4093-31-6

Basic information

• Product Name: Methyl 4-acetamido-5-chloro-2-methoxybenzoate
• Synonyms: 4-(acetylamino)-5-chloro-2-methoxy-benzoicacimethylester;4-ACETYLAMINO-5-CHLORO-2-METHOXY-BENZOIC ACID METHYL ESTER;4-ACETAMIDO-5-CHLORO-2-METHOXYBENZOIC ACID METHYL ESTER;LABOTEST-BB LT00441083;METHYL 4-ACETAMIDO-5-CHLORO-2-METHOXYBENZOATE;METHYL 4-ACETAMIDO-5-CHLORO-O-ANISATE;Methyl 5-chloro-4-acetamino-2-methoxybenzoate;4-Acethylamino-2-Methoxy-5-Nitro Benzoic acid Methyl Ester
• CAS NO: 4093-31-6
• Molecular Formula: C₁₁H₁₂ClNO₄
• Molecular Weight: 257.67
• EINECS: 223-840-1
• Product Categories: Aromatic Esters;(for metoclopramide Hcl);C10 to C11;Carbonyl Compounds;Esters
• Mol File: 4093-31-6.mol
• Article Data: 10

Chemical Properties

• Melting Point: 153-156 °C
• Boiling Point: 440.2 °C at 760 mmHg
• Flash Point: 220 °C
• Appearance: white to light beige fine crystalline powder
• Density: 1.3248 (rough estimate)
• Vapor Pressure: 5.99E-08mmHg at 25°C
• Refractive Index: 1.6000 (estimate)
• Storage Temp.: 2-8°C
• PKA: 13.16±0.70(Predicted)
• Water Solubility: 1.14g/L at 25℃
• CAS DataBase Reference: Methyl 4-acetamido-5-chloro-2-methoxybenzoate(CAS DataBase Reference)
• NIST Chemistry Reference: Methyl 4-acetamido-5-chloro-2-methoxybenzoate(4093-31-6)
• EPA Substance Registry System: Methyl 4-acetamido-5-chloro-2-methoxybenzoate(4093-31-6)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-36/37/38
• Safety Statements: 24/25-36-26
• WGK Germany: 3
• TSCA: Yes
• Hazardous Substances Data: 4093-31-6(Hazardous Substances Data)

Usage

Chemical Properties

white to light beige fine crystalline powder

Uses

Different sources of media describe the Uses of 4093-31-6 differently. You can refer to the following data:
1. Methyl 4-Acetylamino-5-chloro-2-methoxybenzoate is an biotransformed metabolite of Metoclopramide (M338685), an dopamine D2 receptor antagonist and antiemetic agent.
2. Methyl 4-Acetylamino-5-chloro-2-methoxybenzoate (Metoclopramide EP Impurity B; Metoclopramide USP Related Compound B) is an biotransformed metabolite of Metoclopramide (M338685), an dopamine D2 receptor antagonist and antiemetic agent.

InChI:InChI=1/C11H12ClNO4/c1-6(14)13-9-5-10(16-2)7(4-8(9)12)11(15)17-3/h4-5H,1-3H3,(H,13,14)

Synthetic route

methyl 4-(acetylamino)-o-anisate (4093-29-2) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
With N-chloro-succinimide In N,N-dimethyl-formamide at 40 - 65℃; for 9h; Temperature;	90.3%
With palladium diacetate; copper diacetate; copper dichloride In dichloromethane at 90℃; for 48h;	30%
With sodium hypochlorite for 1h; Yield given;
With N-chloro-succinimide In N,N-dimethyl-formamide

methyl 4-amino-5-chloro-2-methoxybenzoate (20896-27-9) + acetic anhydride (108-24-7) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
With acetic acid at 50℃; for 5h;	80%

methyl 4-amino-5-chloro-2-methoxybenzoate (20896-27-9) + acetic acid (64-19-7) + acetyl chloride (75-36-5) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
for 12h; Reflux;	67%

