JP5423854B2 - Pharmaceuticals containing alkylamine derivatives as active ingredients - Google Patents

Description

The present invention relates to a medicament containing an alkylamine derivative or a salt thereof. More specifically, the present invention relates to a hyperparathyroidism, a preventive or therapeutic agent for secondary hyperparathyroidism under maintenance dialysis, a preventive or therapeutic agent for diarrhea and peptic ulcer, The present invention relates to a pharmaceutical for oral administration or intravenous administration during dialysis, and a preparation for dialysis patients.

Calcium sensing receptor (CaS)
R (also called `` R ''), which perceives extracellular calcium (Ca2 +) from bovine thyroid in 1993
It was cloned as a protein-coupled seven-transmembrane receptor (GPCR) (Non-patent Document 1). The calcium receptor senses extracellular Ca 2+ and changes intracellular Ca 2+ concentration, thereby having a function of regulating production of hormones involved in the regulation of Ca 2+ metabolism typified by parathyroid hormone.
In recent years, cinacalcet (CCT), a calcium receptor agonist, acts on the parathyroid calcium receptor to increase the Ca2 + sensitivity of the calcium receptor, thereby suppressing the secretion of parathyroid hormone. It has become clear (Non-Patent Document 2) and is marketed as a therapeutic agent for secondary hyperparathyroidism in dialysis patients (Non-Patent Document 3).
Calcium receptors are also expressed in the kidney, brain, thyroid, bone and gastrointestinal tract, and are thought to be involved in various diseases.
As compounds having an action of activating CaSR, for example, in addition to glutathione, γ-glutamyl peptide derivatives (Non-Patent Documents 4 and 9), pyrrolidine derivatives (Patent Document 1), and the like are known. In addition, CaSR activators such as γ-glutamyl peptide derivatives are preventive or therapeutic agents for acid secretion-related diseases such as preventive or therapeutic agents for diarrhea (Patent Document 2), gastric ulcer, duodenal ulcer, reflux esophagitis (Patent Document) 3) and a therapeutic agent for diabetes or obesity (
It is reported that it is useful as an immunostimulant (Patent Document 5) as well as Patent Document 4). Furthermore, Patent Document 6 and Non-Patent Document 9 describe that a compound having CaSR agonist activity is also useful as a body taste imparting agent.
However, these compounds are structurally different from the alkylamine derivatives of the present invention.
On the other hand, among alkylamine derivatives, γ-glutamylanilide derivatives are known to be used as enzyme activity substrates (Non-patent Documents 5 and 7), and antibacterial agents and antiallergic agents (Non-patent Document 6). , Patent Document 8) and applications as analysis reagents (Non-Patent Documents 7 and 11) are known. In addition, as an L-2-amino-3-N′-substituted ureidopropanoic acid derivative, a use as a synthetic intermediate of an asparagine analog used as an anticancer agent is known (Non-patent Document 8). As an alkylamine derivative, as a leukotriene A4 inhibitor, its use for inflammatory diseases is known (Non-patent Document 10). Moreover, the use (nonpatent literature 12) as an anticancer agent is also known as an alkylamine derivative.
However, the above compounds are known to be used as drugs having CaSR agonist action, particularly as preventive or therapeutic agents for secondary hyperparathyroidism under maintenance dialysis, or as preventive or therapeutic agents for diarrhea and peptic ulcer. It wasn't.

International Publication Pamphlet No. WO2006 / 123725 International Publication Pamphlet No. WO2008 / 139947 International Publication Pamphlet No. WO2009 / 119554 International Publication Pamphlet No. WO2009 / 107660 International Publication Pamphlet No. WO2009 / 128523 International Publication Pamphlet No. WO2007 / 055393 International Publication Pamphlet No. WO2007 / 055393 Japanese Patent Laid-Open No. 06-172287

Nature (1993), 366: 575-580 Current Opinionin Pharmacology (2002), 2: 734-739 “Legpara Tablets (registered trademark) 25 mg / Legpara Tablets (registered trademark) 75 mg” package insert for ethical drugs, revised January 2010 (5th edition) Journal ofBiological Chemistry, (2006), 281 (13), 8864-70 ClinicalChemistry, (1976), 22, 2051 Journal ofMedicinal Chemistry (1965), 8 (3), 398-400 AnalyticaChimica Acta (2004), 519 (2), 181-187 Journal ofMedicinal Chemistry (1971), 14 (5), 465-466 Journal ofBiological Chemistry, (2010), 285 (2), 1016-22 Bioorganic & Medicinal Chemistry, (2008), 16, 4963-4983 Revue Roumainede Chimie (1994), 39 (12), 1435-41 J. Org. Chem. (1958), 23, 1257-1259

There is a demand for provision of a medicine having an excellent CaSR agonistic action, high safety, and particularly suitable for hyperparathyroidism.

As a result of searching for an activator of CaSR, the present inventor has found that a medicine containing the alkylamine derivative of the present invention as an active ingredient has an excellent CaSR agonist action and various disease models. The medicine of the invention is for the prevention or treatment of diarrhea and peptic ulcer,
Furthermore, in addition to oral administration, the present invention was found out that it is useful in administration during dialysis.
That is, the present invention is as follows.
[1] The following formula (I):

[Where:
R ¹ and R ² are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl;
R ³ represents a hydrogen atom, halogeno, or substituted or unsubstituted C _1-6 alkyl;
R ⁴ and R ⁵ are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or Halogeno;
X represents CR ^a R ^b , an oxygen atom, NR ^c , or a sulfur atom (wherein R ^a and R ^b each independently represents a hydrogen atom, C _1-6 alkyl, or halogeno; R ^c Is a hydrogen atom,
Or an _{C 1-6} alkyl. );
Y represents C═O, SO, SO ₂ , C═S, or C═NR ^d (where R ^d is a hydrogen atom,
_Represents C _1-6 alkyl, R ^d and R ⁶ together represent substituted or unsubstituted 5 or 6
Membered heterocycles may be formed);
R ⁶ represents a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2
-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or hydroxy;
G is aryl substituted with R ^7, or represents a heteroaryl substituted with R ^7, heteroaryl substituted with aryl or R ⁷ substituted with the R ⁷ further one or a plurality of R ^Optionally substituted with ⁸ ;
R ⁷ is sulfo, carboxyl, or phosphono;
R ⁸ is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C _{1 -6} alkoxy, nitro, amino, mono C _1-6 alkylamino,
Represents diC _1-6 alkylamino, sulfo, carboxyl, phosphono, C _1-3 alkylcarbonylamino, or mono C _1-6 alkylphosphono, and when there are a plurality thereof, they may be different from each other;
Q is a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6
Alkenyl, substituted or unsubstituted C _2-6 alkynyl, carboxyl, CONR ^e R ^f
, CONNHNHR ^g , COR ^h , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R ^e and R ^f are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted Of C _3-8 cycloalkyl, hydroxy, or C _1-
Represents ₆ alkoxy, or R ^e and R ^f may be combined together to form a substituted or unsubstituted 5- or 6-membered heterocycle optionally having a hetero atom;
R ^g is substituted or unsubstituted C _1-6 alkylcarbonyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and R ^h is substituted or unsubstituted C _{1 -6} alkoxy, substituted or unsubstituted mercapto,
Or the following group:

(In the formula, Z represents a divalent group of a substituted or unsubstituted C _1-6 hydrocarbon, E ¹ represents a substituted or unsubstituted C _1-6 acyloxy, a substituted or unsubstituted C _1-6 alkoxy; Carbonyloxy, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted C _1-
6 alkoxycarbonyl, halogeno, aryl, heteroaryl, substituted or unsubstituted C _1-6 alkoxy, or substituted or unsubstituted carbamoyl, E ² represents a hydrogen atom or C _1-6 alkyl, Z and E ¹ may be integrated to form a ring).
However, X is methylene or an oxygen atom, Y is C = ^O, both the R 1 to R ⁵ hydrogen atom,
When G is phenyl, Q represents a group other than carboxyl and COR ^h . ]
Or a salt thereof as an active ingredient.
[2] The following formula (I):


[Where:
R ¹ and R ² are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl;
R ³ represents a hydrogen atom, halogeno, or substituted or unsubstituted C _1-6 alkyl;
R ⁴ and R ⁵ are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or Halogeno;
X represents CR ^a R ^b , an oxygen atom, NR ^c , or a sulfur atom (wherein R ^a and R ^b each independently represents a hydrogen atom, C _1-6 alkyl, or halogeno; R ^c Is a hydrogen atom,
Or an _{C 1-6} alkyl. );
Y represents C═O, SO, SO ₂ , C═S, or C═NR ^d (where R ^d is a hydrogen atom,
_Represents C _1-6 alkyl, R ^d and R ⁶ together represent substituted or unsubstituted 5 or 6
Membered heterocycles may be formed);
R ⁶ represents a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2
-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or hydroxy;
G is aryl substituted with R ^7, or represents a heteroaryl substituted with R ^7, heteroaryl substituted with aryl or R ⁷ substituted with the R ⁷ further one or a plurality of R ^Optionally substituted with ⁸ ;
R ⁷ is sulfo, carboxyl, or phosphono;
R ⁸ is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C _{1 -6} alkoxy, nitro, amino, mono C _1-6 alkylamino,
Represents di-C _1-6 alkylamino, sulfo, carboxyl, phosphono, or mono-C _1-6 alkylphosphono;
Q is a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6
Alkenyl, substituted or unsubstituted C _2-6 alkynyl, carboxyl, CONR ^e R ^f
, CONNHNHR ^g , COR ^h , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R ^e and R ^f are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted Of C _3-8 cycloalkyl, hydroxy, or C _1-
Represents ₆ alkoxy, or R ^e and R ^f together may form a substituted or unsubstituted 5- or 6-membered heterocycle optionally having a hetero atom;
R ^g is substituted or unsubstituted C _1-6 alkylcarbonyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and R ^h is substituted or unsubstituted C _{1 -6} alkoxy, substituted or unsubstituted mercapto,
Or the following group:


(In the formula, Z represents a divalent group of a substituted or unsubstituted C _1-6 hydrocarbon, E ¹ represents a substituted or unsubstituted C _1-6 acyloxy, a substituted or unsubstituted C _1-6 alkoxy; Carbonyloxy, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted C _1-
Z and E represent ₆ alkoxycarbonyl, halogeno, aryl, heteroaryl, substituted or unsubstituted C _1-6 alkoxy, or substituted or unsubstituted carbamoyl, E ² represents a hydrogen atom or C _1-6 alkyl ¹ may be integrated to form a ring).
However, X is methylene or an oxygen atom, Y is C = ^O, both the R 1 to R ⁵ hydrogen atom,
When G is phenyl, Q represents a group other than carboxyl and COR ^h . ]
The pharmaceutical which uses the compound or its salt as described in said [1] shown by these.
[3] The medicament according to [1] or [2], which is a preventive or therapeutic agent for hyperparathyroidism.
[4] The medicament according to [3], which is a preventive or therapeutic agent for secondary hyperparathyroidism under maintenance dialysis.
[5] The medicament according to [4], which is used for oral administration or intravenous administration during dialysis.
[6] A preparation for a dialysis patient comprising the medicine according to [1] or [2].
[7] The medicament according to [1] to [5], which is used in combination with a calcium preparation or a vitamin D preparation.
[8] The preparation for dialysis patients according to [6], further including a calcium preparation or a vitamin D preparation.
[9] The medicament according to [1] or [2], which is a preventive or therapeutic agent for diarrhea.
[10] The medicament according to [1] or [2], which is a preventive or therapeutic agent for peptic ulcer.

The medicament of the present invention has an excellent CaSR agonistic action, for example, a prophylactic or therapeutic agent for diseases improved by the activation of CaSR, in particular, prevention or treatment of hyperparathyroidism, diarrhea and peptic ulcer Useful as an agent. In addition to oral administration, the medicament of the present invention can sufficiently maintain the PTH secretion inhibitory effect by dialysis administration to maintenance dialysis patients.
It is useful as a preparation for maintenance dialysis patients. By administering the medicine of the present invention intravenously at the time of dialysis of patients under maintenance dialysis, the doctor can always manage the drug administration and reduce the patient's burden, reducing side effects such as vomiting and liver drug interactions. It is also excellent in taking and safety.

2 is a graph comparing the effects of Compound No. 1 and cinacalcet on serum iPTH concentration. 2 is a graph comparing the effects of Compound No. 1 and cinacalcet on serum Ca concentration. 2 is a graph showing the effect of Compound No. 1 and Compound No. 2 on NSAID enterocolitis. (* P <0.05) 2 is a graph showing the effect of Compound No. 3 on NSAID enterocolitis. It is a graph which shows the effect of compound No. 1 with respect to the water | moisture-content absorption effect | action using a large intestine loop method. It is a graph which shows the effect of compound No. 2 with respect to the water | moisture-content absorption effect | action using a large intestine loop method. It is a graph which shows the effect of compound No. 3 with respect to the water | moisture-content absorption effect | action using a large intestine loop method. It is a graph which shows the effect of compound No. 4 with respect to the water | moisture-content absorption effect | action using a large intestine loop method. It is a graph which shows the effect in intravenous administration of compound No. 5 with respect to the persistence of the PTH lowering effect | action using the nephrectomy rat. It is a graph which shows the effect in the oral administration of compound No. 1 with respect to the persistence of the PTH lowering effect | action using the nephrectomy rat.

The terms in this specification have the following meanings.
“Hyperparathyroidism” refers to a condition in which the amount of secretion of parathyroid hormone (PTH) is excessive.
“Secondary hyperparathyroidism” refers to a condition in which the parathyroid hormone PTH is excessively secreted as a compensation mechanism for hypocalcemia.
“Maintenance dialysis” refers to hemodialysis usually performed three times a week for patients with impaired renal function such as renal failure.
“Dialysis” refers to any time point during hemodialysis during each dialysis received by a maintenance dialysis patient, and preferably 30 minutes before to immediately before the end of dialysis.
“Intravenous administration” means administration of a drug into a maintenance dialysis patient's vein, preferably through a cannula inserted into the dialysis patient's vein.
“Dialyzed patient preparation” means a preparation for intravenous administration to a patient during maintenance dialysis,
Preferably, it is a preparation for administration through a cannula inserted into the vein of a dialysis patient.
Specifically, it may be in the form of a liquid preparation containing an active ingredient, or a dry frozen preparation containing an active ingredient dissolved and used at the time of use. Moreover, the form which inject | pours into the chemical | medical solution injection | pouring port of a dialysis apparatus may be sufficient, and the form which can be couple | bonded directly with a chemical | medical solution injection | pouring port and the cannula for dialysis may be sufficient.
The “calcium agent” is a preparation containing an inorganic or organic salt of calcium as an active ingredient. For example, calcium chloride, calcium carbonate, calcium lactate, calcium gluconate, calcium L-aspartate, calcium hydrogen phosphate, etc. And may be an oral preparation or an injection. Intravenous formulations are usually used for dialysis patients.
The “vitamin D preparation” is preferably an active vitamin D ₃ preparation, and may be an oral preparation or an injection. It may be administered as an intravenous preparation to dialysis patients, and specific examples include maxacalcitol and calcitriol which are intravenous preparations.
“Used in combination” means that the above-mentioned calcium preparation or vitamin D preparation is administered to a patient who has been administered the medicament of the present invention. It is also included when administered in Moreover, the administration method may be administered by the same method as the medicament of the present invention, or may be administered by a different method. For example, the medicament of the present invention may be administered intravenously, and the above calcium preparation or vitamin D preparation may be administered orally. In addition, the administration period may be the same as the administration period of the medicament of the present invention, or may be administered during a part of the period overlapping the administration period of the medicament of the present invention.
“Diarrhea” generally refers to a condition in which the amount of stool in an adult exceeds 300 g / day, mainly due to excessive water in the stool. Preferred is diarrhea due to abnormal absorption of water or the like.
A “peptic ulcer” is a part of the gastrointestinal mucosa, usually the upper part of the stomach or duodenum (the first few centimeters)
), A state of erosion that occurs in the small intestine and the like and penetrates the mucosal muscle plate. Specific examples include gastric ulcer, duodenal ulcer, gastritis, NSAIDs-induced enterocolitis, reflux esophagitis, non-erosive gastroesophageal reflux disease, non-steroidal anti-inflammatory drug ulcer and the like. Preferred is NSAIDs-induced enteritis.
Hereinafter, the definition of the substituent of the compound of Formula (I) is demonstrated.
In the present specification, “C _1-6 alkyl” is a monovalent derivative derived by removing any one hydrogen atom from a linear or branched aliphatic hydrocarbon having 1 to 6 carbon atoms. It is a group. Specific examples include methyl, ethyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl and the like. Preferably it is _C1-3 alkyl.
“C _2-6 alkenyl” has at least one double bond (two adjacent sp2 carbon atoms) among a linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms. It is a monovalent group. Specific examples of C _2-6 alkenyl include vinyl, allyl, 1-propenyl, 2-
Examples include propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, hexenyl and the like. C _2-3 alkenyl is preferable.
“C _2-6 alkynyl” has at least one triple bond (two adjacent sp carbon atoms) among a linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms, It is a monovalent group. Specific examples include ethynyl, 1-propynyl, propargyl, 3-butynyl and the like. Preferably, C _2-3 alkynyl is used.

