JPH04149170A - Novel amide compound or its salt - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is alkyl, aralkyl; R<2> is H, OH; R<3> is lower alkyl, phenyl which may have a substituent (lower alkyl or lower alkoxy), indolyl; R<4> is H, lower alkyl; (n) is 0-2] or a salt thereof. EXAMPLE:N<alpha>-[3-(N-hydroxycarbamoyl)-2-propylthiopropionyl]-O-meth yltyrosine N-methylamide. USE:A collagenase-inhibiting agent. Useful for arthritis such as chronic articular rheumatism and degenerative joint diseases, periodontitis, corneal ulcer, epidermolysis bullosa, neoplastic infiltration and bone resorption diseases which are estimated to be mainly caused by the collagen-decomposing activity of the collagenase. PREPARATION:For example, a carboxylic acid of formula II or a reactive derivative thereof is allowed to react with an amine of the formula NH2R<2> to provide the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel amide compound that is useful as a medicine, and in particular, specifically inhibits the action of collagenase.

(Prior Art) Collagen, which is a major component of mammalian connective tissue, is specifically degraded by collagenase (EC3, 4, 23, 7) and not by other proteolytic enzymes. Tissue inhibitors (natural inhibitors of collagenase and metalloproteases) are used to regulate collagen metabolism under normal conditions.
Ti5sue Inhibitorof Metal
It is thought that this is carried out by oprotease (TIMP) and α2-macroglobulin. Diseases in which connective tissue destruction occurs are thought to be due to an imbalance in the levels of proteolytic enzymes and natural inhibitors. Collagenase inhibitors are thought to be able to suppress tissue destruction by suppressing the degradation caused by collagenase. Therefore, collagenase inhibitors are effective against chronic rheumatoid arthritis, osteoarthritis and other arthritis, periodontal disease, corneal ulcer9, epidermolysis bullosa, tumorous infiltration, and bone resorption diseases, which are thought to be mainly caused by collagenase inhibitors. Useful.

Conventionally, as compounds having this collagenase inhibitory effect, for example, JP-A-1-160992 describes certain phosphoric acid derivatives, and JP-A-1-160997 describes peptidylhydroxamic acid derivatives.・
Ru.

(Solution Means) The present inventors completed the present invention as a result of intensive research on compounds having a collagenase inhibitory effect.

That is, the second invention is a novel amide compound represented by the following general formula (I) or a salt thereof.

S(O)yI CH2R' CI )R2-
N) rco-CH2C'HCONH-CH-CONH-
R' (wherein R1 represents an alkyl group or an aralkyl group)
R2 is a hydrogen atom or a hydroxyl group; R3 is a lower alkyl group, a phenyl group optionally substituted with a lower alkyl group or a lower alkoxy group, or an indolyl group; R4
represents a hydrogen atom or a lower alkyl group, and n represents 0.1 or 2. (The same applies hereinafter) In this specification, "lower" means a straight or branched carbon chain having 1 to 5 carbon atoms, unless otherwise specified.

Therefore, a "lower alkyl group" is a methyl group.

Examples include ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ee-butyl group, tert~phthyl group, pentyl group, and inpentyl group.

In addition to the above-mentioned "lower alkyl group", examples of the "alkyl group" include hexyl and heptyl groups.

5-methylhexyl group, octyl group, 6-methylheptyl group, nonyl group, 7-methyloctyl group, decyl group, 8
-methylnonyl group, etc.

“As for lower alkoxy groups, it is methoxy groups.

Ethoxy group, propokine group, isopropoxy group.

Butoxy group, isobutoxy group, 5ee-butquine group.

tert-butoxy group, pentyloquine (amyloxy) group, isopentyloxy group, tert-pentyloxy group, neobentyloquine group, 2-methylbutquine group, 1,2-dimethylpropoxy group.

1-ethylpropoxy group, etc.

Moreover, the term "aralkyl group" means a group in which any hydrogen atom of the above-mentioned "lower alkyl group" or "alkyl group" is substituted with 1 to 3 aryl groups. Examples of the aryl group include a phenyl group, a l-+fur group, and the like.

The compound represented by the general formula (I) has nine asymmetric carbon atoms in the molecule, and the present invention includes a racemic form of compound (I),
All isomers such as optical isomers and diastereomers are included.

Further, examples of the salt of the compound represented by the general formula (I) include sodium, potassium, and alkali metal salts.

