JPH10204054A - Phenylsulfonamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound, having inhibiting actions on matrix metalloproteinases, e.g. gelatinase, collagenase or stromelysin useful for preventing and treating rheumatism, etc. SOLUTION: This compound is represented by formula I [R<1> is H or a 1-4C alkyl; R<2> is COOR<6> (R<6> is H, a 1-8C alkyl, etc.), etc.; R<3> is OR<11> (R<11> is H, a 1-4C alkyl, etc.), etc.; R<4> and R<5> are each H, a (substituted) 1-8C alkyl, etc.; R<25> is H, etc.; E is CH=CH or C≡C; J is a single bond or a 1-8C alkylene; R<25> is H, a 1-4C alkyl, etc.], e.g. N-(4-(6-hydroxy-1-hexynyl)phenylsulfonyl)-D- tryptophan methyl ester. The objective compound is preferably produced by reacting, e.g. a compound represented by formula II (R<4-1> and R<5-1> have each the same meaning as that of R<4> and R<5> ; R<6-1> is a 1-8C alkyl, etc.; X is a halogen) with a compound represented by the formula R<3-1> -J-E<1> (E<1> is CH=CH2 , etc.) in the presence of a base and a cuprous iodide in an organic solvent by using a catalyst at 0-100 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a phenylsulfonamide derivative, a method for producing the same, and a drug containing the derivative as an active ingredient. More specifically, general formula (I)

Embedded image (Wherein all symbols have the same meanings as described below), non-toxic salts thereof, methods for producing them, and matrix metalloproteinase inhibitors containing them.

[0002]

BACKGROUND OF THE INVENTION Matrix metalloproteinases (hereinafter abbreviated as MMPs) are neutral metalloproteinases having zinc (hereinafter abbreviated as Zn ²⁺ ) in the active center, and are used under physiological conditions. Decomposes collagen, laminin, proteoglycan, fibronectin, elastin, gelatin, etc., thereby acting on the growth and remodeling of joint tissues, bone tissues, connective tissues, and the like. As of MMP, ten or more molecular species having different primary structures have been identified so far. Specifically, interstitial collagenase (MMP-1), leukocyte collagenase (MMP-8), gelatinase A (MMP-2), gelatinase B (MMP-9), stromlysin 1 (MM
P-3), stromlysin 2 (MMP-10), matrilysin (MMP-7) and the like.

[0003] As a property common to each of these enzymes,
(1) having Zn ²⁺ in the active center and requiring calcium (Ca ²⁺ ) for enzymatic activity; (2) being secreted as a latent enzyme and being activated extracellularly; (3) Have high homology to amino acid sequences, (4) have the ability to resolve various extracellular matrix components existing in vivo,
(5) It is known that the activity is inhibited by a common inhibitor, tissue metalloproteinase inhibitor (TIMP).

[0004] MMP inhibitors are considered to be useful for the prevention and / or treatment of various diseases caused by abnormally enhanced secretion and activity of MMP. For example, rheumatism, osteoarthritis, pathological bone resorption, osteoporosis, periodontal disease, interstitial nephritis, arteriosclerosis, emphysema, cirrhosis, corneal injury, metastatic invasion and proliferation of cancer cells, autoimmune diseases (Crohn disease,
Shugren's disease), diseases caused by vascular migration or infiltration of leukocyte cells, angiogenesis and the like.

[0005] Several compounds having a matrix metalloproteinase inhibitory action are known. Above all,
Substrate (Gly-Ile-Al) near the breakpoint of collagen
a-Gly or Gly-Leu-Ala-Gly)
Is known to have high affinity for collagenase. A number of chemically modified substrate analog matrix metalloproteinase inhibitors with a zinc affinity group at the cleavage site of this substrate have been studied [Inhibitors o
f matrix metalloproteinases (MMP's), Nigel RABeele
y, Phillip RJ Ansell, Andrew JP Docherty and others Curr. O
pin. Ther. Patents., 4 , 7-16 (1994), Current Drugs
Ltd ISSN 0962-2594]. However, these substrate analog inhibitors are expected to have various problems because they are peptide analogs. For this reason, it is desired to convert these inhibitors into non-peptides, and some have been reported.

For example, in the specification of EP606046, the general formula (X)

Embedded image

(Wherein (a) Ar ^X is a carbocyclic or heterocyclic aryl; R ^X is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, etc .; R1 ^X is hydrogen, lower alkyl, carbocyclic Aryl-lower alkyl and the like; R ^2X is hydrogen or lower alkyl; or (b) R ^X and R ^1X together with the chain to which they are added,
Forming 2,3,4-tetrahydro-isoquinoline, piperidine ring and the like; Ar ^X and R ^2X have the meaning defined in (a); or (c) R ^1X and R ^2X together with the carbon atoms to which are, C3-7 cycloalkane substituted by unsubstituted or lower alkyl, oxa - cyclohexane, thia - cyclohexane; and Ar ^X and R ^2X has the meaning defined (a) . ) Discloses that the arylsulfonamide derivative has a matrix metalloproteinase inhibitory action.

In the specification of WO9535276, the general formula (Y)

Embedded image

(Wherein ^XY is COOH, CONOHOH
R ^1Y is an α-amino acid; R ^2Y is Z ^1Y Q ^Y W ^Y ; Z ^1Y is a hydrogen atom, an aryl group, or the like; (i) Q ^Y W ^Y is a single bond together; (ii) Q ^Y is O, S, W ^Y are C1-20 alkyl groups and the like, (iii) Q ^Y is a single bond, W ^Y is a C9-20 alkyl group and the like, (iv) Q ^Y is a single bond, W ^Y is a C1-8 alkyl group ; Y
^Y represents SO ₂ ; Z ^Y represents an aryl group or a heteroaryl group. ) Is disclosed to have a matrix metalloproteinase inhibitory action.

On the other hand, in the specification of WO9315047, the general formula (Z)

Embedded image

[0011] (wherein, A ^Z is a) -Q ^Z -X ^Z groups (Q ^Z is -
O -, - S -, - NR-, single bond, X ^Z is a 5-membered or 6-membered aromatic ring or a heterocyclic _{ring), b) -CN, -NO 2} , -N 3,
^{-NR Z R 1Z, -OR Z,} -COR Z, -CO 2 R Z group (R ^Z
And R ^1Z are each independently a hydrogen atom, C1-18
Alkyl group, C2～18 alkenyl group); J ^Z is a divalent C1~8 alkanediyl, alkenediyl or alkynediyl group; V ^Z is phenylene, furandiyl, thiophenediyl, thiazolediyl like; q and m are 0
Or 1; Y ^Z is a single _{bond, -CH 2 -, - C (} = O) -,
-C (= S)-, -S (= O) _2- or -P (= O)
(OC1-6 alkyl) -group (provided that ^YZ is -S (=
In the case of O) _2- , Q ^Z does not represent a single bond. ); R ^2Z is hydrogen, Cl to 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -CO (Cl to 6 alkyl) group, -CO ₂ (Cl to 6 alkyl) group or the like; R ^3Z And R ^4Z each independently represent a hydrogen atom, a halogen atom,
C1~6 alkyl group, a natural amino acid side chain or the like; B ^Z is a)
Z ^Z R ^8Z group (Z ^Z is a single bond, -C (= O) -, - C (=
O) O—, —CH ₂ O—, etc., R ^8Z is a hydrogen atom, C1-1
8 alkyl group, C2～18 alkenyl group, C2～18 alkynyl ^{_{group), b) -CH 2 NR 9Z}} R 10Z or -CO
NR ^9Z R ^10Z groups (R ^9Z and R ^10Z are each independently
Hydrogen atom, C1-18 alkyl group, C2～18 alkenyl group, C2～18 alkynyl group), c) E ^Z group (E ^Z is nitrogen atom, an oxygen atom, contain heteroatoms least one selected from a sulfur atom 5, 6-membered heterocycle) or d) -CH
^{_{2 E Z, -C (= O}} ) NHE Z or -C (= O) NHC
Represent H ₂ E ^Z. ) Is disclosed to have PAF antagonistic activity.

[0012]

The present inventors have conducted intensive studies to find compounds having an inhibitory effect on matrix metalloproteinases such as gelatinase, collagenase, and stromelysin, and as a result, the novel compounds represented by the general formula (I) are obtained. It has been found that a novel phenylsulfonamide derivative achieves the object.

[0013]

DISCLOSURE OF THE INVENTION The present invention provides: 1) a compound represented by the general formula (I):

Embedded image

[In the formula, R ¹ represents 1) a hydrogen atom or 2) a C1-4 alkyl group, and R ² represents a 1) —COOR ⁶ group (wherein, R ⁶ represents (1) a hydrogen atom, (2) ) A C1-8 alkyl group, (3) a phenyl group, or (4) a C1-4 alkyl group substituted with one group selected from the following (i) to (iii): (i) a phenyl group, (ii) ) -OCOR ⁸ group (wherein, R ⁸ represents a C1~4 alkyl group.), (iii) -CONR ⁹
R ¹⁰ groups (wherein R ⁹ and R ¹⁰ are each independently
Represents a hydrogen atom or a C1-4 alkyl group. ) Or 2) -CONHOR ⁷ group, wherein R ⁷ is (1) a hydrogen atom, (2) a C1-8 alkyl group, (3) a phenyl group, or (4) a C1 substituted with one phenyl group. -4 alkyl group).