“Halogeno” means fluorine, chlorine, bromine, iodine atom and the like.
“Aryl” means an aromatic hydrocarbon ring group such as phenyl or naphthyl. This is preferably phenyl.
“Heteroaryl” is a 5- to 10-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from N, S, and O. Specific examples of the aromatic heterocycle include Specifically, pyridine, pyridazine, pyrazine, pyrimidine, thiazole, isothiazol, oxazole, isoxazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrrole and the like can be mentioned. Preferred are pyridine, imidazole, thiophene, oxadiazole, and indole. Preferably, it is a 5-membered to 6-membered aromatic heterocyclic ring containing 1 to 2 heteroatoms, and specifically, pyridine and pyrimidine.
“C _1-6 alkoxy” means C _1-6 alkyl-O—. Specifically, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec
-Butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-1-butyloxy, 3-methyl-1-butyloxy, 2-methyl-2
-Butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl-1-propyloxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy and the like.
Preferably it is _C1-3 alkoxy.
_{Examples of} “C _3-8 cycloalkyl” include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferably, it is C _5-7 cycloalkyl.

“Mono C _1-6 alkylamino” means that one hydrogen atom on a nitrogen atom is the above C _1-6.
An amino group substituted by alkyl, meaning C _1-6 alkyl-NH—. Specific examples include methylamino and ethylamino. Preferably, it is mono C _1-3 alkylamino.
“DiC _1-6 alkylamino” is an amino group in which two hydrogen atoms on a nitrogen atom are each substituted by the above C _1-6 alkyl, and (C _1-6 alkyl) ₂ N— means. Each C _1-6 alkyl group may be the same or different. Specific examples include dimethylamino and diethylamino. Preferably, it is _diC1-3 alkylamino.
“C _1-3 alkylcarbonylamino” means a group represented by C _1-3 alkyl-C (O) —NH—. C _1-3 alkylcarbonylamino includes acetylamino,
And groups such as propionylamino. Acetylamino is preferred.

“Mono C _1-6 alkylphosphono” is a phosphono group in which one hydrogen atom on a hydroxyl group is substituted with the above C _1-8 alkyl, and means —PO ₃ H (C _1-6 alkyl). To do. Specific examples include methylphosphono and ethylphosphono. Preferably mono C _1
-3 alkylphosphono.
“C _1-6 alkylsulfonyl” means a group represented by C _1-6 alkyl-S (O) ₂ —, and specific examples include methylsulfonyl, ethylsulfonyl and the like. Preferably, it is C _1-3 alkylsulfonyl.
“Arylsulfonyl” means a group represented by aryl-S (O) ₂ —, and specific examples include phenylsulfonyl and the like.

“C _1-6 alkylcarbonyl” means a group represented by C _1-6 alkyl-C (O) —, and specific examples include methylcarbonyl, ethylcarbonyl and the like. Preferably,
C _1-3 alkylcarbonyl.
“C _1-6 alkoxycarbonyloxy” refers to C _1-6 alkyl-O—C (O) —O.
-Means a group represented by-and includes methoxycarbonyloxy, ethoxycarbonyloxy and the like. Preferably, it is C _1-3 alkoxycarbonyloxy.

The “C _1-6 hydrocarbon divalent group” means a linear or branched chain having 1 to 6 carbon atoms and may contain 1 to several double bonds or triple bonds. It means a divalent group derived by removing two arbitrary hydrogen atoms from a hydrocarbon. Specifically, methylene, ethane-1,1-
Examples include diyl, vinylene, ethynylene, propargyl and the like.
“C _1-6 acyloxy” refers to C _1-6 alkyl-C (O) —O—, C _3-6 cycloalkyl-C (O) —O—, or aryl-C (O) —O—. Means the group indicated.
Examples of C _1-6 acyloxy include groups such as acetyloxy, propionyloxy, cyclohexylcarbonyloxy, and benzoyloxy. Preferably, it is C _1-6 alkyl-C (O) —O—, and more preferably C _1-3 alkyl-C (O) —O—.
“C _1-6 alkoxycarbonyl” means a group represented by C _1-6 alkyl-O—C (O) —, and includes methoxycarbonyl, ethoxycarbonyl and the like. Preferably,
C _1-3 alkoxycarbonyl.

The “5- or 6-membered heterocyclic ring which may further contain a hetero atom” formed integrally with R ^e and R ^f is, in addition to the nitrogen atom to which R ^e and R ^f are bonded,
It means a saturated or unsaturated 5- or 6-membered heterocycle which may further have 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as constituent atoms of the ring.
Examples of saturated 5- or 6-membered heterocyclic groups include pyrrolidin-1-yl, pyrazolidine-1
-Yl, imidazolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl and the like.
Examples of unsaturated 5- or 6-membered heterocyclic groups include pyrrol-1-yl, 2-pyrroline-1
-Yl, 3-pyrrolin-1-yl, pyrazol-1-yl, imidazol-1-yl, 2
-Pyrazolin-1-yl, 3-pyrazolin-1-yl, 2-imidazolin-1-yl, 1
, 2,3-triazol-1-yl, 1,2,4-triazol-1-yl, tetrazol-1-yl, 1,4-oxazin-4-yl, 1,4-thiazin-1-yl and the like Can be mentioned.

R ^d and R ^6, the term "5 or 6 membered heterocyclic ring" formed together, comprise N = C-N where R ^d and R ⁶ are attached as part of the ring, as constituent atom of the ring Further, it means a saturated or unsaturated 5- or 6-membered heterocycle which may have 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, specifically, 2-imidazolidine , Imidazole,
Examples include triazole, tetrazole, 1,4,5,6-tetrahydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyrimidine, 2H-1,2,4-oxadiazine and the like.

The term “which may be further substituted” in G ⁰ is a substitutable position other than R ⁷⁰ ,
For example, cyano, substituted or unsubstituted mercapto, C _1-6 alkyl-C (O) —, C _1
-6 alkyl-C (O) -O-, C _3-6 cycloalkyl, C _1-6 alkyl-O-C (
O) —C _1-6 alkylene-O—, substituted or unsubstituted aryl, substituted or unsubstituted aryl-O—, substituted or unsubstituted aryl-C (O) —, —O—C _1-6 alkylene-O— ,
It means that it may be substituted with a substituent such as substituted or unsubstituted aryl-C _1-6 alkenyl-.
Here, C _1-6 alkylene means a divalent group of the C _1-6 alkyl.

In CO—R ^h in Q, when R ^h is represented by the formula (IIa), the “ring” formed by Z and E ¹ together includes Z—E ¹ as a part of the ring, Means a saturated or unsaturated 5- or 6-membered ring optionally having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms as ring constituent atoms, and further condensed with a benzene ring May be. Preferably, it is a saturated or unsaturated 5- or 6-membered ring optionally having 1 to 3 oxygen atoms as ring constituent atoms.
Specific examples of R ^h when Z and E ¹ are combined to form a ring include the following groups.

The group represented by CO-R ^h is, for example, Prog. Med. 5: 2157-2161 (1985), Development of pharmaceuticals (published in Hirokawa Shoten 1990) Volume 7 Molecular Design p. 163-198, or the latest Drug Discovery Chemistry (Technomic 1999), second volume p. As described in 271-298, a case where a carboxyl group subjected to a prodrug modification, which is converted into a carboxyl group in vivo, is also included.

Substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl,
C _1-6 alkoxy, or C _1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, mercapto, carbamoyl, amino, C _1-6 alkoxycarbonyl, C _1-6 hydrocarbon divalent group, C _1-6 Examples of the substituent in alkoxycarbonyloxy or C _1-6 acyloxy include, for example, a halogen atom (eg, chlorine atom, bromine atom, fluorine atom), hydroxy, cyano, C _1-6 alkoxy (eg, methoxy), C _{1 -6} halogenoalkyl (eg trifluoromethyl), unsubstituted or C _1-6 alkyl mono- or disubstituted carbamoyl, unsubstituted or halogeno, C _1-6 alkyl or C _1-
Examples include aryl substituted with 1-3 alkoxy with ₆ alkoxy and the like, unsubstituted or heteroaryl substituted with 1-3 with halogeno, C _1-6 alkyl, C _1-6 alkoxy and the like. Preferably, carbamoyl mono- or di-substituted with cyano, unsubstituted or C _1-6 alkyl, unsubstituted or aryl 1-3 substituted with halogeno, C _1-6 alkyl or C _1-6 alkoxy, etc. Heteroaryl which is substituted or 1-3 substituted with halogeno, C _1-6 alkyl, C _1-6 alkoxy or the like. The above groups may be substituted by 1 to 3 substitutable positions by a substituent arbitrarily selected from these substituents, and in the case of multiple substitution, each substituent is different. It may be.

Examples of the substituent in the substituted or unsubstituted 5- or 6-membered heterocyclic ring, substituted or unsubstituted aryl, heteroaryl, arylsulfonyl or benzoyl include, for example, a halogen atom (for example, chlorine atom, bromine atom, fluorine atom), hydroxy C _1-6 alkyl (eg methyl, benzyl) _optionally substituted with cyano, aryl (eg phenyl)
, _{C 1-6} alkoxy (e.g., _{methoxy), C 1-6} halogenoalkyl (e.g., trifluoromethyl), unsubstituted or _{C 1-6} alkyl mono- or di-substituted carbamoyl, halogen or _{C 1-6} alkyl And heteroaryl which may be substituted with. Preferable examples include C _1-6 alkyl _optionally substituted with aryl (eg phenyl), heteroaryl optionally substituted with halogen or C _1-6 alkyl, and the like. The above group may be substituted at a substitutable position by a substituent arbitrarily selected from these substituents.
Individual substitutions may be made, and when multiple substitutions are made, the respective substituents may be different.
Examples of the substituent in the substituted or unsubstituted C _3-6 cycloalkyl include oxo and the like in addition to the substituents mentioned as the substituents of the substituted or unsubstituted 5- or 6-membered heterocyclic ring.

R ¹ and R ² are preferably a hydrogen atom or C _1-6 alkyl, and more preferably a hydrogen atom.
R ³ is preferably a hydrogen atom, halogeno, or C _1-6 alkyl, and more preferably a hydrogen atom.
R ⁴ and R ⁵ are preferably a hydrogen atom, C _1-6 alkyl, or halogeno;
More preferably, it is a hydrogen atom.
X is preferably CH ₂ , an oxygen atom, NH, or a sulfur atom, and more preferably NH or a sulfur atom. Particularly preferred is NH.
Y is preferably C═O, SO, SO ₂ or C═S, and more preferably C═O or C═S.
R ⁶ is preferably a hydrogen atom, hydroxy, or C _1-6 alkyl, and more preferably a hydrogen atom.
G is preferably aryl substituted with R ⁷ or a heteroaryl substituted with R ^7, it may be further substituted with 1-3 R ^8. More preferably, phenyl substituted with R ^7, or pyridyl substituted with R ^7, may be further substituted with one to two R ^8.
Also, a phenyl G is substituted with R ^7, when R ⁷ is sulfo, the substitution position of R ⁷ is preferably a 3-position on the phenyl group (general formula (I) in the The carbon in the phenyl group that binds to nitrogen is the 1-position). More specifically, G is preferably 5-chloro-2-hydroxy-3-sulfophenyl, 3-chloro-2-methyl-5-sulfophenyl, or 3-chloro-4-methyl-5-sulfophenyl.
G ⁰ preferably represents unsubstituted or aryl substituted with 1 to 5 R ⁷⁰ , or heteroaryl unsubstituted or substituted with 1 to 5 R ⁷⁰ , more preferably Aryl which is unsubstituted or substituted with 1 to 3 R ⁷⁰ , or unsubstituted or 1 to 3 R ⁷
Heteroaryl substituted with ^0, and most preferably, phenyl substituted with unsubstituted or one to three R ^70, or is pyridyl unsubstituted or substituted by one to three R ⁷⁰ .
Also, a phenyl G ⁰ is substituted with R ^70, when one of R ⁷⁰ is a sulfo, the substitution position of R ⁷⁰ is preferably a 3-position on the phenyl group (general formula (I ⁰ ) the carbon in the phenyl group that binds to the nitrogen in position 1).
R ⁷ is preferably sulfo or carboxyl, and more preferably sulfo.
R ⁷⁰ is preferably C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, halogeno, hydroxy, C _1-6 alkoxy, nitro, amino, mono C _1-6 alkylamino, DiC _1-6 alkylamino or mono C _1-6 alkylphosphono, more preferably C _1-6 alkyl, halogeno, hydroxy, C _1-6 alkoxy,
Nitro, sulfo, carboxyl, phosphono, and most _{preferably, C 1-6} alkyl, halogeno, hydroxy, sulfo.
R ⁸ is preferably C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, halogeno, hydroxy, C _1-6 alkoxy, nitro, amino, mono C _1-6 alkylamino, DiC _1-6 alkylamino, sulfo, carboxyl, phosphono, or mono C _1-6 alkylphosphono, more preferably C _1-6 alkyl, halogeno, hydroxy, nitro, sulfo, most preferred Is C _1-6 alkyl, halogeno, hydroxy.
Q is preferably substituted or unsubstituted C _1-6 alkyl, carboxyl, CONR ^e R ^f , CONNHHR ^g , COR ^h , aryl, or substituted heteroaryl, more preferably (cyano, carbamoyl Or aryl) substituted or unsubstituted C _1-6 alkyl, carboxyl, CONR ^e R ^f , CONNHHR ^g , COR ^h , aryl, or (C _1-6 alkyl, aryl substituted C _1-6 alkyl, C _1-6 alkyl or halogeno-substituted aryl, heteroaryl) substituted heteroaryl, most preferably carboxyl.
Note that when Q is a carboxyl group, R ³ is a hydrogen atom, and X is CR ^a R ^b , an oxygen atom, or NR ^c , the carbon atom to which Q and R ³ are bonded may have an S configuration. preferable. In addition, when Q is a carboxyl group, R ³ is a hydrogen atom, and X is a sulfur atom, the carbon atom to which Q and R ³ are bonded preferably has an R configuration.
R ^e and R ^f are preferably a hydrogen atom, a substituted or unsubstituted C _1-6 alkyl, C _1
-6 alkylsulfonyl, arylsulfonyl, C _3-6 cycloalkyl, hydroxy,
Or C _1-6 alkoxy, more preferably a hydrogen atom, (aryl substituted by heteroaryl, aryl, halogeno or C _1-6 alkoxy) substituted or unsubstituted C _1-6 alkyl, C _{1 -6} alkylsulfonyl, arylsulfonyl, hydroxy, or C _1-6 alkoxy, and most preferably a hydrogen atom, (heteroaryl, aryl) substituted or unsubstituted C _1-6 alkyl, C _1-6 alkyl Sulfonyl, hydroxy.
R ^g is preferably substituted or unsubstituted C _1-6 alkylcarbonyl, more preferably aryl-substituted or unsubstituted C _1-6 alkylcarbonyl.
R ^h is preferably C _1-6 alkoxy, mercapto, or the following group:

(In the formula, Z represents a divalent group of C _1-6 hydrocarbon, E ¹ represents C _1-6 acyloxy, C _{1
-6 represents} alkoxycarbonyloxy, amino, carboxyl, C _1-6 alkoxycarbonyl, halogeno, aryl, heteroaryl, C _1-6 alkoxy, or carbamoyl, E ² represents a hydrogen atom or C _1-6 alkyl, Z and E ¹ together

May be formed).

As the compound (I) which is an active ingredient of the present invention, among the compounds represented by the above [1],
R ¹ and R ² are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl. Representation;
R ⁴ and R ⁵ are each independently a hydrogen atom;
X is CH ₂ , an oxygen atom, NH, or a sulfur atom;
Y represents C═O, SO, SO ₂ , or C═S;
G is aryl substituted with R ^7, or represents a heteroaryl substituted with R ^7, heteroaryl substituted with aryl or R ⁷ substituted with the R ⁷ further 1-5 R ^Optionally substituted with ⁸ ;
R ⁸ is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C _{1 -6} alkoxy, amino, mono C _1-6 alkylamino, di C _1-
Represents ₆ alkylamino, sulfo, carboxyl, phosphono, or mono C _1-6 alkylphosphono, and when there are a plurality thereof, they may be different from each other;
Q is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, carboxyl, CONR ^e R ^f , CON
A compound ^represented by HNHR ^g , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a salt thereof is preferable.

