitate is collected by filtration.
A mixture of 350 mg of this compound, 70 mg of 10% palladium carbon, and 17.5 mL of methanol is stirred at room temperature for 20 hours under a hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated to obtain 211 mg of trans-4- [5- (3-pyridyl) -1,3-oxazol-2-yl] cyclohexylamine (Table 9 Reference Example 8-44). obtain.

Reference Examples 8-45 to 8-56
4-tert-butoxycarbonylamino-4-methylcyclohexanone (compound (3) of Reference Example 6-1) and the corresponding starting material compound (amine compound) in the presence of sodium triacetoxyborohydride for 16 hours at room temperature. After reacting with stirring, acid treatment is performed to remove the protecting group (t-butoxycarbonyl group) to obtain compounds in Table 9 Reference Examples 8-45 to 8-56.

Reference Examples 8-57 to 8-59
300 mg of t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound obtained in item (5) of Reference Example 6-1) mixed with 2 ml of tetrahydrofuran and 0.5 ml of formalin 418 mg of sodium triacetoxyborohydride is added to the product dissolved in, and stirred at room temperature for 16 hours, followed by addition of 10% aqueous sodium hydroxide solution, extraction with chloroform, and drying over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography [solvent: chloroform-methanol-aqueous ammonia (50: 1: 0.1 → 10: 1: 0.1)].
This compound was stirred in 4N hydrochloric acid-dioxane (2 ml) and ethanol (2 ml) for 8 hours. The reaction solution was concentrated, 10% aqueous sodium hydroxide solution was added, extracted with chloroform, dried over sodium sulfate, and the solvent was reduced in pressure. By distilling off, 55 mg of t-4-dimethylamino-1-methyl-r-1-cyclohexylamine (Table 9 Reference Example 8-57) is obtained.
Similarly, the compounds of Table 9 Reference Examples 8-58 to 8-59 are obtained.

Reference examples 9-1 to 9-3
To a solution of 1.04 g of triphosgene in 10 ml of methylene chloride, 1.59 g of N-ethoxycarbonylpiperazine and 1.4 ml of triethylamine in 10 ml of methylene chloride are added under ice-cooling, and the mixture is stirred for 15 minutes. To this is added a solution of 1.00 g of 4-tert-butoxycarbonylaminopiperidine and 0.77 ml of triethylamine in 10 ml of methylene chloride under ice-cooling, and the mixture is stirred overnight at room temperature. The reaction mixture is poured into ice water and extracted with chloroform. The extract is washed with saturated brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel flash column chromatography [solvent; ethyl acetate: hexane = 4: 1] to obtain 0.94 g of 4-tert-butoxycarbonylamino-1- (4-ethoxycarbonyl-1-piperazinyl) carbonylpiperidine.
Dissolve 0.60 g of this compound in 6 ml of methylene chloride, add 2 ml of trifluoroacetic acid and stir at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel flash column chromatography [solvent; chloroform: methanol = 100: 1]
0.42 g of 4-amino-1- (4-ethoxycarbonyl-1-piperazinyl) carbonylpiperidine (Table 10 Reference Example 9-1) is obtained.
Further, 4-tert-butoxycarbonylaminopiperidine and the corresponding starting material compound are used in the same manner as described above to obtain the compounds of Table 10 Reference Examples 9-2 to 9-3.

Reference examples 9-4 to 9-5
(1) Add N-nitrosomethylurea dropwise to a suspension of aqueous potassium hydroxide (4 g KOH / 10 ml water) and 27 mL of ether under ice cooling. After completion of the dropwise addition, the ether layer of the reaction solution is collected, potassium hydroxide is added, and the mixture is left in the refrigerator for 3 hours. To the ether solution of diazomethane, 2.00 g of trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid chloride (the compound obtained in Reference Example 8-35 (1)) is gradually added and stirred at room temperature for 2 hours. The precipitated crystals are collected by filtration and washed with ether to obtain 1.63 g of N-benzyloxycarbonyl-trans-4- (diazoacetyl) cyclohexylamine.

