JPS63215660A - Novel compound, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The invention relates to unique thiol-carboxylic acid derivatives, their preparation and their use as medicaments. especially,
The present invention relates to their use as collagenase inhibitors to treat arthritis and other diseases.

Prior Art The range of therapeutic uses for collagenase inhibitors described below is
Reflecting the fundamental role of collagen in the connective tissue matrix present throughout the body, tissue modification is primarily due to the destruction of collagen, rather than collagen, and is amenable to clinical intervention with collagenase inhibitors. (ti+5au
Many diseases are associated with s renod@lling). In particular, smooth and cutaneous fibroblasts I@,
Chondrocytes, peripheral mononuclear cells.

Inhibition of collagenase released from keratinocytes and gingival tissue, as well as collagenase stored in polymorphonuclear leukocytes (PMNL), has therapeutic value.
The compounds of the present invention are applicable to these and related mammalian collagenases.

In detail, collagenase inhibitors are used to treat rheumatoid arthritis,
Arthritis such as osteoarthritis, soft tissue rheumatoid arthritis, polychondritis and keyitis; bone resorption diseases such as osteoporosis, Meziedz disease, parathyroidism and cholesterinoma; dystrophic epidermolysis bullosa Recessive diseases such as: periodontal disease and gingival collagenase production or PMNL production after cellular infiltration into the inflamed gingiva result in corneal ulcers, such as alkali burns and other burns, group 1 vitamin E deficiency or retinoid deficiency. Often induced by: and cancers in which collagenase is involved in the formation of new blood vessels required for tumor survival and growth, and in the invasion of tumor cells through the basement membrane of blood vessel walls during metastasis. Systemic chemotherapy: may provide useful treatment for.

Cocgenase inhibitors may also be useful in some postoperative conditions, such as colonic anastomoses, where collagenase levels are elevated.

As one example of the therapeutic value of collagenase inhibitors, chronic arthritis greatly reduces the collagen and groteoglycans/components present in the cartilage and bone of inflamed joints. Neutral metalloproteases (particularly collagenases and proteoglycanases) are now considered to be the main enzymes deeply involved in this.

These enzymes have been detected in extracts of synovial and cartilage tissues and have been well studied in tissue cultures of these organs. Apart from the regulation of the biosynthesis or secretion of these enzymes, the most important natural regulation of the activity of collagenases and proteoglycanases in normal and diseased states is that tissue inhibitors of metalloproteases (
Tissue Inhibitor of Metmll
oprotsasa: abbreviated as T IMP) and α
, - it is thought that the production of inhibitors such as macroglostris/. An imbalance in the levels of proteolytic enzymes and natural inhibitors will advance the destruction of connective tissue diseases.

Restoring the collagenase-inhibitor balance by treatment with synthetic collagenase inhibitors provides a useful treatment for a wide range of connective tissue diseases in which collagenase degrading activity is the primary cause.

US Pat. No. 4,595,700 discloses the formula (4): SR
OR.

[In the formula, %"l represents lower alkyl, phenyl or) lower alkyl; R1 and R4 represent lower alkyl; and R3 represents lower alkyl, benzyloxyalkyl, alkoxybenzyl or benzyloxybenzyl. wherein the 7 moiety in oxyalkyl or alkyl contains 1 to 6 carbon atoms): a, b and C represent a central center with any R or S configuration. These compounds have been described as collagenase inhibitors useful in the treatment of rheumatoid arthritis and related diseases in which collagenolytic activity is a likely cause.

A new class of thiol-carboxylic acid derivatives has now been found which, being collagenase inhibitors, have potential for use in the treatment of diseases in which collagenolytic activity and tissue modification are associated.

According to the invention, general formula (I): (wherein R1 is -OH, alkoxy, aryloxy, aralkyloxy, -NR4Ry, where R6 and R7
are each hydrogen or alkyl, or R1
and R7 together with the nitrogen atom to which they are attached form a 5-16- or 7-jj group which may contain oxygen, sulfur or an optionally substituted nitrogen atom] , or a group of the following formula: -NH-CH-C-Rs Rs (where R is hydrogen, alkylC-oH, alkoxy,
-NR, Ry, guanidine, -CO, H, -CONH,
.

SH or S-alkyl) or -CHl-Ar (Ar is optionally substituted aryl), R, is alkoxy, and OH19 is -N
R, R, ] is acyl of -C-Z (Z is optionally substituted aryl); R3 is C1-, alkyl: R4 is hydrogen, Alkyl, -CH, -R, (R, o are optionally substituted 9 phenyl or heteroaryl), or a group of the following formula: CM-0-Rtt H [where R11 is hydrogen, alkyl or 10H, -Ph
(ph is optionally substituted phenyl)
1ff1 is water X or alkyl] and Rs is hydrogen, alkyl, or a group of the following formula:
,.

im [wherein aSS is hydrogen and 9 are alkyl, and R14 is hydrogea, alkoxy7, or -NR,R], or a salt, solvate or hydrate thereof is provided.

For any limitation not specified in lp#, an alkyl or alkyl group may be a Ct-a group, preferably cl-1, and may be a straight or branched chain.

Optional substituents for aryl, phenyl and heteroaryl groups are selected from OH%c, -6 alkyl, Ct-@alkoxy and halogen.

Examples of R1 are hydroxy, C3-alkoxy (e.g. methoxy, ethoxy or t-butyloxy), benzyloxy and -NR,R〒 (where R6 is hydrogen and R
7 is hydrogen or c, +i alkyl such as methyl or ethyl, or -NR, R, is N'-methyl-N
-piperazinyl or N-morpholinyl). Other examples of R8 are -NH-CH, -COOH, -NH-
CH, -CONH,.

-NH-CHl-CO2Et, -NH-CHl-CO,
tBu.

be.

R1 is preferably alkoxy, such as ct-a alkoxy, especially methoxy:amino:alkylamino, especially methylamino or -NH-CH, -Co, H, -C-
CH, and benzoyl.

R1 is preferably C, an alkyl group, such as n-pter,
Isobutyl or 5ee-butyl, especially isobutyl.

When R4 is -CH, -R,, and R1 is heteroaryl, the meaning of RIO includes 5- or 6-membered monomial heteroaryl and 9- or 10-membered bicyclic heteroaryl. Of these, 9- or 10-membered bicyclic heteroaryl is preferred. Furthermore, 5- or 6-membered monocyclic heteroaryls and 9- or 10-membered bicyclic heteroaryls preferably contain 1 or 2 heteroatoms selected from nitrogen% oxygen and sulfur; If there is more than one atom, they may be the same or different. When R1° is a 9- or 10-membered bicyclic heteroaryl, the two rings are preferably fused to one 5- or 6-membered ring containing one heteroatom.

R, is preferably isobutyl, benzyl, or C8-
6-alkoxybenzyl (e.g. 4-methoxy7benzyl)
, 1-(be/silo)ethyl, or a 9- or 10-membered combinatorial bicyclic heteroarylmethyl (e.g. 3-
(indolylmethyl).

Examples of R1 include hydrogen, alkyl (e.g. methyl or ethyl, preferably methyl), and 1-(methoxy7carbonyl)ethyl. Compounds of formula (!) form salts with bases (e.g. sodium hydroxide) can do.

If a basic nitrogen atom is present, the compounds of formula (I) may form acid addition salts, for example with hydrochloric acid. Compounds of this type also form part of the invention.

If the compound of formula (1) or a salt thereof forms a solvate such as a hydrate, these also form part of the invention.

The compound of formula (I) has at least one asymmetric center;
Therefore, it exists as two or more stereoisomers.

The present invention encompasses all such isomers and mixtures thereof, including racemic and diastereomeric mixtures. Preferred isomers are those in formula (1) in which the chiral center marked with an asterisk has the S configuration.

The compounds of formula (1) or their salts, solvates or hydrates are preferably in pharmaceutically acceptable form or substantially pure form. Pharmaceutically acceptable form means a pharmaceutically acceptable level of purity, exclusive of conventional excipients in formulations such as diluents and carriers, and free of substances that would be considered toxic at normal dosage levels. means.

Substantially pure form will generally contain at least 50% by weight, preferably 75%, preferably 90%, even more preferably 95% or 99% or more of the compound of formula (1) or a salt or solvate thereof. will include.

One suitable pharmaceutically acceptable form is the crystalline form.

The present invention discloses the use of formula (1) as an effective therapeutic agent, particularly for the treatment of musculoskeletal disorders resulting from collagenolytic activity and tissue modification (arthritis), or as an agent for systemic chemotherapy of cancer. The present invention provides a compound of 1) or a pharmaceutically acceptable salt or solvate thereof.

The present invention also provides the formula (■): [wherein is a conventional sulfur protecting group, or the group R
-8- (where R is an organic residue such that the group R-8- provides a cleavable disulfide bond)
and R1%R,, R4 and R, are as defined in formula (1)] of a compound of formula (1) where bRt is hydrogen. Provide manufacturing method.

Generally, the protecting group is a substituted benzyl group (e.g. alkoxybenzyl such as 4-methquinbenzyl) or an aliphatic acyl or arylacyl group (e.g. acetyl,
When JLI, which is benzoyl), is acyl, it is of course identical to R8, and thus these formulas (II
) is the compound of the present invention itself. L is R-
8-, the compound of formula (II) is generally a dimer of the compound of formula (1) in which R5 is hydrogen; -Methquinbenzyl), L, is Chem
, Pharm, Bull, 1957.26.15
76, by treatment with mercuric acetate in trifluoroacetic acid containing anisole, followed by reaction with hydrogen sulfide in dimethylformamide.

When Ll is an acyl group, it can be removed by treatment with a base (eg aqueous ammonia or dilute aqueous sodium hydroxide) or by treatment with an acid (eg a methanolic salt IN).

When L, the trimerized compound can be cleaved at the cydisulfide bond by treatment with zinc and hydrochloric acid (#) or by passing hydrogen sulfide through the solution.

Other conventional methods of removing sulfur protecting groups and cleaving disulfide bonds may be used.

The compound of the formula (I): (where R, , R, , R, and R are the same as defined in the formula (1)) is a compound of the formula (I) where p is Ll. (2): Produced by treatment with a thiol of L, -8H(IV) (wherein L1 is the same as defined in formula J). When Ll is R8, the resulting compound (Nita) corresponds to the compound of the present invention.

Compounds of formula (n) also have formula (V): R.

A compound of the formula (■) (wherein, R, and R1 are the same as defined in formula (I)): It can be produced by treatment with a compound.

This reaction is preferably carried out in the presence of a camping agent such as N,N-synchronhexyl/carbodiimide.

Compounds of formula (II) in which L is also prepared by oxidative coupling with iodine or oxygen of compounds of formula (1) in which R8 is hydrogen.

Compounds of formula ω) have different formulas (ω) up to t retaining the same group.
II) and then cleave the group to form R1
Compounds of the invention can be formed in which is hydrogen.

For example, compounds of formula (n) in which R1 is -OH can be hydrolyzed by the hydrolysis of compounds in which R1 is alkoxy, arylox, or aralkyloxy, or in the presence of a catalyst such as palladium black. /zyloxy or substituted benzyloxy compounds under acidic conditions.

The compound of formula (If) where R3 is -NR,R,
prepared by reacting a compound in which is -OH with an amino of the formula NHRsRy in the presence of a coupling agent such as N,N-zinclohequinyllupodiimide or N-ethyl-N'-dimethylaminopropylenelupodiimide. can.

R, is -NH-CH(R,)-COR, formula (II
), similarly, compounds in which aRl is OH are represented by the formula NH
ICH(R,)COR, (where R1 is an alkoxy or amino group) can be produced by reacting with an amino derivative of COR, and then optionally υ hydrolyzed to obtain a compound in which R is a hydroxy group. Can be done.

Furthermore, a compound of the present invention in which R is acyl can be converted into another compound of the present invention by simultaneously cleaving the acyl group to obtain a compound of formula (1) in which R8 is hydrogen.

For example, if %R8 is OH) or R7 is hydrogen, the formula (1
) can be prepared by hydrolyzing a compound in which R8 is alkoxy, aryloxy or aralkyloxy, 6D and R1 is acyl under basic conditions, for example using dilute NaOH.

The intermediate compound of formula (IM) is obtained by reacting a compound of formula (■): (wherein R and R1 are the formulas defined in formula (1)) with a compound of formula (■) as defined above. Manufactured by

Thiols of formula (!l/) are known compounds.