Alternatively, salts with organic bases such as ammonia can be mentioned. Furthermore, the compound of formula (I) or a salt thereof can also take the form of a solvate or hydrate, which also forms part of the present invention.

Among the compounds of the present invention, particularly preferred compounds include the following compounds.

Ne'-[3-(N-1hydroquinecarbamoyl2-
n-Propylthiopropionyl]-〇Methylthyron
N-methylamide N'-[3-(N-hydroxycarbamoyl)-2-methylthiopropionyl]-〇-methyltyrosine N-methylamide, Na-[:3-(N-hydroxycarbamoyl)-2-ethylthiopropionyl]-〇 -Methyltyrosine N-methylamide, N''-[3-(N-hydroquinecarbamoyl)-2-isopropylthiopropionyl]-〇-methyltyrosine N-methylamide, Na
-[3-(N-hydroxycarbamoyl)-2-butylthiopropionyl]-0-methyltyrosine N-methylamide, N"-[3-(N-hydroxycarbamoyl]
-2-ynophthylthioprobionyl]-〇-methyltyrosine N-methylamide, Na-[3-(N-hydroxycarbamoylno-2-pentylthiopropionyl]-
0-Methyltyrosine N-methylamide.

Na-[3-(N-hydroxylnocumoyl)-2-benzylthiopropionyl]-0-methyltyrosine N-
Methylamide (manufacturing method) The compound of the present invention will be explained below.

Regarding the manufacturing method for the first manufacturing method (I)
ONH-R'(I) [In the formula, R1, R2, R3, R4 and n have the above meanings. ] The amide compound represented by the general formula (I), which is a compound of the present invention, can be obtained by combining a carboxylic acid represented by the general formula (n) or a reactive derivative thereof and an amine represented by the general formula (III) using a conventional method. It can be produced by amidation.

Reactive derivatives of compound (II) include acid chloride,
Acid halides such as acid bromides; acid azides; active esters with N-hydroquine benzotriazole, N-hydroxyscunnimide, etc.; symmetrical acid anhydrides; mixed acid anhydrides with alkyl carbonates, p-)luenesulfonic acids, etc. Examples include things.

When compound (If) is reacted with free carboxylic acid, dicyclohexylcarbodiimide (DCC) or 1,1
It is advantageous to carry out in the presence of a condensing agent such as '-carbonyldiimidazole.

The reaction conditions vary depending on the type of raw material compound, especially the reactive derivative of compound (n), such as pyridine, tetrahydrofuran, dioxane, ether, N,N-dimethylformamide, and benzene.

Starting compound (n) in an organic solvent inert to the reaction such as toluene, xylene, methylene chloride, dichloroethane, chloroform, ethyl acetate, etc.
It is advantageous to carry out the reaction using equimolar amounts of (m) to slightly excess molar amount of starting compound (m).

Depending on the type of reactive derivative, or the raw material compound @
) Trimethylamine, triethylamine, pyridine, picoline, lutidine,
Dimethylaniline.

Organic bases such as N-methylmorpholine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate.

It may be advantageous to carry out in the presence of a base, such as an inorganic base such as sodium hydroxide, potassium hydroxide, etc. In addition,
Pyridine can also serve as a solvent.

The reaction temperature varies depending on the type of reactive derivative and is set appropriately.

In addition, when producing hydroxamic acid using hydroxylamine or its salt as compound (III),
Dimethylformamide, ether.

It is advantageous to carry out the reaction at room temperature in an organic solvent inert to the reaction, such as tetrahydrofuran or dioxane, in the presence of an active esterifying agent, such as ester carbonate, and a base, such as triethylamine.

Second production method R1 S(0)m CH2-R'111-→R" -NHCO-CH2-CHCONH-
CHCONHR'(Ib) [wherein R', R', R' and R4 have the above meanings.

m means 1 or 2. Among the compounds of the present invention, there is an S-monoxide form represented by the formula (Ib), and there is an S-dioxide form.

It can be produced by treating a sulfide represented by general formula (Ia) with a vernalizing agent. 9 as an oxidizing agent
m-chloroperbenzoic acid, hydrogen peroxide, selenium dioxide, potassium permanganate, sodium metaperiodate, etc. are used. Types of these oxidizing agents and treatment conditions (reaction time).

Depending on the reaction temperature and the amount of oxidizing agent used, S-monoxide or S-dioxide is produced.

The compound of the present invention thus produced can be produced as a free substance, as a salt when produced as a salt, or as a salt by subjecting the free compound to a commonly used salt-forming reaction, and then isolated and purified. Ru.