(2) Add an aqueous solution of morpholine and silver nitrate (100 mg / 1 ml) to a suspension of 800 mg of the compound obtained in (1) in dioxane (8 ml) and stir at room temperature for 1 hour and then at 60 ° C. for 30 minutes. . The reaction mixture is allowed to cool to room temperature, water is added, and the mixture is extracted with ethyl acetate. The extract is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is suspended in ether, and the deposited precipitate is collected by filtration to obtain 741 mg of N-benzyloxycarbonyl-trans-4- (morpholinocarbonylmethyl) cyclohexylamine.
A suspension of this compound (350 mg) and 10% palladium carbon 70 mg in 4 ml of methanol is stirred in a hydrogen atmosphere at room temperature and normal pressure for 3 hours. The catalyst is removed by filtration, and the filtrate is concentrated to obtain trans-4- (morpholinocarbonylmethyl) cyclohexylamine (Table 10 Reference Example 9-4).

(3) To a solution of 1.00 g of the compound obtained in (1) above in 10 ml of methylene chloride is added 10 ml of 1N hydrochloric acid ether solution under ice cooling, and the mixture is stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution is added to the reaction mixture, and the mixture is extracted with chloroform. The extract is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give N-benzyloxycarbonyl-trans-4- (chloroacetyl) cyclohexylamine.
A mixed solution of this compound (400 mg), 1.12 g of morpholine and 6 ml of methylene chloride is stirred at room temperature overnight. Add water to the reaction mixture and extract with chloroform. The extract is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is suspended in ether, and the deposited precipitate is collected by filtration to obtain 417 mg of N-benzyloxycarbonyl-trans-4- (morpholinomethylcarbonyl) cyclohexylamine.
A suspension of this compound and 10% palladium on carbon (72 mg) in methanol (4 ml) is stirred in a hydrogen atmosphere at room temperature and normal pressure for 1 hour. By filtering off the catalyst and concentrating the filtrate,
trans-4- (morpholinomethylcarbonyl) cyclohexylamine (Table 10 Reference Example 9-5) is obtained.

Reference examples 9-6 to 9-7
According to the method described in the literature (Johnston et al., J. Med. Chem., 1971, Vol. 14, pp. 600-614), ethyl trans-4-aminocyclohexanecarboxylate / hydrochloride (Reference Example 9-6) and Ethyl cis-4-aminocyclohexanecarboxylate · hydrochloride (Reference Example 9-7) is synthesized.

Reference Examples 9-8 to 9-12
To a solution of trans-4- (tert-butoxycarbonylamino) cyclohexanol (1.0 g) and benzyl bromide (873 mg) in tetrahydrofuran (6 mL) was gradually added 60% sodium hydride (204 mg), and dimethyl sulfoxide (0.5 mL) was added. For 2 hours. The reaction mixture is poured into water and extracted with chloroform. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography [solvent: hexane-ethyl acetate (4: 1)], and the obtained powder crystals were suspended in an ethyl acetate-hexane mixed solution and collected by filtration to obtain trans-1-tert- Butoxycarbonylamino-4- (benzyloxy) cyclohexane is obtained.
By adding a 2 N hydrochloric acid-dioxane solution to an ethanol suspension of this compound and deprotecting by stirring at room temperature for 18 hours, trans-4- (benzyloxy) cyclohexylamine hydrochloride (Reference Example 9-8) Get.
In addition, using the corresponding starting material compounds, the compounds of Table 10 Reference Examples 9-9 to 9-12 are obtained in the same manner as described above.

Reference Example 9-13
204 mg of N-tert-butoxycarbonyl-trans-4- (2-propen-1-yloxy) cyclohexylamine (the compound of Reference Example 9-11) is dissolved in 10 ml of methanol. Add 44 mg of 10% palladium on carbon and stir at room temperature for 2 days under hydrogen atmosphere at normal pressure. After removing the catalyst by filtration, the solvent is distilled off and the residue is stirred in 2 ml of trifluoroacetic acid for 3 hours. The solvent was distilled off, 10% aqueous sodium hydroxide solution was added to the residue, the mixture was extracted with chloroform and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain trans-4- (propoxy) cyclohexylamine (Table 10). Reference Example 9-13) 102 mg is obtained.