Intermediate compounds of formula (V) can be produced by reacting compounds of formula (■) as defined above with thiols of formula (IV).

The syl functional group in the carbo in the compound of formula (■) is
It may be necessary, or advantageous, to protect the compound prior to its reaction with a thiol, for example by esterification, and then to remove the protecting group under acidic conditions.

Compounds of formula (■) are known amino acid derivatives or can be prepared from derivatives thereof by known methods.

Some of the intermediates of formulas (III), (V) and (■) are novel, and these novel compounds, together with their preparation, form part of the present invention. The method for producing the compound is shown in Reaction Formula 1 below (here, a compound in which R1 is isobutyl is used). Compound ThA, which is the starting material in Reaction Scheme 1, is the known compound diethyl 3-oxobentanedioate (also known as 3-oxopentanedioic acid diethyl ester).

Formula (■) in which the carboxyl group is protected as above
The method for producing the compound of formula (V) from the compound of is Reaction formula 2 (here, R1 is methylamino/, R5 is isobutyl,
(using a compound in which L is benzoyl and the carboxyl group is protected as t-butyl ester).

(-1, -111) Reaction Scheme 2 When Salts Can Be Formed Pharmaceutically acceptable salts of compounds of formula (1) are conventionally prepared by reaction with a suitable acid or base. Solvates are formed by crystallization from a suitable solvent.

As mentioned above, the compound of formula (1) exists as two or more diastereomers. If the process according to the invention results in a mixture thereof, the individual isomers can be separated from each other by chromatography (eg HPLC).

i91 The individual diastereomeric compounds of formula (1) are:

By using stereoisomerically pure starting materials, or by separating the desired intermediate isomers at any stage of the total synthetic process, these intermediates can then be converted into compounds of formula (1). It can be obtained by converting to .

The present invention further provides a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof, together with a pharmaceutically acceptable carrier. The compositions of the present invention are useful in the treatment of rheumatoid arthritis and other collagen degrading conditions.

Compositions of the invention prepared by mixing generally contain diluents, binders, fillers, disintegrants, flavoring agents, coloring agents, lubricants or preservatives. These conventional excipients are used in common methods such as when preparing compositions of related peptide enzyme inhibitors (eg, the ACEfi inhibitor captopril).

The composition of the present invention can be administered orally, topically, transdermally, rectally or parenterally.
Suitable for intravenous, intramuscular, subcutaneous, intradermal or intraarticular administration, oral administration is preferred.

Preferably, the pharmaceutical compositions of the invention are in unit dosage form and furthermore in a form suitable for use in the medical or veterinary field. For example, this first formulation may be in packaged form with instructions for use as a therapeutic or prophylactic agent for the above-mentioned diseases.

Suitable dosage ranges for the compounds of this invention will vary depending on the particular compound and will also depend on the condition being treated.

It is also influenced by the relationship between potency and absorption rate of the compound and the given mode of administration.

The compounds or compositions of the invention are formulated depending on the route of administration (the preferred route being determined by the disease requiring treatment) and are preferably administered in unit dosage form or in a single dose to a human patient. It has a watery shape.

For example, one of the compositions of the present invention may be tablets, capsules, Sanae preparations (
sachet), vial 1. It can be used in the form of powders, granules, lozenges, ready-to-use powders, liquid preparations (eg bath solutions and suspensions), or suppositories.

Compositions of the invention (e.g. compositions suitable for oral administration) may include binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers such as lactose, sandstone, corn starch, calcium phosphate, sorbitol; or Glykun: a tablet lubricant, such as magnesium stearate; a disintegrant, such as starch, polyvinylpyrrolid 7% sodium starch glycolate, or microcrystalline cellulose; or a pharmaceutically acceptable excipient, such as sodium lauryl sulfate; Contains conventional excipients such as.

Solid compositions are obtained by conventional methods such as mixing, filling, tabletting, etc. Repeated mixing operations are used to homogeneously disperse the active agent throughout the composition using large amounts of bulking agent. When the composition is in the form of a tablet, powder or lozenge,
Any carrier suitable for formulating solid pharmaceutical compositions can be used.
For example, magnesium stearate% starch, glucose,
It contains lactose, sugar, rice flour, and chalk. The tablets can be coated by methods well known in the ordinary pharmaceutical arts and are encapsulated with a 1% enteric coating. The composition can also be in the form of an orally ingestible gelatin capsule containing a compound of the invention and optionally a carrier or other excipient. For example, hard gelatin capsules may contain lubricants (e.g., magnesium stearate), fillers (e.g., microcrystalline cellulose), and disintegrants (e.g., sodium starch glycolate) in powdered or granular form. The required amount of the compound of the invention is included.

Liquid compositions for oral administration may be presented, for example, in the form of emulsions, tablets or elixirs, or as dry preparations for extemporaneous preparation with water or other suitable vehicle prior to use. Liquid compositions of this type may contain suspending agents such as sorbitol, syrup, methylcellulose, gelatin,
hydroxyethylcellulose, carboquine methylcellulose, aluminum stearate gel, or edible hydrogenated fats and oils; emulsifiers, such as Shi7tin, Nurvita/monooleate% or gum arabic; aqueous or non-aqueous vehicles, including edible oils, such as glycerin esters; Contains conventional additives such as propylene glycol, ethyl alcohol, glycerin, water or saline; preservatives such as methyl or propyl p-hydroxybenzoate, or sorbic acid; and optionally conventional flavorings or colorants. do.

Compounds of the invention may also be administered parenterally. In accordance with common formulation methods, the compositions are formulated for rectal administration, eg as suppositories, or for parenteral administration as injections. Compositions of the invention for injection can be prepared as aqueous or non-aqueous solutions, suspensions in pharmaceutically acceptable liquids (e.g., sterile pyrogen-free water or parenterally acceptable oils) or liquid mixtures. bacteriostatic agents, antioxidants or other preservatives, solutes or buffers to make the solution isotonic with blood, thickeners, suspending agents or other pharmaceutically acceptable agents. may contain additives. Compositions of this type may be presented in sterile unit dose forms, such as ampoules or disposable syringes, or in multidose forms, such as dispenser bottles, or in solid or concentrated liquid form, which may be used in the preparation of injectable formulations. will be provided as.

For topical and transdermal administration, the composition may be
It comes as a soft cream, lotion, gel, spray, aerosol, cleanser, skin paint or patch.

Unit doses for inflammation are generally 10-100 OIIF.

Preferably 10-500+v% especially 10.50.100
．． 150.2 (1,0,250%300.350.40
It would contain 0.450 or 5ooar. This composition has a total daily dose of 10-3000 for a 70Kf adult.
Once or more times a day to a range of 19,
For example, it may be administered 2, 3 or 4 times a day. Also, particularly for injections, dosage units may contain from 2 to 20,019 compounds of the invention and may be administered multiple times, if desired, to provide a given daily dose.

The present invention further provides a method for treating rheumatism in mammals, including humans, comprising administering to the mammal an effective amount of the compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof. The present invention provides methods for treating collagenolytic conditions such as arthritis or cancer, or other diseases in which enzyme-mediated degradation of connective tissue components plays a role.

The present invention also provides a formula ( The present invention provides the use of the compound of 1) or a pharmaceutically acceptable salt, solvate or hydrate thereof.

EXAMPLES The following Preparation Examples (Reference Examples) and Examples show the methods for producing the compounds of the present invention, and the subsequent biological data show their pharmacological activities. All temperatures are expressed in °C.

Production Example 1 Diethyl 3-othousobentanedioe) 45.5d (
0.25 mol) of magnesium ethyl alcohol #7 in 275 Nt of dry ethanol.
75 moles) and 0.75 moles of iodine. (prepared from IP) and the mixture was heated under reflux for 90 minutes. Add 1-bromo-2-methylpropane 54-(0.5 mol),
The reaction mixture was heated under reflux for 16 hours. additional 1
-bromo-2-methylpropane 27d (0.25 mol)
was added to the boiling mixture and after 3 hours the solvent was evaporated in vacuo.

The residue was partitioned between 2N hydrochloric acid and ether. After extraction of the aqueous phase with ether, the combined organic phases were washed sequentially with water, 5% sodium bicarbonate, water and brine, followed by Na1S
Dry with O4 and evaporate in vacuo. Distillation of the residue gave the title compound as a colorless oil (4Of, 62H). boiling point 11
8-120℃ (1 HP) δ (CDCIB): 0-
9 (6H, d, J=6Hz), 1.25 (6H.

t, J=7Hz), 1.4-1.9 (3H, m),
3.5 (2H, s).

3.7 (IH, d, J=9Hz) and 4.2 (
4H, q, J=7Hz).

Production example 2 Sodium borohydride 1.1 F (29 mmol)
Diethyl 2-(2-methylpropyl)-3-oxopentanedionyi 1.7,5 t in 75 t of ethanol
(29 mmol) in a water-cooled solution. Add this mixture to 5
Stir at ~10°C for 2 hours, then add 18ml of 2N hydrochloric acid to 0.
C. and the mixture was stirred at room temperature for 45 minutes. After diluting this mixture with 400 d of water, ethyl acetate (
Extracted with 4×100d). The extract was added to water (2X 100
rd) and Fylife (100d), and Na
, dried over SO2 and evaporated in X air to give the title compound as an oil (7.5F).

100 chi).

δ (CDCIs): 0.9 (6H, d, J-5H
z), 1.15 (6H.

t, J=7Hz), 1.1-1.8 (3H, m),
2.2-2.7 (3H.

m) e 3.3 (IH, width 3), 3.7-
4.1 (1,H,m) and 4.1(4H,q,
J-7Hz).

Diethyl 3-hydroxy-2-(2-methylpropyl)
Pentanedioate 26F (100 mmol) was dissolved in phosphorus pentoxide 21.3F (150 mmol) in dry benzene 220°C.
J mol) into a stirred suspension.

This mixture was heated under reflux for 3 hours. 200 g of water was added to the cooled mixture to dissolve the thick colored gum. The phases were separated and the aqueous phase was extracted with ether (4x 150m/).

The combined organic phases were washed with 1 soi water and 300 m brine, dried over Na2SO4 and evaporated in vacuo to give a 4R> colored oil.

The above oil is 80% ethanol 300%! The ethanol was dissolved in a solution of potassium hydroxide 16.8F (300 mmol) in PLt and the mixture was heated under reflux for 3 hours. The ethanol was evaporated in vacuo and the residue was diluted with 400 g of water and ether I washed it with The aqueous solution was acidified with 5N hydrochloric acid and extracted with ether (4×150−). The combined extracts were washed with Bly/(2 x 100d), dried over NaSO and evaporated in vacuo to give a mixture of the title compounds as an oil (slowly solidified) (14.3F, 77
%). The acid mixture was used in the next step without releasing f+.

However, these isomers can be separated by crystallization from ether/pentane and are
methylpropyl) bent-2-dinidioic acid was obtained as a solid. Melting point 129-135°C (chloroform) δ (DMSOda): 0.9 (6H, d,
J=6Hz), 1.3-2.0 (IH, m), 2.1
5 (2H, d, J=7Hz), 3.2 (2H, d.

J=7Hz), and 6.8 (I H,t, J-7
Hz).

By evaporation of the mother liquor, 4-(2-methylpropyl) vent-
2-Enniic acid was obtained as an oil.

δ (CDC13): 0.9 (6H, d, J=6Hz),
1.4-2.3(3)I.

m), 3.4 (IH, m), 5.85 (IH, d, J=
15Hz).

and 7.0 (I H, dd, J-15, 7Hz
).

Preparation Example 4 2-(2-Methylpropyl)bent-2-ennidioic acid 14.3F (77 mmol) in acetic anhydride 40-
The mixture was heated under reflux for a little over 2 hours.

The acetic anhydride was evaporated in vacuo to give a brown oil, which was distilled to give the title compound as a low melting yellow solid (5.8F,
45%). Boiling point 145-155°C (5mH?).

δ (CDC5): 0.9 (6H, d, J=6Hz
), 1.5-2.4 (3H.

m), 3.5 (2H, width d, J=4Hz
), 6.5 (I H, t, J=4Hz)
.