Furthermore, as the compound (I) which is a more preferred active ingredient of the present invention, among the compounds represented by the above [1],
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen atoms;
X is NH or a sulfur atom;
Y is C = O or C = S;
Q is carboxyl or C _1-6 alkoxycarbonyl;
G is aryl substituted with R ^7, or represents a heteroaryl substituted with R ^7, heteroaryl substituted with aryl or R ⁷ substituted with the R ⁷ further 1-5 R ^Optionally substituted with ⁸ ;
R ⁷ is sulfo;
R ⁸ is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C _{1 -6} alkoxy, amino, mono C _1-6 alkylamino, di C _1-
6 alkylamino, sulfo, carboxyl, phosphono, or mono C _1-6 alkylphosphono, and when there are a plurality of them, they may be different from each other;
Or a salt thereof.

On the other hand, in the general formula (I),
When R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen atoms, X is methylene, Y is C═O, and G is pyridyl substituted with carboxyl, A compound in which Q is not methoxycarbonyl is preferred as the medicament of the present invention.

Particularly preferred compounds are
(2R) -2-amino-3-{[(3-sulfophenyl) carbamoyl] sulfanyl}
Propanoic acid;
(2S) -2-Amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl)
Carbamoyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-chloro-4-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-sulfophenyl) carbamothioyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamothioyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-chloro-4-methyl-5-sulfophenyl) carbamothioyl] amino} propanoic acid;
3-[(4S) -4-amino-4- (hydroxycarbamoyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid;
3-[(4S) -4-amino-4- (hydroxycarbamoyl) butanamide] -5-chloro-4-methylbenzene-1-sulfonic acid; and (2S) -2-amino-3-{[(3- Sulfophenyl) carbamoyl] amino} propanoic acid or a salt thereof.

Below, the manufacturing method of compound (I) is described.
The compound represented by general formula (I) which is an active ingredient of the medicament of the present invention can be produced, for example, by the following method.
In the following reaction formula, R ^{1 to} R ⁶ , R ^a , R ^b , R ^c , X, Y, G, and Q are represented by the above formula (
It is the same group as defined in I). In the formula (2), M is XH or the formula (
The functional group which couple | bonds with the compound represented by 3) and forms XY is shown.

(Reaction Formula A)


For example, in the reaction formula (A), when X—Y in the formula (I) represents ^a group —CR ^a R ^b —CO—, it can be produced as follows.
The carboxylic acid derivative (2a) and the amine derivative (3) are dissolved or suspended in a suitable solvent, and dicyclohexylcarbodiimide (DCC), 1-ethyl in the presence or absence of a base such as triethylamine or pyridine. By mixing a condensing agent such as-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and N, N-carbonyldiimidazole (CDI), the reaction system is cooled and heated as necessary, (Ia) can be manufactured. During the condensation, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-
Adjuvants such as 7-azabenzotriazole (HOAt), catalysts and the like may be added. The amide derivative represented by the general formula (Ia) can be produced by removing the protecting group as necessary.

(Reaction Formula B)


Alternatively, the carboxylic acid halide (2a ′) and the amine derivative (3) are mixed in a suitable solvent, and in the presence of a base such as triethylamine or pyridine, for example, 4-dimethylaminopyridine is used as a catalyst and cooled as necessary. The amide derivative (Ia) can be produced by heating and the like. In the reaction formula B2, Hal represents a halogen atom.

(Reaction formula B2)


Moreover, in Reaction formula A, when XY in formula (I) represents a group —O—CO—, it can be produced as follows. The alcohol derivative (2b) and the amine derivative (3) are dissolved or suspended in a suitable solvent, and in the presence or absence of a base such as triethylamine or pyridine, a condensing agent such as CDI, phosgene or triphosgene. Etc.,
The carbamate derivative (Ib) can be produced by cooling, heating, etc. the reaction system as necessary.

(Reaction Formula C)



In addition, for (Ib), for example, thiocarbonyl such as 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson reagent) The O-substituted thiocarbamate derivative (Ib) can be obtained by allowing the agent to act in a suitable solvent with or without heating.
') Can also be manufactured.

(Reaction Formula C2)


In Reaction Formula A and Formula (I), when XY represents a group —NR ^c —CO—, it can be produced, for example, as follows. The amine of the alkylamine derivative shown in (2c) or a salt thereof and the amine derivative of (3) are dissolved or suspended in a suitable solvent, and CDI is added in the presence or absence of a base such as triethylamine or pyridine. ,phosgene,
A urea derivative (Ic) can be produced by mixing a condensing agent such as triphosgene or a carbonyl source such as dimethyl carbonate, and cooling and heating the reaction system as necessary.

(Reaction Formula D)


Alternatively, as shown in Reaction Formula D2, a method using the Lossen rearrangement as described in Org. Lett., Vol. 11, No. 24, 2009, 5622-5625 can be used to obtain the hydroxamic acid derivative (4) and The urea derivative (Ic ′) can also be produced using the amine derivative (3).

(Reaction Formula D2)


Alternatively, the carbamate derivative (3a) can be produced and then substituted with the amine derivative (2c).

(Reaction Formula D3)

Moreover, in Reaction formula A, when XY shows -S-CO- group in Formula (I), it can manufacture as follows. The thiol derivative (2d) and the amine derivative of (3) are dissolved or suspended in a suitable solvent, and condensed in the presence or absence of a base such as triethylamine or pyridine, such as CDI, phosgene, or triphosgene. By mixing a carbonyl source such as an agent or dimethyl carbonate, cooling the reaction system as necessary, heating, etc.
S-substituted thiocarbamate derivatives (Id) can be produced.

(Reaction Formula E)

In the reaction formula A, when X—Y represents a group N—C (═S) — in the formula (I), for example, it can be produced as follows. That is, the amine derivative shown in (3b) is dissolved or suspended in an appropriate solvent, and, for example, thiophosgene, carbon disulfide, etc. are mixed, and in the presence of a base such as sodium carbonate, triethylamine, sodium ethoxide, an intermediate is obtained as an intermediate. Thiocyanate (5) is generated. A commercially available product can be used as the isothiocyanate (5). Isothiocyanate is isolated or dissolved in a suitable solvent without isolation, and then the amine (2c) of the alkylamine derivative is used in the presence or absence of a base such as triethylamine, pyridine, or sodium carbonate as necessary. The thiourea derivative (Ie) can be produced by mixing while cooling and heating.

(Reaction Formula F)


As the amine derivative (3), a commercially available compound can be used, or it can be produced as follows.
For example, the following nitro derivative (4) can be obtained by performing a hydrogenation reaction in the presence of a catalyst using, for example, hydrogen gas or the like as a reducing agent, or by using a general reduction reaction such as the action of tin chloride (3b). ) Can be manufactured.

(Reaction Formula G)



Also Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Or
As shown in ganic Chemistry (1972-1999), 1998, # 3 p. 509-520, (3c) can be produced by selecting an appropriate reducing agent during the reduction.

(Reaction Formula H)



Substituent R ⁷ on G is, for example, a strong base such as n-butyllithium acting on aromatic halide (7), lithium-halogen exchange, and dry ice acting to introduce a carboxyl group. And a reaction in which a transition metal such as palladium is allowed to act on the aromatic halide (7) and carbon monoxide gas is allowed to act. Similarly, for aromatic halides, for example, Synthesis, 1981, # 1 p.56-57 As shown in Reaction Formula J, for example, a sulfonic acid derivative can also be produced by a reaction in which fuming sulfuric acid acts on the aromatic compound (8) with respect to an aromatic compound. In Reaction Formula I, Hal represents a halogen atom or a pseudohalogen atom, V represents a protected nitrogen atom or a group that can be converted to a nitrogen atom, and Prot represents a protecting group or a hydrogen atom.

(Scheme I)

(Reaction Formula J)



Heteroaryls can be synthesized, for example, by methods described in Chemical Reactivity of Aromatic Heterocyclic Compounds and Ring Synthesis (Kodansha Scientific, Sakamoto et al.).
For example, the following heteroaryl can be synthesized by treating a diacylhydrazine derivative with an appropriate dehydrating agent.

The solvent used in the reaction of each of the above steps is not particularly limited as long as it does not inhibit the reaction and dissolves at least a part of the starting material. Examples thereof are given below.
Aliphatic hydrocarbons: hexane, cyclohexane, petroleum ether Aromatic hydrocarbons: benzene, toluene, xylene Amides: dimethylformamide, N-methyl-2-pyrrolidone, dimethylacetamide Amines: triethylamine, diisopropylethylamine, pyridine, 2 , 6-Lutidine Alcohols: methanol, ethanol, 1-propanol, 2-propanol, 1-
Butanol, 2-butanol ethers: diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane ketones: acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone esters: ethyl acetate, isopropyl acetate, butyl acetate Acids: formic acid, acetic acid, propionic acid, tri Fluoroacetic acid, sulfuric acid Sulfoxides: dimethyl sulfoxide, sulfolane Nitriles: acetonitrile, propionitrile Halogenated hydrocarbons: dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene Others: water and mixtures thereof.

In each of the above steps, it may be desirable to introduce a protecting group into the functional group in the formula as necessary. For example, ProtectiveGroups in Organic Synthesis 4th edition (W
The functional group described in ILEY-INTERNATIONAL publication, WUTS, and GREEN) etc. can be used, However, It is not limited to this. The desired compound can be obtained by appropriate protection and deprotection by the methods described in the above documents.
The compound represented by the general formula (I) and the salt thereof thus produced are known separation and purification means such as extraction, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, various chromatographies. It can be isolated and purified by chromatography or the like.

The alkylamine derivative used in the present invention includes a salt form. When the alkylamine derivative which is an active ingredient of the present invention can form a salt form, the salt may be a pharmaceutically acceptable salt or an edible salt, such as a carboxyl group in the formula For acidic groups, ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, pyrrolidine, piperidine And salts with organic amines such as piperazine and dicyclohexylamine, and salts with basic amino acids such as arginine and lysine. In the case where a basic group is present in the formula, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, citric acid,
Benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hibenzic acid,
Salts with organic carboxylic acids such as pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid, and organic sulfones such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Mention may be made of salts with acids. These salts are produced by contacting the compound with an acid or base that can be used in the production of a pharmaceutical product.

In the present invention, the compound represented by the formula (I) or a salt thereof may be an anhydride, or may form a solvate such as a hydrate or an alcohol adduct. “Solvation” as used herein refers to a phenomenon in which a solute molecule or ion strongly attracts a solvent molecule adjacent to it in a solution to form a single molecular group. For example, hydration is performed when the solvent is water. The solvate may be either a hydrate or a non-hydrate. As the non-hydrate, alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide and the like can be used.

In addition, the compound which is an active ingredient of the present invention and a salt thereof can exist in several tautomeric forms such as enol and imine form, keto and enamine form, and mixtures thereof. Tautomers exist as a mixture of tautomeric sets in solution. In the solid form, one tautomer is usually predominant. Although one tautomer may be described, the present invention includes all tautomers of the compound which is the active ingredient of the present invention.

The present invention includes all stereoisomers (eg, enantiomers, diastereomers (including cis and trans geometric isomers)) of the compounds represented by formula (I), racemates of the isomers, and others. A mixture of For example, the compound which is an active ingredient of the present invention has the formula (I
) May have one or more asymmetric points, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

When the compound according to the present invention is obtained as a free form, it can be converted into a salt which may be formed by the compound or a hydrate or solvate thereof according to a conventional method.

In addition, when the compound according to the present invention is obtained as a salt, hydrate, or solvate of the compound, it can be converted into a free form of the compound according to a conventional method.

The present invention includes all isotopes of the compounds represented by formula (I). The isotope of the compound which is the active ingredient of the present invention is one in which at least one atom is replaced with an atom having the same atomic number (number of protons) and a different mass number (sum of the number of protons and neutrons). . Examples of isotopes contained in the compound which is an active ingredient of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom,
Sulfur atom, a fluorine atom, include a chlorine atom, ^{respectively, 2 H, 3 H, 13} C, 14 C,
¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and the like are included. In particular, unstable radioisotopes that emit radioactivity and emit neutrons, such as ³ H and ¹⁴ C, are useful in the tissue distribution test of pharmaceuticals or compounds. Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity. The isotope of the compound which is the active ingredient of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.

The compound which is an active ingredient of the present invention can be used as a medicine, in particular, as a CaSR agonist agent, and can be used as a prophylactic or therapeutic agent for diseases improved by the activation of CaSR.
CaSR is expressed in various tissues and has various physiological actions. CaSR has a function of detecting an increase in blood calcium concentration in the parathyroid gland, suppressing secretion of parathyroid hormone (PTH), and correcting the blood calcium concentration. Therefore, compounds that activate CaSR are not only the above-mentioned hyperparathyroidism but also bone diseases, upper lower digestive organ diseases (The Journal)
of Clinical Investigation, 1997, Vol. 99, p.2328-2333 and The American Journal o
f Physiology-Gastrointestinal and LiverPhysiology, 2002, 283, p.G240-G250
Diabetes (The Journal of Biological Chemistry, 1999, 274, p.20561-20568
And The Journal of Biological Chemistry, 2000, Vol. 275, p.18777-18784) ・ A variety of hypophyseal hypofunction / hyperhypophysis (Molecular Endocrinology, 1996, p.555-565) It is expected to be a therapeutic drug for diseases.

In addition to calcium regulation, in adipocytes, both mature and undifferentiated adipocytes are CaS.
R is expressed and is involved in suppression of differentiation (Endocrinology. 2005 May; 146 (5): 217
6-9., Exp CellRes. 2004 Dec 10; 301 (2): 280-92.) In bone marrow cells, it is expressed in erythroblasts, megakaryocytes and platelets and is involved in hematopoietic regulation 1997 Dec; 12 (12):
1959-70), expressed in gastric wall cells and involved in gastric acid secretion (J Clin Endocrino
l Metab. 2005 Mar; 90 (3): 1489-94.) has been reported. Other than the above, duodenum, jejunum, ileum (Am J Physiol Gastrointest Liver Physiol. 2002 Jul; 283 (1): G240-50.), Large intestine (Am J Physiol Gastrointest Liver Physiol. 2002 Jul; 283 (1): G240-50 .), Epidermal keratinocytes (Cell Calcium. 2004Mar; 35 (3): 265-73.), Liver cells (J Biol Chem. 2001 Feb
9; 276 (6): 4070-9.), Lens epithelium (Biochem Biophys Res Commun. 1997 Apr 28; 233 (3): 8
01-5.), Pancreatic islets of Langerhans beta cells (Endocrine. 1999 Dec; 11 (3): 293-300.), Lungs (J Clin Endocrinol Metab.1998 Feb; 83 (2): 703-7.), Monocytic cells (J Clin Invest. 2
000 May; 105 (9): 1299-305.), Osteoblast (Endocrinology. 2004 Jul; 145 (7): 3451-62., A
m J Physiol Endocrinol Metab. 2005Mar; 288 (3): E608-16. Epub 2004 Nov 16.), etc., suggesting that it is involved in the functional regulation of these tissues.

In particular, calcium receptors are expressed in gastric G cells and mural cells, and have been shown to promote gastrin and gastric acid secretion (Journalof Clinical Investiga
tion (1997), 99: 2328-2333, Gastroenterology 1999; 116: 118-126). Calcium receptors are expressed in the large intestine and regulate water secretion (The American Journal of Physiology-Ga
stroinstinal and Liver Physiology (2002), 283: G240-G250). Calcium receptor agonists such as cinacalcet and γ-glutamyl peptide derivatives showed inhibitory effects in animal models of diarrhea (WO2008 / 139947), bicarbonate secretion promoting action or somatostatin secretion promoting action, non-steroidal anti-inflammatory In an animal model of drugs (NSAIDs) -induced enterocolitis, it has been shown to have an effect of reducing the area of injury (WO2009 / 119554). It has been shown to be useful as a preventive or therapeutic agent for acid secretion-related diseases such as esophagitis and an appetite regulating agent.
Furthermore, peptides or low molecular weight compounds having calcium receptor activation are intestinal STCs.
-1 cells and GLUTag cells have been shown to promote secretion of GLP-1 and CCK (WO2009 / 11221), CaSR agonistic compounds are useful as prophylactic or therapeutic agents for diabetes and obesity. Usefulness has been shown.
Furthermore, cinacalcet and γ-glutamylvaline have been confirmed to have an ability to promote IgA production by LPS stimulation and an effect to promote IgG production by ConA stimulation (WO2009 / 128523). The compound is useful as an immunostimulating agent, or as a therapeutic or prophylactic agent for diseases in which it is effective to prevent or treat immunity, such as various infectious diseases, diarrhea, polyps, tumors, enteritis, or allergies It is shown.