R ³ is 1) —OR ¹¹ group (wherein R ¹¹ is (1) a hydrogen atom, (2)
C1-4 alkyl group, (3) C2-4 acyl group, (4)
Phenyl group, (5) C1 substituted by one phenyl group
To 4 alkyl groups, (6) —NR ¹⁵ R ¹⁶ groups (wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, or
Represents a 4-alkyl group. ) Or (7) represents a heterocyclic group. ), 2) -NR ¹² R ¹³ group (wherein, R ¹² and R ¹³ each independently represent a hydrogen atom or a C1~4 alkyl group,.), 3) -COOR ¹⁴ group (in radical, R ¹⁴ is (1) a hydrogen atom,
(2) a C1-4 alkyl group, (3) a phenyl group, or (4) a C1-4 alkyl group substituted with one phenyl group. ) Or 4) —NR ²³ COR ²⁴ (wherein R ²³ is a hydrogen atom or C
R ²⁴ represents a C 1-4 alkyl group, a phenyl group, a heterocyclic group, a C 1-4 alkyl group substituted with one phenyl group, or a C 1-4 substituted with one hetero ring group. Represents a 4-alkyl group. )

[0016] R ⁴ and R ⁵ are each independently 1) hydrogen atom, 2) one carbon atom may be replaced by a sulfur atom C1~8 alkyl group, 3) -COR ¹⁷ group (wherein, R ¹⁷ is (1) a hydroxyl group, (2)
C1-8 alkyl group, (3) C1-8 alkoxy group,
(4) a phenoxy group, (5) a C1-4 alkoxy group substituted with one phenyl group, and (6) a —NR ²⁰ R ²¹ group (wherein R ²⁰ and R ²¹ are each independently a hydrogen atom, C
Represents a 1-4 alkyl group, a phenyl group, or a C1-4 alkyl group substituted with one or two phenyl groups. ), 4) a carbocyclic group (this carbocyclic group is a C1-4 alkyl group,
It may be substituted with 1-3 substituents selected from 1-4 alkoxy groups, halogen atoms, hydroxyl groups, or trifluoromethyl groups. ), 5) a heterocyclic group (the heterocyclic group is substituted with 1 to 3 substituents selected from a C1-4 alkyl group, a C1-4 alkoxy group, a halogen atom, a hydroxyl group, and a trifluoromethyl group) Or

[0017] 6) below (i) ~ (C1-8 alkyl group substituted by one group selected from viii); (i) -COR ¹⁷ group (wherein, R ¹⁷ are as defined above ), (Ii) a C1-4 alkoxy group, (iii) a hydroxyl group, (iv) a benzyloxy group, (v) a guanidino group,
(Vi) -NR ¹⁸ R ¹⁹ group (wherein, R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, C1 -4 alkyl group or -
A COOR ²² group (wherein R ²² represents a C 1-4 alkyl group or a benzyl group), (vii) a carbocyclic group (this carbon ring group is a C 1-4 alkyl group, a C 1-4 alkoxy group,
It may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a trifluoromethyl group. ), (Viii) a heterocyclic group (this heterocyclic group is
4 alkyl groups, C1-4 alkoxy groups, halogen atoms,
1 selected from a hydroxyl group and a trifluoromethyl group
It may be substituted with up to 3 substituents. )

E is

Embedded image Represents

J represents 1) a single bond or 2) a C1-8 alkylene group, and R ²⁵ represents 1) a hydrogen atom, 2) a C1-4 alkyl group, 3) a C1-4 substituted with one phenyl group. Represents an alkyl group, 4) a C1-8 alkoxycarbonyl group, or 5) a C1-4 alkoxycarbonyl group substituted with one phenyl group.

However, 1) E is

Embedded image And J represents a single bond, R ³ represents —CO
Only an OR ¹⁴ group (wherein R ¹⁴ has the same meaning as described above);

Embedded image And J represents a single bond, R ³ represents —CO
OR ¹⁴⁰ group (wherein, R ¹⁴⁰ is. Representing a C1~4 alkyl group, a phenyl group or a C1~4 alkyl group substituted with a phenyl group) is intended to refer only. A phenylsulfonamide derivative or a non-toxic salt thereof,

2) A method for producing a phenylsulfonamide derivative represented by the general formula (I) and a non-toxic salt thereof,
And 3) a drug containing a phenylsulfonamide derivative represented by the general formula (I) and a non-toxic salt thereof as an active ingredient.

In the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, the alkoxy group and the alkylene group include straight-chain and branched ones. Double bonds in alkenylene groups include those that are E, Z and EZ mixtures. Also,
Also included are isomers resulting from the presence of asymmetric carbon atoms, such as when branched alkyl, alkoxy, and alkylene groups are present.

In the general formula (I), R ¹ , R ⁸ , R ⁹ , R ¹⁰ ,
^{R 11, R 12, R 13} , R 14, R 15, R 16, R 18, R 19, R
^20, the C1~4 alkyl group represented by ^{R 21, R 22, R 23} , R 24, R 25, R 140, methyl, ethyl, propyl, butyl and isomeric groups thereof. In the formula (I), ^{R 7, R 11, R 14} , R 24, R 25, C1~4 alkyl group substituted with one phenyl group represented by R ¹⁴⁰ is substituted with one phenyl group Methyl, ethyl, propyl, butyl groups and isomers thereof. In the general formula (I), the C1-4 alkyl group substituted by one heterocyclic group represented by R ²⁴ means a methyl, ethyl, propyl, butyl group substituted by one heterocyclic group, Isomer.

In the general formula (I), (4) a C1-4 alkyl group substituted with one group selected from the following (i) to (iii) in the R ⁶ group means phenyl, -OCOR ⁸ , −
A methyl, ethyl, propyl, butyl group and an isomer thereof substituted with one group selected from CONR ⁹ R ¹⁰ groups. In the general formula (I), C 1 -C 1 substituted with one or two phenyl groups represented by R ²⁰ and R ²¹ .
A 4-alkyl group is a methyl, ethyl, propyl, butyl group substituted with one or two phenyl groups and isomers thereof.

[0025] In the formula (I), carbocyclic group in R ¹⁷ group or The C1~4 alkyl group represented by a substituent of the heterocyclic group, include methyl, ethyl, propyl, butyl and isomeric groups thereof It is. In the general formula (I), R ⁶ ,
The C1~8 alkyl group represented by R ^7, R ^17, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof.

In the general formula (I), a C1-8 alkyl group in which one carbon atom represented by R ⁴ and R ⁵ may be replaced by a sulfur atom includes methyl, ethyl, propyl,
It means butyl, pentyl, hexyl, heptyl, octyl and isomers thereof, or one in which one —CH ₂ — group of the alkyl group is replaced by a sulfur atom. One -CH ₂ -, for example, as a specific example although groups is replaced by a sulfur atom, -SH, -CH ₂ -
SH, etc. -CH ₂ CH ₂ -S-CH ₃ and the like.

In the general formula (I), 6) in the R ¹⁷ group, the C1-8 alkyl group substituted with one group selected from the following (i) to (viii) means —COR ¹⁷ , C 1 4 alkoxy group, hydroxyl group, benzyloxy group, guanidino group,-
A methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof substituted with one group selected from NR ¹⁸ R ¹⁹ , a carbocyclic group or a heterocyclic group. In the formula (I), a C2~4 acyl groups represented by R ^11, acetyl, propionyl, butyryl group and isomers thereof.

Among the R ¹⁷ groups in the general formula (I), 6) C 1 -C 1 -alkyl represented by a substituent of a C 1 -C 8 alkyl group substituted by one group selected from the following (i) to (viii):
The 4 alkoxy groups are methoxy, ethoxy, propoxy, butoxy groups and isomers thereof. In general formula (I), C substituted with one phenyl group in R ¹⁷ group
1-4 alkoxy groups are methoxy, ethoxy, propoxy, butoxy groups substituted with one phenyl group and isomers thereof. In the general formula (I), C represents a substituent represented by a carbocyclic or heterocyclic group in the R ¹⁷ group.
1-4 alkoxy groups are methoxy, ethoxy, propoxy, butoxy groups and isomers thereof. In the formula (I), is C1~8 alkoxy group represented by R ^17, methoxy, ethoxy, propoxy, butoxy,
Pentyloxy, hexyloxy, heptyloxy, octyloxy groups and isomers thereof.

In the general formula (I), the C1-4 alkoxycarbonyl group substituted by one phenyl group in the R ²⁵ group includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group and isomers thereof. is there. In the general formula (I), the C1-8 alkoxycarbonyl group represented by R ²⁵ means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl and isomers thereof.

In the general formula (I), C represented by J
The 1-8 alkylene group is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof.