Production Example 5 960~(5.7 mmol) of 2-(2-methylpropyl)bent-2-ennicarboxylic anhydride was dissolved in concentrated sulfuric acid (10~).
The solution was dissolved in water and immediately poured into water-cooled methanol. This solution was diluted with 100 m of water and ether (3X50
wt). This extract was washed with prine and Mg
50, and the solvent was evaporated in vacuo to give the title compound as a pale yellow solid (96 lv, 84%), mp 40
~45°C (hexane).

δ(CDCIg): 0.9 (6H, d, J=6
Hz), '1.4-2.0 (IH, m), 2.2
(2H, d, J=6Hz), 3.55 (2H, d.

7Hz) e 6.2 (I H, t, J=7Hz
) and 9.6 (IH.

Toshihiro S).

νm1! (Nujol): 1735, 1690 and 1635 cM - 4-methoxycarbonyl-2-(2-methylpropyl)but-2-enoic acid in dry dichlorometh/30-500
! To a water-cooled solution of (2,5 mmol) and 520q (2,5 mmol) of 0-methyl-L-tyrosine N-methylamide was added 515 q (2,5 mmol) of N,N-dicyclohexylcarbodiimide, and the mixture was Stirred at room temperature for 18 hours.

The precipitated solid was filtered and washed with a small amount of dichloromethane, and the organic solution was washed successively with IN salt #120, IN sodium bicarbonate (20 MIt), and water.

This bath solution was dried with MgSO4, and the residual solid O, which was evaporated in vacuo, was purified by column chromatography (Silica 30F: 5%
Elution with methanol/dichloromethane) gave the title compound (520v, 53%).

Melting point 142-144℃ (dichloromethane/pentane) δ
(CDCII): 0.82 (3H, d, J=7Hz
), 0.83 (3H.

d, J = 7Hz), 1.58 (IH, m), 2
．． 18 (2H, d, J = 7Hz), 2.72 (3
H, d, J=5Hz), 3.02 (2H, m).

3.16 (2H, d, J = 7Hz), 3.70 (
3H, a), 3.78 (3H, a), 4.57 (IH
, m), 5.70 (11, width a).

6.32 (IH, t, J=7Hz), 6.45 (I
H, d, J=8Hz).

6.83 (2H, d, J = 8Hz) and 7.12 (2
H, d, J -8Hz).

Preparation Example 7 The title compound was prepared from dibenzyl alcohol by method D5 in a yield of 91%.

A sample was recrystallized from ether/pentane to give white needles. Melting point 72-73.5°C (actual value: C, 69,55:H, 7,38°C, H
, o04 calculation value C, 69, 54: H, 7, 30%).

δ(CDCII): 0.9 (6H, d, J=6
Hz)t 1.4-2.0 (IH.

m), 2.16 (2H, d, J=6Hz), 3.
63 (2H, d, J=7Hz), 5.08 (2H,
s) e 6.23 (LH, t, J=7Hz).

and 7.2 (5H, s). Preparation Example 8 NtW - Benzyl ester (D7) 26.46 r (0,096 mol) in acetonitrile 500 - dried under ambient air
was cooled to 0°C in a water bath and treated portionwise with 1,1'-carbonyldiimidazole 15.69F (0,096 mol). After 1 hour at 0°C, dry acetonitrile 200
A solution of 0-methyl-L-tyrosine N-methylamide 20 f (0,096 mol) in rRt was added dropwise with stirring. After the addition was complete, the mixture was kept at 0° C. for 1 hour and then warmed to room temperature. Stirring was continued overnight, after which the solvent was removed in vacuo and the residue was dissolved in ethyl acetate. INHCI(
Wash with 2×200t/).

After the combined aqueous phases were extracted with ethyl acetate (3X100d), the combined organic phases were washed with 100srt of water and anhydrous Mg
Dry over 5O, filter and evaporate to dryness to give a red oil. Purification by chromatography (silica gel; chloroform followed by 2 time baths in chloroform) afforded the title compound as a yellow gum (41.01F
, 92%). A sample was recrystallized from ethyl acetate/beta/thane to give a white crystalline product. Melting point 98-101C.

(Actual measurement value: C, 69, 38; H, ?, 50; N,
5.73. CtyHsaN, 0. The calculated value of C, 69
, 51; H, 7, 34; N, 6.00 chi).

Preparation Example 9 Globil) Boudot 2-enoic acid (D9) 2-(2-Methyl 10-biru) bent-2-2/dicarbo 7tR anhydride 1.3? in dry ether 25? After passing a slow stream of anhydrous methylamino through the solution for 01 hours, the methylamino source was removed. , this bath was evaporated to dryness under vacuum.

The residue was dissolved in ethyl acetate and extracted with a 10% sodium carbonate aqueous solution. The aqueous phase was acidified with dilute hydrochloric acid and re-extracted with ethyl acetate.

The extract was washed with water, dried over MgSO, and evaporated to dryness to give the title compound as a white solid (0.75t
, 49%). Melting point 1 after finely grinding with ether
20-122℃.

(Actual measurements: C, 60, 4: H, 8, 5S N, 6
．． 95° self. Calculated value of H*yNOs C,60,3: H
, 8, 6: N, 7.05%).

δ (d, -DMSO): 0.85 (6H, d, J=8
Hz), 1.75 (LH, m), 2.15 (2H,
d, J=6Hz), 2.7 (3H.

d, J=5Hz), 3.3 (2H, d, J=8Hz),
6.05 (IH.

t, J=8Hz), 7.8 (IH, wide S) and 12
．． 4 (IH.

Width 8).

4-Methylaminocarbonyl- in chloroform 35-
2-(2-methyl-10-biru)budo-2-enoic acid 2.42
The suspension was treated with 30 g of excess inbutylene and 3 drops of concentrated sulfuric acid were added as a catalyst. This mixture was stirred in a closed container at room temperature for 8 days. The product was purified by chromatography on silica gel (eluting with a 1:1 mixture of chloroform/pentane) to yield the title compound 2.5? (81chi)
I got it.

Melting point 35-36°C (pentane).

δ (CDC13): 0.85 (6H, d, J=8
Hz), 1.5 (9H.

s ) t 1.7 (IH, m), 2.1 (2H, d,
J=8Hz), 2-8(2H,d, J=6)Iz
), 3.2 (2H, d, J=10Hz), 5-9
(IH, t, J=10Hz) and 6.5 (IH, width s).

Production example 11 y1! f! t-Butyl ester (Dll) 4-methylaminocarbonyl-2-(2-methylpropyl)budo 2
A mixture of 1.25 F (4.9 mmol) of t-enoic acid 7'' methyl ester and 1.3 (9.4 mmol) of thiobenzoic acid was heated at 80 DEG C. for 48 hours under nitrogen.

The product was chromatographed on 50 t of neutral alumina (bathed with chloroform) to give 0.52 ml of foam containing the title compound as the main component.

δ(CDCIs): 0.9 (m), 1.45 (
m), 1.65 (m).

2.6 (m) −L 8 (d e J =5
Hz)-2,82(d-J=5Hz)-3,
0 (m), 3.2 (m), 4.3 (m), 5.9 (m)
, 7.4 (m).

7,55 (m) and 7.95 (m) o Observed mass F'AB (Eng + H) + 394°C□H,,N
Calculation quality of O,S jM 393゜Production Example 12 Methyl ester (012) 4-methoxycarbonyl-2-(
2-methylpropyl)boudo-2-enoic acid 2.0f (10
mmol) and L-phenylalanine-N-methylamide 1. , 87 f (10,5 mmol). The product was chromatographed on silica gel (bathed out with a mixed solvent of methanol/dichloromethane 1:24).
The title compound 2. as a foam by applying K. ! M (69%) was obtained. Melting point 78-83°C. (Actual value: C, 66, 7;
H, 8, 2: N, 7.6°C1°H□N, 0.0
Calculated value C, 66, 65: I (, 7, 85: N.

7.75+%).

Acid (D13) Methyl ester (D6) 7.2t in methanol 80
A solution of was treated with 1.1 F of sodium hydroxide in 20 sd of water and the solution was stirred at room temperature overnight.

The solution was diluted with water, the methanol was removed in vacuo, and the aqueous solution was washed with ethyl acetate. The aqueous solution was acidified with 5N HCA and extracted with ethyl acetate (3X50mg). The combined organic extracts were dried over Na1SO4, filtered and the solvent was evaporated in vacuo to give the title compound 6.62 as a foam.

Preparation Example 14 Q:3)-x-at-butyl ester (D14) 6-methyl-4-[((1-(S)) in dichloromethane 50d
-[(methylamino)carbonyl]-2-(4-methodiphenyl)ethyl]amino]carbonyl]hept-3
- A solution of 6.6 t of enoic acid (013) and excess imbutere/ were placed in a closed container with concentrated sulfuric acid for 7 days. 1
After washing with water, the organic extract was dried over Na1SOa, filtered and evaporated to dryness to give a red oil 4, IP. Column chromatography on silica gel yielded the title compound 3 as a foam by elution with 10 timethanol/chloroform.
．． I got 2f.

(Actual measurement value: C, 66, 51; H, 8, 31: N, 6
．． 37°C□H,,N! 0. Calculated value: C,66,6
4; H, 8, 39; N, 6.48%) observed mass F
'AB (M 10H) + 433: C14H311Nt
Calculation of Ggy 432° Preparation Example 15 and 3)-Enoic acid methyl ester (D15) 3.1r of methyl ester (D5) in dry acetonitrile 75-
The mixture was cooled to 0°C in an ice bath and treated portionwise with 1,1'-carbonyldiimidazole at 2.47F. 1 at 0℃
After an hour, O-benzyl-
I,-) A bath solution of 3.44 F of rheoene N-methylamide was added dropwise. The bath was stirred at room temperature overnight, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate. IN HCl
After washing with (2X25-) and extracting the combined aqueous phases with ethyl acetate (3X50+d), the combined organic phases were
Washed with 0ml, dried over Na, So, filtered and evaporated to dryness to give an oil. Chromatography on silica gel eluting with chloroform followed by 1c5ts methanol/chloroform gave the title compound 4.42 as a foam.

(Actual measurement value: C, 65, 51; H, 8, 03: N, 6
．． Calculated value of 80°C*tHst Nt Os C, 65,
32:H, 7,97;N.

6.92) Production Example 16 4-Methoxycarbonyl-2-(
2-methylpropyl)boudo-2-enoic acid L 75 F
(8,75 mmol) and L-tryptophy-N-
Prepared from methylamide 2.64F (13 mmol). The product was chromatographed on silica gel,
The title compound was obtained as a foam by bathing with methanol/I/chloroform (1:99) at 2.8 F (80
h) was obtained. Melting point 60-65°C.

(Actual measurements: C, 66,07, H, 7,37; N, 1
0.53:.

cwt Lll”mo4 calculated value C, 66, 14:H,
7,32;N.

10.52ch).

6-methyl-4[((1-(S)-[(
A solution of methylamino)carbonyl]-2-(2-methylpropyl)ethylamino]carbonyl]hept-3-enoic acid methyl ester (D15) 50011P (1,3 mmol/L/) was stirred at room temperature for 14 days. , then evaporated to dryness under vacuum. The residue was subjected to column chromatography (silica 30P) IC and eluted with 10-25% ethyl acetate/dichloromethane to obtain the title compound 10.
019 (17chi) was obtained. Melting point 118-135C6 parent 0
"Mass 466.2137: CtsHtaNtOe
Calculated mass of S 466% 2136° HPLC for separation (Lichroaorb d/I/: Lichroaorb d
iol) and bathed with 20/80 (1-4 methanol/dichloromethane)/hexane to give 28i of the title compound.
0 Heteroisomer A (melting point 162-165
C) had a relatively long retention time.

δ (CDCI, ): 0.85 (3H, d, J=7
Hz), 0.87 (3H.

d, J=7Hz), 1.2-1.7(m), 2.
31 (3H, s), 2.45 (IH, dd, J=8
．． 17Hz), 2.63 (IH, dd, J=5゜1
7Hz), 2.6 (IH, m), 2.71 (3H,
d, J=5Hz).

2.95 (IH, dd, J=7.14Hz), 3.
03 (IH, dd.

J=7.14Hz), 3.78(3H,s)s3
．． 66 (3H, s).

3.89 (IH, m), 4.55 (IH, q, J=
8Hz), 5.58 (IH9 width d)t 6.33
(IH, d, J=8Hz), 6.83 (2H,
d, J=9Hz) and 7.14 (2H,d, J=
9Hz).