Isolation and purification include filtration, extraction, recrystallization, and reprecipitation.

This can be carried out by applying ordinary chemical operations such as various chromatography methods.

(Production method of raw material compound) The production method of the raw material compound of the nine compounds of the present invention will be described below.

First step (V) [wherein R3 and R4 mean the above. ] General formula (
The amide compound (V) can be produced by acylating the starting compound represented by rV) with maleic anhydride.

Second step CH2-R' HOOC-CH=CH-CONl(-CHCONH(V
) R'+ CH, C03H 3COCH3CH2-R3 ->HOOC-CH2-CH-CONH-CHCONH
-R'(IV) [wherein R4 and R4 have the same meanings as above. ] By adding thioacetic acid to the double bond of the amide compound (V) obtained in the first step.

Acetylthiocarboxylic acid with the formula (rV) can be prepared.

Third step 5 COCH, CH, -R3 HOOC-CH2-CHCONH-CHCONH-R'
+X-R' (■) (■) S -R'CH2-R' -+ HOOC-CH2-CHCONH-CHCONH
-R'(■) [wherein ER3 and R4 have the above meanings.

X means a halogen atom. ] Acetylthiocarboxylic acid (Th7) obtained in the second step
A sulfide represented by formula 9 (■) can be produced by reacting a compound represented by formula (■) with -.

Note that the raw material compound can also be produced by using a method in which an alkyl or aralkylthioconoholic acid mono-lower alkyl ester is used as a starting compound and is acylated as in the first step, followed by hydrolysis. In addition, maleic acid lower alkyl ester can also be used as a starting compound, and in this case, it is produced as in the 1st to 3rd steps, but in the 3rd step, after hydrolysis, the S-ester is sulfidized. , a starting compound which is a carboxylic acid can be obtained.

(Effects of the Invention) Compound (I) of the present invention or its salt, solvate or hydrate has a collagenase inhibitory effect on corneal ulcers that are thought to be mainly caused by collagen degrading activity.

It is effective against epidermolysis bullosa, tumorous invasion, bone resorption diseases, etc.

The method for measuring the inhibitory activity against collagenase and its results are described below.

Method for measuring inhibitory activity against collagenase M, buty
ricum 10 mg/mZ (fluid rough in) was administered at 0.1 mZ to the ridge of Lewja rats for 3 to 4 days.
After a week, periosteal tissues including the patella are collected from the knee joints of rats that develop adjuvant arthritis. This is cultured in 02% lactalbumin MEM medium for 2 days. Inhibition of collagenase in the culture supernatant was performed using the method of Nagai et al. [Inflammation 4
f2), 123 (1984), using fluorescently labeled collagen.

Collagenase in the culture supernatant is activated with trypsin, while trypsin is then inactivated with excess soybean tryfusin inhibitor. Next, an inhibitor is added and then a matrix collagen is added and reacted at 36°C. After 2 to several hours, the reaction is stopped with EDTA, and only collagen degradation products are extracted with 70% ethanol. This is centrifuged, and the fluorescence intensity of the extracted decomposition product is measured at 520 nm (Em)/495 nm (Ex).

The activity of collagenase inhibitors was expressed as the amount of compound that inhibits a known amount of the enzyme by 50% (Ncso).

result Among the 9 compounds (I) of the present invention in this assay method.

For example, the compound of Example 1 has an IC,o value of 9.23.
It showed a high collagenase inhibitory activity of X10-'M.

-Preparations containing one or more of the compounds represented by formula (I), or their salts, solvates, or hydrates as active ingredients, are prepared using commonly used carriers and excipients. , 9 tablets with other additives.

Prepared as powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc., and administered orally (including sublingually) or parenterally. .

The clinical dosage of the compound of the present invention is appropriately determined taking into account the patient's symptoms, weight, age, gender, etc., but is usually 10 to 500 I! per adult. Ig, which is administered once or in several doses.

(Example) The present invention will be described in more detail with reference to Examples below. Production examples of raw material compounds used in Examples are shown as reference examples.

Reference example 1 Maleic anhydride 0.98g, O-methyltyrosine N-
21 g of methylamide and 1.5 m7 of dry chloroform
The mixture was stirred at room temperature for 3 hours. The resulting precipitate was collected and N'-(3-carboxy-2-propeonyl)-〇-
Methyltyrosine N-methylamide 2.4g
Get it.

Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 307
(M+1) nuclear magnetic resonance spectrum (DMSO-d@,
TMS internal standard) δ: 2.60 (3H, d, J
=8 Hz, NCHs), 2.72 (IHy d
, d.

0CHs), 4.48 (IH, ITL, CH-C
Ht+OMe).

6.24 (IH, d, J=16Hz, CH=CH-),
6.42 (IH.

d, J=16Hz, CH=CH-), 6.84 (2H,
d, J = 10Hz.

Benzene ring-H), 7.16 (2H, d, J=10
Hz, benzene ring-H), 8.06 (IH, NH-),
9.24 (IH, NH-) 114.4 (I H, br
, C00H) Reference Example 2 N"-(3-carboxy-2-propeonyl)-〇-methyltyrosine 24g of N-methylamide was dissolved in 10% of thioacetic acid.
mA and stirred at room temperature for 2 days.

After concentration under reduced pressure, the residue was subjected to silica gel chromatography.

Elution was performed with chloroform-methanol-acetic acid (100:5:3) to obtain 0.5 g of N''-(2-acetylthio-3-carboxyprobionyl)-0-methyltyrosine N-methylamide.

Physical and chemical properties Mass spectrometry value (m/z): FAB Mas+s 3
83 (M”+1) Nuclear Magnetic Resonance Spectrum (CDCI)
,, TMS internal standard) δ: 2.16 (3H2s,
5COC & ), 2.70 (3H, d, J = 8Hz
, N-CH5)t 3.0-2.90 (3H),
3.10 (IH, d, dJ=8.8Hz, 14Hz
, CHt+OMe), 3.98 (3H.

s, 0CHa ), 4.40 (I H, t, J =
3.9 Hz, CH-8COCI(x).

4.5-4.6 (I H, m, CH-CHt+OM
e), 6.82 (2H.

d, J=8.8Hz, benzene ring-H), 7.1
(2H, d, J=8.8Hz, benzene ring-H] Reference example 3゜N"=(2-acetylthio-3-carboxypropionyl)-0-methyltyrosine N-1fk amide 0.95
g, 1N sodium hydroxide 5rn1. A mixed solution of 20 ml of methanol was stirred in an argon stream for 30 minutes to 1 hour. Thereafter, 0.95 g of inglovir iodide was added and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was mixed with 50 mt of ethyl acetate and 10 mt of 1N hydrochloric acid! ll was added. After separating the organic layer, it was washed with saturated brine. Dry, concentrate,
N″-(3-carboxy-2-isopropylthiopropionyl)-〇-methyltyrosine N-methylamide 06
I got g.

Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 383
(M”+1) Nuclear magnetic resonance spectrum (DMso-d
6. TMS internal standard) δ: 112-1.20 (6H2
CH(CH*)t), 2.34(IH,d,d.

J=8 Hz, 15Hz, CH2+OMe),
2.56 (3H, d.

J = 8.0 Hz, N-CH5), 2.60-2.
70 (-m, CHt-CoOH).

2.95 (I H, d, d, J = 8.0 H
z, 15Hz, cH, +OMe).

3.04 (IH, m, CH(CH”), 3.5
0 (LH, d, d, J = 8 CMJ Hz, 8Hz, 5-CH-Co), 3.70 (3H, s
, QC)(s).

4.36 (IH9rn=CHCHt80Me)
, 6.82 (2H1J=8Hz, benzene ring-H),
7.12 (2H, d, J=8Hz, benzene ring -H
), 1.2.4 (I H, br, C00H) The following compounds were synthesized in the same manner.

Reference example 4 N"-(3-carboxy-2-n-furohylthiopropionyl)-〇-methyltyrosine N-methylamide Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 38
3 (M+1) nuclear magnetic resonance spectrum (CDC1,-
DMSO-d.

TMS internal standard) δ: 0.90 (3L t, J=7.2Hz, -8
(CHJtC&), 1.45(2H,m, -5cH,
clcu, ), 2.26 (2H,t, J=7.2H
z.

S CHtCHtCHs ), 2.58 (I H,d
d, J = 4.8Hz, 17.2Hz.

-CHtCOtH2,73(3H,d, J=8.0H
z, -NHCHa).

2.95 (IH, dd, J=8.8Hz, 14H
z, -CH, -Ph-CHJ).

3.54 (IH, dd, J=4.8Hz, 9.6
Hz, -CH8-).

4.62-4.68 (I H2m, CHCHtP h
ocks), 6.81 (2H.

d+ J-8-8Hzvbenzene ring-H), 6.96
(IH, d.