6-amino-5-nitro-pyridine-2-carboxylic acid methyl ester (538372-32-6) → imidazo[4,5-b]pyridine-pyrrole + methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
hydrogen In palladium-carbon	A n/a B 63%

Methyl 4-amino-2-methoxybenzoate (27492-84-8) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2O / 1.) room temp., 30 min., 2.) 60-70 deg C, 1 h 2: aq. sodium hypochlorite / 1 h View Scheme
Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 3 h / Reflux 2: 12 h / Reflux View Scheme

methyl 4-amino-5-chloro-2-methoxybenzoate (20896-27-9) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
With acetic acid In acetic anhydride

methyl 4-acetamido-2-hydroxybenzoate (4093-28-1) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / N,N-dimethyl-formamide 2: N-chloro-succinimide / N,N-dimethyl-formamide View Scheme

4-Aminosalicylic acid (65-49-6) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / 2 h / 20 °C 2: acetic acid / 1 h 3: sodium hydroxide / N,N-dimethyl-formamide 4: N-chloro-succinimide / N,N-dimethyl-formamide View Scheme

methyl 4-aminosalicylate (4136-97-4) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid / 1 h 2: sodium hydroxide / N,N-dimethyl-formamide 3: N-chloro-succinimide / N,N-dimethyl-formamide View Scheme

4-amino-5-chloro-2-methoxybenzoic acid (7206-70-4) → methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / 5 h / 80 °C 2: acetic acid / 5 h / 50 °C View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → methyl 4-acetylamino-5-chloro-2-hydroxybenzoate (24190-77-0)

Conditions	Yield
Stage #1: methyl 2-methoxy 4-acetamido 5-chloro benzoate With boron trichloride In dichloromethane at 0 - 15℃; for 4h; Stage #2: With water In dichloromethane	95%
Stage #1: methyl 2-methoxy 4-acetamido 5-chloro benzoate With aluminum (III) chloride In 1,2-dichloro-ethane for 8h; Heating / reflux; Stage #2: With hydrogenchloride; water In dichloromethane; 1,2-dichloro-ethane at 0℃;

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) + phenylboronic acid (98-80-6) → 2-acetamino-4-methoxy-5-methoxycarbonyl-1,1'-biphenyl (1058140-74-1)

Conditions	Yield
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate In tetrahydrofuran; water at 70℃; for 3h; Suzuki-Miyaura cross-coupling;	95%

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 4-acetylamino-5-chloro-2-methoxy-3-nitro-benzoic acid methyl ester (126463-85-2)

Conditions	Yield
With nitric acid at -35 - -30℃; for 0.166667h;	93.8%
With nitric acid at 20℃; for 0.166667h;	91%
With sulfuric acid; nitric acid at 0 - 10℃; for 0.5h;	85%

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → C11H11(2)HClNO4

Conditions	Yield
With [(1,5-cyclooctadiene)Ir(1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)(PPh3)]PF6; deuterium In dichloromethane at 20℃; for 2h; Sealed tube;	92%

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 4-(acetylamino)-5-chloro-2-methoxybenzoic acid (24201-13-6)

Conditions	Yield
	88%
With sodium hydroxide In water	85%
With sodium hydroxide In methanol at 60℃; for 1h;	84%

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 4-amino-5-chloro-2-methoxybenzoic acid (7206-70-4)

Conditions	Yield
With hydrogenchloride In ethanol; water	84%
With potassium hydroxide In ethanol; water Heating / reflux;
Stage #1: methyl 2-methoxy 4-acetamido 5-chloro benzoate With sodium hydroxide In ethanol Stage #2: With hydrogenchloride In water

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) + chloroacetyl chloride (79-04-9) → C12H11Cl2NO5

Conditions	Yield
Stage #1: chloroacetyl chloride With aluminum (III) chloride In dichloromethane at 0 - 10℃; for 0.5h; Stage #2: methyl 2-methoxy 4-acetamido 5-chloro benzoate In dichloromethane at 0 - 10℃; for 4h;	83%