In the general formula (I), the halogen atom represented by the substituent of the carbocyclic or heterocyclic group in R ¹⁷ is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In the general formula (I), the carbocyclic group in the R ¹⁷ group is
Represents a C5-10 carbocyclic aryl. For example, C5-1
Examples of the 0-carbon ring aryl include cyclopentadiene, benzene, pentalene, indene, naphthalene, azulene and the like.

In the general formula (I), the heterocyclic group in R ¹⁷ and R ²⁴ means an unsaturated group containing 1 to 2 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom, A partially or fully saturated 5- to 15-membered monocyclic or bicyclic heterocyclic group. For example, as an unsaturated, partially or fully saturated 5- to 15-membered monocyclic or bicyclic heterocyclic group containing 1 to 2 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom, , Indole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiane (thiopyran), tiepin, oxazole, isoxazole, thiazole, isothiazole, oxazi Azole, oxaazine, oxadiazine, oxaazepine, oxadiazepine, thiadiazole, thiaazine, thiadiazine, thiazepine, thiadiazepine, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole Quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, dihydrofuran , Dihydropyran, tetrahydropyran,
Dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroiso Thiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole , Perhydroindazole,
Dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,
Dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzo Oxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole ring, and the like.

In the general formula (I), the groups represented by R ⁴ and R ⁵ sometimes represent α-amino acid side chains. Examples of the α-amino acid include glycine, alanine, serine, threonine, cysteine, valine, methionine, leucine, isoleucine, phenylalanine, tyrosine, aspartic acid, glutamic acid, asparagine, arginine, lysine, histidine, tryptophan, glutamine and the like. The α-amino acids also include α-amino acid derivatives, D-forms, L-forms, DL-mixtures, and allo-form α-amino acids.

[0034]

[Salts] The present invention includes all non-toxic salts.
For example, common salts, acid addition salts, hydrate salts and the like can be mentioned.

The compound of the present invention represented by the general formula (I)
It is converted to the corresponding salt by known methods. The salt is preferably a non-toxic, water-soluble salt. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine) , Dimethylamine, cyclopentylamine, benzylamine,
Phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl)
Amine, lysine, arginine, N-methyl-D-glucamine, etc.).

The compound of the present invention represented by the general formula (I)
It is converted to the corresponding acid addition salt by known methods. The acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate Like, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate Organic acid salts.
Further, the compound of the present invention represented by the general formula (I) or a salt thereof can be converted into a hydrate by a known method.

Among the compounds of the present invention represented by the general formula (I), preferred compounds are those represented by the general formula (Ia):

[0038]

Embedded image (Wherein all symbols have the same meanings as described above) or general formula (Ib):

[0039]

Embedded image (Wherein all symbols have the same meanings as described above) or general formula (Ic):

[0040]

Embedded image (Wherein all symbols have the same meanings as described above) or general formula (Id):

[0041]

Embedded image (Wherein all symbols have the same meanings as described above) or a non-toxic salt thereof.
Specific compounds include the compounds described in Tables 1 to 4 below, their non-toxic salts, and the compounds described in Examples. Me in each table represents a methyl group, and the other symbols have the same meanings as described above.

[0042]

[Table 1]

[0043]

[Table 2]

[0044]

[Table 3]

[0045]

[Table 4]

[0046]

[Table 5]

[0047]

[Table 6]

[0048]

[Table 7]

[0049]

[Table 8]

[0050]

[Table 9]

[0051]

[Table 10]

[0052]

[Table 11]

[0053]

[Table 12]

[0054]

[Table 13]

[0055]

[Table 14]

[0056]

[Table 15]

[0057]

[Table 16]

[0058]

[Table 17]

[0059]

[Table 18]

[0060]

[Table 19]

[0061]

[Table 20]

[0062]

[Method for producing the compound of the present invention]

(A) Among the compounds represented by the general formula (I), R ² is-
COOR ⁶ groups, R ³ groups, R ⁴ groups, R ⁵ groups and —CO
None of the OR ⁶ groups represent a —COOH group or a group containing the same, and none of the R ⁴ and R ⁵ groups represent a hydroxyl group or a group containing the same, and R ³ , R ⁴ and A compound in which none of the R ⁵ groups represents an amino group or a group containing the same, that is, a compound represented by the general formula (IA1)

[0063]

Embedded image

[0064] (wherein, the R ^3-1 are as defined R ^3, -COOH group or an amino group include groups or it is represented by R ^3-1 each represent a protected group, R ^{4 -1} has the same meaning as R ⁴ , but a group represented by R ^4-1 or a -COOH group contained therein,
Hydroxy or amino groups each represent a protected group, R ^5-1 is the same meaning as R ^5, -COOH groups contained group or it is represented by R ^5-1, a hydroxyl group or an amino group protected respectively Represents a group represented by
^6-1 C1~8 alkyl group, a phenyl group or a phenyl group,, -OCOR ⁸ group (wherein, R ⁸ are as defined above.), - in CONR ⁹ R ¹⁰ (group, all symbols have Represents the same meaning as described above.), And represents a C1-4 alkyl group substituted with one group selected from the groups described above, and the other symbols have the same meanings as described above. The compound of the present invention represented by the general formula (II)

[0065]

Embedded image (Wherein X represents a halogen atom, and other symbols have the same meanings as described above), and a compound represented by the general formula (III)

[0066]

Embedded image R ^3-1 -JE ¹ (III) (wherein E ¹ is

[0067]

Embedded image And the other symbols have the same meanings as described above. )
The compound can be produced by reacting a compound represented by the following formula: The halogen atom of the benzene ring represented by the general formula (II) and the general formula (III)

[0068]

The reaction with a compound represented by R ^3-1 -JE ¹ (III) (wherein all symbols have the same meanings as described above) is known, and examples thereof include an organic solvent (acetonitrile, Dimethylformamide, tetrahydrofuran, etc.) in the presence or absence of a base (triethylamine, etc.) and cuprous iodide, using a catalyst (tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, etc.)
The reaction can be performed at 0 to 100 ° C.

(B) In the compound represented by the general formula (I), R ² is a —COOR ⁶ group, and any one of R ³ , R ⁴ , R ⁵ and —COOR ⁶ is A —COOH group or a group containing the same, or any of R ⁴ and R ⁵ represents a hydroxyl group or a group containing the same, or any of R ³ , R ⁴ and R ⁵ Wherein the group represents an amino group or a group containing the same, that is, a compound represented by the general formula (IA-2)

[0070]

Embedded image (Wherein, R ^3-2 , R ^4-2 , R ^5-2 and R ^6-2 each represent R
³ , R ⁴ , R ⁵ and R ⁶ have the same meanings, but at least one of them represents a —COOH group, a hydroxyl group or an amino group or a group containing them, and other symbols are as defined above. Indicates meaning. The compound of the present invention represented by the general formula (IA-1)
It can be produced by subjecting it to a deprotection reaction under alkaline hydrolysis and / or acid conditions.

The alkali hydrolysis reaction is known. For example, alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide) and alkaline earth metals in an organic solvent (eg, methanol, tetrahydrofuran, dioxane) are used. The reaction is performed at a temperature of 0 to 40 ° C. using a metal hydroxide (eg, calcium hydroxide) or a carbonate (eg, sodium carbonate, potassium carbonate) or an aqueous solution thereof or a mixture thereof.

The deprotection reaction under acidic conditions is known,
For example, in an organic solvent (methylene chloride, chloroform, dioxane, ethyl acetate, anisole, etc.), an organic acid (trifluoroacetic acid, methanesulfonic acid, trimethylsilyl iodide, etc.) or an inorganic acid (hydrochloric acid, etc.) or a mixture thereof (bromide) (Hydrogen acetic acid, etc.) at a temperature of 0 to 90 ° C.

(C) Among the compounds represented by the general formula (I), a compound wherein R ² represents a —CONHOR ⁷ group, that is, a compound represented by the general formula (I-B1)

Embedded image (Wherein all symbols have the same meanings as described above), are represented by the general formula (I-B2)

[0074]

Embedded image (Wherein all symbols have the same meanings as described above) and general formula (V)

[0075]

A compound represented by the formula: H ₂ N-OR ⁷ (V) wherein R ⁷ has the same meaning as described above, or a protected hydroxylamine (for example, H ₂ N—O—C) (CH ₃ ) ₂ —OCH ₃ , HN (Bo
c) -O-Boc (Boc represents a t-butoxycarbonyl group) or the like) and subjected to an amidation reaction. If necessary, it can also be produced by subjecting it to hydrolysis under alkaline conditions and / or deprotection under acidic conditions.

The amidation reaction is known, for example, (1)
Examples thereof include a method using an acid halide, (2) a method using a mixed acid anhydride, and (3) a method using a condensing agent. To illustrate these methods,

(1) A method using an acid halide is, for example, a method in which a carboxylic acid is mixed with an acid halide (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent. The reaction is carried out at −20 ° C. to reflux temperature, and the obtained acid halide is converted to a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.).
In the presence of an amine and an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.)
The reaction is carried out at 0 to 40 ° C.