-CONHCHCO-), 7.16 (2H,d,
J=8.4Hz, benzene ring-H), 7.34 (I
H, d, J=8.0Hz, -NHCHs)+3.
78(3H,m,Ph0C&) N'-(3-carboxy-2-methylthiopropionyl)-〇-methyltyrosine N-methylamide.

N'-(3-carboxy-2-ethylthiopropionyl)-〇-methyltyrosine N-methylamide.

N"=(3-carboxy-2-butylthiopropionyl)-〇-methyltyrosine N-methylamide.

N"-(3-carboxy-2-inbutylthiopropionyl)-0-methyltyrosine N-methylamide.

N″-(3-carboxy-2-penkerthioprohionyl)-〇-methyltyrosine N-methylamide.

N"-(3-carboxy-2-pendylthiopropionyl)-〇-methyltyrosine N-methylamide Example 1 N(alpha)-(3-carboxy-2-n-propylthiopropionyl)-〇-methyltyrosine In a solution of 840,111 g of N-methylamide in 10 ml of tetrahydrofuran, 0.4.6 ml of triethylamine and 0.42 rnl of ethyl chlorocarbonate were sequentially added at -5°C.

After stirring at 0°C for 30 minutes, hydroxylamine/hydrochloric acid [3
2 ml of a dimethylformamide solution containing 1 g of 061T was added dropwise, 0.6 rnl of triethylamine was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and 100 tnl of ethyl acetate was added to the residue, which was washed successively with 130 ml of INHC and 30 ml of saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, dryness under reduced pressure and silica gel column chromatography (acetic acid/methanol/chloroform:
115/200) to produce N(alpha)-[3-(N-(hydroquinecarbamoyl)-
400 μm of 2-n-propylthiopropionyl]-〇-methyltyrosine N-methylamide was obtained as a white powder.

Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 39
8 (M+1) nuclear magnetic resonance spectrum (DMSO-d
a, TMS internal standard) δ: 0.77 (3H, t,
J=7Hz, -8(CH,),CH,), 1.26
~1.33 (2H,m, -8CH,CH,CH,)
, 1.97-2.04 (IH.

m, -8CHtCHtCHa), 2.09-2.16
(I H9rrh -8CHtCHtCHa), 2.
22 (IH, dd, J = 6.8Hz, 15.1
Hz.

-CH,CH3-), 2.43 (IH, dd, J
=6.8Hz, 15.2Hz.

-CHtCH8-), 2.60 (3H, d, J =
4.4 Hz, -NHCH,)-2,65(IH,d,
J=13.7Hz, -CH2PhoCHs),
3.09 (IH, dd, J=3Hz, 13.7Hz
, -CHtPhoCHs).

3.63 (I H9t, J = 7.3 Hz, -CH
tCH8-)t 3.69 (3H.

S, -PhoCHs) + 4.31 (I L
mt -CONHCHCO-)*6.80 (2H, d
, J=8.3Hz, benzene ring-H), 7.16(2
H, d, J=8.3Hz, benzene ring-H), 7.8
2 (IH.

d, J=4.4Hz, -NHCHs), 8
．． 39 (IH, d, J=8.3Hz.

-CONHCHCO-), 8.84 (IH,s,HON
H-) The following compound was synthesized in the same manner as in Example 1.

Example 2 N' [3-(N-hydroxylnocumoyl)-2-methylthiopropionyl]-0-methyltyrosine N-methylamide raw material compound: N"-(3-carboxy-2-methylthiopropionyl)-〇-methyl Tyrosine N-methylamide physical and chemical properties Mass spectrometry value (m/z): FAB Mass 37
0 (M+1) nuclear magnetic resonance spectrum (DMSO-d
o, TMS internal standard) δ: 1.65 (3H,!l
, -sc apricot), 2.23 (IH, dd, J=6.
8Hz, 1.5.2I(z, -NHCOCHtCH
-), 2.46 (LH, dci.

J=8.4Hz, 15.2Hz, -NHCOCH,
CH-), 2.60 (3H.

d, J=4.8Hz, -NHCHs), 2.65
(IH, da, J=3.5Hz, 14.0) (z
, -CHtPhOCHa), 3.08 (IH,
da.

J = 3.2 Hz, 14.0 Hz, -CH!
Ph0CI(s), 3.63 (IH.

t, J=7.2Hz, -CHtCH6-), 3.
70 (3H,s, -Ph.