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) + methyl iodide (74-88-4) → 4-(N-acetyl-N-methylamino)-5-chloro-2-methoxybenzoic acid methyl ester (202822-76-2)

Conditions	Yield
With sodium hydride In tetrahydrofuran for 5h; Heating;	45%
With NaH In tetrahydrofuran; water; ethyl acetate	4.77 g (45%)

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) + ethyl iodide (75-03-6) → 4-(N-acetyl-N-ethyl)amino-5-chloro-2-methoxybenzoic acid (483303-91-9)

Conditions	Yield
Stage #1: methyl 2-methoxy 4-acetamido 5-chloro benzoate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: ethyl iodide In tetrahydrofuran at 20℃;	10 g

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 4-(N-ethyl-N-methylamino)-5-chloro-2-methoxybenzenemethanol (202822-77-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 45 percent / NaH / tetrahydrofuran / 5 h / Heating 2: 89.5 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 3-[5-chloro-4-[(ethylmethylamino)-2-methoxyphenyl]-methyl]-1,3,4-oxadiazol-2-(3H)-one (202822-84-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 45 percent / NaH / tetrahydrofuran / 5 h / Heating 2: 89.5 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h 3: 60 percent / PPh3; DEAD / tetrahydrofuran / 24 h / 0 °C View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 3-[5-chloro-4-[(ethylmethylamino)-2-hydroxyphenyl]-methyl]-1,3,4-oxadiazol-2-(3H)-one

Conditions	Yield
Multi-step reaction with 4 steps 1: 45 percent / NaH / tetrahydrofuran / 5 h / Heating 2: 89.5 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h 3: 60 percent / PPh3; DEAD / tetrahydrofuran / 24 h / 0 °C 4: pyridine hydrochloride / 1 h / Heating View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 3,4-diamino-2-methoxy-benzoic acid methyl ester (538372-37-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / HNO3 / 0.17 h / 20 °C 2: 94 percent / aq. H2SO4 / methanol / 9 h / Heating 3: H2; Et3N / Pd/C / 6 h / 3800 Torr View Scheme
Multi-step reaction with 3 steps 1: nitric acid / 0.33 h / 20 °C 2: sulfuric acid / methanol / Reflux 3: palladium on activated charcoal; triethylamine / methanol / 16 h / 3040.2 Torr / Inert atmosphere View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 4-amino-5-chloro-2-methoxy-3-nitro-benzoic acid methyl ester (457947-61-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 91 percent / HNO3 / 0.17 h / 20 °C 2: 94 percent / aq. H2SO4 / methanol / 9 h / Heating View Scheme
Multi-step reaction with 2 steps 1: nitric acid; sulfuric acid / 1 h / 0 °C 2: sulfuric acid / methanol / 7 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: nitric acid / 0.33 h / 20 °C 2: sulfuric acid / methanol / Reflux View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 2-(4-amino-1-methyl-1H-pyrrol-2-yl)-4-methoxy-3H-benzoimidazole-5-carboxylic acid methyl ester