Therefore, the compound which is an active ingredient of the present invention can be used as an active ingredient of a medicament for preventing or treating a disease ameliorated by the activation of CaSR.
Here, the “disease ameliorated by CaSR activation” is a disease or dysfunction characterized by abnormal calcium homeostasis, or a disease or symptom induced by CaSR functional decline, specifically, , Diarrhea, gastrointestinal acid secretion-related diseases, eating disorders such as increased appetite, hyperparathyroidism (primary and secondary hyperparathyroidism, secondary hyperparathyroidism under maintenance dialysis), Diabetes, obesity, hypoimmune function, Paget's disease, malignant hypercalcemia, osteoporosis, hypertension and the like can be mentioned.
Gastrointestinal acid secretion-related diseases include ulcers and inflammatory diseases in the gastrointestinal tract such as the stomach and small intestine (duodenum, jejunum, ileum), and are due to endogenous factors such as stress and drugs (nonsteroidal anti-inflammatory) Exogenous substances induced by drugs, alcohol, etc.) are also included.

The medicament of the present invention is administered as it is or as a pharmaceutical composition containing the compound which is the active ingredient of the present invention as an active ingredient. The method for applying such a pharmaceutical composition is not particularly limited, and invasive administration, suppository administration, or transdermal administration using oral administration, injection, or the like can be employed. The active ingredient can be mixed with a solid or liquid non-toxic pharmaceutical carrier suitable for administration methods such as oral and injection, and administered in the form of a conventional pharmaceutical preparation.
Examples of such formulations include solid forms such as tablets, granules, pills, powders, capsules, suppositories, dragees or depots, liquid forms such as solutions, suspensions and emulsions, freezing. Examples include desiccant forms. These preparations can be prepared by conventional means on the preparation.

Examples of the non-toxic pharmaceutical carrier include glucose, lactose, sucrose, starch, calcium carbonate, calcium phosphate, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, Examples include gelatin, albumin, amino acids, water, and physiological saline. Further, if necessary, conventional additives such as a stabilizer, a wetting agent, an emulsifier, a binder, and an isotonic agent can be appropriately added.

The pharmaceutical of the present invention is not particularly limited in dosage form and administration form, and may be oral administration, or parenteral administration (intake) such as infusion administration, injection administration (intravenous administration), etc. . In particular, when administered to a patient under maintenance dialysis, intravenous administration is preferable during dialysis, but is not limited thereto.

Oral dosage forms include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, (micro) capsules, chewables, syrups, juices, liquids, suspensions, emulsions, etc. In addition, general dosage forms of pharmaceutical preparations such as preparations that prolong the release of active substances can be employed.
The parenteral administration agents are mainly used as injections, specifically for direct intravenous infusion, infusion administration, and the like, and a form that can be easily administered during dialysis is preferable.

In the case of oral administration, the dose varies depending on the symptom, age, and administration method of the patient to be administered. For example, in the case of oral administration, the amount of CaSR activator per day for an adult is usually preferably 0.001 mg to 10 mg per kg body weight, more preferably 0.1 mg to 1 mg per kg body weight.
In addition, regarding the dosage in the case of parenteral administration such as infusion administration, injection administration (intravenous administration),
It is preferably about 10 to 20 times less than the preferable dose (intake) range for oral administration.
In the case of intravenous administration, for example, a single dose is preferably 0.001 mg to 10 mg per kg body weight, and more preferably 0.01 mg to 0.5 mg per kg body weight.

The medicament of the present invention can be formulated by a conventional method. Various pharmacologically acceptable substances for preparation (as adjuvants etc.) can be blended as required in the preparation. The substance for the preparation can be appropriately selected depending on the dosage form of the preparation. For example, the excipient, the diluent, the additive, the disintegrant, the binder, the coating agent, the lubricant, the lubricant, the lubricant, and the flavoring agent. , Sweeteners, solubilizers and the like. Furthermore, specific examples of the pharmaceutical substance include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, Examples include sterilized water and mono- or polyhydric alcohols such as glycerol.

In addition to conventional methods, the medicament of the present invention can also be formulated in the form of various pharmaceutical preparations to be developed in the future. A method developed in the future can be appropriately adopted for the preparation.

The medicine of the present invention may contain a description containing instructions for use in a package containing them. Examples of what is described include so-called books that describe the use / efficacy and administration methods.
The dosage and usage of the calcium preparation and vitamin D preparation used in combination with the medicament of the present invention are appropriately determined according to the level of blood calcium concentration.

The following examples illustrate the invention in detail. These are preferred embodiments of the present invention and are not limited to these examples. Tables 1 to 15 show the structures and MS values or NMR measurement values of the compounds synthesized according to the method shown below.
In the production example, the purification step A is subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contains 0.1% of trifluoroacetic acid (v / v).
The step of elution with a mixed solution of water and acetonitrile and freeze-drying the target fraction. The ordinary method means a method generally used in synthetic chemistry, for example, solvent extraction, back extraction, washing, neutralization, drying and the like.

Production Example 1 Synthesis of (2S) -2-amino-4-[(pyridin-2-yl) carbamoyl] butanoic acid trifluoroacetate Cbz-Glu-OBzl 70 mg (0.188 mmol, 1 equivalent), O- (7 -Azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium 85 mg (0.226 mmol) hexafluorophosphate (HATU) in 1 ml DMF
Then, 39 μl (0.282 mmol) of triethylamine was added and stirred for 5 minutes. 2-
18 mg of amino-pyridine was added and stirred overnight at room temperature. Work-up was carried out according to a conventional method, and the resulting crude product was dissolved in 3 ml of acetic acid, a catalytic amount of palladium carbon (Pd / C) was added, and the mixture was stirred overnight under a hydrogen atmosphere. After filtering the catalyst, the solvent was distilled off, and the resulting residue was purified using purification step A to give the title compound.
Yield: 23.1 mg

Production Example 2 Synthesis of (2S) -2-amino-4-[(5-bromo-6-methylpyridin-2-yl) carbamoyl] butanoic acid trifluoroacetate Boc-Glu-OtBu 100 mg (0.33 mmol), 1 -Hydroxy-7-azabenzotriazole 53.8 mg (0.40 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate 150. 4 mg (0.40 mmol) was dissolved in 1 ml of DMF, 68.5 μl (0.49 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 5 minutes. 6-amino-3-
Bromo-2-methylpyridine (61.7 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature overnight. After diluting the reaction solution with water and acetonitrile, purification step A was used to obtain 109.3 mg of a crude product of the protected title compound. To the obtained crude product, 2 ml of trifluoroacetic acid was added and stirred overnight at room temperature. After the solvent was distilled off, purification was performed using purification step A to obtain the title compound.
Yield: 43.36 mg

Production Example 3
Synthesis of (2S) -2-amino-4-[(3-sulfophenyl) sulfamoyl] butanoic acid Med. Chem. 1999, 42, 5197-5111 as an intermediate 2-{[(benzyloxy) carbonyl] amino} -4-[(3-{[
0.24 g (0.425 mmol) of (benzyloxy) carbonyl] amino} -4-methoxy-4-oxobutyl) disulfanyl] butanoate was obtained. The resulting intermediate 0.
To 24 g, 2 ml of acetic acid and 0.5 ml of water were added, and 87 μl (1.7 mmol) of bromine was added under ice cooling. After stirring for 20 minutes, the solvent was distilled off, and after-treatment according to a conventional method using ethyl acetate and 1M hydrochloric acid, the solvent was distilled off. To the obtained residue, 191 mg of 3-aminobenzenesulfonic acid (1
. 1 mmol) was added and suspended in 5 ml of methylene chloride. Thereto was added 0.52 ml (3 mmol) of N, N-diisopropylethylamine, and the mixture was stirred overnight. After distilling off the solvent,
Using purification step A, 33.2 mg of crude product was obtained.
The obtained crude product was dissolved in 1 ml of tetrahydrofuran, 0.5 ml of methanol and 0.5 ml of water, and 9 mg of lithium hydroxide was added. After stirring for 1 hour, the solvent was distilled off. 3 ml of 48% hydrobromic acid solution was added to the resulting residue and stirred for 1 hour. After the solvent was distilled off, the title compound was obtained by purification using purification step A.
Yield: 9.2 mg

Production Example 4
(2R) -2-amino-3-{[(3-sulfophenyl) carbamoyl] sulfanyl}
Synthesis of propanoic acid Di-t dissolved in 2 ml of tetrahydrofuran by adding 171 mg (1 mmol) of L-cysteine methyl ester hydrochloride to 2 ml of tetrahydrofuran and 0.3 ml of triethylamine
218 mg (1 mmol) of ert-butyl dicarbonate was added and stirred at room temperature for 2 hours. After treatment with ethyl acetate and 10% aqueous citric acid solution according to a conventional method, Boc-Cys-O
A crude product of Me was obtained. The obtained crude product and 191 mg of 3-aminobenzenesulfonic acid
Triphosgene (100 mg, 0.33 mmol) was added and suspended in 3 ml of methylene chloride. Thereto was added 3 mmol of N, N-diisopropylethylamine, followed by stirring for 2 hours. After distilling off the solvent, the residue was diluted with water and acetonitrile, and purified step A was used to obtain 72 mg of a crude product of the protected title compound. 72 mg of the resulting crude product was dissolved in 1 ml of tetrahydrofuran, 0.5 ml of methanol and 0.5 ml of water, 17 mg of lithium hydroxide was added, and 2 ml at room temperature was added.
Stir for hours. After the solvent was distilled off, 2 ml of trifluoroacetic acid was added and stirred for 2 hours. The obtained residue was purified by purification step A to obtain the title compound.
Yield: 44.0 mg

Production Example 5
(2R) -2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl)
Synthesis of carbamoyl] sulfanyl} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 4 was converted to 3-amino-5-chloro-2
-The title compound was obtained by replacing with hydroxybenzenesulfonic acid and carrying out in the same manner.
Yield: 15.0mg

Production Example 6
(2S) -2-Amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl)
Synthesis of carbamoyl] amino} propanoic acid 3-amino-N- (tert-butoxycarbonyl) -L-alanine tert-butyl ester hydrochloride 297 mg (1 mmol), 3-amino-5-chloro-2-hydroxybenzenesulfonic acid 223 mg (1 mmol), triphosgene 100 mg (0.33 mm)
ol) was suspended in methylene chloride (3 ml), 0.8 ml of pyridine was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the resulting residue was purified using purification step A to obtain a protected form of the title compound. 3 ml of trifluoroacetic acid was added to the obtained protected form, and the mixture was stirred for 5 hours. The solvent was distilled off, and the resulting residue was purified using purification step A to obtain the title compound.
Yield: 20.1 mg

Production Example 7
3-({[(2S) -2-amino-propoxy] carbonyl} amino) -5-chloro-2
-Synthesis of hydroxybenzene-1-sulfonic acid (S) -2- (tert-butoxycarbonylamino) -1-propanol (Boc-
Ala-ol) 75 mg (1 mmol), 3-amino-5-chloro-2-hydroxybenzenesulfonic acid 223 mg (1 mmol), triphosgene 100 mg (0.33 mmol)
) Was suspended in 3 ml of methylene chloride and 0.7 ml of pyridine was added. After stirring overnight at room temperature, the solvent was distilled off and the residue was purified using purification step A to obtain a crude product of the title compound in the protected form.
To the obtained crude product, 2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the resulting residue was added with water and acetonitrile. Obtained.
Yield: 140.1 mg

Production Example 8
3-({[(2S) -2-Amino-3-methylbutoxy] carbonyl} amino) -5-chloro-2-hydroxybenzene-1-sulfonic acid The Boc-Ala-ol used in Production Example 7 (S )-(−)-2- (butoxycarbonylamino-3-methyl 1-butanol (Boc-Val-ol)) was carried out in the same manner to give the title compound.
Yield: 108.5 mg

Production Example 9
3-({[(2S) -2-Amino-3-phenylpropoxy] carbonyl} amino) -5
-Synthesis of chloro-2-hydroxybenzene-1-sulfonic acid (S) -2- (benzyloxycarbonylamino) -3-phenyl-1-propanol 285 mg (1 mmol), 3-amino-5-chloro-2-hydroxy 223 mg (1 mmol) of benzenesulfonic acid and 100 mg (0.33 mmol) of triphosgene were suspended in 3 ml of methylene chloride, and 0.7 ml of pyridine was added dropwise. After stirring overnight at room temperature, the solvent was distilled off and the residue was purified using purification step A to obtain a crude product of the title compound in the protected form. Add 2 ml of 48% hydrobromic acetic acid solution to the crudely purified product and stir at room temperature for 2 hours, then evaporate the solvent, add water and acetonitrile to the resulting residue, and filter the precipitated solid. Gave the title compound.
Yield: 151.6 mg

Production Example 10
3-({[(2S) -2-amino-2-phenylethoxy] carbonyl} amino) -5-
Synthesis of chloro-2-hydroxybenzene-1-sulfonic acid Boc-Ala-ol used in Production Example 7 was replaced with (S) -N- (tert-butoxycarbonyl) -2-phenylglycinol, and the same procedure was carried out. This gave the title compound.
Yield: 55.2 mg

Production Example 11
3-({[(2S) -2-amino-4-carbamoylbutoxy] carbonyl} amino)-
Synthesis of 5-chloro-2-hydroxybenzene-1-sulfonic acid Boc-Ala-ol used in Production Example 7 was converted to (S) -tert-butyl 5-amino-1
The title compound was obtained by substituting -hydroxy-5-oxopentan-2-ylcarbamate (Boc-Gln-ol) and carrying out in the same manner.
Yield: 25.2 mg

Production Example 12
Synthesis of 3-({[(2S) -2-amino-4-cyanobutoxy] carbonyl} amino) -5-chloro-2-hydroxybenzene-1-sulfonic acid Obtained as a by-product during Preparation Example 11 synthesis .
Yield: 6.2mg

Production Example 13
Synthesis of (2S) -2-amino-3-{[(3-chloro-4-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid 3-amino-N- (tert-butoxycarbonyl) -L-alanine Methylene chloride was added to 100 mg (0.336 mmol) of tert-butyl ester hydrochloride, 74 mg (0.336 mmol) of 5-amino-3-chloro-2-methylbenzenesulfonic acid, 55 mg (0.336 mmol) of N, N-carbonyldiimidazole. 1 ml and 0.25 ml of pyridine were added and stirred overnight at room temperature. The solvent is distilled off and the resulting residue is purified using purification step A,
A protected form of the title compound was obtained. 3 ml of trifluoroacetic acid was added to the obtained protected form, and the mixture was stirred for 2 hours. Then, the solvent was distilled off, and the resulting residue was purified using the purification step A to obtain the title compound.
Yield: 43.98 mg

Production Example 14
Synthesis of (2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid In Production Example 13, 5-amino-3-chloro-2-methyl The title compound was obtained in the same manner using 3-amino-5-chloro-4-methylbenzenesulfonic acid instead of benzenesulfonic acid.
Yield: 4.0mg

Production Example 15
3-[(4S) -4-amino-4- (5-methyl-1,3,4-oxadiazol-2-
Yl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid (step 1)
(4S) -4-{[(tert-butoxy) carbonyl] amino} -4- (5-methyl-1,3,4-oxadiazole-2-
Yl) butanoic acid Synthesis of benzyl ester (S) -5- (benzyloxy) -2- (tert-butoxycarbonylamino) -5
To 674 mg (2 mmol) of oxopentanoic acid (Boc-Glu (OBzl) -OH) and 148 mg (2 mmol) of acetohydrazide, 5 ml of tetrahydrofuran was added, and N, N-
356 mg of carbonyldiimidazole was added and stirred at room temperature overnight. The solvent was distilled off and the residue was purified using purification step A, and (4S) -4- (N′-acetylhydrazinecarbonyl) -4-
A crude product of {[(tert-butoxy) carbonyl] amino} butanoic acid benzyl ester was obtained. The obtained crude product was dissolved in 2 ml of methylene chloride, and Burgess reagent 72 was added.
mg was added and stirred at room temperature overnight. Further, 72 mg of Burgess reagent was added and stirred for 2 days. After the solvent was distilled off, the title compound was obtained by purification using purification step A.