CHs), 4.33 (IH, m, -NHCHCONH-
), 6.80 (2H.

d+ J” &8 HzI benzene ring-H), 7.16
(2H, d, J = 8.4Hz, benzene ring-H), 7
．． 83 (IH, d, J=4.4Hz.

-NHCL), 8.35 (IH,d, J=8
．． 4 Hz, -CONHCHCO-).

~
~I8.84 (I H,s, /H
ONHCO-) Example 3 N“-[3-(N-hydroxycarbamoyl)-2-Z
-F-ruthioflobionyl)-0-methyltyrosine N
-Methylamide raw material compound 2N"-(3-carboxy-2-ethylthiopropionyl)-0-methyltyrosine N-methylamide physical and chemical properties Mass spectrometry value (m/z): FAB Mass 38
4 (M+1) nuclear magnetic resonance spectrum (DMSO-
da -TMS internal standard) δ: 0.92 (3H,t,
J==7.2Hz, 5CHtCHs), 1.91~
2.00 (1, H, m, -8CHtCHs), 2
．． 04-2.10 (IH, m.

-S C% CI(s)+ 2.19 (I H9d
d, J ~6.4 Hz, 15.2 Hz.

-NHCOCH,CH-), 2.43 (IH, dd, J
=8.8Hz, 15.2Hz, -NHCOCHtCH
)-2,61(3H,d,J~4.4 Hz.

-NHCH) + 3.11 (I H-ddt J
~13.6 Hz, -CLPh-OCHx),
3.64 (IH, dd, J=6.4Hz, 8.
8Hz, -CHtCH), 3.70 (3H,s,
-Ph! 9CHs)-4,31(IH9rrh-NH
CHCONH-), 6.81 (2H, d, J=8
．． 4Hz, benzene 1~ ring-H), 7.16 (2Hx d, J=8.4
Hz, benzene ring -H), 7.94 (1,H, -N
HCHa), 8.41 (IH, d, J=8.4
Hz, -CONHCHCONH) Example 4゜N''-[3-(N-hydroxycarbamoyl)-2-n
-butylthioglobionylco〇-methyltyrosine N
-Methylamide raw material compound 2N''-(3-carboxy-2-n-butylthiopropionyl)-0-methyltyrosine N-methylamide Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 41
2 (M+1) nuclear magnetic resonance spectrum (DMSO-d
6. TMS internal standard) δ: 0.80 (3H,t,
J=6.8Hz, -s (5 CHs).

1.13~],,20 (2H,m, -8(CHJt
CHtCHs ), 1.21-1.29 (2H, m
, -8CLCHyCHtCHs), 2.03-2.
08 (I H, m, -8CHt (CHritCHs
)-2,11-2.18 (IH.

m, -8CHt(CHJtCHs), 2.22 (
IH, dd, J=6.4Hz.

], 5.2Hz, -CLCH3), 2.60(3H
,d, J=4.4Hz.

-NHCHs), 2-64 (I H, dd, J
=2.8Hz, 14Hz.

CH, Ph0C1(, le 3.08(IH, dd, J=
3.2Hz, 14Hz.

-CHt Ph 0CHs ), 3.65 (I H9
dd, J~6.4 Hz, 8.8 Hz.

CH2CH3-), 3.70 (3H9s, -P hO
cHa), 4.30-4.33 (1,H,m, -
CONHCHCOl, 6.80 (2H, d, J=
8.8Hz, benzene ring-H), 7.16 (2H,
d, J=8Hz, benzene ring-H), 7.82 (
IH,d, J-4,4Hz, -NHCL).

8.38 (I H, d, J ~8.4 Hz, -
CONHCHCO-) Example 5 N”-[3-(N-hydroxycarnocumoyl)-2n
-pentylthiopropionyl]-0-methyltyrosine
N-methylamide raw material compound: Na-(3-carboxy-2-n-pentylthiopropionyl)-0-methyltyrosine N-methylamide physical and chemical properties Mass spectrometry value (m/z): FAB Mass 426 (M
+1) Nuclear magnetic resonance spectrum (DMSO-d, TM
S internal standard) δ: 0.84 (3I(,t, J~6.
8Hz, -8 (CH, input CH,), 1.10~1
．． 30(6I(, m, 5CHt (CHt)s, CHs
), 1.99-2.06 (IH, m, 5CHz (C
Hz)sC)(s), 2.11-2.18(IH,m,
-8CH, (CH2)3CH, ), 2.12(IH
, dd, J=6.4Hz, 15.2Hz, -CH2
CH3), 2.44(1)Ldd.