Isomer B (melting point 116-118°C) had a relatively short retention time.

δ (CDCI, ): 0.84 (3H, d, J=7Hz
), 0.86 (3H.

d, J = 7Hz), 1.2-1.7(m), 2
．． 32 (3H, a), 2.49 (2H, d, J=
7Hz), 2.7 (IH, m), 2.72 (3H,
d.

J=5Hz), 2.97(IH, dd, J=7.14H
z), 3.04 (IH, dd, J=7.14Hz),
3.78 (3H, ts), 3.66 (3H, s
), 3.97 (IH, m), 4.52 (IH, q,
J=8Hz), 5.67 (IH, wide s)
, 6.43 (IH, d, J=8Hz)t 6.83
(2H, d, J=9Hz), and 7.15 (2H
.

d, J=9Hz).

methylamino)carbonyl)-2-(2-methylpropyl)ether]amino]carbonyl]heptanoic acid methyl ester (El) 100IIIP (0.21 mmol)
A water-cooled solution of was treated with 0.5 d of 35% ammonia water bath and the reaction mixture was stirred under N for 20 hours. The bath was evaporated in vacuo, mashed finely with water, washed with F and dried to give the title compound 46WIf (52%). Melting point 8
0-86℃. Observed mass 424.2028:C,,
H□0. Calculated mass of N, 8 424.2033° Separated diastereomers 5-15w9 of the S-acetyl compound of Example 1 were separately prepared using nitrogen-sparged methanol 1-
and treated with 0.1-35% aqueous ammonia solution. The solution was stirred at room temperature under N for 2 hours, then evaporated in vacuo, and the residue was triturated with water and dried to give the isomers Human and B.

Isomer A (melting point 193-196°C): δ (CDCIm): 0.87 (6H, d, J =
6Hz), 1.2-1.7 (3H, m), 1.67
(IH, d, J=9Hz), 2.32 (IH.

(2H, d, J=8Hz), 3.21 (IH, m)
, 3.70 (3H.

s), 3.78 (3H, s), 4.59 (IH, q
, J = 7Hz).

5.66 (IH, width d)e 6.34 (IH
,d, J=8Hz )e6.83 (2H,d,
J=9Hz) and 7.13 (2H,d, J=
9Hz).

Observed quality t 424.2039; C*5Hat
Nt Os S O calculated mass 424.2031 Isomer B: a (cDct, ): 0.86 (6H, t, J = 7Hz
), 1.2-1.7 (3H, m), 2.00 (IH, d
, J=9Hz), 2.49 (IH.

m), 2.51 (IH, da, J=9.15Hz)
, 2.68 (IH, dd.

J=5.16Hz), 2.73(3H,d, J=5Hz
), 2.97 (IH.

dd, J-7, 13Hz), 3.07 (IH, dd, J
=7H, 13Hz).

3.28 (IH, m), 3.72 (3H, m), 3.7
9(3H,5)t4.55(IH,q,J=7Hz),
5.64 (IH, width a), 6.33 (IH, d, J=
7 Hz), 6.84 (2H, d, J=8 Hz), and 7.14 (2H, d, J=7 Hz).

Observed mass 424a 2024; CHHmtN
*OwS') Calculated mass 424.2031° Rubonylheptanoic acid benzyl ester (K3) Benzyl ester (D8) 414 (0,088 mol) was dissolved in 170-thiol acetic acid and left under nitrogen at room temperature for 19 days. . The volatiles were removed in vacuo and the residue was chromatographed on 7 silica gel.

At first, I bathed in ether, and after seven minutes I gradually increased the amount to ethyl acetate. After removing high Rf impurities, the title compound was obtained as a diastereomeric mixture in pale yellow foam (29
．． 76? , 62.4chi).

(Real d4 direct: C, 64, 29: H, 7, 16
;N, 4.86.

C,,H8,N,S 0.12) Calculated value C,64,1
8:H, 7,06:N, 5.16%) The subsequent fractions are olefins'i! j (D8).

However, a more complete reaction is obtained by addition of a suitable base (e.g. triethylamino). Aliquots 2d are removed from the above reaction mixture after 14 days and treated with triethylamine; It was left for another 5 days. Work-up was carried out in the same manner as the bulk reaction mixture described above to obtain only a diastereomeric mixture (E3) with no remaining olefinic material.

3-Mercapto-6-methyl-4-[((1-(S)-
[(Methylamino)carbonyl)-2-(2-methylpropyl)ethyl]amino]carbonyl]heptanoic acid benzyl ester (E4. Isomer A) 2.0F (0,004
mol) t-ff Chloroform lO〇- under 1X atmosphere
dissolved in. The reaction mixture was cooled to 0° C. and 2.04 F (0.02 mol) of acetic anhydride was added followed by 2.02 F (0.02 mol) of N-methylmorpholine. The reaction mixture was warmed to room temperature and then stirred under nitrogen for 3 days.

The chloroform solution was washed with a 10% aqueous citric acid bath and then with water, dried over Mg5Oa, and concentrated in vacuo to give a white solid, which was recrystallized from ether to give the title compound as a single isomer (isomer A). Obtained (1.4r) o melting point 89~
90°C 0 (actual value: C, 63,94; H, 7,25; N, 5.
13:C□H,,N,0. Calculated value of S C,64,1
8:H, 7,06:N.

5.16%) δ (CDCIg): 0.84 (6H, t, J=7Hz)
, 1-17-1.71 (3H, m), 2.27 (3H,
s), 2.45-2-7 (3H, m), 2.7 (3
H, d, J = 5Hz), 2.85-3.04 (2H, m
), 3.78 (3H, a), 3.92 (IH, m).

4.52 (IH, q, J=8Hz), 5.12 (2H,
s), 5.52 (IH, width d), 6.32 (IH,
d, J=8Hz), 6.79(2H,d, J=9Hz
), 7.12 (2H,d, J = 9Hz) and 7
．． 36 (5H, m).

Example 4 Heptanoic acid benzyl ester (E4) 3-acetylmercapto-6-methyl-4-[((1-(S)-[
(Methylamino)carbonyl)-2-(2-methylpropyl)ethyl]amino]carbonyl]heptanoic acid be/dyl ester (E3) 1 F (2 mmol) in ice-cooled bath solution was added to 35% ammonia water bath solution IO-. Processed. This mixture was stirred at room temperature under nitrogen for 3 hours, and 100% of the precipitated solid
I left 19 by 7. 7 was evaporated in vacuo and the residue was crystallized from methanol 5 and ether 120.

300 ap of a single isomer of the title compound was obtained. Melting point 199-20 IC0 (actual value: C, 64,77; H, 7,31: N, 5
．． 6B.

C,,H,,N,0. Calculated value of S C, 64, 77: H
,7,25;N.

5.60%).

δ (CDCIB): 0.84 (3H, d, J=7Hz
), 0.86 (3H.

d, J=7Hz), 1.3-1.7 (3H, m), 1.
66 (IH, d.

J=9Hz), 2.38(IH, dd, J=9.15H
z), 2.41 (IH, m), 2.66 (IH, dd,
J=4.15Hz), 2.73(3H,d, J=5Hz
), 2.97 (2H, d, J=8Hz).

3.22 (IH, m), 3.74 (3H, @), 4.5
7 (LH, q.

J=8Hz), 5.14 (2H,s), 5.
63 (IH, width d).

6.33 (IH, d, J=8Hz), 6.81 (2H,
d, J=9Hz).

7.12 (2H, d, J-9Hz) and 7.36 (
5H, m).

Two additional single diastereomers were obtained by column chromatography of the mother liquor on silica gel, eluting with ether/chloroform (3:1)-t'.

Isomer B (relatively slow to bathe out) was obtained as a foam, which solidified on standing. Melting point 133-135℃
.

(Actual measurements: C, 64, 66; H, 7, 41: N, 5.
58゜C□H1゜N, calculated value of 0.8C, 64,77
: H,? , 25. N.

5.60%).

δ (CDCII): 0.73 (3H, d, J=7Hz
), 0.79 (3H.

d, J=7Hz), 1-2-1.7 ('i/H,
m), 1.90 (IH, d.

J=9Hz), 2.36 (IH, m), 2.64 (IH
, dd, J = 9.17Hz), 2.69 (3H, d, J
=6Hz), 2.81 (IH.

dd, J = 4.17Hz), 2.94 (IH, dd, J
=7.16Hz).

3.03 (IH, dd, J-7, 16Hz), 3.26
(IH, m).

3.78 (3H, a), 4.59 (IH, q, J=7H
z), 5.15 (2H, m), 5.98 (IH, width d
), 6.16 (IH,, d.

J=8Hz), 6.82 (2H, d, J=9Hz), 7
．． 10 (2H, d.

J=9Hz) and 7.36 (5H, m).

Isomer C (relatively fast eluting) was obtained as a gum.

δ (CDCIg): 0.81 (3H, d, J=6H
z), 0.83 (3H.

d, J=6Hz), 1.2-1.7 (3H, m),
1.99 (IH, d.

J=9Hz), 2.47 (IH, m), 2.56 (IH
, dd, J=8°15Hz), 2.72 (IH, m),
2.72 (3H, d, J=6Hz).

2.96 (IH, dd, J=7.15Hz), 3.
04 (IH, dd.

J-7, 15Hz), 3.29 (IH, m), 3.
77 (3H, tr).

4.55 (IH, q, J-7Hz), 5.16 (2
H, a), 5.75 (IH2 width d), 6.38 (
IH, d, J = 8Hz), 6.81 (2H, d, J = 9
Hz), 7.12 (2H, d, J=9Hz).

and 7.36 (5H, m).

For isomers, a mixture of isomers B and D was prepared in 18/82 (1
% methanol/dichloromethane)/hexa/hexane.

δ (CDC14): 0.68 (3H, dd, J
=7Hz), 0.78 (3H.

d, J-7Hz), 1.1-1.6 (3H, m),
2.09 (IH, d.

J-10Hz), 2.36 (IH, m), 2.63
(IH, dd, J=6.17Hz), 2.74 (2H
, d, J=6Hz), 2.85 (IH.

dd, J=5.17Hz), 2.99(IH, dd
, J = 7.16 Hz).

3.09 (IH, dd, J=7.16Hz), 3.
29 (IH, m).

3. 79 (3H, s), 4.68 (IH, q, J
=7Hz), 5.91(IH,d, J=8Hz
)t 6.24 (I H, width d), 6.82 (2
H, d, J=9Hz), and 7.10 (2H, d,
J=9Hz).

3-acetylmercapto-6-methyl-4-[((1-(S)-[(methylamino)carbonyl)-2-(7phenyl in 4-meth)ethyl in 4,5% formic acid/methanol 6- A solution of 300 q (0.55 mmol) of [amino]carbonyl]heptanoic acid benzyl ester (E3) was dissolved in palladium black 3101 in the same solvent 15- under nitrogen.
Added to 1F stirred suspension.

After 90 minutes the mixture was filtered through diatomaceous earth and evaporated in vacuo. Column chromatography using reverse phase 7 Lika 30F and eluting with 25% aqueous methanol provided two single diastereomers of the title compound as monohydrates.

Isomer A: Melting point 92-95°C (54■) (Actual value: C
,56,34:H,7,11:N, 6.08°Ctz
Calculated value C of Ha z Nt Os S - Ht O,
56,15;H.

7.28:N, 5.95%).

δ(CDCls)” 0-85 (3Ht
d-J = 6 Hz), 0-91 (3H-d,
J=6Hz), 1.2-1.7 (3H, m)
, 2.31 (3H,a), 2.50 (IH
, dd, J=3. 17Hz), 2.67(I
H, dd, J = 7.17Hz), 2.68 (3H, d,
J=5Hz).

2.85-3.0 (2H, m), 3.15 (LH, t,
J=10Hz).

3.74C3H,s), 3.80(IH,m), 4.8
0(IH,q.

J=8Hz), 6.36 (IH,m), 6.
77 (2H, d, J=9Hz).

7.07 (2H, d, J=9Hz), and 8.41
(LH, d, J=10Hz).

Isomer B: melting point 106-110°C (70Hz) (actual value: C, 56,33:H, 7,17;N, 6.15°C□Hs z Nt Os S , calculated value of Hz O C
, 56,15; H, 7,28: N, 5.95%).

δ (CDC13): 0.77 (3H, a), 0.86 (
3H, g).