Reference Examples 9-14 to 9-29
(1) Suspend 9.33 g of sodium borohydride in 200 ml of tetrahydrofuran, and add boron trifluoride diethyl complex under ice cooling. After stirring for 30 minutes under ice cooling, a solution of 40 g of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid in 150 ml of tetrahydrofuran is added under ice cooling. After stirring at room temperature for 4 hours, the reaction mixture is poured into ice water and extracted with chloroform. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to obtain 20 g of N-tert-butoxycarbonyl-trans-4- (hydroxymethyl) cyclohexylamine.
(2) Using the compound obtained in (1) and the corresponding starting material compound, the compounds of Table 10 Reference Examples 9-14 to 9-29 are obtained in the same manner as in Reference Example 9-8.

Reference examples 9-30 to 9-33
(1) To a suspension of trans-4- (tert-butoxycarbonylamino) cyclohexanol in 5.00 g of methylene chloride, add 4.86 ml of triethylamine and 3.09 g of methanesulfonyl chloride at 0 ° C. and stir for 10 minutes. Add water to the reaction mixture and extract with ethyl acetate. The extract is washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is suspended in a mixed solvent of ethyl acetate-isopropyl ether and collected by filtration to obtain 6.19 g of trans-4-tert-butoxycarbonylaminocyclohexyl methanesulfonate.

(2) To a solution of 2-mercaptopyridine-5-carbonitrile in 10 ml of dimethylformamide, add 0.818 g of 60% sodium hydride under ice cooling and stir at room temperature for 1 hour. To this was added 2.00 g of the compound obtained in (1) above, and the mixture was stirred at room temperature overnight and at 80 ° C. for 8 hours, and then allowed to cool to room temperature. Water and ethyl acetate are added to the reaction solution, and the organic layer is separated. The extract is washed with an aqueous sodium hydroxide solution, water and saturated brine in that order, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel flash column chromatography [solvent: ethyl acetate hexane (1: 6)] to obtain 0.977 g of cis-1-tert-butoxycarbonylamino-4- (5-cyano-2-pyridylthio) cyclohexane.
0.977 g of this compound is dissolved in chloroform, 4 ml of 4N-dioxane hydrochloride solution is added, and the mixture is stirred at room temperature for 4 hours. A small amount of methanol is added to the reaction solution to crystallize the desired product, and then the solvent is concentrated to dryness. The residue is suspended in a mixed solvent of methanol: diisopropyl ether and collected by filtration to obtain 0.787 g of cis-4- (5-cyano-2-pyridylthio) cyclohexylamine (Table 10 Reference Example 9-30).
In addition, using the corresponding starting material compounds, the compounds of Table 10 Reference Examples 9-31 to 9-33 are obtained in the same manner as described above.

Reference Example 10-1
(1) To a suspension obtained by adding 42.8 g of 5-nitroisoindoline to an aqueous potassium carbonate solution (108 g of potassium carbonate, 200 ml of water), a solution of 31.2 ml of chloroacetyl chloride in 200 ml of ethyl acetate was dropped at 0 ° C. over 1 hour. To do. After stirring at 0 ° C. for a further 45 minutes, the precipitate is collected by filtration. The obtained solid is treated with activated carbon in ethyl acetate and then recrystallized to obtain 2-chloroacetyl-5-nitroisoindoline.

(2) Stir 1.21 g of the compound obtained in (1) above, 1.07 g of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine and 1.39 g of potassium carbonate in 10 ml of N, N-dimethylformamide at room temperature for 20 hours. To do. The reaction solution is poured into water, and the precipitated solid is collected by filtration, washed with water, dried and then purified by silica gel column chromatography (solvent, chloroform-methanol = 98: 2-95: 5) to give N-tert-butoxycarbonyl- trans-4-[(5-Nitro-2-isoindolinyl) carbonylmethylamino] cyclohexylamine is obtained. 284 mg of this compound is dissolved in 3 ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, and the residue is basified with 10% sodium hydroxide and extracted with chloroform. The extract is dried over sodium sulfate and concentrated under reduced pressure to obtain trans-4-[(5-nitro-2-isoindolinyl) carbonylmethylamino] cyclohexylamine (Table 11 Reference Example 10-1).