(2) A method using a mixed acid anhydride is, for example, a method in which a carboxylic acid is dissolved in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran or the like) or in the absence of a tertiary amine (pyridine, triethylamine, dimethylaniline). , Dimethylaminopyridine, etc.) in the presence of an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate, isobutyl chloroformate, etc.) at -20 to 40 ° C to obtain a mixed acid anhydride. The reaction is carried out by reacting the compound with a corresponding amine at 0 to 40 ° C. in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.).

(3) Condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3-
(Dimethylamino) propyl] carbodiimide (ED
C), 2-chloro-1-methylpyridinium iodine,
For example, a method in which 1,1′-carbonyldiimidazole (CDI) or the like is used as a mixture is described by, for example, mixing a carboxylic acid and an amine in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether, tetrahydrofuran, or the like), or With or without the use of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) as a solvent, using a condensing agent,
The reaction is carried out at 0 to 40 ° C. with or without hydroxybenzotriazole (HoBt).

The reactions (1), (2) and (3) are desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions. Alkaline hydrolysis and deprotection under acid conditions can be carried out in the same manner as described above.

As can be easily understood by those skilled in the art, the protecting groups for carboxyl group and hydroxyl group include t-butyl group, benzyl group and the like, but other than that, they can be easily and selectively eliminated. It is not particularly limited as long as it is a group. For example, TW Greene, Protective Groups in Organi
c The one described in Synthesis, Wiley, New York, 1991 is used. Examples of the amino-protecting group include a benzyloxycarbonyl group and a t-butoxycarbonyl group, but are not particularly limited as long as they can be easily and selectively eliminated. Examples of the hydroxylamine-protecting group include a t-butyl group and a benzyl group, but other groups are not particularly limited as long as they can be easily and selectively eliminated. For example -C (CH _{3) 2} -OCH
₃ etc. are used. By properly using these protecting groups, the desired compound of the present invention can be easily produced.

The compound represented by the general formula (II) can be produced by, for example, a known method, a method represented by the following reaction scheme 1, or a method described in Examples. It is not limited.

Embedded image (In the reaction schemes, all symbols have the same meanings as described above.)

Each reaction of the above reaction scheme is carried out by a known method. In the above reaction schemes, the compounds represented by the general formulas (VI) and (VII) used as starting materials are known per se or can be easily produced by known methods. The other starting materials and each reagent in the present invention are known per se or can be produced by a known method.

In each reaction in the present specification, the reaction product is purified by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or It can be purified by column chromatography or a method such as washing and recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions.

[0085]

[Pharmacological activity] The following experiment proved that the compound of the present invention represented by the formula (I) has matrix metalloproteinase inhibitory activity.

(1) Gelatinase A inhibitory activity [Experimental method] 10 mM p-aminophenylmercury acetate (10 μm) was added to an assay buffer (90 μl) solution of progelatinase A (7 μl) purified from human normal skin fibroblasts (HNDF). (APMA) (10 μl) was added and preincubated at 37 ° C. for 1 hour to activate the enzyme.

Synthetic substrate (MOCAc-Pro-Leu-Gly-A ₂ pr (Dnp)-
Ala-Arg-NH ₂ ) (890 μl; final concentration 13.5 μM) and various concentrations of test compound solutions or solutions without test compound (10 μl) were preincubated at 37 ° C. for 5 minutes. The activated enzyme prepared above (7 μl / tube, 100 μl) was added thereto, and the mixture was added at 37 ° C. for 2 hours.
After incubation for 0 minutes, the enzymatic reaction was stopped by adding 0.1 M sodium acetate buffer (2 ml; pH 4.0). Gelatinase activity was calculated by measuring the fluorescence intensity (Ex = 328 nm and Em = 393 nm) of the reaction solution. Table 5 shows the results.

[0088]

[Table 21]

(2) Collagenase inhibitory activity [Experimental method] 1 mg / ml trypsin (45 μl) was added to an assay buffer (105 μl) solution of procollagenase (5 μl) purified from human normal skin fibroblasts (HNDF). The enzyme was activated by preincubation at 37 ° C. for 1 minute. 5 mg /
ml of soybean trypsin inhibitor
tor) (SBTI; 50 μl) was added to inactivate trypsin. Synthetic substrate (Ac-Pro-Leu-Gly- [2-mercapto
4-methyl-pentanoyl] -Leu-Gly-OEt) (105 μl; final concentration 1.33 mM) and various concentrations of test compound solutions or solutions (20 μl) to which test compounds were not added were added.
Preincubation was performed at 6 ° C for 5 minutes. There, the activated enzyme prepared above (75 μl / tube, 50 μl)
Was added and incubated at 26 ° C. for 10 minutes.
During these 10 minutes, a total of 40 points of absorbance at 324 nm were measured, and Vmax at 30 points was defined as a measured value. Table 6 shows the results.

[0090]

[Table 22]

[0091]

[Toxicity] The toxicity of the compound of the present invention is very low,
It can be determined that it is safe enough for use as a medicine.

[0092]

[Application to pharmaceuticals] In animals including humans, particularly humans, inhibition of matrix metalloproteinases such as gelatinase, collagenase, or stromlysin, results in rheumatism, osteoarthritis, pathological bone resorption, osteoporosis, periodontal disease. , Interstitial nephritis, arteriosclerosis, emphysema, cirrhosis, corneal injury, metastatic invasion and proliferation of cancer cells, autoimmune diseases (such as Crohn's disease and Shugren's disease), and diseases caused by vascular migration and infiltration of leukocyte cells , Angiogenesis and the like.

In order to use the compound of the present invention represented by the general formula (I), a non-toxic salt, an acid addition salt, or a hydrate thereof for the above-mentioned purpose, it is usually required to be orally or systemically or locally. It is administered in parenteral form. Dosage should be based on age, weight,
Depending on symptoms, therapeutic effect, administration method, treatment time, etc., it is usually 1 mg to 10 mg per adult.
Orally in the range of 00 mg once to several times a day,
Or 1 mg to 100 per adult
The parenteral administration (preferably, intravenous administration) is performed once to several times a day in the range of mg, or 1 hour to 24 hours a day.
It is continuously administered intravenously for a time range. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or may be required beyond the range.

When the compound of the present invention is administered, it is used as a solid composition, a liquid composition and other compositions for oral administration and an injection, an external preparation, a suppository and the like for parenteral administration. Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.

In such a solid composition, the one or more active substances comprise at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, It is mixed with magnesium metasilicate aluminate. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. The tablet or pill may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers, if necessary. . Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. The composition may further comprise a buffering agent which provides isotonicity with a stabilizer other than the inert diluent, such as sodium bisulfite,
For example, they may contain isotonic agents such as sodium chloride, sodium citrate or citric acid. Methods for producing sprays are described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.

The injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). . These are sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions, for example, sterilized or dissolved in sterile distilled water for injection or other solvents before use of the lyophilized product. Other compositions for parenteral administration include external solutions, ointments, containing one or more active substances, and formulated in a conventional manner.
It includes a liniment, a suppository for rectal administration, a pessary for vaginal administration, and the like.

[0098]

EXAMPLES The present invention will now be described in detail with reference to Examples and Examples, but the present invention is not limited thereto. Chromatographic separation point and TLC
The solvent in parentheses shown in the above indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. The solvent in parentheses shown in the NMR section indicates the solvent used for the measurement.

Reference Example 1 N- (4-bromophenylsulfonyl) -D-tryptophan methyl ester

Embedded image

4-Bromobenzenesulfonyl chloride (1.28 g) was gradually added to a solution of D-tryptophan methyl ester (1.27 g) in pyridine (10 ml) under ice cooling. The mixture was removed from the ice bath and stirred at room temperature for 1 hour. The reaction mixture was concentrated and extracted with ethyl acetate. The extract was washed with 1N-hydrochloric acid, water, and saturated saline in this order, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (2.08 g) having the following physical data in 95% yield.

TLC: Rf 0.5 (ethyl acetate: hexane = 1: 1); NMR (CDCl ₃ ): δ 8.10 (1H, s), 7.48 (2H, d, J = 8.4 Hz),
7.40 (2H, d, J = 8.4Hz), 7.39-6.96 (5H, m), 5.28 (1H, d, J =
8.6Hz), 4.35-4.18 (1H, m), 3.54 (3H, s), 3.33-3.10 (2H,
m).

Reference Example 1 (1) to 1 (3) The same operation as in Reference Example 1 was carried out using 4-bromobenzenesulfonyl chloride and the corresponding amino acid derivative.
The following compound was obtained.

Reference Example 1 (1) N- (4-bromophenylsulfonyl) -D-alanine.t-butyl ester

Embedded image

TLC: Rf 0.31 (ethyl acetate: hexane = 1: 4); NMR (CDCl ₃ ): δ 7.72 (2H, d, J = 8.6 Hz), 7.62 (2H, d, J =
8.6Hz), 5.25 (1H, d, J = 8.7Hz), 3.92-3.78 (1H, m), 1.34
(3H, d, J = 7.0Hz), 1.28 (9H, s).

Reference Example 1 (2) N'-methyl-N'-phenethyl-N- (4-bromophenylsulfonyl) -D-glutamine.t-butyl ester

Embedded image The obtained compound was used for the next reaction without purification.