1.1-1.7 (3H, m), 2.34 (3H, s)
t 2.73 (2H.

d, J=4Hz), 2.82 (3H, d, J=4Hz)
, 2.8-3.0 (3H, m), 3.75 (3H, s)
, 3.88 (IH, width d.

J=11Hz), 4.80 (LH, q, J=8Hz)
, 6.61 (IH.

m), 6.78 (2H, d, J=9Hz), 7-11 (
2H,d.

J-9Hz), and 8.53 (I H,d, J=
9Hz).

A similar treatment of the single isomer of the acetyl mercapto compound (E3° isomer A) 1.4 F (2,6 mmol) yields the title compound 98 as a single isomer (isomer A).
Individual isomers of the S-acetyl compound of Example 5 27-4
2jvt-7 were separately bath dissolved in 4 d of methanol bubbled with nitrogen and treated with 0.4 d of 35% ammonia water bath solution. This f# solution was stirred at room temperature under nitrogen for 6 hours,
It was then evaporated in vacuo and the residue was finely triturated with ether to give the isomers Human and B.

Isomer A: Melting point 171-176°C δ (CDCIs): 0.86 (6H, t, J = 6Hz
), 1.3-1.7 (3H, m), 1.79 (LH,
d, J=9Hz), 2.43 (IH, aa.

J=5.15Hz), 2.66 (IH, dd, J
=4.15Hz), 2.72(3H,d,J-5Hz
), 2.8-3.1 (4H, m), 3.74 (3H, s
), 4.73 (IH, q, J=7Hz), 6.
29 (IH.

Width s), 6.89 (2H, d, J=9Hz), 7.0
9 (2H, d.

J=9Hz) and &02(IH, width d, J=9Hz
).

Isomer B: Melting point 107-110°C δ (CDC1,): 0.76 (3H, d, J=7H
z), 0.79 (3H.

d, J=7Hz), 2.34(IH, d, J=1
0Hz), 2.73 (2H, d, J=6Hz),
2.80 (3H, d, J=6Hz).

2.85-3.2 (4H, m), 3.77 (3H, s)
, 4.71 (LH.

q, J=8Hz) t 6.26 (L H, width s) t 6.79 (2H, d.

J = 9Hz), 7.09 (2H, J = 9Hz
) and 7.94 (IH.

Width d, J = 9Hz).

Example 7 3-benzoylmercapto-NS-methyl-Nl-2-
(1-benzoylmercapto-2-[methylaminocarbonyl]pentanediamide, 4-methylpentane mt-
Butyl ester (Dll) 0.5F was treated with 10-trifluoroacetic acid at 0°C for 2 hours, then evaporated to dryness under vacuum to give 2-(1-benzoylmercapto-2-[methylaminocarbonyl]ether). -4- Menal Penta 7
rRk obtained O[δ(CDCIg) 1.59 pm indicating the absence of no signal Ht-butyl group. ] N, N-Zinchlorohexylcarbondiimide 235
q and 145 v hydroxybenzotriazole of the above acid and O-methyl-
It was added to an ice-cold solution of 220q of L-tyrosine-N-methylamide and the mixture was stirred at room temperature for 18 hours. The precipitated solid was evaporated and washed with a small amount of dichloromethane, then the organic solution was washed successively with IN sodium bicarbonate and water. The solution was dried over Mg5O, and evaporated to dryness under vacuum.

The remaining solids are chromatographed on neutral alumina.
Elute with chloroform-pentane (1:1).9. The solid product was triturated with ether to give the title compound 130 as a mixture of diastereomers. Melting point 140~
144C.

Observed mass M”527,2449°C,,H,,N
, O,S Engineering 527,2453゜Example 8 0biru) bemethanediamide (E8) 3-benzoylmercapto-MS-methyl-Nl-(1-(S)-[( A water-cooled solution of methylamino)carbonyl)-2-(7phenyl in 4-meth)-ethyl)-2-(2-methylpropyl)pentanediamide (E7) 4019 was diluted with 35% ammonia
The reaction mixture was treated with an aqueous solution of 2.5-2.
Stir for hours. The solution was treated with P and the P solution was evaporated to dryness under vacuum. The residue was filtered with ether through a fine mash and dried to give the title compound 2 as a mixture of diastereomers.
019 (62%) was obtained with a melting point of 175-190'C.

Observed mass M”423,2190; C□HHNs
Calculated mass of Oa S M423,2191゜3-acetylmercapto-Ni-methyl-Nl-(1
-(S)-[(methylamino)carbonyl]-2-(2
-methylpropyl)-ether]-2-(2-methylpropyl)pentanediamide (Ell, isomer A) 4811
F (0.1 mmol) was treated similarly to give 28 Mg (64%) of the title compound as a single isomer (isomer A).

Melting point: 243-250°C.

(Actual measurements: C, 59,89:H, 7,86:N, 9
．． 55゜C□H□N, O, S calculated value C, 59, 55
:H, 7, 85:N.

9.92%).

δ (CDCI, -) d, -DMSO dropped): 0
．． 83 (3H, d.

J=8Hz), 0.85(3H,d, J=8Hz
), 1.2-1.6 (3H.

m), 1.74 (IH, d, J=7Hz), 2.
0 (IH, dd, J = 11, 13Hz), 2.10
(IH, dd, J-3, 13Hz), 2.65 (
6H, d, J=5Hz), 2.79 (IH, dd,
J = 9.13Hz).

2.98 (IH, dd, J=5.13Hz), 3.
73 (3H, s) t4.56 (IH, m), 6.8
7 (2H, d, J=9Hz), 7.15 (2H, d
, J=9Hz), 7.55 (2H, m) and 7.
98 (I H, d, J = 9 Hz).

Example 9 l-8)-[6-Methyl-4-[((1-(S)-
A solution of [(methylamino)carbonyl-2-phelethyl]amino]hept-3-enoic acid methyl ester (012) 2.3 f (6,3 mmol) was stirred at room temperature for 14 days, then Evaporate to dryness under vacuum. The product was chromatographed on silica gel 100F and washed with 10-25% ethyl thiacetate/bemethane to give the title compound as a diastereomeric mixture, 1.35%.
t (49%).

This product was recrystallized twice from ethyl acetate to give a solid 0.7
I got 1. Melting point 188-189°C. This solid has NMRf
C! It was found to be a mixture of diastereomers of D2Ms (3:1 ratio).

(Actual measurements: C, 60, 9: H, 7, 3: N, 6.
Calculated value of 350C2tH3tNtO5S C, 60, 55
;H,7,45;N.

6.4ch).

δ (CDCIs): 0.85 (6H, m), 1.2-1
．． 7 (3H, m).

2.3(s) and 2.32(II) (total 3H), 2
．． 4 (IH, m), 2.6 (2H, m), 2.71 (
3H, d, J=6Hz), 3.07 (2H, m).

3,66 (s) and 3.68 (s) (ratio 3:1-
Total 3H), 3.9(If(.

m), 4.65 (IH, m), 5.78 (width d) and 5.83 (width d) (ratio 3:1 - total I H) t
6.43 (d, J=8Hz).

and 6.51 (d, J=8Hz) (ratio 3
:1-total IH) and 7.25 (5I(,m).

3-acetylmercapto-6-methyl-4-[((1-(S)-[(methylamino)carbonyl-2-phenylethyl]amino]carbonyl]heptanoate methyl ester/L in nitrogen-sparged methanol 5- / (E
A water-cooled solution of 9% mp 188-189C) 10019 was treated with 35% aqueous ammonia solution 2-.

The reaction mixture was stirred under nitrogen for 3.5 hours. The bath solution was then filtered and the %P solution was evaporated to dryness under vacuum. The residue was triturated with water, and the solid was collected and recrystallized from acetic acid ether-ether to give the title compound 25q as a single diastereomer. Melting point 169-1
71CO (actual value: C, 60,65:H, 7,85;
N, 7.05゜ctokls. Calculated value C of N, O, S
,60,9;H,7,65:N.

7.1%).

δ(CDCII): 0.85 (6H, d, J=5Hz)
, 1.2-1.7 (3H, m), 1.64 (IH, d,
J-9Hz), 2.3 (IH, dd.

J=9.16Hz), 2.42 (IH, m), 2.58
(IH, dd.

J4, 16Hz), 3.07 (IH, d, J=8Hz)
, 3.2 (IH.

m), 3.68 (3H, s), 4.65 (IH, q, J
=8Hz).

5.75 (IH, width d), 6.39 (LH, d, J=
8Hz), and 7.25 (5H, m).

Example 11 Diisopropylethylamino 0.13 tRt(0,7
mmol) and chloroformate ether 0.07 d (0,7
3-acetylmercapto-6-methyl-4-ccct-(S) in THE'IOd dried at -200 mmol)
-[(methylami/)carbonyl]-2-(2-methylpropyl)ethyl]amino]carbonyl]heptanoic acid (
E5. Isomer A) was added to a solution of 300 Wq (0.66 mmol). A bath solution of ~720 methyl amide in 0.8 d of 155+1 THF was added dropwise and the mixture was stirred in a water bath for 3 hours. The solvent was evaporated in vacuo and the dichlorometh/A residue bath was washed sequentially with water, 1M hydrochloric acid, water, hydrated sodium bicarbonate and prine. This bath liquid is Mg5O
.

and evaporated in vacuo. The title compound was obtained by applying a column chromatogram on silica 10F to 2 filtration baths and bathing with 5% methanol/ethyl acetate. Melting point 195-199c0 (actual value: C, 58,97; H, 7,78; N, 8
．． 92°C O5H1IN, QIS calculated value C,59,3
3;H, 7,58:N, 9.03ch).

δ (CDCI, ): 0.84 (6H, q, J-3Hz)
, 1.2-1.7 (3H, m), 2.10 (IH, dd
, J=7.15Hz), 2.30(3H,a),
2.31 (IH, dd, J=5.15Hz),
2.68 (IH, m), 2.74 (3H, d, J=5
Hz), 2.76 (3H, d.

J=5Hz), 2.95 (IH, dd, J=6
．． 14Hz), 3.08 (IH, dd, J=6.14
Hz), 3.78 (3H, s), 3.83 (IH, m
), 4.63 (IH, q, J = 7Hz), 5.49 (H
.

width s), 5.88 (IH, width s), 6.68 (IH
, d, J=7)Lz), 6.82(2H, d, J=
8) (z), and 7.14 (2H, d.

J=8Hz).

Example 12 Butyl ester (E12) 3-acetylmercapto-6- in dichloromethane 2-
Methyl-4-[((1-(S)-[(methylamino)carbonyl)-2-(2-methylpropyl)ethyl]amino]carbonyl]heptanoic acid (E5. Isomer A) 90s
v (0,2 mmol), N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride 42q (0,22 mmol), 1-hydroxy 7penzotriazole 34+9
(0.22 mmol)% t-butylglycide/hydrochloride 3
A solution of 71119 (0.22 mmol) and diisopropylethylamino 0.07 m (0.4 mmol) was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, followed by saturated sodium bicarbonate, water, 1M
Washed with citric acid and brine. Add this solution to Na2
5O, and evaporated in vacuo to obtain the single isomer (isomer A).
) was obtained as the title compound 74q (68ti). Melting point 19
2-194C (ethyl acetate).

(Actual measurements: C, 59, 51:H, 7, 70:N, 7
．． Calculated value of 33°C,,H,,N,O,S,C,59,4
5:H, 7,66;N.

7.43chi).

δ (CDCI, ): 0.77 (3H, d, J=6H
z), 0.83 (3H.

d, J = 6Hz), 1.2-1.7 (3H, m)
, 1.47 (9H,s).

2.30 (3H, s) e 2.35 (2H, m), 2.
56 (IH, m).

2.77 (3H, d, J=5Hz), 3. QO(I
H, dd, JzlO.

15Hz), 3.10 (IH, dd, J = 7.1
5Hz), 3.70 (IH.

dd, J=6.19Hz), 3.78(IH,s
)t 3.95 (IH, dd.

J = 6.19Hz), 4-00 (IH, m), 4
．． 64 (IH, q, J-7Hz) * b-05 (I
H-tn) -6-33 (I He width t).

6.83 (2H, d, J=9Hz), 7.14 (2
H, d, J-9Hz).

and 7.43 (IH, d, J-7Hz).