Reference Examples 10-2 to 10-13
1 g of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine, 632 mg of 3-pyridinecarboxylic acid, 1.07 g of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, and 757 mg of 1-hydroxybenzotriazole Of N, N-dimethylformamide is stirred for 24 hours at room temperature. Saturated aqueous sodium hydrogen carbonate is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is washed with diethyl ether to give N-tert-butoxycarbonyl-trans-4- (3-pyridylcarbonylamino) cyclohexylamine. A mixture of 1.27 g of this compound and 13 ml of 15% hydrochloric acid-ethanol solution is stirred and stirred at 50 ° C. for 2 hours. After cooling, the precipitate is filtered and washed with diethyl ether to obtain 1.12 g of trans-4- (3-pyridylcarbonylamino) cyclohexylamine dihydrochloride (Table 11 Reference Example 10-2).
Moreover, the compound of Table 11 reference examples 10-3 to 10-4 is obtained in the same manner using the corresponding raw material compounds.

Also, using t- or c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound of Reference Example 6-1 (5) or (6)) and the corresponding starting material compound, Similarly, the compounds of Table 11 Reference Examples 10-5 to 10-10 are obtained. (However, the resulting hydrochloride is treated with an aqueous potassium carbonate solution to form a free form.)
Further, using t- or c-4-tert-butoxycarbonylamino-4-hydroxymethyl-r-1-cyclohexylamine (Reference Example 6-2) and the corresponding starting compound, Table 11 Reference Example 10- 11 to 10-13 compounds are obtained.

Reference examples 10-14 to 10-17
(1) To a solution of 16.93 g of 4- (tert-butoxycarbonylamino) cyclohexanone and 10.55 ml of N-methylbenzylamine in 160 ml of methylene chloride, 19.08 g of sodium triacetoxyborohydride was added with ice cooling, followed by stirring at room temperature for 14 hours. To do. The reaction is diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is suspended in hexane and collected by filtration. The mother liquor was concentrated, the residue was purified by NH-silica gel chromatography, [solvent: hexane-ethyl acetate (97: 3-83: 17)], and the residue was suspended in hexane and collected by filtration. In combination with the one collected by filtration, 13.55 g of N′-benzyl-N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine is obtained.
A suspension of 13.53 g of this compound and 2.00 g of palladium hydroxide-carbon in methanol is catalytically hydrogenated at atmospheric pressure and room temperature for 5 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to obtain 9.93 g of N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine.

(2) 500 mg of the compound obtained in the above (1), 326 mg of 2-pyrazinecarboxylic acid,
1-hydroxybenzotriazole 355 mg, O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate 997 mg, N-methylmorpholine 578 μl, and N, N-dimethyl A mixture of 11 ml of formamide is stirred at room temperature for 14 hours. Water and then saturated aqueous sodium hydrogen carbonate solution are added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure.
The obtained residue is suspended in diisopropyl ether and collected by filtration to obtain N-tert-butoxycarbonyl-N′-methyl-N ′-(2-pyrazinylcarbonyl) -trans-1,4-cyclohexanediamine. .
Next, 420 mg of this compound is dissolved in 6 ml of dioxane, 5 ml of 4N hydrochloric acid-dioxane is added, and the mixture is stirred at room temperature for 15 hours. The reaction solution is diluted with ether, and the deposited precipitate is collected by filtration and washed with ether to obtain a powder. An aqueous solution obtained by dissolving the obtained powder in water is saturated with potassium carbonate, and extracted with chloroform. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methyl-N- (2-pyrazinylcarbonyl) -trans-1,4-cyclohexanediamine (Table 11 Reference Example 10-14). Get.
Further, the compounds of Reference Examples 10-15 to 10-17 in Table 11 are obtained in the same manner as described above using the compound obtained in (1) and the corresponding raw material compound (carboxylic acid compound).