J=8.8H,z, 15.2Hz, -CH2CH8
), 2.60 (3H, d.

J==4.8Hz, NHCHs), 2.66(IH
, dd, J=2.8Hz.

13.6 Hz, CH2P h OCHs ), 3.0
8 (I H9d d, J ~3.2Hz, 13.6
Hz, -CHzPhOCHs), 3.64 (IH, dd
.

J=6.4Hz, 8.8Hz, -CH, CH8), 3.
70 (3H, S.

-PhOCH,), 4.30(LH,m, -CONHC
HCO-).

6.80 (2H, d, J = 8.8Hz, benzene ring -H
), 7.16(2)Ld, J=8.8HZ, benzene ring-H), 7.83(IH.

d, J: 4.8 Hz, NHCH3) 18.39 (I
H, d, J=8.4Hz, -CONHCHCO), 8.
84(IH,S,HONHCO)N"-[3-(N-hydroxycarbamoyl)-2-isopropylthiopropionyl]-0-methyltyrosine N-methylamide Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 398 (M
”+1) Nuclear magnetic resonance spectrum (DMSO-d,,TM
S internal standard) δ: 0.86 (3H, d, J=8.
6Hz, CH<. H: ), 1.04 (3H.

d, J=8.6Hz, CH(CH3)2), 2.60(
3H, d, J=5.4Hz, N-CH2), 3.1
0 (3H, S, 0CH3), 4.30 (IH.

m, Cdan−CH2+OMe), 6.82 (2H
, J=10Hz.

Benzene ring -H), 7.16 (2H, d, J=]OHz
, benzene ring-H), 8.04 (IH, br, NH)
Example Nc'-[1-(N-hydroquinecarbamoyl)-2-
isobutylthiopropionyl]-〇-methylthyron
N-Methylamide raw material compound: N''-(3-carboxy-2-isobutylthiopropionyl)-〇-methylthyronine N-methylamide Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 4] 2(M
+1) Nuclear magnetic resonance spectrum (DMSO-d,, TMS
internal standard) δ: 0°84 (3H, d, J = 6.1lH (
z, 5CHzCH(CHs)t).

0.85 (3H, d, J = 6.8T (z, 5CH2
CH(CHs)t).

1. 64(1)L m, 5CHtCH(CHs)
z), 2.24 (IH, dd.

J=7.6Hz, 14.4Hz, -CT(,CH8-)
, 2.28 (2H.

dd, J = 2.8Hz, 6.8Hz, -3C
H3CH(CH3)ri, 2.38(IH, dd, J
=-7.2Hz, 14.4Hz, -CH,CH3-).

2.55(3)L d, J=4.8H1,-NHCH2
), 2.76(])(.

3.62 (IIL t, J=7.2Hz, -C
H, CH8-), 4.34 (IH, m, -CONH
CHCONH-), 6.80 (2H, d.

J"8.4Hz, benzene ring-H), 7.10 (2H,
d, J=8.8 Hz, benzene ring-H), 7.85
(IH, d, J=4.4) (z.

NHCHs), 8.19 (IH, d, J = 8.4Hz,
C0NHCHCo-), 8.82 (IH,s,HO
NHCO) Example N''-(:1-(N-Hydroxycarbamoyl)-2benzylthiofropionyl]-0-#f Rutyrosine N-
Methylamide raw material compound: N'-(3-carboxy-2-benzylthiopropionyl)-〇-methyltyrosine N-methylamide mass spectrometry value (m/zCFAB Ma, ss 446 (M
+1) Nuclear magnetic resonance spectrum (DMSO-d6.TM
S internal standard) δ: 2.26 (IH, dd, J = 6.4
Hz, 14.8Hz, -CH2CH3), 2.62(3
H4d, J=4.8Hz, NHCHs), 2.6
8 (1, H,, dd, J=2.4Hz, 13.6H
z, -CH2PhOCH3).

3.12 (IH, dd, J=3.6Hz, 13.6
Hz-CH, Ph0CH3).

3.23 (1...d, J=12Hz, -8-CH2
-Ph)+3.39(lH,d, J=12Hz,
c'H2ph), 3.52 (3H9s.

-PhOCH,), 3.7C1-3,74(IH,m
, -CH2CH3-).

4.36-4.41 (IH, m, -CONHCHC
O-), 6.74 (2H, d, J=8.4Hz, -
PhOCH, benzene ring -H).