Process 2
The compound obtained in Step 1 was dissolved in ethyl acetate, a catalytic amount of Pd / C was added, and the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered off and the solvent was distilled off to obtain a crude product. The obtained crude product was
Amino-5-chloro-2-hydroxybenzenesulfonic acid 6 mg, 1-hydroxy-7-
Azabenzotriazole 4.3 mg, O- (7-azabenzotriazol-1-yl)-
N, N, N ′, N′-tetramethyluronium hexafluorophosphate 12 mg,
0.5 ml of DMF and 11 μl of triethylamine were added and stirred overnight. After diluting with water and acetonitrile, a crude product obtained by purification in purification step A was obtained. To the obtained crude product, 1 ml of trifluoroacetic acid was added and stirred for 1 hour, then the solvent was distilled off, and the resulting residue was purified in purification step A to obtain the title compound.
Yield: 5.2mg

Production Example 16
3-[(4S) -4-amino-4- (5-benzyl-1,3,4-oxadiazol-2)
-Yl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid synthesis (step 1)
(4S) -4- (5-Benzyl-1,3,4-oxadiazol-2-yl) -4-{[(tert-butoxy) carbonyl]
Synthesis of amino} butanoic acid benzyl ester Boc-Glu (OBzl) -OH 337 mg (1 mmol) and 2-phenylacetohydrazide 150 mg (1 mmol) were dissolved in methylene chloride to give 1- (3-dimethylamino-propyl) -3- Ethylcarbodiimide hydrochloride 235 mg, 1-hydroxybenzotriazole monohydrate 183 mg, and triethylamine 278 μl were sequentially added. 3 at room temperature
After stirring for hours, the mixture was post-treated with ethyl acetate, 1M aqueous sodium hydroxide solution, 1M hydrochloric acid and saturated brine, and then the solvent was distilled off to obtain 0.392 g of a crude product. The obtained crude product was dissolved in 5 ml of methylene chloride, 260 mg of Burgess reagent was added, and the mixture was stirred for 3 days. After post-treatment with ethyl acetate, 1M aqueous sodium hydroxide, 1M hydrochloric acid and saturated brine, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain the title compound.
Yield: 96mg

Process 2
The title compound was obtained by performing the same operations as in Production Example 15, Step 2 on the compound obtained in Step 1.
Yield: 27.6 mg

Production Example 17
Synthesis of 3-[(4S) -4-amino-5-oxo-5- (2-phenylacetohydrazide) pentanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid Obtained as product.
Yield 44.4 mg

Production Example 18
3-[(4S) -4-amino-4- (5-benzyl-1,3,4-oxadiazole-2)
-Yl) butanamide] Synthesis of benzene-1-sulfonic acid The same procedure as in Production Example 16 was carried out except that 3-amino-5-chloro-2-hydroxybenzenesulfonic acid used in Step 2 was replaced with 3-aminobenzenesulfonic acid. As a result, the title compound was obtained.
Yield: 15.6 mg

Production Example 19
3-[(4S) -4-amino-4- [5- (4-bromophenyl) -1,3,4-oxadiazol-2-yl] butanamide] -5-chloro-2-hydroxybenzene-1 —Synthesis of Sulfonic Acid The title compound was obtained in the same manner by substituting 4-bromobenzhydrazide instead of 2-phenylacetohydrazide used in Step 1 of Production Example 16.
Yield: 48.9 mg

Production Example 20
Synthesis of 3-[(4S) -4-amino-4- [5- (4-bromophenyl) -1,3,4-oxadiazol-2-yl] butanamide] benzene-1-sulfonic acid Production Example 16 4-bromobenzhydrazide is used instead of 2-phenylacetohydrazide used in Step 1 above, and 3-aminobenzenesulfonic acid used in Step 2 is replaced with 3-aminobenzenesulfonic acid. To give the title compound.
Yield: 73.2 mg

Production Example 21
3-[(4S) -4-amino-4- (5-phenyl-1,3,4-oxadiazol-2)
-Yl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid synthesis Step 1 and Step 2 were carried out using benzhydrazide instead of 2-phenylacetohydrazide used in Step 1 of Preparation Example 16. As a result, the title compound was obtained.
Yield: 25.6 mg

Production Example 22
Synthesis of 3-[(4S) -4-amino-4- (benzylcarbamoyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid Boc-Glu (OBzl) -OH 2.0 mmol, 1- (3-dimethylamino-
Propyl) -3-ethylcarbodiimide hydrochloride 2.2 mmol, 1-hydroxybenzotriazole monohydrate 2.2 mmol was dissolved in methylene chloride and 2.5 mL of triethylamine was added. Benzylamine 2.0 mmol was added there and it stirred all night. After post-treatment with ethyl acetate, 1M aqueous sodium hydroxide solution, 1M hydrochloric acid and saturated brine, the solvent was distilled off. The obtained residue was dissolved in 5 ml of THF, 2.5 ml of methanol, and 2.5 ml of water, 90 mg of lithium hydroxide was added, and the mixture was stirred at room temperature for 2 hours. After post-treatment with ethyl acetate, 1M hydrochloric acid and saturated brine, the solvent was distilled off to obtain 440 mg of residue. To the obtained residue, 261 mg of 1-hydroxy-7-azabenzotriazole, O- (7-
Azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium
730 mg of hexafluorophosphate and 330 mg of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid were added and dissolved in 5 ml of DMF. Triethylamine 4 there
12 μl was added and stirred overnight at room temperature. After distilling off the solvent, purification was performed using purification step A to obtain a crude product of the protected title compound. The obtained crude product was dissolved in 5 ml of methylene chloride and 3 ml of trifluoroacetic acid and stirred for 2 hours. After the solvent was distilled off, purification was performed using purification step A to obtain the title compound.
Yield: 76.3 mg

Production Example 23
Synthesis of 3-[(4S) -4-amino-4-[(2-phenylethyl) carbamoyl] butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid Boc-Glu (OMe) -OH 0 mmol, 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride 2.2 mmol, 1-hydroxybenzotriazole monohydrate 2.2 mmol was dissolved in methylene chloride and triethylamine 2.5 m was dissolved.
mol was added. To this, 2.0 mmol of 2-phenylethylamine was added and stirred overnight. After post-treatment with ethyl acetate, 1M aqueous sodium hydroxide solution, 1M hydrochloric acid and saturated brine, the solvent was distilled off. The obtained residue was dissolved in THF 5 ml, methanol 2.5 ml, water 2.5 m.
Dissolve in 1 and add 90 mg of lithium hydroxide and stir at room temperature for 2 hours. Ethyl acetate, 1M
After post-treatment with hydrochloric acid and saturated brine, the solvent was distilled off to obtain 440 mg of residue. To the obtained residue, 261 mg of 1-hydroxy-7-azabenzotriazole, 730 mg of O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, 3 -330 mg of amino-5-chloro-2-hydroxybenzenesulfonic acid was added and dissolved in 5 ml of DMF. Thereto 412 μl of triethylamine
And stirred at room temperature overnight. After distilling off the solvent, purification was performed using purification step A to obtain a crude product of the protected title compound. The obtained crude product was dissolved in 5 ml of methylene chloride and 3 ml of trifluoroacetic acid and stirred for 2 hours. After distilling off the solvent, water and acetonitrile were added and the precipitated solid was filtered off to obtain the title compound.
Yield: 151.9 mg

Production Example 24
Synthesis of 3-[(4S) -4-amino-4-[(3-phenylpropyl) carbamoyl] butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid 3 of 2-phenylethylamine of Preparation Example 23 -The title compound was obtained by carrying out in the same manner replacing with phenylpropylamine.
Yield: 126.7 mg

Production Example 25
Synthesis of 3-[(4S) -4-amino-4-[(5-phenylbutyl) carbamoyl] butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid -The title compound was obtained in the same manner by replacing with phenylbutylamine.
Yield: 135.9 mg

Production Example 26
3-[(4S) -4-amino-4- {5- [4- (dimethylamino) phenyl] -1,3
, 4-Oxadiazol-2-yl} butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid 4- (dimethyl instead of 2-phenylacetohydrazide used in Step 1 of Production Example 16 The title compound was obtained by carrying out Step 1 and Step 2 using amino) benzhydrazide.
Yield: 48.6 mg

Production Example 27
3-[(4S) -4-Amino-4- [5- (thiophen-2-yl) -1,3,4-oxadiazolo-2-yl] butanamide] -5-chloro-2-hydroxybenzene-1- Synthesis of Sulfonic Acid The title compound was obtained by carrying out Step 1 and Step 2 using 2-thiophenecarboxylic acid hydrazide instead of 2-phenylacetohydrazide used in Step 1 of Production Example 16.
Yield: 40.1mg

Production Example 28
Synthesis of (2S) -2-amino-3-{[(2-hydroxy-3-sulfophenyl) carbamoyl] amino} propanoic acid The compound obtained in Production Example 6 was dissolved in water and methanol, and a catalytic amount of Pd / C was added and stirred for 3 days under a hydrogen atmosphere. After the catalyst was filtered off, the solvent was distilled off and the residue was purified using purification step A to obtain the title compound.
Yield: 1.2mg

Production Example 29
Synthesis of 3-{[(2-aminoethyl) carbamoyl] amino} -5-chloro-2-hydroxybenzene-1-sulfonic acid 3-amino-N- (tert-butoxycarbonyl) -L used in Preparation Example 6 -The title compound was obtained by carrying out similarly using tert-butyl N- (2-aminoethyl) carbamate instead of -alanine tert-butyl ester hydrochloride.
Yield: 1.0 mg

Production Example 30
Synthesis of 3-[(4S) -4-amino-4-{[2- (1H-indol-3-yl) ethyl] carbamoyl} butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid Production Example The title compound was obtained in the same manner using tryptamine instead of 2-phenylethylamine used in No. 23.
Yield: 61.9 mg

Production Example 31
Synthesis of 3-[(4S) -4-amino-4-{[2- (3-methoxyphenyl) ethyl] carbamoyl} butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid Used in Preparation Example 23 The title compound was obtained in the same manner using 3-methoxyphenethylamine instead of 2-phenylethylamine.
Yield: 80.8mg

Production Example 32
Synthesis of 3-[(4S) -4-amino-4-{[2- (3-chlorophenyl) ethyl] carbamoyl} butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid Used in Preparation Example 23 The title compound was obtained in the same manner using 3-chlorophenethylamine instead of 2-phenylethylamine.
Yield: 122mg

Production Example 33
Synthesis of 3-[(4S) -4-amino-4-{[3- (1H-imidazol-1-yl) propyl] carbamoyl} butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid Production Example The title compound was obtained in the same manner using 1- (3-aminopropyl) imidazole instead of 2-phenylethylamine used in No. 23.
Yield: 20mg

Production Example 34
3-[(4S) -4-amino-4- (methanesulfonylcarbamoyl) butanamide]-
Synthesis of 5-chloro-2-hydroxybenzene-1-sulfonic acid 337 mg (1 mmol) of Boc-Glu (OBzl) -OH, 95 mg (1 mmol) of methanesulfonamide, 250 mg of dicyclohexylcarbodiimide (1.2 mmo)
l) A catalytic amount of 4- (dimethylamino) pyridine was added and dissolved in 5 ml of methylene chloride. After stirring at room temperature overnight, the insoluble material was filtered off, the solution was distilled off, ethyl acetate, 1M hydrochloric acid,
Work-up with saturated saline. The resulting residue was dissolved in ethyl acetate and a catalytic amount of Pd / C
And stirred overnight under a hydrogen atmosphere. After the catalyst was filtered off, the solvent was distilled off to obtain a residue. To the obtained residue, 220 mg of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid was added, and 150 mg of 1-hydroxy-7-azabenzotriazole, O- (7-azabenzotriazol-1-yl) -N, 400 mg of N, N ′, N′-tetramethyluronium hexafluorophosphate was added, and 1 ml of DMF was added. Triethylamine 200μ
After adding 1 and stirring overnight, confirming the progress of the reaction, dilute the reaction solution with water and acetonitrile,
Purified in purification step A. The resulting crude product was methylene chloride (2 ml) and trifluoroacetic acid (2 m).
I. After stirring for 2 hours, the solvent was distilled off and the residue was purified by purification step A to obtain the title compound.
Yield: 15.3 mg

Production Example 35
Synthesis of 3-[(4S) -4-amino-4- (methanesulfonylcarbamoyl) butanamide] benzene-1-sulfonic acid Instead of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid used in Preparation Example 34 The title compound was obtained by conducting the same operation using 3-aminobenzenesulfonic acid.
Yield: 7.6 mg

Production Example 36
5-[(4S) -4-amino-4- (methanesulfonylcarbamoyl) butanamide]-
Synthesis of 3-chloro-2-methylbenzene-1-sulfonic acid 5-amino-3-chloro-2-methylbenzene instead of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid used in Production Example 34 The title compound was obtained by the same operation using sulfonic acid.
Yield: 108.4 mg

Production Example 37
3-[(4S) -4-amino-4- (methanesulfonylcarbamoyl) butanamide]-
Synthesis of 5-chloro-4-methylbenzene-1-sulfonic acid 3-amino-5-chloro-4-methylbenzene instead of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid used in Production Example 34 The title compound was obtained by the same operation using sulfonic acid.
Yield: 86.8mg

Production Example 38
Synthesis of 3-[(4S) -4-amino-4- (hydroxycarbamoyl) butanamide] benzene-1-sulfonic acid 337 mg (1 mmol) of Boc-Glu-OBzl, 173 mg (1 mmol) of 3-aminobenzenesulfonic acid, O— 420 mg (1.1 mmol) of (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate is dissolved in 2 ml of DMF, 200 μl of triethylamine is added, and the mixture is stirred at room temperature overnight. Stir. After dilution with water and acetonitrile, a crude product was obtained using purification step A. 50 mg of the obtained crude product was dissolved in 1 ml of ethanol, and 200 μl of 50% aqueous hydroxylamine solution was added. After stirring at room temperature overnight, the solvent was distilled off and the residue was purified using purification step A to obtain the title compound.
Yield: 7.49 mg

Production Example 39
Synthesis of 5-[(4S) -4-amino-4- (hydroxycarbamoyl) butanamide] -3-chloro-2-methylbenzene-1-sulfonic acid In Production Example 38, instead of 3-aminobenzenesulfonic acid, The title compound was obtained in the same manner using 5-amino-3-chloro-2-methylbenzenesulfonic acid.
Yield: 5.4 mg

Production Example 40
Synthesis of 3-[(4S) -4-amino-4- (hydroxycarbamoyl) butanamide] -5-chloro-4-methylbenzene-1-sulfonic acid In Production Example 38, instead of 3-aminobenzenesulfonic acid, The title compound was obtained in the same manner using 3-amino-5-chloro-4-methylbenzenesulfonic acid.
Yield: 7.88 mg

Production Example 41
Synthesis of 3-[(4S) -4-amino-4- (hydroxycarbamoyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid In Production Example 38, instead of 3-aminobenzenesulfonic acid, The title compound was obtained in the same manner using 3-amino-5-chloro-2-hydroxybenzenesulfonic acid.
Yield: 5.7 mg

Production Example 42
Synthesis of (2S) -2-amino-4-[(6-sulfopyridin-2-yl) carbamoyl] butanoic acid trifluoroacetate Boc-Glu-OtBu 50 mg (0.16 mmol), 1- (3-dimethylamino -Propyl) -3-ethylcarbodiimide hydrochloride 35 mg (0.16 mmol),
28 mg (0.16 mmol) of 1-hydroxybenzotriazole monohydrate was suspended in 1.0 ml of methylene chloride, and 28 mg (0.1% of 6-amino-2-pyridinesulfonic acid)
6 mmol) was added. After stirring at room temperature overnight, the mixture was extracted with ethyl acetate / water. The organic layer was washed with saturated brine, dried by adding sodium sulfate. The organic layer was concentrated under reduced pressure, 4.0 ml of TFA was added to the resulting residue, and the mixture was stirred overnight. 5. Title compound using purification step A
5 mg was obtained.
Yield: 6.5mg

Production Example 43
(2S, 3S) -2-Amino-3-{[(3-sulfophenyl) carbamoyl] oxy}
Synthesis of butanoic acid (step 1)
Synthesis of Boc-Allo-Thr-OMe 340 mg (2.0 mmol) of Allo-Thr-OMe hydrochloride was added to methylene chloride 8.0.
dissolved in ml, triethylamine 558 μl (4.0 mmol), di-tert-
436 mg (2.0 mmol) of butyl dicarbonate was added. The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and extracted with ethyl acetate / water. The organic layer was washed with a saturated saline solution and then dried by adding sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound.
Yield: 460 mg
MS (ESI, m / z): 234 [M + H] +

Process 2
(2S, 3S) -2-Amino-3-{[(3-sulfophenyl) carbamoyl] oxy}
117 mg of the compound obtained in butanoic acid synthesis step 1, 148 mg (0.5 mmol) of triphosgene, 3
-87 mg (0.5 mmol) of aminobenzenesulfonic acid in 2.0 ml of methylene chloride
Into the solution, 70 μl (0.5 mmol) of triethylamine was added and stirred overnight at room temperature. After adding 1.0 ml of ammonia-methanol solution, the solvent was distilled off. Purification step A
(2S, 3S) -2- (N-tert-butoxycarbonylamino) -3-{[
A crude product of (3-sulfophenyl) carbamoyl] oxy} butanoic acid methyl ester was obtained. To this was added 20 mg (1.2 mmol) of lithium hydroxide and 2.0 ml of water,
Stir at room temperature overnight. Subsequently, 4.0 ml of TFA was added, and the mixture was further stirred at room temperature for 5 hours. After the solvent was distilled off, the purification step A was used to obtain 5.2 mg of the title compound.
Yield 5.2mg