Reference Examples 10-18 to 10-20
To a methylene chloride solution of 500 mg of N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine ((1) of Reference Example 10-14) and 763 μl of triethylamine was added 254 μl of methanesulfonyl chloride. Stir at room temperature for 14 hours. Water and then saturated aqueous sodium hydrogen carbonate solution are added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is suspended in diisopropyl ether and collected by filtration to obtain N-tert-butoxycarbonyl-N′-methyl-N′-methylsulfonyl-trans-1,4-cyclohexanediamine. This compound is then treated with hydrochloric acid to give N-methyl-N-methylsulfonyl-trans-1,4-cyclohexanediamine (Table 11 Reference Examples 10-18).
In addition, using the corresponding starting material compound (chloride), the compounds of Reference Examples 10-19 to 10-20 in Table 11 are obtained in the same manner as described above.

Tables 1 to 11 below show chemical structural formulas and physical property values of the compounds of the above Examples and Reference Examples.
(In the table, “Me” represents a methyl group. In the table, MS · APCI (m / z) represents a mass analysis value (atmospheric pressure chemical ionization mass spectrum).)

Claims (9)

Formula [I]

[The symbols in the formula have the following meanings.
A: —CH ₂ — or —S—,
B: CH or N,
R ¹ : H, lower alkyl group, hydroxy lower alkyl group or
A lower alkoxy lower alkyl group,
X: a single bond, -CO -, - Alk-CO -, - COCH 2 -,
_{-Alk-O -, - O-} CH 2 -, - SO 2 -, - S -, - COO-,
^{-CON (R 3) -, -} Alk-CON (R 3) -,
_{^{-CON (R 3) CH 2 -}} , - Alk-CON (R 3) CH 2 -,
^{_{-COCH 2 N (R 3) -}} , - SO 2 N (R 3) - or -NHCH ₂ -,
(The bond shown at the right end in each definition of X represents a bond with B)
R ³ : a hydrogen atom or a lower alkyl group,
Alk: lower alkylene group,
R ² : a group selected from the following (1), (2) and (3);
(1) a group which may be substituted and the cyclic group part is (i) a monocyclic or bicyclic hydrocarbon group or (ii) a monocyclic or bicyclic heterocyclic group;
(2) an amino group substituted with one or two identical or different substituents selected from a substituted or unsubstituted lower alkyl group; and (3) a lower alkyl group, a carboxy lower alkyl group, a lower alkoxy group, a lower alkenyl. Group, lower alkoxy-substituted lower alkyl group, phenoxy group, phenoxy-substituted lower alkyl group or phenyl lower alkenyl group.
However, when X is a single bond, B is N, and R ² is a group selected from the above (1) and (2).
In addition, when X is —CO—, B is N. ]
Or a pharmacologically acceptable salt thereof. The compound according to claim 1, wherein R ² is a group selected from the following (1), (2) and (3).
(1) A cyclic group optionally having 1 to 3 substituents selected from the following group A substituents, wherein the cyclic group moiety is (i) monocyclic or bicyclic A group which is a formula hydrocarbon group or (ii) a monocyclic or bicyclic heterocyclic group;
(2) The same or different 1 selected from “a lower alkyl group optionally substituted with a group selected from a cyano group, a lower alkoxy group, a phenyl group and a nitrogen-containing monocyclic 6-membered aromatic heterocyclic group” An amino group substituted with 2 substituents; and (3) a lower alkyl group, a carboxy lower alkyl group, a lower alkoxy group, a lower alkenyl group, a lower alkoxy substituted lower alkyl group, a phenoxy group, a phenoxy substituted lower alkyl group or A phenyl lower alkenyl group.
Group A substituents:
Halogen atom, cyano group, nitro group, amino group, oxo group, lower alkyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower cycloalkanoyl group, halo lower alkyl group, halo lower Alkylcarbonyl group, nitrogen-containing monocyclic 5- to 6-membered aliphatic heterocyclic group-substituted carbonyl group, nitrogen-containing monocyclic 6-membered aromatic heterocyclic group, monocyclic aryl group, monocyclic aryl group-substituted aryl lower alkyl A carbonylamino group, a lower alkylthio group and an aminosulfonyl group. R ² is an optionally substituted cyclic group, and the cyclic group moiety is a group selected from the following (i), (ii) and (iii): The compound according to 1.
(I) a monocyclic hydrocarbon group having 3 to 7 carbon atoms,
(Ii) a monocyclic heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and
(Iii) A bicyclic heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and two 5- to 7-membered rings are condensed. R ² is a cyclic group which may have 1 to 3 substituents which are the same or different, and the cyclic group moiety is
Phenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl group, cyclopropyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxolanyl group, thiolanyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group , Triazolyl group, tetrazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridinyl group, pyrimidinyl group, pyrazinyl group Group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group, perhydroazepinyl group, perhydrothiazepinyl group, indolinyl group, Soindolinyl group, indolyl group, indazolyl group, isoindolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzodioxolyl group, benzothienyl group, benzofuryl group, thienopyridyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group , A quinolyl group, an isoquinolyl group, a quinoxalinyl group, a quinazolinyl group, a phthalazinyl group, a cinnolinyl group, a chromanyl group, an isochromanyl group, a naphthyridinyl group, and a cyclic group in which some or all of them are saturated The compound of any one of Claims 1-2. R ² is a cyclic group which may have a substituent, and the cyclic group portion is a phenyl group, a cyclohexyl group, a cyclopropyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a pyrrolyl group. , Imidazolyl, pyrazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl Group, indolinyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, benzoxazolyl group, quinolyl group, isoquinolyl group, quinazolinyl group, isoindolyl group, indolyl group, and some or all of which are saturated Base The compound of any one of Claims 1-2 which is group selected from these. R ² is an optionally substituted cyclic group, and the cyclic group moiety is selected from a piperidyl group, piperazinyl group, morpholinyl group, indolinyl group, isoindolinyl group and thiazolopyridyl group The compound according to claim 1, which is a group. R ² is a cyclic group optionally having 1 to 3 substituents selected from the following A ′ group substituents, and the cyclic group is a piperidyl group, piperazinyl group, morpholinyl group The compound according to any one of claims 1 to 2, wherein the compound is a group selected from an indolinyl group, an isoindolinyl group, and a thiazolopyridyl group.
A ′ group substituents:
An oxo group, a lower alkanoyl group, a lower cycloalkanoyl group, a lower alkoxycarbonyl group, and a nitrogen-containing aliphatic heterocyclic group-substituted carbonyl group. B is CH and the following partial structure