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 91 percent / HNO3 / 0.17 h / 20 °C 2.1: 94 percent / aq. H2SO4 / methanol / 9 h / Heating 3.1: H2; Et3N / Pd/C / 6 h / 3800 Torr 4.1: HBTU; DIEA / dimethylformamide / 36 h 4.2: 494 mg / AcOH / 7 h / 90 °C 5.1: H2 / Pd/C / dimethylformamide / 5 h / 7600 Torr View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 4-methoxy-2-(1-methyl-4-nitro-1H-pyrrol-2-yl)-3H-benzimidazole-5-carboxylic acid methyl ester (538372-38-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 91 percent / HNO3 / 0.17 h / 20 °C 2.1: 94 percent / aq. H2SO4 / methanol / 9 h / Heating 3.1: H2; Et3N / Pd/C / 6 h / 3800 Torr 4.1: HBTU; DIEA / dimethylformamide / 36 h 4.2: 494 mg / AcOH / 7 h / 90 °C View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 2-(4-tert-butoxycarbonylamino-1-methyl-1H-pyrrol-2-yl)-4-methoxy-3H-benzimidazole-5-carboxylic acid methyl ester (538372-39-3)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 91 percent / HNO3 / 0.17 h / 20 °C 2.1: 94 percent / aq. H2SO4 / methanol / 9 h / Heating 3.1: H2; Et3N / Pd/C / 6 h / 3800 Torr 4.1: HBTU; DIEA / dimethylformamide / 36 h 4.2: 494 mg / AcOH / 7 h / 90 °C 5.1: H2 / Pd/C / dimethylformamide / 5 h / 7600 Torr 6.1: 248 mg / DIEA / dimethylformamide View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 2-(4-tert-butoxycarbonylamino-1-methyl-1H-pyrrol-2-yl)-4-methoxy-3H-benzimidazole-5-carboxylic acid (538372-40-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: 91 percent / HNO3 / 0.17 h / 20 °C 2.1: 94 percent / aq. H2SO4 / methanol / 9 h / Heating 3.1: H2; Et3N / Pd/C / 6 h / 3800 Torr 4.1: HBTU; DIEA / dimethylformamide / 36 h 4.2: 494 mg / AcOH / 7 h / 90 °C 5.1: H2 / Pd/C / dimethylformamide / 5 h / 7600 Torr 6.1: 248 mg / DIEA / dimethylformamide 7.1: 73 percent / aq. NaOH / dioxane / 20 - 50 °C View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 5-chloro-4-ethylamino-2-methoxybenzoic acid (206434-46-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: NaH / tetrahydrofuran / 1 h / 0 - 20 °C 1.2: 10 g / tetrahydrofuran / 20 °C 2.1: 20 percent aq. NaOH / 15 h / Heating View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate (126463-86-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 73 percent / conc. H2SO4; fuming HNO3 / 0.08 h / 10 °C 2: 96 percent / H2 / Raney-Ni / ethanol; H2O / 1 h / 20 °C / 3344 Torr View Scheme
Multi-step reaction with 2 steps 1: 62 percent / HNO3 2: H2 / Ra-Ni View Scheme
Multi-step reaction with 2 steps 1: 93.8 percent / HNO3 fuming / 0.17 h / -35 - -30 °C 2: H2 / 10percent Pd/C / methanol; tetrahydrofuran / 4 h / 760 Torr / Ambient temperature View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → methyl 7-chloro-4-methoxy-2-methyl-1H-benzimidazole-5-carboxylate (126463-87-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 73 percent / conc. H2SO4; fuming HNO3 / 0.08 h / 10 °C 2: 96 percent / H2 / Raney-Ni / ethanol; H2O / 1 h / 20 °C / 3344 Torr 3: 100 percent / p-TsOH*H2O / toluene / 1 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 93.8 percent / HNO3 fuming / 0.17 h / -35 - -30 °C 2: H2 / 10percent Pd/C / methanol; tetrahydrofuran / 4 h / 760 Torr / Ambient temperature 3: 6N aq. HCl / acetic acid / 2 h / Heating View Scheme
Multi-step reaction with 3 steps 1: sulfuric acid; nitric acid / 0.5 h / 0 - 10 °C 2: hydrogen / nickel / ethanol; water / 5 h / 20 °C / 1551.49 Torr 3: toluene-4-sulfonic acid / toluene / 1 h / Heating / reflux View Scheme

methyl 2-methoxy 4-acetamido 5-chloro benzoate (4093-31-6) → 7-chloro-4-methoxy-1H-benzotriazole-5-carboxylic acid (199931-42-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 73 percent / conc. H2SO4; fuming HNO3 / 0.08 h / 10 °C 2: 96 percent / H2 / Raney-Ni / ethanol; H2O / 1 h / 20 °C / 3344 Torr 3: conc. H2SO4; aq. NaNO2 / 1 h / 5 °C 4: 4.7 g / H2O / 18 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 62 percent / HNO3 2: H2 / Ra-Ni 3: aq. H2SO4, NaNO2 / 0 °C 4: Heating View Scheme