Production Example 44
Synthesis of (2S, 3S) -2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl) carbamoyl] oxy} butanoic acid 3-aminobenzenesulfonic acid used in Production Example 43 3-amino-5-chloro-2
-The title compound was obtained by replacing with hydroxybenzenesulfonic acid and operating in the same manner.
Yield: 32.1 mg

Production Example 45
Synthesis of (2S, 3R) -2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl) carbamoyl] oxy} butanoic acid In Step 2 and subsequent steps of Production Example 43, Boc-Allo-Thr -OMe to Boc-Th
The title compound was obtained by replacing r-OMe and 3-aminobenzenesulfonic acid with 3-amino-5-chloro-2-hydroxybenzenesulfonic acid and operating in the same manner.
Yield: 33.4 mg

Production Example 46
Synthesis of (2S) -2-amino-3-{[(3-sulfophenyl) carbamothioyl] amino} propanoic acid 35 mg (0.2 mmol) of 3-aminobenzenesulfonic acid, sodium bicarbonate
57 mg (0.68 mmol) was added to a mixed solvent of 2.0 ml of water and 0.5 ml of THF, and the mixture was stirred at room temperature for 15 minutes. Add 20 μl (0.26 mmol) of thiophosgene and stir for an additional 40 minutes at room temperature, followed by (2S) -3-amino-2-{[(tert-butoxy)
Carbonyl] amino} propanoic acid tert-butyl hydrochloride 60 mg (0.2 mmol)
) And stirred overnight. After extraction with ethyl acetate, the solvent was distilled off, 4.0 ml of trifluoroacetic acid was added to the residue, and the mixture was stirred at room temperature for 5 hours. After distilling off the solvent, purification step A was used to obtain 3.5 mg of the title compound.
Yield: 3.5mg

Production Example 47
Synthesis of (2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamothioyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 46 3-amino-5-chloro-4
-The title compound was obtained by replacing with methylbenzenesulfonic acid and operating in the same manner.
Yield: 6.9 mg

Production Example 48
Synthesis of (2S) -2-amino-3-{[(3-chloro-4-methyl-5-sulfophenyl) carbamothioyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 46 5-Amino-3-chloro-2
-The title compound was obtained by replacing with methylbenzenesulfonic acid and operating in the same manner. Yield: 5.8 mg

Production Example 49
Synthesis of 3-[(4S) -4-amino-4- (carbamoyl) butanamide] benzene-1-sulfonic acid (Step 1)
Synthesis of (4S) -4- (N-tert-butoxycarbonylamino) -4- (carbamoyl) butanoic acid Boc-Glu (OBzl) -OH 1010 mg (3.0 mmol), ethyl chloroformate 316 μl (3.3 mmol), 460 μl (3.3 mmol) of triethylamine
Was suspended in 12.0 ml of tetrahydrofuran, and 2.0 ml of concentrated aqueous ammonia solution was added. After stirring at room temperature overnight, the mixture was extracted with ethyl acetate / water. The organic layer was washed with saturated brine, dried by adding sodium sulfate. The organic layer was concentrated under reduced pressure and 10% Pd was added to the resulting residue.
/ C 100 mg and methanol 12.0 ml were added, and the mixture was stirred overnight at room temperature under a normal pressure hydrogen atmosphere. After the reaction, the catalyst was removed by filtration, and then the solvent was distilled off to obtain a crude product of the title compound.
MS (ESI, m / z): 275 [M + H] +

(Process 2)
3-[(4S) -4-amino-4- (carbamoyl) butanamide] -benzene-1-sulfonic acid compound 100 mg (0.37 mmol) obtained in O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate 190 mg (0.5 mmol), 1-hydroxy-7-azabenzotriazole 70 mg (0.5 mmol), 3-aminobenzenesulfone 65 mg of acid (0.
37 mmol) was suspended in 2.0 ml of methylene chloride, 0.5 ml of pyridine was added, and the mixture was stirred at room temperature overnight. After distilling off the solvent, 3-[(4S) -4- (N-
A crude product of tert-butoxycarbonylamino) -4- (carbamoyl) butanamide] -benzene-1-sulfonic acid was obtained. To this, 4.0 ml of TFA was added and stirred at room temperature for 2 hours. After distilling off the solvent, purification step A was used to obtain 1.6 mg of the title compound.
Yield: 1.6mg

Production Example 50
3-[(4S) -4-Amino-4- (carbamoyl) butanamide] -5-chloro-2-
Synthesis of hydroxybenzene-1-sulfonic acid 3-aminobenzenesulfonic acid used in Production Example 49 was converted to 3-amino-5-chloro-2.
-The title compound was obtained by replacing with hydroxybenzenesulfonic acid and operating in the same manner.
Yield: 4.1mg

Production Example 51
5-[(4S) -4-Amino-4- (carbamoyl) butanamide] -3-chloro-2-
Synthesis of methylbenzene-1-sulfonic acid 3-aminobenzenesulfonic acid used in Production Example 49 was converted to 3-amino-5-chloro-6.
-The title compound was obtained by replacing with methylbenzenesulfonic acid and operating in the same manner.
Yield: 5.3mg

Production Example 52
3-[(4S) -4-amino-4- (5-ethyl-1,3,4-oxadiazole-2-
Yl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid (step 1)
Synthesis of (4S) -4- (N-tert-butoxycarbonylamino) -4- (N′-propionylcarbohydrazide) butanoic acid benzyl ester Boc-Glu (OBzl) -OH 674 mg (2.0 mmol), 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 420 mg (2.2 mmo
l), 1-hydroxybenzotriazole monohydrate, 336 mg (2.2 mmol),
Propionic acid hydrazide (230 mg, 2.6 mmol) was suspended in methylene chloride (5.0 ml), and triethylamine (557 μl, 4.0 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure, and the crude product of the title compound was obtained using purification step A.
Yield: 500mg
MS (ESI, m / z): 380 [M + H] +

(Process 2)
(4S) -4- (N-tert-butoxycarbonylamino) -4- (5-ethyl-1,
Synthesis of 3,4-oxadiazol-2-yl) butanoic acid 500 mg of the compound obtained in Step 1, Burgess reagent 182 mg (0.76 m)
mol) was dissolved in 4.0 ml of methylene chloride and stirred overnight at room temperature. After the solvent was distilled off, the residue was roughly purified using silica gel column chromatography. 10% Pd / C 5 in the residue
0 mg and 4.0 ml of ethyl acetate were added, and the mixture was stirred overnight at room temperature under a normal pressure hydrogen atmosphere. After the reaction, the catalyst was removed by filtration, and then the solvent was distilled off to obtain a crude product of the title compound.
Yield: 270 mg
MS (ESI, m / z): 300 [M + H] +

(Process 3)
3-[(4S) -4-amino-4- (5-ethyl-1,3,4-oxadiazole-2-
yl) Butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid synthesis 270 mg of the compound obtained in Step 2, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N'-tetramethyluronium hexafluorophosphate 26
6 mg (0.7 mmol), 1-hydroxy-7-azabenzotriazole 100 mg
(0.7 mmol), 3-amino-5-chloro-2-hydroxybenzenesulfonic acid 1
60 mg (0.7 mmol) was suspended in 4.0 ml of methylene chloride, 0.3 ml of triethylamine was added, and the mixture was stirred at room temperature overnight. After distilling off the solvent, the purification step A was used and 3- [
(4S) -4- (N-tert-butoxycarbonylamino) -4- (5-ethyl-1,
A crude product of 3,4-oxadiazol-2-yl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid was obtained. To this was added 4.0 ml of TFA and 2 at room temperature.
Stir for hours. After distilling off the solvent, purification step A was used to obtain 9.0 mg of the title compound.
Yield: 9.0mg

Production Example 53
Synthesis of 3-[(4S) -4-amino-4- (N′-propanoylhydrazinecarbonyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid By-product in Step 3 of Preparation 52 Got as.
Yield: 12.8 mg

Production Example 54
3-[(4S) -4-amino-4- (5-propyl-1,3,4-oxadiazole-2)
-Yl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid synthesis The title compound was obtained by replacing propionic acid hydrazide used in Step 1 of Production Example 52 with butyric acid hydrazide and operating in the same manner. Got.
Yield: 12.0mg

Production Example 55
3-[(4S) -4-amino-4- [5- (propan-2-yl) -1,3,4-oxadiazol-2-yl] butanamide] -5-chloro-2-hydroxybenzene- Synthesis of 1-sulfonic acid Propionic acid hydrazide used in Step 1 of Production Example 52 was replaced with isobutyl acid hydrazide, and the same operation was performed to obtain the title compound.
Yield: 11.8mg

Production Example 56
Synthesis of 3-[(4S) -4-amino-4- (ethylcarbamoyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid (Step 1)
Synthesis of (4S) -4- (N-tert-butoxycarbonylamino) -4- (ethylcarbamoyl) butanoic acid Boc-Glu (OBzl) -OH 337 mg (1.0 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 191 mg (1.0 mmo
1) 152 mg (1.0 mmol) of 1-hydroxybenzotriazole monohydrate and 0.5 ml of triethylamine were suspended in 4.0 ml of DMF, and 150 μl of 33% ethylamine aqueous solution was added. After stirring at room temperature overnight, the mixture was extracted with ethyl acetate / water. The organic layer was washed with saturated brine, dried by adding sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was dissolved in 4.0 ml of 10% aqueous sodium hydroxide solution and stirred overnight. Purification step A was used to obtain a crude product of the title compound.
MS (ESI, m / z): 275 [M + H] +

(Process 2)
Synthesis of 3-[(4S) -4-amino-4- (ethylcarbamoyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid 220 mg (0.8 mmol) of the compound obtained in Step 1, O -(7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate 300 mg (0.8 mmol), 1-hydroxy-7-azabenzotriazole 110 mg (0. 8 mmol), 180 mg (0.8 mmol) of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid was suspended in 4.0 ml of methylene chloride, 0.5 ml of triethylamine was added, and the mixture was stirred at room temperature overnight. After distilling off the solvent, 3-[(4S) -4- (N-tert-butoxycarbonylamino) -4-
160 mg of a crude product of (ethylcarbamoyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid was obtained. 144 mg of this crude product was added to TFA 4.0 m.
in 1 and stirred at room temperature for 2 hours. After distilling off the solvent, 5.8 mg of the title compound was obtained using purification step A.
Yield: 5.8mg

Production Example 57
Synthesis of 3-[(4S) -4-amino-4- (butylcarbamoyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid The ethylamine aqueous solution used in Step 1 of Production Example 56 was dissolved in n- Replaced with butylamine,
The title compound was obtained by the same operation.
Yield: 11.5mg

Production Example 58
Synthesis of 3-[(4S) -4-amino-5- (morpholin-4-yl) -5-oxopentanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid In Step 1 of Preparation 56 The title compound was obtained by replacing the aqueous ethylamine solution used with morpholine and operating in the same manner.
Yield: 7.6 mg

Production Example 59
3-[(4S) -4-amino-4- (cyclohexylcarbamoyl) butanamide] -5
Synthesis of -Chloro-2-hydroxybenzene-1-sulfonic acid The ethylamine aqueous solution used in Step 1 of Production Example 56 was replaced with cyclohexylamine, and the same operation was performed to obtain the title compound.
Yield: 3.9 mg

Production Example 60
3-[(4S) 4-Amino-4- (cycloheptylcarbamoyl) butanamide] -5
Synthesis of chloro-2-hydroxybenzene-1-sulfonic acid The ethylamine aqueous solution used in Step 1 of Production Example 56 was replaced with cycloheptylamine, and the same operation was performed to obtain the title compound.
Yield: 1.6mg

Production Example 61
Synthesis of 3-[(4S) -4-amino-4-[(benzenesulfonyl) carbamoyl] butanamide] benzene-1-sulfonic acid (Step 1)
Synthesis of (4S) -4- (N-tert-butoxycarbonylamino) -4-[(benzenesulfonyl) carbamoyl] butanoic acid Boc-Glu (OBzl) -OH 1.7 g (5.0 mmol), dicyclohexylcarbodiimide 03 g (5.0 mmol), 4- (dimethylamino) pyridine 6
11 mg (5.0 mmol) was suspended in 20 ml of methylene chloride, and 866 mg (5.0 mmol) of benzenesulfonamide was added. After stirring overnight at room temperature, ethyl acetate / 1
The mixture was extracted with N hydrochloric acid, and the organic layer was washed with saturated brine, and then dried by adding sodium sulfate.
The organic layer was concentrated under reduced pressure, and 10% Pd / C 100 mg, methanol 20 was added to the obtained residue.
ml was added, and the mixture was stirred overnight under a normal pressure hydrogen atmosphere. After removing the catalyst by filtration, the solvent was distilled off, and purification step A was used to obtain a crude product of the title compound.
MS (ESI, m / z): 387 [M + H] +

(Process 2)
Synthesis of 3-[(4S) -4-amino-4-[(benzenesulfonyl) carbamoyl] butanamide] benzene-1-sulfonic acid 100 mg of the compound obtained in Step 1, O- (7-azabenzotriazole-1- Yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate 11
4 mg (0.3 mmol), 1-hydroxy-7-azabenzotriazole 40 mg (
0.8 mmol), 55 mg (0.3 mmol) of 3-aminobenzenesulfonic acid was suspended in 1.0 ml of methylene chloride, 0.1 ml of triethylamine was added, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, purification step A was used to prepare 3-[(4S) -4- (N-tert-butoxycarbonylamino) -4-[(benzenesulfonyl) carbamoyl] butanamide] benzene-1-sulfonic acid. A crude product was obtained. This crude product was dissolved in 4.0 ml of TFA and stirred at room temperature for 2 hours. After distilling off the solvent, the title compound 14 was purified using purification step A.
. 1 mg was obtained.
Yield: 14.1 mg

Production Example 62
Synthesis of 3-[(4S) -4-amino-4-[(benzenesulfonyl) carbamoyl] butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid 3-aminobenzene used in Preparation Example 61, step 2 The title compound was obtained by replacing the sulfonic acid with 3-amino-5-chloro-2-hydroxybenzenesulfonic acid and operating in the same manner.
Yield: 3.2mg

Production Example 63
Synthesis of 3-[(4S) -4-amino-4-[(benzenesulfonyl) carbamoyl] butanamide] -5-chloro-4-methylbenzene-1-sulfonic acid 3-aminobenzene used in Preparation Example 61, step 2 The title compound was obtained by replacing the sulfonic acid with 3-amino-5-chloro-4-methylbenzenesulfonic acid and operating in the same manner.
Yield: 31.4 mg

Production Example 64
3-[(4S) -4-amino-4- (methylcarbamoyl) butanamide] benzene-1
-Synthesis of sulfonic acid

(Process 1)
Synthesis of (4S) -4- (N-tert-butoxycarbonylamino) -4- (methylcarbamoyl) butanoic acid Boc-Glu (OBzl) -OH 1010 mg (3 mmol), 1- (3-dimethylaminopropyl) -3 -Ethylcarbodiimide hydrochloride 600 mg (3.2 mmol)
), 1-hydroxybenzotriazole monohydrate 460 mg (3.1 mmol)
The suspension was suspended in 12 ml of F, and 300 μl (2.0 mmol) of 40% aqueous methylamine solution was added. After stirring at room temperature overnight, the mixture was extracted with ethyl acetate / water. The organic layer was washed with saturated brine, dried by adding sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was dissolved in 10 ml of methanol. After adding 100 mg of 10% Pd / C, the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was removed by filtration, the solvent was distilled off, and then purification step A was used to obtain a crude product of the title compound.
MS (ESI, m / z): 261 [M + H] +

Process 2
3-[(4S) -4-amino-4- (methylcarbamoyl) butanamide] benzene-1
-Synthesis of sulfonic acid 100 mg of the compound obtained in step 1, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate 76
mg (0.2 mmol), 1-hydroxy-7-azabenzotriazole 28 mg (0
. 2 mmol) and 36 mg (0.2 mmol) of 3-aminobenzenesulfonic acid were suspended in 1.0 ml of methylene chloride, 0.1 ml of triethylamine was added, and the mixture was stirred at room temperature overnight. After distilling off the solvent, purification step A was used to obtain a crude product of 3-[(4S) -4- (N-tert-butoxycarbonylamino) -4- (methylcarbamoyl) butanamide] benzene-1-sulfonic acid Got. This crude product was dissolved in 4.0 ml of TFA and stirred at room temperature for 2 hours. After the solvent was distilled off, 9.9 mg of the title compound was obtained using purification step A.
Yield: 9.9 mg