The compound of any one of Claims 1-7 which has these. Formula [II]

(In the formula, A represents —CH ₂ — or —S—, and Z ¹ represents a reactive residue.)
And a compound of the general formula [III]

[The symbols in the formula have the following meanings.
B: CH or N,
R ¹ : H, lower alkyl group, hydroxy lower alkyl group or
A lower alkoxy lower alkyl group,
X: a single bond, -CO -, - Alk-CO -, - COCH 2 -,
_{-Alk-O -, - O-} CH 2 -, - SO 2 -, - S -, - COO-,
^{-CON (R 3) -, -} Alk-CON (R 3) -,
_{^{-CON (R 3) CH 2 -}} , - Alk-CON (R 3) CH 2 -,
^{_{-COCH 2 N (R 3) -}} , - SO 2 N (R 3) - or -NHCH ₂ -,
(The bond shown at the right end in each definition of X represents a bond with B)
R ³ : a hydrogen atom or a lower alkyl group,
Alk: lower alkylene group,
R ² : a group selected from the following (1), (2) and (3);
(1) a group which may be substituted and the cyclic group part is (i) a monocyclic or bicyclic hydrocarbon group or (ii) a monocyclic or bicyclic heterocyclic group;
(2) an amino group substituted with one or two identical or different substituents selected from a substituted or unsubstituted lower alkyl group; and (3) a lower alkyl group, a carboxy lower alkyl group, a lower alkoxy group, a lower alkenyl. Group, lower alkoxy-substituted lower alkyl group, phenoxy group, phenoxy-substituted lower alkyl group or phenyl lower alkenyl group.
However, when X is a single bond, B is N, and R ² is a group selected from the above (1) and (2).
In addition, when X is —CO—, B is N. ]
Or a salt thereof, and if desired, the product is converted into a pharmacologically acceptable salt, if desired.

(In the formula, the symbols have the same meaning as described above.)
A process for producing an aliphatic nitrogen-containing five-membered ring compound represented by the formula: or a pharmacologically acceptable salt thereof.