Reference Example 1 (3) N'-benzyl-N'-methyl-N- (4-bromophenylsulfonyl) -D-glutamine.t-butyl ester

Embedded image

TLC: Rf 0.47 (hexane: ethyl acetate = 1: 1); NMR (CDCl ₃ ): δ 7.70 and 7.69 (2H, d and d, J = 8.8 and 8.8 Hz in total), 7.61 and 7.60 (combined) 2H,
d and d, J = 8.8 and 8.8 Hz), 7.41-7.15 (5H, m), 5.46 (1
H, t, J = 9.0Hz), 4.62 and 4.54 (2H, s and
s), 3.84 (1H, m), 2.97 and 2.93 (3H, s and
s), 2.70-2.40 (2H, m), 2.35-2.10 (1H, m), 1.95-1.70 (1
H, m), 1.27 and 1.24 (9H, s and s in total).

Example 1 N- (4- (4-hydroxy-1-butynyl) phenylsulfonyl) -D-tryptophan methyl ester

Embedded image

To the compound (1.0 g) produced in Reference Example 1 were added triethylamine (5.4 ml) and acetonitrile (2.9 g).
ml), and triphenylphosphine (96 ml) was added.
mg), cuprous iodide (17 mg) and 10% palladium on carbon (82 mg). Reaction mixture solution at 80 ° C
For 4 hours. The reaction mixture was filtered, and the filtrate was concentrated. The obtained residue is subjected to silica gel column chromatography (chloroform: ethyl acetate = 3: 1 → 2: 1).
The compound of the present invention (0.947) having the following physical data.
g) was obtained with a yield of 97%.

TLC: Rf 0.10 (hexane: ethyl acetate = 1: 1); NMR (CD ₃ OD): δ 7.5 (2H, d, J = 8 Hz), 7.4-7.2 (4H, m),
7.2-6.9 (3H, m), 4.15 (1H, t, J = 6Hz), 3.76 (2H, t, J = 7Hz),
3.47 (3H, s), 3.18 (1H, dd, J = 12,6Hz), 3.03 (1H, dd, J = 1
2,7Hz), 2.67 (2H, t, J = 7Hz).

Examples 1 (1) to 1 (14) The compound prepared in Reference Example 1, the compound prepared in Reference Example 1 (1), the compound prepared in Reference Example 1 (2) or Reference Example 1 (3) Using the compound produced in and the corresponding acetylene derivative or olefin derivative, the following operation was carried out in the same manner as in Example 1.

Example 1 (1) N- (4- (6-hydroxy-1-hexynyl) phenylsulfonyl) -D-tryptophan methyl ester

Embedded image

TLC: Rf 0.32 (ethyl acetate: chloroform = 1: 1); NMR (CDCl ₃ ): δ 8.18-8.07 (1H, br), 7.58-6.99 (10H,
m), 5.28-5.10 (1H, br), 4.27-4.16 (1H, m), 3.74-3.58 (2
H, br), 3.41 (3H, s), 3.17 (2H, d, J = 6Hz), 2.43 (2H, t, J = 6
Hz), 1.82-1.50 (4H, m).

Example 1 (2) N- (4- (5-hydroxy-1-pentynyl) phenylsulfonyl) -D-tryptophan methyl ester

Embedded image

TLC: Rf 0.30 (ethyl acetate: chloroform = 1: 1); NMR (CDCl ₃ ): δ 8.16-8.06 (1H, br), 7.63-6.98 (10H,
m), 5.23-5.12 (1H, br), 4.34-4.20 (1H, m), 3.87-3.70 (2
H, m), 3.47 (3H, s), 2.59 (2H, t, J = 7Hz), 2.39 (2H, t, J = 7H
z), 1.88 (2H, tt, J = 7,7Hz).

Example 1 (3) (E) -N- (4- (4-acetyloxy-1-butenyl) phenylsulfonyl) -D-tryptophan methyl ester

Embedded image

TLC: Rf 0.43 (hexane: ethyl acetate = 1: 1); NMR (CDCl ₃ ): δ 8.10 (1H, br), 7.63 (2H, d, J = 8.6 Hz),
7.45 (1H, d, J = 7.5Hz), 7.31 (3H, m), 7.20-7.00 (3H, m),
6.46 (1H, d, J = 16.0Hz), 6.28 (1H dt, J = 16.0,6.8Hz), 5.1
5 (1H, d, J = 10.0Hz), 4.22 (3H, m), 3.45 (3H, s), 3.24 (2H,
d, J = 5.6Hz), 2.58 (2H, m), 2.07 (3H, s).

Example 1 (4) N- (4- (4- (tetrahydropyran-2-yloxy) -1-butynyl) phenylsulfonyl) -D-tryptophan methyl ester

Embedded image

TLC: Rf 0.44 (ethyl acetate: hexane = 1: 1); NMR (CDCl ₃ ): δ 8.17 (1H, s), 7.58 (2H, d, J = 8.8 Hz),
7.43 (1H, d, J = 7.4Hz), 7.39-7.27 (3H, m), 7.22-7.02 (2H,
m), 6.97 (1H, d, J = 2.6Hz), 5.23 (1H, d, J = 9.2Hz), 4.75-4.
65 (1H, m), 4.32-4.20 (1H, m), 4.00-3.82 (2H, m), 3.72-
3.46 (2H, m), 3.45 (3H, s), 3.30-3.12 (2H, m), 2.73 (2H, m
t, J = 7.0Hz), 2.00-1.40 (6H, m).

Example 1 (5) N- (4- (3- (tetrahydropyran-2-yloxy) -1-propynyl) phenylsulfonyl) -D-tryptophan methyl ester

Embedded image TLC: Rf 0.2 (ethyl acetate: hexane = 1: 1).

Example 1 (6) N- (4- (6-hydroxy-1-hexynyl) phenylsulfonyl) -D-alanine.t-butyl ester

Embedded image

TLC: Rf 0.35 (ethyl acetate: hexane = 1: 1); NMR (CDCl ₃ ): δ 7.75 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J =
8.6Hz), 5.29 (1H, d, J = 8.4Hz), 3.94-3.75 (1H, m), 3.75-
3.60 (2H, m), 2.55-2.38 (2H, t, J = 6.5Hz), 1.84-1.60 (4H,
m), 1.35 (3H, d, J = 7.2Hz), 1.30 (9H, s).

Example 1 (7) (E) -N- (4- (4-hydroxy-1-butenyl)
Phenylsulfonyl) -D-alanine t-butyl ester

Embedded image

TLC: Rf 0.44 (hexane: ethyl acetate = 1: 2); NMR (CDCl ₃ ): δ 7.77 (2H, d, J = 9.0 Hz), 7.45 (2H, d, J =
9.0Hz), 6.52 (1H, d, J = 15.9Hz), 6.36 (1H, dt, J = 15.9,6.5
Hz), 5.50 (1H, d, J = 9.0Hz), 3.80 (3H, m), 2.52 (2H, m),
1.30 (12H, m).

Example 1 (8) N- (4- (3-hydroxy-1-propynyl) phenylsulfonyl) -D-alanine.t-butyl ester

Embedded image

TLC: Rf 0.66 (ethyl acetate: hexane = 4: 1); NMR (CDCl ₃ ): δ 7.79 (2H, d, J = 8.4 Hz), 7.51 (2H, d, J =
8.4Hz), 5.34 (1H, d, J = 8.8Hz), 4.52 (2H, brs), 3.95-3.7
8 (1H, m), 2.02-1.86 (1H, brs), 1.35 (3H, d, J = 7.4Hz), 1.
29 (9H, s).

Example 1 (9) (E) -N- (4- (2- (ethyloxycarbonyl)
Ethenyl) phenylsulfonyl) -D-alanine.t-
Butyl ester

Embedded image TLC: Rf 0.7 (ethyl acetate: methylene chloride = 1:
9).

Example 1 (10) N'-methyl-N'-phenethyl-N- (4- (4-hydroxy-1-butynyl) phenylsulfonyl) -D-
Glutamine t-butyl ester

Embedded image The obtained compound was used for the next reaction without purification.

Example 1 (11) N'-benzyl-N'-methyl-N- (4- (4-hydroxy-1-butynyl) phenylsulfonyl) -D-glutamine.t-butyl ester

Embedded image

TLC: Rf 0.48 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 7.75 and 7.74 (2H, d and d, J = 8.8 and 8.8 Hz in total), 7.48 and 7.47 (total 2H,
d and d, J = 8.8 and 8.8 Hz), 7.40-7.15 (5H, m), 5.47 (1
H, t, J = 9.0Hz), 4.61 and 4.53 (2H, s and
s), 3.83 (3H, m), 2.97 and 2.93 (3H, s and
s), 2.71 (2H, t, J = 6.2Hz), 2.63-2.40 (2H, m), 2.30-2.10
(1H, m), 1.95-1.70 (1H, m), 1.27 and 1.24 (9
H, s and s).