Production Example 65
Synthesis of 3-[(4S) -4-amino-4- (methylcarbamoyl) butanamide] -5-chloro-4-methylbenzene-1-sulfonic acid 3-aminobenzenesulfonic acid used in Production Example 64, Step 2 The title compound was obtained by replacing with 3-amino-5-chloro-4-methylbenzenesulfonic acid and operating in the same manner.
Yield: 4.1mg

Production Example 66
3-({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl}
Synthesis of amino) benzene-1-sulfonic acid (2S) -3-amino-2-{[(tert-butoxy) carbonyl] amino} propanoic acid methyl ester hydrochloride 127 mg (0.5 mmol), 3-aminobenzenesulfonic acid 87 mg (0.5 mmol), N, N-carbonyldiimidazole 97 mg (0.6
mmol) was added with 1 ml of methylene chloride and 1 ml of tetrahydrofuran, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, purification was performed using purification step A to obtain a crude product of the protected title compound. To the resulting crude product, 1 ml of methylene chloride and 1 ml of trifluoroacetic acid were added,
Stir at room temperature for 5 hours. After the solvent was distilled off, purification was performed in purification step A to obtain the title compound.
Yield: 33.15 mg

Production Example 67
3-({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl}
Synthesis of Amino) -5-chloro-2-hydroxybenzene-1-sulfonic acid The 3-aminobenzenesulfonic acid used in Production Example 66 was replaced with 3-amino-5-chloro-2-hydroxybenzenesulfonic acid in the same manner. The title compound was obtained by carrying out.
Yield 19.1 mg

Production Example 68
5-({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl}
Synthesis of amino) -3-chloro-2-methylbenzene-1-sulfonic acid 3-aminobenzenesulfonic acid used in Production Example 66 was replaced with 5-amino-3-chloro-2-methylbenzenesulfonic acid in the same manner. The title compound was obtained by carrying out.
Yield 11.84 mg

Production Example 69
3-({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl}
Synthesis of Amino) -5-chloro-4-methylbenzene-1-sulfonic acid The 3-aminobenzenesulfonic acid used in Production Example 66 was replaced with 3-amino-5-chloro-4-methylbenzenesulfonic acid in the same manner. The title compound was obtained by carrying out.
Yield 14.57mg

Production Example 70
3-({[(2S) -2-amino 2- (methylcarbamoyl) ethoxy] carbonyl}
Synthesis of amino) benzene-1-sulfonic acid (step 1)
N-[(1S) -2-hydroxy-1- (methylcarbamoyl) ethyl] carbamic acid
Synthesis of t-butyl Boc-Ser (OBzl) -OH 885 mg (3.0 mmol), 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride 600 mg (3.2 mm)
ol), 460 mg (3.1 mmol) of 1-hydroxybenzotriazole monohydrate was dissolved in 12 ml of DMF, and 300 μl of 40% aqueous methylamine solution was added. After stirring overnight at room temperature, the mixture was extracted with ethyl acetate / 1N hydrochloric acid, and the organic layer was washed with saturated brine, and dried by adding sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was methanol 12.
After dissolving in ml, 100 mg of 10% Pd / C was added and stirred overnight in a hydrogen atmosphere. Purification step A was used to obtain a crude product of the title compound.
MS (ESI, m / z): 219 [M + H] +

(Process 2)
3-({[(2S) -2-amino-2- (methylcarbamoyl) ethoxy] carbonyl}
80 mg (0.37 mmol) of the compound obtained in the synthesis step 1 of amino) benzene-1-sulfonic acid, 40 mg of triphosgene (0
. 1 mmol), 60 mg (0.35 mmol) of 3-aminobenzenesulfonic acid was suspended in 2.0 ml of methylene chloride, 0.5 ml of pyridine was added, and the mixture was stirred at room temperature overnight. After distilling off the solvent, purification step A was used to obtain an intermediate. This crude product is converted to trifluoroacetic acid.
Dissolved in 4.0 ml and stirred at room temperature for 15 minutes. After distilling off the solvent, 6.79 mg of the title compound was obtained using purification step A.
Yield: 6.79 mg

Production Example 71
3-({[(2S) -2-amino-2- (methylcarbamoyl) ethoxy] carbonyl}
Synthesis of amino) -5-chloro-2-hydroxybenzene-1-sulfonic acid 3-aminobenzenesulfonic acid used in Production Example 70 was converted to 3-amino-5-chloro-2
-The title compound was obtained by replacing with hydroxybenzenesulfonic acid and operating in the same manner.
Yield: 26.3 mg

Production Example 72
3-({[(2S) -2-amino-2- (methylcarbamoyl) ethoxy] carbonyl}
Synthesis of amino) -5-chloro-4-methylbenzene-1-sulfonic acid 3-aminobenzenesulfonic acid used in Production Example 70 was converted to 3-amino-5-chloro-4
-The title compound was obtained by replacing with methylbenzenesulfonic acid and operating in the same manner.
Yield: 0.8mg

Production Example 73
Synthesis of 3-({[(2S) -2-amino-2-[(benzenesulfonyl) carbamoyl] ethoxy] carbonyl} amino) benzene-1-sulfonic acid (Step 1)
Synthesis of t-butyl N-[(1S) -1-[(benzenesulfonyl) carbamoyl] -2-hydroxyethyl] carbamate Boc-Ser (OBzl) -OH 885 mg (3.0 mmol), dicyclohexylcarbodiimide 620 mg (3. 0 mmol), 4- (dimethylamino) pyridine
370 mg (3.0 mmol) was dissolved in 12 ml of methylene chloride, and 470 mg (3.0 mmol) of benzenesulfonamide was added. After stirring overnight at room temperature, ethyl acetate /
The mixture was extracted with 1N hydrochloric acid, and the organic layer was washed with saturated brine, dried by adding sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was dissolved in 12 ml of methanol and 10% Pd
100 mg of / C was added and stirred overnight under a hydrogen atmosphere. Purification step A was used to obtain a crude product of the title compound.
ESI (m / z): 345 [M + H] +

(Process 2)
Synthesis of 3-({[(2S) -2-amino-2-[(benzenesulfonyl) carbamoyl] ethoxy] carbonyl} amino) benzene-1-sulfonic acid 80 mg (0.23 mmol) of the compound obtained in Step 1; Triphosgene 40mg (
0.1 mmol), 40 mg (0.23 mmol) of 3-aminobenzenesulfonic acid was suspended in 2.0 ml of methylene chloride, 0.5 ml of pyridine was added, and the mixture was stirred at room temperature overnight.
After distilling off the solvent, purification step A was used to obtain an intermediate. This crude product was dissolved in 4.0 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. After distilling off the solvent, 21.2 mg of the title compound was obtained using purification step A.
Yield: 21.2 mg

Production Example 74
Synthesis of 3-({[(2S) -2-amino-2-[(benzenesulfonyl) carbamoyl] ethoxy] carbonyl} amino) -5-chloro-2-hydroxybenzene-1-sulfonic acid Used in Preparation Example 73 3-aminobenzenesulfonic acid was converted to 3-amino-5-chloro-2
-The title compound was obtained by replacing with hydroxybenzenesulfonic acid and operating in the same manner.
Yield: 8.36 mg

Production Example 75
Synthesis of 3-({[(2S) -2-amino-2-[(benzenesulfonyl) carbamoyl] ethoxy] carbonyl} amino) -5-chloro-4-methylbenzene-1-sulfonic acid Used in Preparation Example 73 3-aminobenzenesulfonic acid was converted to 3-amino-5-chloro-4
-The title compound was obtained by replacing with methylbenzenesulfonic acid and operating in the same manner.
Yield: 8.8 mg

Production Example 76
(2S) -4-[(5-Chloro-2-hydroxy-3-sulfophenyl) carbamoyl]
Synthesis step 1 of 2- (dimethylamino) butanoic acid
Synthesis of (2S) -2-amino-4-[(5-chloro-2-hydroxy-3-sulfophenyl) carbamoyl] butanoic acid Boc-Glu-OtBu 101 mg (0.33 mmol), HATU 130 mg (
0.33 mmol), HOAt 45 mg (0.33 mmol), 3-amino-5-chloro-2-hydroxybenzenesulfonic acid 77 mg (0.33 mmol) in DMF2.
Suspended in 0 ml, 0.5 ml of pyridine was added and stirred at room temperature overnight. After distilling off the solvent, purification step A was used to obtain an intermediate. This crude product was dissolved in 2.0 ml of TFA and stirred at room temperature for 90 minutes. After distilling off the solvent, purification step A was used to obtain the title compound.
Yield: 90mg
ESI (m / z): 353, 355 [M + H] +

Process 2
(2S) -4-[(5-Chloro-2-hydroxy-3-sulfophenyl) carbamoyl]
2- (dimethylamino) butanoic acid 35 mg (0.1 mmol) of the compound obtained in Synthesis Step 1 and 30 mg of Pd / C were suspended in 1.0 ml of a 37% aqueous formaldehyde solution, and stirred overnight in a hydrogen atmosphere. Pd / C
Was removed by filtration, and then purification step A was used to obtain 11.2 mg of the title compound.
Yield: 11.2 mg

Production Example 77
Synthesis of (2S) -2-amino-3-{[(3-sulfophenyl) carbamoyl] amino} propanoic acid
(2S) -3-Amino-2-{[(tert-butoxy) carbonyl] amino} propanoic acid tert-butyl ester hydrochloride (Boc-DAP-OtBu · HCl) 100 mg, N, N′-carbonyldiimidazole (CDI ) 65 mg was dissolved in acetonitrile and stirred at room temperature for 10 minutes. Thereto was added 60 mg of 3-aminobenzenesulfonic acid, and the mixture was stirred at 50 ° C. for 5 hours. The solvent was distilled off, extracted with ethyl acetate, the organic layer was collected and dried, and the solvent was distilled off to obtain a protected crude product of the title compound. To the obtained crude product, 5 ml of trifluoroacetic acid was added and stirred overnight. The solvent was distilled off, and the resulting residue was purified in purification step A to obtain the title compound.
Yield: 4.93mg

Production Example 78
Synthesis of (2S) -4-[(5-chloro-2-hydroxy-3-sulfophenyl) carbamoyl] -2- (methylamino) butanoic acid 3-[(4S) -4-amino-5- (benzyloxy ) -5-Oxopentanamide] -5-chloro-2-
To 75 mg of hydroxybenzene-1-sulfonic acid, 1 ml of methylene chloride, 41 mg of 2-nitrobenzenesulfonyl chloride and 50 μl of triethylamine were added. After stirring for 1 hour, extraction with ethyl acetate gave 100 mg of a crude product. 23 mg of potassium carbonate was added to the resulting crude product.
, 1 ml of DMF and 10.5 μl of methyl iodide were added, and the mixture was stirred at room temperature overnight. Diluted with water and acetonitrile, and purified by purification step A. The obtained crude product was dissolved in 1 ml of THF, 0.5 ml of ethanol and 0.5 ml of water, and 10 mg of lithium hydroxide was added. While confirming the progress of the reaction, sodium hydroxide was appropriately added. After completion of the reaction, 2 ml of ethyl acetate was added and stirred.
The solvent was distilled off, water was added and lyophilized. The obtained lyophilizate is dissolved in 1 ml of DMF,
45 μl of 1-dodecanethiol, 60 μl of 28% sodium ethoxide in ethanol
Was added and stirred for 1 hour. Further, 45 μl of 1-dodecanethiol and 60 μl of 28% sodium ethoxide ethanol solution were added and stirred. The reaction solution was diluted with water and acetonitrile, and then purified using purification step A to obtain the title compound.
Yield: 2.4mg

Production Example 79
Synthesis of (2S) -3-{[(3-Chloro-4-methyl-5-sulfophenyl) carbamoyl] amino} -2- (methylamino) propanoic acid
100 mg of Boc-DAP-OtBu hydrochloride and 60 mg of CDI were dissolved in 1 ml of acetonitrile and stirred for 5 minutes. 5-
75 mg of amino-3-chloro-2-methylbenzenesulfonic acid was added and stirred overnight. Extraction with ethyl acetate gave a crude product. To the obtained crude product, 1.5 ml of dioxane and 0.5 ml of dioxane solution containing 4N hydrochloric acid were added and stirred for 2 hours. The solvent was distilled off to obtain a crude product. To the obtained crude product, 2 ml of methylene chloride was added, and 52 mg of 2-nitrobenzenesulfonyl chloride and 0.14 ml of triethylamine were added. The mixture was stirred for 2 hours and extracted with ethyl acetate to obtain a crude product. The resulting crude product was mixed with 50 mg potassium carbonate, 2 ml DMF, methyl iodide 0
. 1 ml was added and stirred at room temperature overnight. Extraction with ethyl acetate and evaporation of the solvent gave a crude product. 3 ml of trifluoroacetic acid was added to the obtained crude product, and the mixture was stirred at room temperature for 5 hours. The solvent was removed and the residue was lyophilized. 1 ml of DMF was added to the resulting lyophilized product, and 1-dodecanethiol 5 was added.
4 μl, 28% sodium ethoxide ethanol solution 80 μl was added and stirred at room temperature. Dilution with water and acetonitrile and purification using purification step A gave the title compound.
Yield: 18.4mg

Production Example 80
Synthesis of (2S) -2-amino-3-{[(4-methyl-3-sulfophenyl) carbamoyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino-2- The title compound was obtained in the same manner as the methylbenzenesulfonic acid.
Yield: 6.86mg

Production Example 81
Synthesis of (2S) -2-amino-3-{[(4-methoxy-3-sulfophenyl) carbamoyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino-2-methoxy The title compound was obtained by carrying out in the same manner replacing with benzenesulfonic acid.
Yield: 3.5mg

Production Example 82
Synthesis of (2S) -2-amino-3-{[(2-methoxy-5-sulfophenyl) carbamoyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-4-methoxy The title compound was obtained by carrying out in the same manner replacing with benzenesulfonic acid.
Yield: 6.22mg

Production Example 83
Synthesis of (2S) -2-amino-3-{[(3-acetamido-2-hydroxy-5-sulfophenyl) carbamoyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 3- ( Acetylamino) -5-amino-4-
The title compound was obtained in the same manner as the hydroxybenzenesulfonic acid.
Yield: 5.81mg

Production Example 84
Synthesis of (2S) -2-amino-3-{[(2-hydroxy-3-nitro-5-sulfophenyl) carbamoyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 3-aminobenzene The title compound was obtained by carrying out the same operation while substituting for -4-hydroxy-5-nitrobenzenesulfonic acid.
Yield: 6.1mg

Production Example 85
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) benzoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was replaced with 3-aminobenzoic acid in the same manner. The title compound was obtained by carrying out.
Yield: 2.66mg

Production Example 86
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2,5-dichlorobenzoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-2 The title compound was obtained by carrying out in the same manner substituting for 1,5-dichlorobenzoic acid.
Yield: 7.56mg

Production Example 87
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2-methylbenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-2-methylbenzoic acid. The title compound was obtained by carrying out in the same manner as above.
Yield: 10.76mg

Production Example 88
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -4-chlorobenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-4-chlorobenzoic acid. The title compound was obtained in the same manner as the acid replacement.
Yield: 2.3mg

Production Example 89
Synthesis of (2S) -2-amino-3-{[(2,4-dimethyl-5-sulfophenyl) carbamoyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino-2 , 4-Dimethylbenzoic acid was used in the same manner to obtain the title compound.
Yield: 1mg

Production Example 90
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2-hydroxybenzoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was replaced with 3-aminosalicylic acid In the same manner, the title compound was obtained.
Yield: 10.5mg

Production Example 91
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -4-methoxybenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-4-methoxy. The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 4.72mg

Production Example 92
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -5-nitrobenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-5-nitro. The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 3.5mg

Production Example 93
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -4-methylbenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-4-methyl. The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 20.4mg

Production Example 94
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -4-hydroxybenzoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-4-hydroxy The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 5.6mg

Production Example 95
Synthesis of 5-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2-chlorobenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino-2-chloro. The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 24.4mg

Production Example 96
Synthesis of 5-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2-hydroxybenzoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino-2-hydroxy The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 2.75mg

Production Example 97
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -4-fluorobenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-4- The title compound was obtained by carrying out the same operation while substituting for fluorobenzoic acid.
Yield: 31.92mg

Production Example 98
Synthesis of 5-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2-methoxybenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino-2-methoxy. The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 9.1mg

Production Example 99
Synthesis of 5-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2-methylbenzoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino-2-methyl The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 4.3mg

Production Example 100
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2-methoxybenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-2- The title compound was obtained by carrying out the same operation while replacing with methoxybenzoic acid.
Yield: 2.35mg