7゜08(2)(, d, J=7.2Hz, -3CH,
Benzene ring H), 7.18 (2H, d, J=8.
4Hz, -PhOCH, benzene ring -H), 7.2
2-7.28 (3H, m, benzene ring -H of -8CH2Ph), 7.86 (IH, d, J = 4.4
Hz.

NHCHs), 8.47 (I H, d, J = 8.4
Hz, C0NHCH#O), 8.86 (IH,s,
HONHCO-) Example 9゜N'-[3-(N-Hydroquinecarbamoyl)-20-
Propylsulfinylpropionyl]-〇Methyltyrosine-N-methylamide Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 4] 4(M
+1) Nuclear magnetic resonance spectrum (DMSO-d,, TMS
internal standard) δ: 0.75-0.83(3)(, m,
5on(CH2)2cH3), 1.43-1.53
(2H,m, -3o,CH,CHCH,), 1.7
3 to 1.83 (1, H, m, -8o, CH, CH, C
H3), 2.24-2.32 (LH.

m, -8o, CH, CH, CH3), 2.49~2
．． 66 (5H, m).

3.18(], H, dd, J=3.4.14.2Hz
.

(LH, m, CHCHz+ 0CH3), 6.83(
2H, a.

J = 8.3 Hz, benzene ring-H), 7.1
7 (2H, d, J=8.3Hz, benzene ring-H),
8.00 (IH, d, J=4.4Hz.

C0NHCH5), 8.79 (IH, d, J = 8.3H
z, -CONHCHCO-), 8.94 (LH, br,
HONH-) Example] 0 Na-[3-(N-hydroxycarnogumoyl)-2n
-Propylsulfonylpropionyl]-〇Methyltyrosine-N-methylamide Physical and chemical properties Mass spectrometry value (m/zCFAB Mass 430 (M+
1) Nuclear magnetic resonance spectrum (DMSO-d6.TMS internal standard) δ: 0.8 s~o, s9 (3Hlm,
S 02 CH2CH2CHs ), 1.53-1.
60 (2H, m, -3o2CH2CHICHs),
2.54-2.61 (3H, m, -NHCH3), 2
．． 64-2.80 (2H, m), 3.06-3.1.2
(IH, m, -cH, (yocH,), 3.70
(3H.

s, -0CHs), 4.36 (IH, dd, J=4.0
．． 10.8Hz.

-CH-6O2), 4.39-4.43 (IH, m.

CH-CH2(yOCH,), 6.82(2I(,d
, , 1T=8.3Hz, benzene ring-H), 7.
15 (2H, d, J=8.8Hz, benzene ring-H)
, 7.79 (IH, d, J=4.4Hz.

C0NHCH, ), 8.83 (IH, d, J = 8.4H
z, -CONH-CHCO), 8.96 (IH, s,
HONH-) Example N'-[3-(N-hydroxycarbamoyl)-2n-
Propylthiopropionyl]-phenylalanine amide Physical and chemical properties Mass spectrometry value (m/z): FAB Mass 354
(M+1) Nuclear magnetic resonance spectrum (DMSO-d6.T
MS internal standard) δ: 086 (3H, t, J = 72Hz
, -3(CH2)2CH,).

1.38-], 46 (2H,m, -3CH2CH
,CH,), 2.20-2.26(],H,m,,
human), 2.32-2.36 (LH, m.

CH2 S′・. H2 people)・2.39 (2H, t・J near, 2H・・
-3CHICH.

C) (3), 2.84 (IH,, dd, J-=9
．． 6.13.6Hz-CH20).

3.05(]IHdd, J=4.8Hz, 13.6Hz
.

7.10 (LH, S), 7.16-1.27 (5H, m
) + 7.38 (IH.

S), 8.1.8 (LH, d, J = 8.4Hz, -CO
Ndan-), 8.80 (IH, S, -NHOH) Patent applicant Yamanouchi Pharmaceutical Co., Ltd. Agent Patent attorney Shozo Nagai

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is an alkyl group or an aralkyl group, R
^2 is a hydrogen atom or a hydroxyl group, R^3 is a lower alkyl group, a phenyl group optionally substituted with a lower alkyl group or a lower alkoxy group, or an indolyl group, R
^4 represents a hydrogen atom or a lower alkyl group, and n represents 0, 1 or 2. ) A novel amide compound or a salt thereof. (2) N^α-[3-(N-hydroxycarbamoyl)
-2-propylthiopropionyl]-O-methyltyrosine N-methylamide or a salt thereof.