Example 1 (12) N-4- (6-dimethylamino-1-hexynyl) phenylsulfonyl-D-tryptophan methyl ester

Embedded image

TLC: Rf 0.18 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.83 (1H, s), 8.70-8.40 (1H, br),
7.54 (2H, d, J = 8.4Hz), 7.39 (2H, d, J = 8.4Hz), 7.36-7.22
(2H, m), 7.10-6.86 (3H, m), 4.06-3.90 (1H, m), 3.34 (3H, m
s), 3.07 (1H, dd, J = 7.0,14.4Hz), 2.90 (1H, dd, J = 7.6,14.
4Hz), 2.61-2.40 (4H, m), 2.36 (6H, s), 1.74-1.48 (4H,
m).

Example 1 (13) N- (4- (3-((Imidazol-4-ylmethylcarbonyl) amino) -1-propynyl) phenylsulfonyl) -D-tryptophan methyl ester

Embedded image

TLC: Rf 0.34 (chloroform: methanol = 4: 1); NMR (DMSO-d ₆ ): δ 12.10-11.70 (1H, br), 10.82 (1H,
s), 8.70-8.40 (2H, br), 7.68-7.51 (3H, m), 7.50-7.39 (2
H, m), 7.38-7.20 (2H, m), 7.18-6.80 (4H, m), 4.26-3.92
(3H, m), 3.34 (3H, s), 3.17 (2H, d, J = 4.8Hz), 3.05 (1H, d
d, J = 5.4,14.0Hz), 2.90 (1H, dd, J = 8.3,14.0Hz).

Example 1 (14) N- (4- (3-methoxy-1-propynyl) phenylsulfonyl) -D-tryptophan methyl ester

Embedded image

TLC: Rf 0.40 (ethyl acetate: hexane = 1: 1); NMR (CDCl ₃ ): δ 8.10 (1H, brs), 7.62 (2H, d, J = 8.4H)
z), 7.5-7.0 (6H, m), 6.98 (1H, d, J = 2.2Hz), 5.20 (1H, d, J
= 9.2Hz), 4.33 (2H, s), 4.38 (1H, m), 3.47 (3H, s), 3.46
(3H, s), 3.23 (2H, d, J = 6Hz).

Reference Example 2 N- (4- (3- (1,3-isoindolinedione-2)
-Yl) -1-propynyl) phenylsulfonyl) -D
-Tryptophan methyl ester

Embedded image

Using the compound produced in Reference Example 1 and the corresponding acetylene derivative, the same procedure as in Example 1 was carried out to give the title compound having the following physical data. TLC: Rf 0.32 (ethyl acetate: hexane = 1:
1); NMR (CDCl ₃ ): δ 8.16-8.06 (1H, br), 7.95-7.86 (2H,
m), 7.80-7.70 (2H, m), 7.57 (2H, d, J = 8.8Hz), 7.48-7.02
(6H, m), 6.96 (1H, d, J = 2.4Hz), 5.19 (1H, d, J = 9.2Hz), 4.
70 (2H, s), 4.30-4.16 (1H, m), 3.46 (3H, s), 3.30-3.10 (2
H, m).

Example 2 N- (4- (6-acetyloxy-1-hexynyl) phenylsulfonyl) -D-alanine butyl ester

Embedded image

The compound (523) produced in Example 1 (6)
mg) in pyridine (3 ml).
l) was added and the mixture was stirred at room temperature for 3 hours. 1 in the reaction mixture
N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. 1N organic layer
-Washed sequentially with hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, concentrated, and used for the next reaction. TLC: Rf 0.75 (ethyl acetate: hexane = 1:
1).

Example 2 (1) N- (4- (3-acetyloxy-1-propynyl) phenylsulfonyl) -D-alanine.t-butyl ester

Embedded image Using the compound prepared in Example 1 (8) and operating in the same manner as in Example 2, the compound of the present invention was obtained. TLC: Rf 0.32 (ethyl acetate: hexane = 3:
7).

Example 3 N- (4- (4-hydroxy-1-butynyl) phenylsulfonyl) -D-tryptophan

Embedded image

To a solution of the compound (4.26 g) prepared in Example 1 in dioxane (1 ml) was added dropwise a 1N aqueous solution of sodium hydroxide (4.4 ml) under ice cooling, and the mixture was stirred at room temperature overnight. 1N-HCl was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to give the compound of the present invention (120 mg) as a white powder having the following physical data in a yield of 29%.

TLC: Rf 0.74 (ethyl acetate: methanol: acetic acid = 90: 30: 1); NMR (DMSO-d ₆ ): δ 8.40-8.01 (1H, br), 7.56-7.42 (2
H, m), 7.41-7.24 (4H, m), 7.10-6.87 (4H, m), 5.20-4.80 (1
H, br), 3.86 (1H, m), 3.59 (2H, t, J = 7Hz), 3.05 (1H, dd, J =
14,5Hz), 2.84 (1H, dd, J = 14,8Hz), 2.57 (2H, t, J = 7Hz).

Examples 3 (1) to 3 (10) Using the compounds prepared in Examples 1 (1) to 1 (7), Examples 2-2 (1) and Example 1 (9), The same operation as in Example 3 (deprotection under acidic conditions; for example, using a solution of trifluoroacetic acid and hydrogen chloride in dioxane) or the same operation as the above (for example, alkali hydrolysis)
Was carried out to obtain the following compound.

Example 3 (1) N- (4- (6-hydroxy-1-hexynyl) phenylsulfonyl) -D-tryptophan

Embedded image

TLC: Rf 0.84 (ethyl acetate: methanol: acetic acid = 100: 10: 1); NMR (CD ₃ OD): δ 7.44-6.82 (10H, m), 4.08 (1H, dd, J =
8,5Hz), 3.62 (2H, t, J = 4Hz), 3.21 (1H, dd, J = 14,5Hz), 2.
97 (1H, dd, J = 14,8Hz), 2.47 (2H, t, J = 6Hz), 1.81-1.61 (4
H, m).

Example 3 (2) N- (4- (5-hydroxy-1-pentynyl) phenylsulfonyl) -D-tryptophan

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TLC: Rf 0.58 (ethyl acetate: methanol: acetic acid = 100: 10: 1); NMR (CD ₃ OD): δ 7.43-6.88 (10H, m), 4.04 (1H, dd, J =
8,5Hz), 3.70 (2H, t, J = 6Hz), 3.21 (1H, dd, J = 14,5Hz), 2.
97 (1H, dd, J = 14,8Hz), 2.52 (2H, t, J = 7Hz), 1.81 (2H, tt, J
= 7,6Hz).

Example 3 (3) (E) -N- (4- (4-hydroxy-1-butenyl)
Phenylsulfonyl) -D-tryptophan

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TLC: Rf 0.35 (chloroform: methanol: acetic acid = 80: 20: 1); NMR (CD ₃ OD): δ 7.50 (1H, d, J = 8.0 Hz), 7.42 (2H, d, J =
8.6Hz), 7.23 (1H, d, J = 8.0Hz), 7.19 (2H, d, J = 8.6Hz), 7.
03 (1H, m), 6.99 (1H, s), 6.91 (1H, m), 6.44 (1H, d, J = 15.6
Hz), 6.34 (1H, td, J = 15.6,6.0Hz), 3.91 (1H, dd, J = 7.6,4.
6Hz), 3.70 (2H, t, J = 6.6Hz), 3.22 (1H, dd, J = 14.6,4.6H
z), 2.99 (1H, dd, J = 14.6,7.6Hz), 2.46 (2H, m).

Example 3 (4) N- (4- (3- (tetrahydropyran-2-yloxy) -1-propynyl) phenylsulfonyl) -D-tryptophan

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TLC: Rf 0.47 (chloroform: methanol: acetic acid: water = 50: 10: 1: 1); NMR (CDCl ₃ ): δ 8.18 (1H, br), 7.47 (3H, m), 7.35-7.
00 (5H, m), 6.88 (1H, s), 5.46 (1H, d, J = 8.8Hz), 4.70 (1H,
m), 4.24 (1H, m), 4.0-3.5 (4H, m), 3.20 (2H, m).

Example 3 (5) N- (4- (3- (tetrahydropyran-2-yloxy) -1-propynyl) phenylsulfonyl) -D-tryptophan

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TLC: Rf 0.24 (chloroform: methanol = 9: 1); NMR (CDCl ₃ + CD ₃ OD): δ 9.84-8.78 (1H, m), 7.40-6.80
(9H, m), 4.90 (1H, s), 4.50 (2H, s), 4.21-4.06 (1H, m),
3.99-3.82 (1H, m), 3.62-3.50 (1H, m), 3.28-2.90 (3H, m),
2.00-1.46 (6H, m).

Example 3 (6) N- (4- (6-hydroxy-1-hexynyl) phenylsulfonyl) -D-alanine

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TLC: Rf 0.20 (chloroform: methanol: acetic acid = 90: 10: 1); NMR (DMSO-d ₆ ): δ 8.30-7.90 (1H, br), 7.73 (2H, d, J =
8.6Hz), 7.53 (2H, d, J = 8.6Hz), 3.80-3.62 (1H, m), 3.44
(2H, t, J = 6.2Hz), 2.46 (2H, t, J = 6.6Hz), 1.70-1.50 (4H, t
m), 1.15 (3H, d, J = 7.4Hz).