Example 13 Monomethoxyphenyl)ethyl]amino]carbonyl]heptanoylamino]ethanoic acid tert-pteroate 2-[3-acetylmercapto-6-methyl-4-[((1- (S)-[(Methylamino)carbonyl]-2-(2-methylpropyl)ethyl]amino]carbonyl]heptanoylamino]ethanoic acid t-butyl ester (E12. Isomer A) 30s+
(0,053 mmol) in an ice-cold bath was treated with 0.3 - of 35% aqueous ammonia solution under nitrogen and stirred at electric temperature for 2 hours.

The solvent was evaporated in vacuo and the residue was triturated with hexane to give the title compound as a single isomer (isomer A). Melting point: 223-226°C.

(Actual measurements: c, 59.52:H, 7, 68:N, 7.
88°C, , H, , N, O, S calculated value C, 59, 63
:H,7,89;N.

8.02%) 0 δ (CDCI, ): 0.84 (6H, dd, J=6.
8Hz), 1.3-1.7 (3H, m), 1.48
(9H,s)t 2.24(IH,d, J=10H
z), 2.28 (LH,m)e 2.45 (I
H, dd,, J-15°5Hz), 2.50 (IH,
m), 2.76 (3H, d, J=5Hz).

2.99 (IH, dd, J=15.9Hz), 3
．． 09 (IH, dd, J=15, 7Hz), 3.
12 (IH, m), 3.77 (3H, m), 3.
89 (IH, dd, J=5.7Hz), 4.64
(IH, qt J=8Hz).

5.98 (II (, width d), 6.47 (IH, width t)
), s, 54 (2H, d, J=9Hz), 7.15 (2
H, d, J = 9 Hz) and 7, 18 (I H, width 8).

2-[3-acetylmercapto-6-methyl-4-(
[, (1-(S)-[(methylamino)carbonyl]-
A solution of 2-(2-methylpropyl)ethyl]amino]carbonyl]heptanoylamino]ethane mt-butyl ester (El2, isomer A)6oHI(o,t11 ml) was dissolved in a water bath for 1 hour, then at room temperature for 2 hours. Stir for hours.

The solvent was evaporated in vacuo and the residue was azeotropically dried with toluene to give the title compound as a single isomer. Melting point 188-192°C.

Example 15 (2-methylpropyl)ethyl]amino]carbonyl]
Heptanoylamino]ethanoic acid (El5) Nitrogen-infused methanol 5#! 2-[3-acetylmercapto-6-methyl-4-[((1-(S)-[(methylamino)carbonyl)-2-(2-methylpropyl)ethyl]amino]carbonyl]heptanoyl in / Amino]ethane eR (El: 14, isomer A) 15'IP (0,02
A solution of 9 mmol) was cooled in water and treated with 0.3-35 thiammonium aqueous solution. After 2 hours the solvent was evaporated in vacuo and the residue triturated finely with ethyl acetate to give the title compound xxar(sots) as a single isomer (isomer A).
I got it. Melting point 228-231C.

Example 16 N''-(1-(S)-[(3-2 cetylmercapto-6-methyl-4-[((1-(S)-[(methylamino)carbonyl in methylazichloromethane) )-2-(4-methquinphenyl)ether]amino]
carbonyl]heptanoic acid (E5, isomer A) 226■(
0.5 mmol), N-ether-N'-dimethylamino/
Furovircarbodiimide hydrochloride 116~(0.6 mmol), 1-hydrocype/citriazole 90M? (0
, 58 mmol), glyci/amide hydrochloride 6419 (0
, 58 mmol) and diimpropylethylamino 0
．． A mixture of 2rILt (1.14 mmol) was heated at 5°C with 2
hours and then stirred at room temperature overnight. The mixture was cooled in water and the solid was collected by filtration and washed thoroughly with dichloromethane. This solid was finely mashed with 1M citric acid, filtered, washed with water and dried. Recrystallization from methanol/ether gave the title compound 75q (30%) as a single isomer.

Melting point 218-219C.

δ(d, -DMSO): 0.78 (6H,t, J=7
Hz), 1.1-1.5 (3H, m), 2.1-2.
3 (2H, m), L24 (IH, m).

2.55 (3H, d, J=5Hz), 2.74
(IH, dd, J-10, 14Hz).

2.85(1)I, dd, J=5.14Hz),
3.56 (2H, d, J=6Hz), 3.68 (3
1,s), 3.77(IH,m), 443(1:E
.

rn), 6.81 (2H, d, J=9Hz), 7.10
(2H, width d).

7.14 (2H, d, J=9Hz), 7.79 (
IH, width q), 8.00 (IH,t, J=6Hz
) and 8.12 (I H, d, J-8Hz)
.

Example 1 Fluvonyl)-2-(2-methylpropyl)pentanediamide, 2-(2-methylglobil)pe/tanediamide
(E17) 3-acetylmercapto-Nll-(aminocarbonylcomethyl-Nl-) in nitrogen-sparged methanol 5-
-(1-(S)-[(methylamino)carbonyl)-2
-(2-methylpropyl)pentanediamide, 2-(2
A water-cooled solution of 44 q (0,087 mmol) of diamide (E16, isomer A) was treated with 0.4 st of 35% aqueous ammonia solution and stirred at room temperature for 2.5 hours. The solvent was evaporated in vacuo and the residue was triturated with ether to obtain the single isomer (isomer A).
) The title compound 2811Ig (70%) was obtained. 8
Points 247-252C.

δ(d@-DMSO): 0.77 (3H, d,
J=6Hz), 0.82(3H,d, J=6Hz
), 1.2-1.5 (3H, m), 2.04 (
2H.

m), 2.30 (IH, d, J=7Hz), 2.33 (
IH, m).

2.57 (3H, d, J=5Hz), 2.70
(IH, d, J=10°14Hz), 2.86 (IH,
dd, J=5.14Hz), 3.08 (IH.

m), 3.62 (2H, q, J = 5Hz), 3.67 (
3H, a), 4.46 (IH, m), 6.80 (2H,
d, J=9Hz), 7.10 (2H.

Width d), 7.15 (2H, d, J = 9Hz
), 7.81 (IH, m).

8.06 (I H,t, J = 5Hz) and 8
．． 18 (IH, d, J=8Hz).

Example 18 0M dichloromethane 8-3-acetylmercapto-6-
Methyl-4-[((1-(S)-[(methylamino)carbonyl)-2-(2-methylpropyl)ethyl]amino]carbonyl]heptanoic acid (E5% isomer A) 2
26q (0,5 mmol), N,N'-dicyclohexylcarbodiimide 10311P (Q, 5 mmol), 1-hydroquine benzotriazole 76q (0,5
mmol) and N-methylbiperazine 9.05d (0
, 5 mmol) was stirred at 5° C. for 1 hour and then at room temperature overnight. After cooling, the precipitated solid was removed, and the solution was diluted with dichloromethane and extracted with 0.25 M citric acid. The extract was washed with dichloromethane, made basic with %XOS sodium carbonate, and extracted with ether. The ether extract was washed with brine, dried over Na, So, and evaporated in vacuo. The oily residue was treated with ether and the resulting solid was recrystallized from ethyl acetate/hemusan to give the title compound vIJ98 (37%) as a single isomer. Melting point 133-138C.

(Actual measurements: C, 60, 48: H, 8, 15; N, 1
0.40°Ctl Hat N404 S calculated value C'
, 60.65:H, 7,92:N.

10.48ch).

δ (CDC14): 0.85 (6H, q, J=3H
z), 1.2-1.5 (3H, rn), 2.30 (6H
, s), 2.38 (4H, width s).

2.33-2.8 (3H, m), 2.70 (3H, d,
J=5Hz), 2.98(2H,d, J-7Hz
), 3.4 (2H, width s), 3.5-3.7
(2H9 width m), 3.78 (3H, s), 3-95 (
IH,q.

J=6Hz), 4.54 (IH, q, J=7Hz), 5
．． 71 (IH.

Width d), 6.64 (IH, width d), 6.82
(2H, d, J=9Hz), and 7.15 (2
H, d, J = 9Hz).

Example 19 1-[3-acetylmercapto-6 in methanol 5d
-Methyl-4-[((1-(S)-[(methylamino/)
carbonyl)-2-(4-methoxy7phenyl]ethyl]
A solution of 60aF (0,112 mmol) of amino]carbonyl]heptanoyl]-4-methylpiperazine (E18, isomer A) was bubbled with nitrogen and cooled in ice for 35 minutes.
It was treated with a thiammonia water bath solution of 0 and 4 TILt. After 6 hours at room temperature, the solvent was evaporated and the residue was triturated with hexane to give the title compound as a single isomer (isomer A). Melting point 65-68C0 δ (CDCIB): 0.87 (6H, d, J-6
Hz), 1.3-1.7 (3H, m), 1.85 (
IH, d, J = 8Hz), 2-35 (7H, m)
.

2-42 (IH, dd, J=8.16Hz), 2.
54 (IH, m), 2.61 (IH, dd, J=4.
16Hz), 2.74 (3H, d, J=5Hz)
.

3.01 (2H, d, J=8Hz), 3.30 (I
H, m), 3.48 (2H9 width s), 3.6
5 (2H, width m), 3.79 (3H, s)e
4.58 (I H, q, ≠; wJ=8Hz), 5.
35 (IH, width m).

5.74 (IH, width d), 6.52 (IH
, d, J = 8 Hz), 6.82 (2H, d,
J=9Hz) and 7.15 (2H,d, J=+=
9Hz).

Example 20 (E20) 3-acetelmercagto 6 in acetonitrile 10-
-Methyl-4-[((1-(S)-[(methylamino)
carbonyl)-2-(2-methylpropyl)ethyl]amino]carbonyl]heptane rR (E5. isomer A)2
90111F (0.64 mmol) at 0°C.
104q (0.64 mm!J mol) of 1'-carbonyldiimidazole was added and the solution was stirred at 0 DEG C. for 1 hour under nitrogen. Morpholine 56■(0) in acetonitrile 2d
, 64 mmol) was added dropwise, and the solution was then left overnight at room temperature. The mixture was evaporated to dryness under vacuum, dissolved in a mixture of ethyl acetate/chloroform (4:1) and washed successively with sodium carbonate, 1M hydrochloric acid and water. The organic phase was dried over Mg5O.

The title compound 7O was obtained as a single isomer (isomer A) by column chromatography on silica gel 60 (100F) and eluting with 5-thimethanol/ethyl acetate.
N! I got it. Melting point after crushing pears with ether: 146~
149℃.

(Actual measurements: C, 57, 73:H, 7, 64:N, 7
．． 59°C, H□N, 0. Calculated values of S, H, O C,5
7,86:II, 7.66:N, 7.79%).

δ(CDCIg): 0.86 (d, J=Hz)
and 0.87 (d, J=5Hz) (total 6H),
1.2-1.7 (2H, m), 2.32 (3H, s).

2.48 (IH, dd, J=4.16Hz), 2.
62 (IH, dd, J=4.18Hz), 2.72 (
4H, width d, J=5Hz), 2.98(2
H, d, J=7)1z), 3.3-3.75(8H
, m), 3.76 (3H,s), 3.96 (IH
, q, J=6Hz), 4.54 (IH, q.

J = 6Hz), 5.69 (IH, width d)
, 6.61 (IH, d, J=7Hz), 6.84
(2H, d, J=8Hz) and 7.16 (2H.

d, J=8Hz).゛Example 21 1-[3-acetylmercapto-6 in methanol 3-
-Methyl-4-[((1-(S)-C(methylamino)
carbonyl)-2-(2-methylpropyl)ethyl]amino]carbonyl]hebutanoyl 3-morpholine (E20
, isomer A) 121IP bath solution Vc9 was blown into the solution and cooled with ice. This solution was treated with 1.5 d of 35 clb7yq=2y aqueous solution under OC for 0.5 h and then warmed to room temperature. After 1.5 hours at room temperature, the solution was evaporated to dryness under vacuum and the residue was washed twice with ether to give the title compound as a single isomer. Melting point 106-108
℃.

(Actual measurement value: C, 58, 81: f(, 7, 92; N,
8.75°Cw*HstNsOsS 0.5H10 calculation value C, 58,99°H, 7,83; N, 8.60
%).

δ (CDCII): 0.87 (6H, d, J=7
Hz), 1.35-1.5 (2H, m), 1.84 (
IH, d, J=9Hz), 2.40 (IH, dd.