Production Example 101
Synthesis of 3-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -5-methoxybenzoic acid 3-Aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-5- The title compound was obtained by carrying out the same operation while replacing with methoxybenzoic acid.
Yield: 2.42mg

Production Example 102
Synthesis of 5-({[(2S) -2-amino-2-carboxyethyl] carbamoyl} amino) -2-fluorobenzoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino-2-fluoro The title compound was obtained by carrying out in the same manner replacing with benzoic acid.
Yield: 16.73mg

Production Example 103
Synthesis of (2S) -2-amino-3-{[(3,4-dimethyl-5-sulfophenyl) carbamoyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 5-amino- The title compound was obtained by carrying out in the same manner replacing with 2,3-dimethylbenzenesulfonic acid.
Yield: 3.33mg

Production Example 104
Synthesis of (2S) -2-amino-3-{[(2-fluoro-5-sulfophenyl) carbamoyl] amino} propanoic acid 3-aminobenzenesulfonic acid used in Production Example 77 was converted to 3-amino-4- The title compound was obtained by carrying out in the same manner replacing with fluorobenzenesulfonic acid.
Yield: 2.54mg

Example I Evaluation of CaSR Agonist Activity (CaSR Gene Preparation)
The CaSR gene was prepared using the method described in Example 1 of WO07 / 55393. Using the obtained recombinant plasmid, human CaSR expression plasmid hCaSR / pcDN
A3.1 was created.
(CaSR agonist evaluation method)
293E cells (EBNA1-expressing IIEK293 cells, ATCC No. CRL-10852) are 250
DMEM (1.0 g / ml Glucose) containing 10% fetal calf serum in the presence of μg / ml G418
(Dulbecco's modified Eagle medium, Nacalai Tesque). 1.8 × 10 ⁶ cel
ls / 15ml in a 10cm diameter petri dish, allowed to stand in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 24 hours, and then transfected with the human CaSR expression plasmid hCaSR / pcDNA3. using the transfection reagent MirusTrans IT 293 (Takara Bio). 1 was transfected. After standing for 24 hours in a CO ₂ incubator, the cells were collected in DMEM containing 10% fetal bovine serum and 15,000 cel
It seed | inoculated to poly-D-lysinecoat 384 well plate (Falcon) by ls / well. After standing for 24 hours in a CO ₂ incubator, the medium was removed and AssayBuffer (146 mM NaCl, 5 mM KCl, 1 mM MgS
Ca ²⁺ fluorescent indicator Calc dissolved in O ₄ , 1 mg / ml Glucose, 20 mM HEPES (PH7.2), 1.5 mM CaCl ₂ )
50 μl / well of ium 4 Assay Kit (Molecular Devices) was added and allowed to stand at 37 ° C. for 1 hour and then at room temperature for 30 minutes to incorporate the indicator. The 384 well plate is FLIPR (Molecular Devices)
12.5 μl / well of a compound dissolved in 0.1% BSA-containing Assay Buffer was added, and the change in fluorescence intensity was measured for 3 minutes.
(EC ₅₀ calculation method)
The difference (RFU (Max-Min)) between the maximum value and the minimum value of fluorescence intensity before and after compound addition was determined by automatic calculation of FLIPR. 100% RFU (Max-Min) at maximum compound concentration, DM at the same concentration instead of compound
The activity rate in which RFU (Max-Min) at the time of SO addition was defined as 0% was calculated, and curve fitting was performed with a spreadsheet software XLfit to obtain an EC ₅₀ value that is a compound concentration at an activity rate of 50%. The results are shown in Tables 16 and 17. From these results, it is considered that the medicament of the present invention has good CaSR agonist activity and is useful as a CaSR agonist agent.

Example II iPTH lowering effect by single intravenous administration in rats (method) Under the anesthesia of pentobarbital, male SD (IGS) rats were administered once from the tail vein and the changes in serum iPTH and serum Ca concentrations were examined. It was. Blood was collected before administration, 5 minutes, 15 minutes, 30 minutes, and 60 minutes after administration.
Compound No. 1 (the compound described in Production Example 6) was dissolved in physiological saline. Incidentally, cinacalcet as a control substance was dissolved in a PEG400: Saline = 1: 1 solution.
The results are shown in FIGS. Compound No. 1 in Table 1 showed serum iPTH and serum Ca lowering effects almost equal to cinacalcet at 0.1 mg / kg. Therefore, it was suggested that the medicament of the present invention has an iPTH lowering action and is useful as a preventive or therapeutic agent for hyperparathyroidism.

Example III Effect on non-steroidal anti-inflammatory drug (NSAID) -induced enterocolitis (Method) Compound NO.1 or Compound NO.2 (compound described in Preparation Example 14) (10 mg / kg) in non-fasted rats Or compound NO.3 (compound described in Production Example 48) (3, 10, 30 mg / kg)
) Was administered orally. 30 minutes later, loxoprofen (60 mg / kg) was orally administered and left for 24 hours. 30 minutes before necropsy, 1 ml of 1% (w / w) Evans blue dye was intravenously administered. After removing the small intestine (from the duodenum to the ileum) of an animal killed under ether deep anesthesia, the small intestine was fixed from the serosa side by immersing in 2% formalin for 10 minutes, and the incision was made from the opposite side of the mesentery. The small intestine injury area (mm2) was measured under a dissecting microscope of 10 magnification. Statistical test was t-test or Dunnett test, p <0.05 was considered significant.
The results are shown in FIG. 3 and FIG. Compound NO.1 significantly improved the injury area. In addition, Compound No. 2 and Compound No. 3 showed a tendency to improve the injury area. Therefore, it was shown that the medicament of the present invention is useful as an agent for preventing or treating peptic ulcer.

Example IV Effect of CaSR agonist on water absorption using rat large intestine loop method (Method) Under pentobarbital anesthesia, the cecum and large intestine were removed from the abdomen of male SD (IGS) rats, and 5 cm was ligated from directly under the cecum. Created a loop. Immediately after loop preparation, PGE2 (4 μg / ml
/ kg, SIGMA) was administered intraperitoneally and 2 ml of Tyrode solution (NaCl) into the loop prepared 30 minutes later.
_{136.9mM, KCl 2.7mM, CaCl 2 ·} 2H 2 O 1.8mM, MgCl 2 · 6H 2 O 1.04mM, NaH 2 PO 4 · 2H 2 O 0.0
4 mM, NaH ₂ PO ₄ .2H ₂ O 0.04 mM, Glucose 5.55 mM, NaHCO ₃ 11.9 mM). One hour later, the loop weight, the weight excluding the liquid in the loop, and the loop area were measured to calculate the liquid weight per unit area remaining in the loop.
As compounds to be tested, the above compounds NO.1 to NO.3 and compound NO.4 (compound described in Production Example 47) were used, and the drug was dissolved in Tyrode solution.
Residual liquid volume per unit area (g / cm ² ) = (Loop weight – loop weight with liquid removed) /
The area of the loop.
The moisture absorption was evaluated by calculating the moisture regulating action (%) from the following formula.
Moisture regulation (%) = 100− (remaining liquid volume per unit area by drug−average remaining liquid volume per unit area of base) / (average remaining liquid volume per unit area of vehicle−per unit area of base) Average residual liquid volume) x100.
The results are shown in FIGS. Compound NO.1, Compound NO.2, Compound NO.3 and Compound NO.4 promoted water absorption in a dose-dependent manner. Therefore, it was shown that the medicament of the present invention is useful as an agent for preventing or treating diarrhea.

Example V Examination of persistence of PTH lowering effect by intravenous administration to nephrectomized rats
(Method) Both kidneys of male SD (IGS) rats were removed under anesthesia with pentobarbital. Compound No. 5 (compound described in Production Example 13) (3 mg / kg) was administered once from the tail vein, and the change in serum iPTH concentration was examined. Blood was collected before administration, 3 hours, 24 hours, 48 hours, and 72 hours after administration. The compound was dissolved in physiological saline.
The results are shown in FIG. Compound No. 5 sustained the serum iPTH lowering action for 72 hours by one administration.
Therefore, it was shown that the medicament of the present invention is useful as a preventive or therapeutic agent for secondary hyperparathyroidism under maintenance dialysis administered intravenously during dialysis.

Example VI Examination of persistence of PTH lowering effect by oral administration to nephrectomized rats
(Method) Both kidneys of male SD (IGS) rats were removed under anesthesia with pentobarbital. Compound No. 1 (30 mg / kg) was orally administered once, and the change in serum iPTH concentration was examined. Blood was collected before administration and 3 hours, 24 hours, and 48 hours after administration. The compound was dissolved in physiological saline.
The results are shown in FIG. Compound No. 1 sustained the serum iPTH lowering action for 48 hours after one administration.
Therefore, it was shown that the medicament of the present invention is useful as an agent for preventing or treating secondary hyperparathyroidism under maintenance dialysis that is orally administered during dialysis.

The medicament of the present invention exhibits an excellent CaSR agonistic action and is useful as a preventive or therapeutic agent for diseases that are improved by the activation of CaSR, particularly hyperparathyroidism, diarrhea and peptic ulcer. In addition, the medicament of the present invention is effective when administered orally or intravenously at the time of dialysis, and is advantageous in terms of dose and safety.

Claims (6)

Formula (I) below:


[Where:
R ¹ and R ² are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl;
R ³ represents a hydrogen atom, halogeno, or substituted or unsubstituted C _1-6 alkyl;
R ⁴ and R ⁵ are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or Halogeno;
X represents CR ^a R ^b , an oxygen atom, NR ^c , or a sulfur atom (wherein R ^a and R ^b each independently represents a hydrogen atom, C _1-6 alkyl, or halogeno; R ^c Represents a hydrogen atom or C _1-6 alkyl);
Y represents C═O, SO, SO ₂ , C═S, or C═NR ^d (where R ^d represents a hydrogen atom, C _1-6 alkyl, and R ^d and R ⁶ are May form a substituted or unsubstituted 5- or 6-membered heterocycle);
R ⁶ represents a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or hydroxy;
G is phenyl substituted with R ⁷ , or pyridine, pyridazine, pyrazine, pyrimidine, thiazol, isothiazole, oxazole, isoxazole, oxadiazole, pyrazole, imidazole, furan, substituted with R ⁷ , thiophene, and represents a heteroaryl is an aromatic heterocyclic group selected from pyrrole, heteroaryl substituted with phenyl or R ⁷ substituted with the R ⁷ further one or a plurality of R ⁸ May be substituted;
R ⁷ is sulfo, carboxyl, or phosphono;
R ⁸ is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C _{1 -6 represents} alkoxy, nitro, amino, mono C _1-6 alkylamino, diC _1-6 alkylamino, sulfo, carboxyl, phosphono, C _1-3 alkylcarbonylamino, or mono C _1-6 alkylphosphono If there are several, they can be different;
Q is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, carboxyl, CONR ^e R ^f , CONNHHR ^g , COR ^h , substituted Or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R ^e and R ^f are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted _Represents a C _3-8 cycloalkyl, hydroxy, or C _1-6 alkoxy, or R ^e and R ^f may be substituted or unsubstituted, which may have a hetero atom together. May form a 5- or 6-membered heterocycle;
R ^g is substituted or unsubstituted C _1-6 alkylcarbonyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and R ^h is substituted or unsubstituted C _{1 -6} alkoxy, substituted or unsubstituted mercapto, or the following groups:

(In the formula, Z represents a divalent group of a substituted or unsubstituted C _1-6 hydrocarbon, E ¹ represents a substituted or unsubstituted C _1-6 acyloxy, a substituted or unsubstituted C _1-6 alkoxy; Carbonyloxy, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted C _1-6 alkoxycarbonyl, halogeno, aryl, heteroaryl, substituted or unsubstituted C _1-6 alkoxy, or substituted or unsubstituted carbamoyl And E ² represents a hydrogen atom or C _1-6 alkyl, and Z and E ¹ may form a ring together.
Wherein 1) substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, or C _1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, As a substituent in mercapto, carbamoyl, amino, C _1-6 alkoxycarbonyl, C _1-6 hydrocarbon divalent group, C _1-6 alkoxycarbonyloxy, or C _1-6 acyloxy, a halogen atom, hydroxy, cyano , _{C 1-6 alkoxy, C 1-6} halogenoalkyl, unsubstituted or _{C 1-6} alkyl mono- or disubstituted carbamoyl, unsubstituted or _halogeno, 1 by _{C 1-6} alkyl or _{C 1-6} alkoxy 3-substituted aryl, and unsubstituted or _{halogeno, C 1-6} alkyl or _{C 1-6} a Is selected from 1-3 substituted heteroaryl in Kokishi,
2) As a substituent in a substituted or unsubstituted 5- or 6-membered heterocyclic ring, substituted or unsubstituted aryl, heteroaryl, arylsulfonyl or benzoyl, C ₁ which may be substituted with a halogen atom, hydroxy, cyano or aryl _-6 alkyl, C _1-6 alkoxy, C _1-6 halogenoalkyl, carbamoyl which is unsubstituted or mono- or disubstituted with C _1-6 alkyl, and hetero optionally substituted with halogen or C _1-6 alkyl Selected from aryl,
3) As a substituent in the substituted or unsubstituted C _3-6 cycloalkyl, a C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogeno which may be substituted with a halogen atom, hydroxy, cyano, aryl Selected from alkyl, unsubstituted or carbamoyl mono- or di-substituted with C _1-6 alkyl, heteroaryl optionally substituted with halogen or C _1-6 alkyl, and oxo.
However, when X is a methylene or oxygen atom, Y is C═O, R ^{1 to} R ⁵ are all hydrogen atoms, and G is phenyl, Q represents a group other than carboxyl and COR ^h . ]
A pharmaceutical agent which is a prophylactic or therapeutic agent for hyperparathyroidism, comprising a compound represented by the above or a salt thereof as an active ingredient. In formula (I):
R ¹ and R ² are each independently a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl. Representation;
R ⁴ and R ⁵ are each independently a hydrogen atom;
X is CH ₂ , an oxygen atom, NH, or a sulfur atom;
Y represents C═O, SO, SO ₂ , or C═S;
G represents phenyl substituted with R ⁷ , and the phenyl substituted with R ⁷ may be further substituted with 1 to 5 R ⁸ ;
R ⁸ is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C _{1 -6 represents} alkoxy, amino, mono C _1-6 alkylamino, di-C _1-6 alkylamino, sulfo, carboxyl, phosphono, or mono C _1-6 alkylphosphono, and when there are a plurality of them, each is different Can be;
Q is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, carboxyl, CONR ^e R ^f , CONNHNHR ^g , substituted or unsubstituted Or an aryl of substituted or unsubstituted heteroaryl; In formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen atoms;
X is NH or a sulfur atom;
Y is C = O or C = S;
Q is carboxyl or C _1-6 alkoxycarbonyl;
G is phenyl substituted with R ⁷ , or pyridine, pyridazine, pyrazine, pyrimidine, thiazol, isothiazole, oxazole, isoxazole, oxadiazole, pyrazole, imidazole, furan, substituted with R ⁷ , thiophene, and represents a heteroaryl is an aromatic heterocyclic group selected from pyrrole, heteroaryl substituted with phenyl or R ⁷ substituted with the R ⁷ further with 1-5 R ⁸ May be substituted;
R ⁷ is sulfo;
R ⁸ is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, or substituted or unsubstituted C _2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C _{1 -6 represents} alkoxy, amino, mono C _1-6 alkylamino, di-C _1-6 alkylamino, sulfo, carboxyl, phosphono, or mono C _1-6 alkylphosphono, and when there are a plurality of them, each is different The medicament according to claim 1, which is a compound represented by: or a salt thereof. (2R) -2-amino-3-{[(3-sulfophenyl) carbamoyl] sulfanyl} propanoic acid;
(2S) -2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl) carbamoyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-chloro-4-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-sulfophenyl) carbamothioyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamothioyl] amino} propanoic acid;
(2S) -2-amino-3-{[(3-chloro-4-methyl-5-sulfophenyl) carbamothioyl] amino} propanoic acid;
3-[(4S) -4-amino-4- (hydroxycarbamoyl) butanamide] -5-chloro-2-hydroxybenzene-1-sulfonic acid;
3-[(4S) -4-amino-4- (hydroxycarbamoyl) butanamide] -5-chloro-4-methylbenzene-1-sulfonic acid; and (2S) -2-amino-3-{[(3- 2. A medicament according to claim 1 selected from sulfophenyl) carbamoyl] amino} propanoic acid.   The medicament according to any one of claims 1 to 4, wherein the preventive or therapeutic agent for hyperparathyroidism is a preventive or therapeutic agent for secondary hyperparathyroidism under maintenance dialysis. The medicament according to claim 5, which is used for oral administration or intravenous administration during dialysis.