Example 3 (7) (E) -N- (4- (4-hydroxy-1-butenyl)
Phenylsulfonyl) -D-alanine

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TLC: Rf 0.35 (chloroform: methanol: acetic acid = 80: 20: 1); NMR (CDCl ₃ + CD ₃ OD): δ 7.77 (2H, d, J = 8.4 Hz), 7.45 (2
H, d, J = 8.4Hz), 6.52 (1H, d, J = 16.0Hz), 6.38 (1H, dt, J = 6.
4,16.0Hz), 3.91 (1H, q, J = 7.2Hz), 3.75 (2H, t, J = 6.4Hz),
2.50 (2H, m), 1.37 (3H, d, J = 7.2Hz).

Example 3 (8) N- (4- (6-acetyloxy-1-hexynyl) phenylsulfonyl) -D-alanine

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TLC: Rf 0.33 (chloroform: methanol: acetic acid = 90: 10: 1); NMR (DMSO-d ₆ ): δ 7.76 (2H, d, J = 8.6 Hz), 7.48 (2H, d,
J = 8.6Hz), 7.20-6.94 (2H, br), 5.48 (1H, d, J = 8.6Hz), 4.
14 (2H, t, J = 6.0Hz), 4.10-3.92 (1H, m), 2.48 (2H, t, J = 6.6
Hz), 2.06 (3H, s), 1.90-1.60 (4H, m), 1.41 (3H, d, J = 7.4H
z).

Example 3 (9) N- (4- (3-acetyloxy-1-propynyl) phenylsulfonyl) -D-alanine

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TLC: Rf 0.39 (chloroform: methanol: acetic acid = 90: 10: 1); NMR (DMSO-d ₆ ): δ 12.80-12.40 (1H, br), 8.25 (1H, d,
J = 8.4Hz), 7.78 (2H, d, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz),
4.95 (2H, s), 3.88-3.68 (1H, m), 2.09 (3H, s), 1.17 (3H,
d, J = 7.4Hz).

Example 3 (10) (E) -N- (4- (2- (ethyloxycarbonyl)
Ethenyl) phenylsulfonyl) -D-alanine

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TLC: Rf 0.46 (chloroform: methanol: acetic acid = 100: 20: 1); NMR (CD ₃ OD): δ 7.87 (d, 2H, J = 8 Hz), 7.75 (d, 2H, J = 8H)
z), 7.71 (d, 1H, J = 16Hz), 6.65 (d, 1H, J = 16Hz), 4.25 (q, 2
H, J = 7Hz), 3.92 (q, 1H, J = 7Hz), 1.32 (t, 3H, J = 7Hz), 1.30
(d, 3H, J = 7Hz).

Example 3 (11) N- (4- (3-hydroxy-1-propynyl) phenylsulfonyl) -D-tryptophan

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Using the compound prepared in Example 3 (5), the same operation as in Example 3 (deprotection under acidic conditions; for example, using trifluoroacetic acid, hydrogen chloride in dioxane) or the same purpose as described above (For example, alkali hydrolysis) to obtain the compound of the present invention.

TLC: Rf 0.14 (chloroform: methanol: acetic acid: water = 100: 10: 1: 1); NMR (CD ₃ OD): δ 7.58-7.44 (1H, m), 7.46 (2H, d, J = 8H
z), 7.24 (2H, d, J = 8Hz), 7.08-6.84 (3H, m), 4.41 (2H, s),
4.01-3.80 (1H, m), 3.30-2.82 (2H, m).

Examples 3 (12) to 3 (16) Using the compounds prepared in Examples 1 (10) to 1 (14), the same operation as in Example 3 (deprotection under acidic conditions; for example, Trifluoroacetic acid, a dioxane solution of hydrogen chloride) or the same operation (eg, alkali hydrolysis) was performed to obtain the following compound.

Example 3 (12) N'-methyl-N'-phenethyl-N- (4- (4-hydroxy-1-butynyl) phenylsulfonyl) -D-
glutamine

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TLC: Rf 0.51 (chloroform: methanol: acetic acid = 80: 20: 1); NMR (DMSO-d ₆ ): δ 7.72 and 7.71 (2H, d in total)
And d, J = 8.6 and 8.6 Hz), 7.53 and 7.51 (together
2H, d and d, J = 8.6,8.6Hz), 7.26 (5H, m), 3.65 (1H, m),
3.60 and 3.59 (2H, t and t, J = 6.6 and 6.6
Hz), 3.40 (2H, m), 2.76 (3H, s), 2.70 (2H, m), 2.59 and
2.57 (total 2H, t and t, J = 6.6 and 6.6Hz), 2.14
(2H, m), 1.95-1.50 (2H, m).

Example 3 (13) N'-benzyl-N'-methyl-N- (4- (4-hydroxy-1-butynyl) phenylsulfonyl) -D-glutamine

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TLC: Rf 0.5 (chloroform: methanol: acetic acid = 80: 20: 1); NMR (CD ₃ OD): δ 7.78 and 7.75 (2H, d and d, J = 8.4 and 8.0 Hz in total), 7.51 And 7.48 (2H,
d and d, J = 8.4 and 8.0 Hz), 7.40-7.20 (5H, m), 4.57-
4.52 (2H, m), 3.91 (1H, m), 3.73 (2H, t, J = 6.6Hz), 2.90
And 2.88 (3H, s and s in total), 2.65 (2H, t, J = 6.6H
z), 2.48 (2H, m), 2.15 (1H, m), 1.85 (1H, m).

Example 3 (14) N- (4- (6-dimethylamino-1-hexynyl) phenylsulfonyl) -D-tryptophan

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TLC: Rf 0.30 (chloroform: methanol: acetic acid: water = 14: 6: 1: 1); NMR (DMSO-D ₆ ): δ 10.76 (1H, s), 7.60 (2H, d, J = 8.4) H
z), 7.50-7.35 (3H, m), 7.29 (1H, d, J = 7.8Hz), 7.10-6.82
(3H, m), 3.80-3.64 (1H, m), 3.16-2.86 (2H, m), 2.60-2.4
0 (4H, m), 2.31 (6H, s), 1.68-1.40 (4H, m).

Example 3 (15) N- (4- (3-((Imidazol-4-ylmethylcarbonyl) amino) -1-propynyl) phenylsulfonyl) -D-tryptophan

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TLC: Rf 0.23 (chloroform: methanol: acetic acid: water = 14: 6: 1: 1); NMR (DMSO-D ₆ + CD ₃ OD): δ 7.55 (1H, s), 7.50 (2H, d) , J =
8.4Hz), 7.42-7.20 (4H, m), 7.10-6.80 (4H, m), 4.14 (2H, m
s), 3.94-3.82 (1H, m), 3.40 (2H, s), 3.05 (1H, dd, J = 14.
1,5.4Hz), 2.86 (1H, dd, J = 14.1,8.3Hz).

Example 3 (16) N- (4- (3-methoxy-1-propynyl) phenylsulfonyl) -D-tryptophan

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TLC: Rf 0.31 (chloroform: methanol: acetic acid = 90: 10: 1); NMR (DMSO-d ₆ ): δ 12.80-12.55 (1H, brs), 10.78 (1H,
s), 8.34 (1H, d, J = 8.8Hz), 7.52 (2H, d, J = 8.4Hz), 7.39 (2
(H, d, J = 8.4Hz), 7.36-7.26 (2H, m), 7.12-6.88 (3H, m), 4.
36 (2H, s), 4.00-3.82 (1H, m), 3.36 (3H, s), 3.08 (1H, dd,
J = 14.2,6.0Hz), 2.86 (1H, dd, J = 14.2,8.2Hz).

Example 4 N- (4- (3-amino-1-propynyl) phenylsulfonyl) -D-tryptophan methyl ester

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To a solution of the compound prepared in Reference Example 2 (2.93 g) in methanol (10 ml) was added hydrazine monohydrate (5
42 μl) and stirred at room temperature for 2 hours. Ethyl acetate (100 ml) was added and the mixture was filtered. The obtained filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate → chloroform: methanol = 95: 5).
→ 90: 10) to give the compound of the present invention (1.01 g) having the following physical data in a yield of 45%.

TLC: Rf 0.33 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.82 (1H, s), 7.70-7.22 (7H, m),
7.20-6.84 (3H, m), 4.10-3.90 (1H, m), 3.55 (2H, s), 3.38
(3H, s), 3.06 (1H, dd, J = 6.5,13.6Hz), 2.92 (1H, dd, J = 7.
0,13.6Hz).

Example 5 N- (4- (3-amino-1-propynyl) phenylsulfonyl) -D-tryptophan

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Using the compound prepared in Example 4, the same operation as in Example 3 (deprotection under acidic conditions; for example, using a solution of trifluoroacetic acid and hydrogen chloride in dioxane) or the same operation as the above (for deprotection) For example, alkali hydrolysis was performed to obtain the following compound.