Upstream product

• 20896-27-9 methyl 4-amino-5-chloro-2-methoxybenzoate 
• 64-19-7 acetic acid 
• 75-36-5 acetyl chloride 
• 7206-70-4 4-amino-5-chloro-2-methoxybenzoic acid 
• 538372-32-6 6-amino-5-nitro-pyridine-2-carboxylic acid methyl ester 
• 27492-84-8 Methyl 4-amino-2-methoxybenzoate 
• 4093-29-2 methyl 4-(acetylamino)-o-anisate 
• 4136-97-4 methyl 4-aminosalicylate 
• 65-49-6 4-Aminosalicylic acid 
• 4093-28-1 methyl 4-acetamido-2-hydroxybenzoate 
• 108-24-7 acetic anhydride 

Downstream Products

• 1388193-47-2 Br^(1-)*C₃₀H₃₂ClN₂O₇⁽¹⁺⁾ 
• 1388193-49-4 Br^(1-)*C₃₁H₃₄ClN₂O₇⁽¹⁺⁾ 
• 1388193-50-7 Br^(1-)*C₃₁H₃₄ClN₂O₇⁽¹⁺⁾ 
• 172679-60-6 4-amino-5-chloro-2-methoxybenzoic acid 2-bromoethyl ester 
• 364-62-5 metoclopramide 
• 126463-85-2 4-acetylamino-5-chloro-2-methoxy-3-nitro-benzoic acid methyl ester 
• 182808-04-4 methyl 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylate 
• 143878-29-9 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester 
• 1404449-51-9 methyl 4-acetamido-3-amino-2-methoxybenzoate 
• 1312608-71-1 C₄₂H₅₁N₉O₇ 
• 1312610-74-4 C₃₈H₄₅N₇O₅ 
• 1312610-73-3 C₃₆H₄₅N₇O₅ 
• 1312610-72-2 C₃₆H₄₂ClN₇O₇ 
• 1312610-71-1 C₃₇H₄₄ClN₇O₇ 

Relevant articles and documents

Preparation method of methyl 5-chloro-4-acetamido-2-methoxybenzoate

The invention discloses a preparation method of methyl 5-chloro-4-acetamido-2-methoxybenzoate, and belongs to the technical field of chemical synthesis, the preparation method comprises the following steps: dissolving 4-acetamido-2-methoxybenzoic acid methyl ester in N, N-dimethylformamide, adding N-chlorosuccinimide, carrying out a heat preservation reaction, obtaining a crude product of methyl 5-chloro-4-acetamido-2-methoxybenzoate, and then refining the crude product of methyl 5-chloro-4-acetamido-2-methoxybenzoate. A microporous filter membrane is used in the refining process, an antibacterial filler is prepared in the process of preparing the microporous filter membrane, the antibacterial filler can reduce the activity of metabolic enzymes in microbial cells so as to hinder the respiratory action of the microbial cells, and interferes the generation of substances required by bacterial production so that the phenomenon of mildew growth of the microporous filter membrane is prevented, antibacterial components in the microporous filter membrane cannot be lost after the microporous filter membrane is used for many times, and thus the microporous filter membrane still has a good antibacterial effect after being used for many times.

Preparation method of methyl 4-acetamido-5-chloro-2-methoxybenzoate

The invention relates to the technical field of chemical synthesis, and concretely relates to a preparation method of methyl 4-acetamido-5-chloro-2-methoxybenzoate. The method comprises the following steps: dissolving methyl 4-acetamido-2-methoxybenzoate in N,N-dimethyl formamide, adding N-chlorosuccimide, carrying out a heat insulation reaction to obtain crude methyl 4-acetamido-5-chloro-2-methoxybenzoate, separating out the crude methyl 4-acetamido-5-chloro-2-methoxybenzoate to obtain an N,N-dimethyl formamide mother liquor, and directly using the N,N-dimethyl formamide mother liquor as a solvent for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate without treatment. The preparation method has the advantages of high mole yield, low cost, safety and environmental protection.

HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK

Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.