J=8Hz), 2.54(IH,m), 2.57(
IH, dd, J=4°3.78 (3H, m), 4.
58 (IH, q, J = 8Hz), 5.77 (IH9 width d), 6.58 (IH, d, J = 8Hz)
), 6.82 (2H.

d, J=8Hz) and 7.15 (2H, d, J=
8Hz).

Example 22 Rubonyl]heptanoic acid t, 7'thyl ester (E2
2) 6-methyl-4-[((1
-(S)-[(methylamino)carbonyl]-2-(2
-methylpropyl)ethyl]amino]carbonyl]7
A solution of )-2(o!hi3)-x-at-butyl ester (D14)3F was left at room temperature for 14 days and then evaporated to dryness under vacuum. 7 by column chromatography on silica gel and elution with a mixed solvent of ethyl acetate/penta/(1:1). The title compound 1.22 was obtained as a mixture of isomers.

A single diastereomer (heterosexual person) is 15/85 (1
% methanol/dichloromethane)/hexane) by preparative HPLC (liclosorg diol). Melting point 147-151℃ (from nityl/pentane)
.

(Actual measurement value: C, 61,08; H, 7,94: N, 5
．． 53゜Cts H+a4I) Nt OlS calculation value C
, 61, 39; H, 7, 93; N, 5.51 h).

δ(CDCIB): 0.84 (d, H=5Hz) and 0.86 (d.

J=5Hz) (total 6H), 1.2-1.7 (2H,
m), 1.44 (9H, s ), 2.30 (3H, a
), 2.49 (IH, dd, J=7°17Hz)
, 2.58 (IH, dd, J-5, 17Hz),
2.60 (IH, m), 2.70 (3H, d, J
=5Hz), 2.93(IH, dd.

J=8.14Hz), 3.04 (IH, dd, J
=7.14Hz), 3.79(3H,s)t3
．． 92 (IH, q, J=6Hz), 4.52 (IH
,q.

J=7Hz)e 5.52 (IH width a)t
6.37 (IH, d, J=8Hz), 6.8
2 (2H, d, J=8Hz) and 7.15 (2
H.

d, J=8Hz).

Example 23 3-acetylmercapto-6-methyl-4-[((1-(S)-[(methylamino)carbonyl)-2-(4-methquinphenyl)ethyl in nitrogen-sparged methanol 3- A water-cooled solution of [amino]carbonyl]heptanoic acid t-butyl ester (E22) 23~ was treated with 359b aqueous ammonia & 1.5- and the reaction mixture was stirred under nitrogen for 3 hours.

The solution was filtered and Part F was evaporated to dryness under vacuum. The residue was partitioned between 5 d of chloroform and 2 d of water. The organic phase was dried over Mg5O, and evaporated to dryness under vacuum. The product was recrystallized from ether/hexasan to give the title compound (isomer A). Melting point 133-137C0 (actual value: C, 61, 72: f(, 8, 45; N,
5.90ON, 6.00%).

δ (CD013): 0.86 (6H, d, J=5Hz)
, 1.3-1.75 (2H, m), 1.46 (9H, s
), 165 (IH, d, J=9Hz).

2.25 (IH, dd, J=8.14Hz), 2.44
(IH, m), 2.55 (IH, dd, J=4.14H
z), 2.72(3H, d, J=5Hzλ3.02(2
f(, d, J=7Hz), 3.20 (IH, m), 3.
77 (3H, a).

4.59 (IH, q, J=7Hz), 5.77 (IH,
Width d), 6.44 (IH, d, J=8Hz), 6
．． 82 (2H, d, J=8Hz) and 7, 15
(2H, d, J=8Hz).

6-Methyl-4-C [(2-(
R)-benzyloxy-1-(S)-[(methylamino)carbonyl]propyl]amino]carbonyl]hept-2(and 3)-enoic acid methyl ester (D15) 4
．． The 4F solution was left at room temperature for 21 days and then evaporated to dryness under vacuum to give 7Licagel 150? chromatography. Elution with ethyl acetate/pe/tan (1:1) gave the title compound 1.7F as a 3:2 mixture of diastereomers (isomers A/B). Melting point 105-106℃
(from ether/pentane).

(Actual value: C, 59,95: H7,74; N, 5.84
Calculation of ゜Ct* Hw N* O@S M, C$ 59
-98: H-7,55e N-5483%).

δ(CDCIm): 0.9 (7'(m), 1-
11 (d, J-5Hz), and 1.15 (d,
J=5Hz) (Taku 3:2), 1.33(m), 1
．． 53 (m), 1.68 (m), 2.32 (s), 2.
6-2.85 (m).

3.66 (s) p and 3.67 (3) (ratio 3:
2), 4.08 (rn).

4.55 (width s), 4.67 (s) t 6
．． 45 (width 8), 6.75 (d, J-6Hz)
, 6.84 (d, J=6Hz) and 7.35
(m).

Further elution yielded the title compound 2.19 as a 2=1 mixture of diastereomers (isomers C/D). Melting point 111-113°C (from ether/pentane).

(Actual measurement value: C60, 35; H, 7, 25; N, 5.
Calculated value of 84°CuHsaNxOsS C, 59, 98;
H#7.55; Nl2.83ch).

δ (CDCA's): 0.88 (rrjt 1.1
3(t, J=5Hz), 1.32(i, 15
2 (m), 1.62-1.80 (m), 2.
33 (s), 2.6-2.82 (m), 3.6
4(s).

3.66 (s), 4.0-4.5 (m), 4.
19-4.24 (m), 4.50 (m),
4.58-4.64 (m)j6.62 (m) $
6.79 (m) and 7.3 (m).

Example 25 Diastereomeric mixtures (A/B and C/D) of the S-acetyl compound of Example 24 were each separately added to 35%
Treatment with aqueous ammonia in the usual manner gave the title compound.

Isomers (A/B) (diastereomer ratio 3:2
) Melting point 113-119°C (from H,O).

(Actual measurements: C, 59,04: H, 7,88; N, 6
．． 26°C, tHl, N, 0. SO, 5H! Calculated value of 0 C, 57, 87; H, 7, 95; N, 6.
13%').

δ(CDCIs): 0.94 (m), 1.12
(d, J-5Hz), 1.13(d, J=5Hz
), 1.38 (m), 1.5 (m), 1
．． 71 (mm).

1.90 (0.6H, d, J=8Hz)t 2
．． 06 (0,4H,d, J=8Hz included 2.57
(m), 2.82 (m), 337 (ml 3.72
(g), 4.14 (m), 4.59 (width yr),
4-67(a), 6.5(m), 6.78(m) and 7.33(m).

Isomers (C/D) (diastereomer ratio 2:1
) Melting point: 72-76°C (from ether) 0 (Actual value: C, 60, 33: H, 7, 97: N, 6
．． 40°C□H,,N, 0. Calculated value of S C, 60,
25:) I,? , 81; N, 6.39%).

δCDCIs): 0.95 (m), 1.15
(t, J=6Hz), 1.3 (m).

1.41 (m), 1.75 (m), 2.01
(0,66H,d, J=8Hz).

2.21 (0,33H,d, J=8H), 2.54(
m), 2.66 (m).

2.82 (m), 3.37 (m), 3.72 (a), 4
．． 2 (m), 4.38 (m)), 4.6 (m),
6.55 (width d, J=8Hz), 6.7 (m).

6.9 (width S) and 7.35 (m).

Example 26 6-Methyl-4-[((1-
(S)-[(methylamino)carbonyl]-2-(3-
indolyl)ethyl[amino]carbonyl]hep)-2
(and 3)-di/acid methyl ester (D16) 2.5
The solution of P was left at room temperature for 28 days.

It was then evaporated to dryness under vacuum. The residue was subjected to column chromatography (1502), first with ether-t
0.32 t of the title compound as a single isomer (isomer A) by first bathing with ether/chloroform (1:1)
I got it. Melting point 134-136°C (from ether).

(Actual value: C, 60, 32: H: 6.88; N, 8.
80゜c**Hss Nm0m Calculated value of S C, 60,
61:H, 6,99:N, 8.83ch).

δ(CDC13): 0.84 (d, J=5H
z ) > and 0.85 (d.

J=5Hz) (example t6H), 1.2-1.75 (2H
, m), 2.29(3H*a)-2-5-2-7
(3P-m)-2,64(3i(-d-J =5Hz
), 3.11 (IH, dd, J=@14Hz)
, 3.3 (IH.

dd, J=6.14Hz), 3.62(3H,s
)t 3.94 (IH, m).

4.72 (IH, q, J=7Hz), 5.64 (IH,
Width d).

6.52 (IH, d, J-8Hz), 7.05-7
．． 25 (3H, m).

'7.36 (IH, d, J=7Hz), 7.72
(IH, d, J=7Hz) and 8.17(11(,
s).

Example 27 3-acetylmercapto-6-methyl-4-[((1-(S)-[(methylamino)carbonyl)-2-(3-indolyl)ethyl]amino] in 5 ml of nitrogen-sparged methanol. Carbonyl]heptanoic acid methyl ester (g26) 0.1 t of ice-cooled bath solution was treated with 1.5 T!1 t of 35% ammonia water bath solution. The mixture was stirred at room temperature under nitrogen for 2 hours. This bath solution was evaporated to dryness under pure nitrogen, and the residue was crushed finely with cold Nitera to give the title compound 52 as a single isomer (isomer A).

Melting point 73-75C0 (actual value: C, 60, 69; H7
, 35:N, 9.64%.

C22H□N, 0. Calculated value of S C, 60, 95: H
, 7, 21; N, 9.69%).

δ (CDCII): 0.87 (6H, d, J=6Hz
), 1.4-1.7 (2H, m ), 1.67 (
IH, d, J=9Hz), 2.37 (IH, dd.

J=5.15Hz), 2.41 (IH, m), 2.
60 (IH, dd.

J=3.15Hz), 2.65(3H,d, J=5
Hz), 3.13 (IH.

dd, J=7.14Hz), 3.21 (II(,
m), 3.30 (LH, dd.

J=7.14Hz), 3.67 (3H,s),
4.75 (LH, q.

J=7Hz), 5.68 (IH, width d),
6.53 (IH, d.

J=8Hz), 7.05-7.25(3H, m),
7.35 (IA, d.

J=8Hz), 7.71 (IH,d, J=8
Hz) and 8.13 (LH.

s).

Example 28 The title compound is prepared from the compound of Example 5 and ammonia by a method analogous to that described in Example 11. The title compound is prepared from the compound of Example 28 by a method analogous to that described in Example 10. was manufactured.

Melting point 221-225°C.

Example 30 The title compound was prepared from the compound of Example 5 and etherglycine hydrochloride by a method similar to that described in Example 2. Melting point 190-198CQ Example 31 3-mercapto-6-methyl-4-[((1-S-[(
Methylamino)carbonyl)-2-(41) The title compound was back-channeled from the compound of Example 30 in a manner analogous to that described in Example 10.

Melting point: 221-228°C.

King x7. z(E-seeking U By a method similar to that described in Example 26.

6-methyl-4-[((1-(aminocarbonyl)-2
-7myl ether]amino]carbonyl]hept-2(
and 3) -The title compound was prepared from enoic acid methyl ester and thiol acetic acid. The diastereomeric mixture (isomers A/B) was chromatographed on silica gel.
), melting point 160-1164°C and (isomer C/D )
The intermediate hept-2 (and 3)-enoic acid, which obtained a melting point of 50-54°C, was prepared from the 4-methoxyca A/honyl-2-(2-methylglobyl)budo 2 described in Preparation Example 12.
- prepared from enoic acid and L-phenylalanine.

3-Mercapto-6-methyl-4-[((1-(S)(
g33) A method similar to that described in Example 10.

The title compound is prepared from the compound of Example 32 and is a mixture of diastereomers (isomers A/B) and (isomers C/D).
), melting point 64-66°C. The crude product is 7
It was purified by chromatography on silica gel, eluting with ethyl acetate.

Example 34 (4-Methodiphenyl)ethylcoaminocarbonyl]heptanoyl-D-leucine t-butyl (E34) By a method similar to that described in Example 12.

The title compound was prepared from the compound of Example 5 and t-butylroy 7nohydrochloride. Melting point 148-157℃ Example 3
Example 34 by a method similar to that described in Example 14.
The title compound was prepared from the following compound.

Melting point 195-200℃ Example 36 By a method similar to that described in Example 15.