TLC: Rf 0.29 (chloroform: methanol: acetic acid: water = 14: 6: 1: 1); NMR (DMSO-D ₆ ): δ 10.75 (1H, s), 7.62 (2H, d, J = 8.4) H
z), 7.50-7.40 (3H, m), 7.30 (1H, d, J = 8.2Hz), 7.18-6.84
(3H, m), 3.82-3.70 (1H, m), 3.63 (2H, s), 3.09 (1H, dd, J =
14.2,5.6Hz), 2.94 (1H, dd, J = 14.2,6.6Hz).

Example 6 N-hydroxy-N-((N'-4- (4-hydroxy-1-butynyl) phenylsulfonyl) -D-tryptofil) amide

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The compound (1.45) produced in Example 3 (4)
g) in dimethylformamide (20 ml) solution
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (865 mg), 1-hydroxybenzotriazole monohydrate (671 mg) and N- (1
-Methoxy-1-methylethoxy) amine (1.31 g) was added, and the mixture was stirred at room temperature for 1 hour. Add water (10
0 ml) and extracted with ethyl acetate (100 ml). The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1). The purified product (1.42 g) was dissolved in methanol (10 ml), 1N hydrochloric acid (2 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized and concentrated. The residue was extracted with ethyl acetate (100 ml), and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give the compound of the present invention (641 mg) having the following physical data at a yield of 64%.

TLC: Rf 0.19 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.75 (1H, s), 10.74-10.50 (1H, b)
r), 9.00-8.70 (1H, br), 8.44-8.08 (1H, br), 7.50 (2H, d,
J = 8.4Hz), 7.42-7.16 (4H, m), 7.15-6.86 (3H, m), 5.02-
4.85 (1H, br), 3.64 (1H, m), 3.70-3.50 (2H, m), 2.96 (1H,
dd, J = 14.2,6.8Hz), 2.69 (1H, dd, J = 14.2,7.4Hz), 2.59 (2
H, t, J = 6.8Hz).

Example 6 (1) N-hydroxy-N-((N'-4- (4-hydroxy-1-butynyl) phenylsulfonyl) -N "-methyl-N" -phenethyl-D-glutamyl ) Amide

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The same operation as in Example 4 was performed using the compound prepared in Example 3 (12) to obtain the compound of the present invention having the following physical data. TLC: Rf 0.38 (chloroform: methanol: acetic acid = 90: 10: 1); NMR (CD ₃ OD): δ 7.77 and 7.76 (2H, d and d, J = 8.8 and 8.4 Hz in total), 7.53 and 7.52 ( 2H,
d and d, J = 8.8 and 8.4 Hz), 7.22 (5H, m), 3.73 and
3.72 (2H, t and t, J = 6.6 and 6.6Hz in total), 3.60-
3.40 (3H, m), 2.88-2.75 (5H, m), 2.64 and 2.63 (2H, t and t, J = 6.6 and 6.6Hz in total), 2.25 (1H, m), 2.
05 (1H, m), 1.98-1.50 (2H, m).

[0191]

Formulation Example Formulation Example 1 The following components were mixed in a conventional manner and tabletted to give 100 tablets each containing 50 mg of the active ingredient. · N-4- (4-hydroxybutynyl) phenylsulfonyl-D-alanine ··· 5.0 g · Calcium carboxymethylcellulose (disintegrant) ··· 0.2 g · Magnesium stearate (lubricant) ··· 0.1 g Microcrystalline cellulose 4.7g

Formulation Example 2 After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled into ampoules in 5 ml portions, freeze-dried by a conventional method, and contains 20 mg of the active ingredient in one ampule. 100 ampoules were obtained.・ N-4- (4-hydroxybutynyl) phenylsulfonyl-D-alanine ・ ・ ・ ・ ・ ・ 2.00g ・ Mannitol ・ ・ ・ ・ ・ ・ 20g ・ Distilled water ・ ・ ・ ・ ・ ・ 500ml

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 403/12 209 C07D 403/12 209 405/12 209 405/12209 // A61K 31/18 ABG A61K 31/18 ABG ABL ABL ACD ACD ADU ADU ADU 31/195 ADT 31/195 ADT 31/215 ABX 31/215 ABX 31/405 AED 31/405 AED 31/415 ABB 31/415 ABB

Claims (1)

[Claims] 1. A compound of the general formula (I) [Wherein, R ¹ represents 1) a hydrogen atom, or 2) a C1-4 alkyl group, and R ² represents a 1) —COOR ⁶ group (wherein, R ⁶ is (1) a hydrogen atom, (2) C1 8-alkyl group, (3) phenyl group, or (4) C1-4 alkyl group substituted with one group selected from the following (i) to (iii); (i) phenyl group, (ii) -OCOR ⁸ groups (in the group, R ⁸ represents a C1-4 alkyl group), (iii) -CONR ⁹
R ¹⁰ groups (wherein R ⁹ and R ¹⁰ are each independently
Represents a hydrogen atom or a C1-4 alkyl group. ) Or 2) -CONHOR ⁷ group, wherein R ⁷ is (1) a hydrogen atom, (2) a C1-8 alkyl group, (3) a phenyl group, or (4) a C1 substituted with one phenyl group. Wherein R ³ is 1) —OR ¹¹ group (wherein R ¹¹ is (1) hydrogen atom, (2) C 1-4 alkyl group, (3) C 2-4 acyl group) , (4) phenyl, (5) a C1~4 alkyl group substituted with a phenyl group, (6) -NR ¹⁵ R ¹⁶ group (wherein, R ¹⁵ and R ¹⁶ are each independently a hydrogen atom , or represents a C1~4 alkyl group.), or represents a (7) tetrahydropyran-2-yl group.), 2) -NR ¹² R ¹³ group (wherein, R ¹² and R ¹³ are each independently represents a hydrogen atom or a C1~4 alkyl group,.), 3) -COOR ¹⁴ group (wherein . R ¹⁴ is (1) hydrogen atom, (2) C1 -4 alkyl group, (3) represents a phenyl group or (4) a C1 -4 alkyl group substituted with a phenyl group), or 4) - NR ²³ COR ²⁴ (wherein, R ²³ is a hydrogen atom or C
R ²⁴ represents a C 1-4 alkyl group, a phenyl group, a heterocyclic group, a C 1-4 alkyl group substituted with one phenyl group, or a C 1-4 substituted with one hetero ring group. Represents a 4-alkyl group. )
R ⁴ and R ⁵ are each independently 1) a hydrogen atom, 2) a C1-8 alkyl group in which one carbon atom may be replaced by a sulfur atom, 3) a —COR ¹⁷ group (wherein R ¹⁷ is (1) hydroxyl group, (2) C1-8 alkyl group, (3) C1-8 alkoxy group, (4) phenoxy group, (5) C1-4 alkoxy group substituted with one phenyl group, (6)- An NR ²⁰ R ²¹ group (wherein R ²⁰ and R ²¹ are each independently a hydrogen atom, a C 1-4 alkyl group, a phenyl group, or a C 1-4 alkyl group substituted with one or two phenyl groups; 4) a carbocyclic group (this carbocyclic group is a C1-4 alkyl group,
It may be substituted with 1-3 substituents selected from 1-4 alkoxy groups, halogen atoms, hydroxyl groups, or trifluoromethyl groups. ), 5) a heterocyclic group (the heterocyclic group is substituted with 1 to 3 substituents selected from a C1-4 alkyl group, a C1-4 alkoxy group, a halogen atom, a hydroxyl group, and a trifluoromethyl group) . or), or 6) below (i) ~ (C1-8 alkyl group substituted by one group selected from viii); (i) -COR ¹⁷ group (wherein, R ¹⁷ is as defined above (Ii) a C1-4 alkoxy group, (iii) a hydroxyl group, (iv) a benzyloxy group, (v) a guanidino group,
(Vi) -NR ¹⁸ R ¹⁹ group (wherein, R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, C1 -4 alkyl group or -
A COOR ²² group (wherein R ²² represents a C 1-4 alkyl group or a benzyl group), (vii) a carbocyclic group (this carbon ring group is a C 1-4 alkyl group, a C 1-4 alkoxy group,
It may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a trifluoromethyl group. ), (Viii) a heterocyclic group (this heterocyclic group is
4 alkyl groups, C1-4 alkoxy groups, halogen atoms,
1 selected from a hydroxyl group and a trifluoromethyl group
It may be substituted with up to 3 substituents. ), And E is And J represents 1) a single bond, or 2) a C1-8 alkylene group, R ²⁵ represents 1) a hydrogen atom, 2) a C1-4 alkyl group, 3) a C1-4 substituted with one phenyl group. Represents an alkyl group, 4) a C1-8 alkoxycarbonyl group, or 5) a C1-4 alkoxycarbonyl group substituted with one phenyl group. However, 1) E is And J represents a single bond, R ³ represents —CO
Only an OR ¹⁴ group (wherein R ¹⁴ has the same meaning as described above), and 2) E is And J represents a single bond, R ³ represents —CO
OR ¹⁴⁰ group (wherein, R ¹⁴⁰ is. Representing a C1~4 alkyl group, a phenyl group or a C1~4 alkyl group substituted with a phenyl group) is intended to refer only. Or a non-toxic salt thereof.