The title compound was prepared from the compound of Example 35.

The title compound was prepared from the compound of Preparation Example 7 by a method analogous to that described in Example 32 using L-loinloom-alanine methyl ester, mp 216-220C. The title compound was isolated as a hygroscopic form.

(grave 133 N-(N-[3-mercapto-2-,,2-methylpropyl)-1-oxo-4-11 (phenylmeth) Example 1
The title compound was prepared from the compound of Example 37 by a method analogous to that described in Example 37.

The title compound is a mixture of diastereomers (isomers A/B
, 1:1). Melting point 106-110°C Efficacy of the Invention Collagenase Inhibitor Assay This test is based on Cavston and Barrett, AnaL Bioc.
hem, 99. 340" 345 (1979). Compounds to be tested were dissolved in methanol and added to eel bone collagenase in buffer. 5-15 min at 37°C. After incubation for 1 minute, the assay test tube was cooled to 4°C, and 14C-acetylated wet skin type I collagen was added.
Collagen is an insoluble fiber (ft.
brtt).

To terminate the assay, the tubes were centrifuged at 12000 rpm for 15 minutes. Undigested 14C-collagen is precipitated and digested 14C-collagen is present in the supernatant as a soluble peptide. A sample of the supernatant was taken for counting in a liquid scintillation counter.

The activity of collagenase inhibitors is expressed as the amount of compound that inhibits up to 50 times a known amount of the enzyme (rcgo).

The activity of representative compounds of the present invention according to the above test method is shown in the table below: 2 A 3.9-6.4
(2 experiments) 2 B
724 A 314
B 2704
C230 4D 12600 8 A 4.7-14
(3 experiments) 10 A
8.3 Agent: Patent attorney Masamitsu Akizawa and one other person Voluntary procedure amendment ■, Indication of the case Patent application No. 12, No. 12, No. 1982-3, 26'lS 2, Title of the invention: New compound, its manufacturing process, and the same Pharmaceutical composition 3, relationship to the amended person's case Application address Beecham House, Great West Road, Blendford, Middlesex, United Kingdom (no street address) Name Beecham Group LLC 4, agent

Claims (11)

[Claims] (1) Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is -OH, alkoxy, aryloxy, aralkyloxy, -NR_6R_7 [here R_
6 and R_7 are each hydrogen or alkyl, or R_6 and R_7 together with the nitrogen atom to which they are attached may contain oxygen, sulfur or an optionally substituted nitrogen atom in the ring 5-, 6- or 7
- forming a membered ring], or a group of the following formula: ▲Mathematical formula, chemical formula, table, etc.▼ [Here, R_8 is hydrogen, alkyl (-OH, alkoxy, -NR_6R_7, guanidine, -CO_2H, CO
NH_2, SH or S-alkyl), or -CH_2-Ar (Ar is optionally substituted aryl), and R_9 is alkoxy, OH or -NR_6R_7] ; R_2 is hydrogen, ▲ has a mathematical formula, chemical formula, table, etc. ▼ alkyl, or ▲ has a mathematical formula, chemical formula, table, etc. ▼ (where Z is an optionally substituted aryl); R_3 is C_3_-_6 alkyl; R_4 is hydrogen, alkyl, -CH_2-R_1_0 (where R_1_0 is an optionally substituted phenyl or heteroaryl), or a group of the formula: ▲ can be a mathematical formula, a chemical formula, a table, etc. ▼ [where R_1_1 is hydrogen, alkyl, or -CH_
2Ph (where Ph is an optionally substituted phenyl) and R_1_2 is hydrogen or alkyl]; and R_5 is hydrogen, alkyl, or a group of the following formula: ▲ where the mathematical formula, chemical formula, table, etc. Yes▼ [Here, R_1_3 is hydrogen or alkyl, and R_
1_4 is hydroxy, alkoxy or -NR_6R_
7) or a salt, solvate or hydrate thereof. (2) R_1 is hydroxy, C_1_-_4 alkoxy, benzyloxy, amino, methylamino, N^1-methyl-N-piperazinyl, N-morpholinyl, or -
NH-CH(R_8)COR_9 (where R_8 is hydrogen or isobutyl and R_9 is OH, NH_
2, ethoxy or t-ptoxy); R_2 is hydrogen, acetyl or benzoyl; R_
3 is n-butyl, isobutyl or sec-butyl; R_4 is isobutyl, benzyl, 4-methoxybenzyl, 1-(benzyloxy)ethyl or 3-indolylmethyl; and R_5 is hydrogen, methyl or 1- The compound according to claim 1, which is (methoxycarbonyl)ethyl. (3) R_1 is methoxy, amino, methylamino or -NHCH_2CO_2H; R_2 is hydrogen, acetyl or benzyl; R_3 is isobutyl; R_4 is benzyl or 4-methoxybenzyl; and R_5 is methyl , a compound according to claim 1. (4) In equation (I), the chiral center marked with an asterisk is S
Any one of claims 1 to 3 having the arrangement
Compounds described in. (5) 3-acetylmercapto-6-methyl-4-[[
[1-(S)-[(methylamino)carbonyl]-2-
(4-Methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid methyl ester, 3-mercapto-6-methyl-4-[[[1-(S)-
[(Methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid methyl ester, 3-mercapto-6-methyl-4-[[[1-(S)-]
[(Methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid, 3-mercapto-N^5-methyl-N^1-[1-(S
)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]-2-(2-methylpropyl)
Pentanediamide, 2-[3-mercapto-6-methyl-4-[[[1-(
S)-[(Methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoylamino]ethanoic acid, N^5-(aminocarbonyl)methyl-3-mercapto-N^1 -[1-(S)-[
(Methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]-2-(2-methylpropyl)pentanediamide, 3-mercapto-6-methyl-4-[[
1-(S)-[(methylamino)carbonyl]-2-(
4-methoxyphenyl)ethyl]amino]carbonyl]
heptanoylleucine, 3-acetylmercapto-6-methyl-4-[[[1-
(S)-[(methylamino)carbonyl]-2-(4-
methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid benzyl ester, 3-mercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl) )ethyl]amino]
carbonyl]heptanoic acid benzyl ester, 3-acetylmercapto-6-methyl-4-[[[1-
(S)-[(methylamino)carbonyl]-2-(4-
methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid, 3-benzoylmercapto-N^5-methyl-N^1-
[1-(S)-[(methylamino)carbonyl]-2-
(4-methoxyphenyl)ethyl]-2-(2-methylpropyl)pentanediamide, 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2 -Phenylethyl]amino]carbonyl]heptanoic acid methyl ester, 3-mercapto-6-methyl-4-[[[1-(S)-
[(Methylamino)carbonyl]-2-phenylethyl]amino]carbonyl]heptanoic acid methyl ester, 3-acetylmercapto-N^5-methyl-N^1-[
1-(S)-[(methylamino)carbonyl]-2-(
4-methoxyphenyl)ethyl]-2-(2-methyl-
propyl)pentanediamide, 2-[3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl [Heptanoylamino]
Ethanoic acid t-butyl ester, 2-[3-mercapto-6-methyl-4-[[[1-(
S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoylamino]ethanoic acid t-butyl ester, 2-[3-acetylmercapto-6-methyl-4 −〔〔
[1-(S)-[(methylamino)carbonyl]-2-
(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoylamino]ethanoic acid, 3-acetylmercapto-N^5-(aminocarbonyl)methyl-N^1-[1-(S)-[(methylamino )
carbonyl]-2-(4-methoxyphenyl)ethyl]
-2-(2-methylpropyl)pentanediamide, 1-[3-acetylmercapto-6-methyl-4-[[
[1-(S)-[(methylamino)carbonyl]-2-
(4-Methoxyphenyl)ethyl]amino]carbonyl]heptanoyl]-4-methylpiperazine, 1-[3-mercapto-6-methyl-4-[[[1-(
S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoyl]-4-methylpiperazine, 1-[3-acetylmercapto-6-methyl-4-[[
[1-(S)-[(methylamino)carbonyl]-2-
(4-Methoxyphenyl)ethyl]amino]carbonyl]heptanoyl]morpholine hydrate, 1-[3-mercapto-6-methyl-4-[[[1-(
S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoyl]morpholine hemihydrate, 3-acetylmercapto-6-methyl-4-[[[1- (S)-[(Methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid t-butyl ester, 3-mercapto-6-methyl-4-[[[1-( S
)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid t-butyl ester, 1-[3-acetylmercapto-6-methyl-4-[[
[2-(R)-benzyloxy-1-(S)-[(methylamino)carbonyl]propyl]amino]carbonyl]heptanoic acid methyl ester, 3-mercapto-6-methyl-4-[[[2-( R)-benzyloxy-1-(
S)-[(methylamino)carbonyl]propyl]amino]carbonyl]heptanoic acid methyl ester, 3-acetylmercapto-6-methyl-4-[[[1-
(S)-[(methylamino)carbonyl]-2-(3-
indolyl)ethyl]amino]carbonyl]heptanoic acid methyl ester, 3-mercapto-6-methyl-4-[[[1-(S)-
[(Methylamino)carbonyl]-2-(3-indolyl)ethyl]amino]carbonyl]heptanoic acid methyl ester, 3-acetylmercapto-N^1-[1-(S)-[(
methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]-2-(2-methylpropyl)pentanediamide, 3-mercapto-N^1-[1-(S)-[(methylamino)carbonyl ]-2-(4-methoxyphenyl)ethyl]-2-(2-methylpropyl)pentanediamide, 3-acetylmercapto-6-methyl-4-[[[1-
(S)-[(methylamino)carbonyl]-2-(4-
methoxyphenyl)ethyl]amino]carbonyl]heptanoylglycine ethyl ester, 3-mercapto-6-methyl-4-[[[1-(S)-
[(Methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoylglycine ethyl ester, 3-acetylmercapto-6-methyl-4-[[[1-
(S)-(aminocarbonyl)-2-phenylethyl]
Amino]carbonyl]heptanoic acid methyl ester, 3-mercapto-6-methyl-4-[[[1-(S)-
(aminocarbonyl)-2-phenylethyl]amino]
carbonyl]heptanoic acid methyl ester, 3-acetylmercapto-6-methyl-4-[[[1-
(S)-[(Methylamino)carbonyl]2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoyl-D-leucine t-butyl ester, 3-acetylmercapto-6-methyl-4-[[[ 1-
(S)-[(methylamino)carbonyl]-2-(4-
methoxyphenyl)ethyl]amino]carbonyl]heptanoyl-D-leucine, 3-mercapto-6-methyl-4-[[[1-(S)[(methylamino)carbonyl]-2-(4-methoxyphenyl ) ethyl]amino]carbonyl]heptanoyl-D-leucine, N-[N-[3-acetylmercapto-2-(2-methylpropyl)-1-oxo-4-[(phenylmethoxy)carbonyl]butyl]- L-leucyl-L-alanine methyl ester, or N-[N-[3-mercapto-
The compound according to claim 1, which is 2-(2-methylpropyl)-1-oxo-4-[(phenylmethoxy)carbonyl]butyl]-L-leucyl-L-alanine methyl ester. (6) A method for producing the compound according to claim 1, wherein (a) Formula (III): ▲There are numerical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R_1, R_3, R_4 and R_5 is the formula (I
) with a thiol of formula (IV): L_1-SH, where L_1 is a common sulfur protecting group; or (b) a compound of formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, R_1 and R_3 are as defined in formula (I), and L is a general sulfur protecting group L_1 or a group R-S- (wherein R is an organic residue such that the group R-S- provides a cleavable disulfide bond) is L_2] of the formula (VI): ▼ (VI) (In the formula, R_4 and R_5 are as defined in formula (I)) to react with a compound of formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (in the formula R_1, R_3, R_4 and R_5 are represented by the formula (I
), where L is L_1 or L_2), and then removing the group L when R_2 is hydrogen in the compound of formula (I); . (7) The method according to claim 6, wherein L is L_1 (where L_1 is acetyl or benzoyl). (8) A pharmaceutical composition containing the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier. (9) Compounds according to any one of claims 1 to 5 for use as therapeutic active substances. (10) A compound according to any one of claims 1 to 5 for use in treating collagenolytic conditions such as connective tissue disorders in mammals. (11) Use of the compound according to any one of claims 1 to 5 for producing a medicament for treating collagen decomposition symptoms such as connective tissue disorders.