KR20010100983A - Cystine derivatives as therapeutic agents for matrix metalloprotease related diseases - Google Patents

Abstract

Subjects of the present invention are directed to inflammatory diseases such as tumor growth and metastasis, osteoarthritis and rheumatoid arthritis, diseases caused by bacteria such as osteoporosis, multiple sclerosis, periodontitis, restenosis, meningitis, sun aging skin and Alzheimer's disease For the treatment of a novel composition of formula (I) and a pharmaceutical composition containing a non-peptidic cystine derivative of formula (I), a pharmaceutically acceptable salt thereof and its optically active form and a pharmaceutically acceptable carrier It is about:

[Formula I]

Wherein R ₁ and R ₃ may be the same or different and represent a hydrogen, aromatic or non-aromatic carbocyclic or heterocyclic ring or a C _1-15 straight or branched chain saturated or unsaturated alkyl group (which may be heteroatomic and Optionally substituted with an aromatic or non-aromatic carbocyclic or heterocyclic ring),

R ₂ and R ₄ may be the same or different and are hydrogen or a C _1-15 straight or branched chain, saturated or unsaturated alkyl group, which is heteroatomic capable and substituted by aromatic or non-aromatic carbocyclic or heterocyclic ring Available),

A is a valence bond or a -CO-, -SO _2- , -NHCO-, -NHCS- or -O-CO- group).

Description

Cystine derivatives for treating matrix metalloprotease-related diseases {CYSTINE DERIVATIVES AS THERAPEUTIC AGENTS FOR MATRIX METALLOPROTEASE RELATED DISEASES}

The present invention relates to the use of the compound of formula (I) as a drug and to diseases such as tumor growth and metastasis, inflammatory diseases such as osteoarthritis and rheumatoid arthritis, osteoporosis, multiple sclerosis, periodontitis, restenosis, meningitis, sun aging skin And the use of such drugs as medicaments for the treatment of diseases such as Alzheimer's disease.

Matrix metalloproteases (MMPs) are a class of several diseases in which these enzymes are involved in tissue remodeling and connective tissue replacement and (i) acute extracellular matrix degradation occurs, such as congestive heart failure and highly metastatic tumor cells. Diseases occurring during extravasation, or (ii) several diseases in which latent extracellular matrix degradation occurs, such as atheromatous plaque lesion formation and rupture, loss of cartilage matrix in osteoarthritis, bone matrix degradation in osteoporosis, periodontal disease It has been a major target for drug design because it is involved in diseases such as gingival degradation, matrix reshaping due to Alzheimer's plaque formation and precipitation and rheumatoid arthritis.

Currently, there are seventeen in the MMP family, thirteen of which are secreted from cells in soluble form and four are membrane binding enzymes. MMPs are zinc dependent and calcium required enzymes that are inhibited by one of the members of the metalloproteinase (TIMP) family of tissue inhibitors. Synthetic inhibitors for this class of enzymes have been developed not only by using thiol groups as ligands for active site zinc atoms, but also as hydroxyxamate, N-carboxyalkyl derivatives, phosphonamidates and phosphinates.

In addition to the N-terminal propeptide of about 80 residues, the structure of the proenzyme of MMP-3 was revealed, as well as the three-dimensional structure of the complex between the catalytic region of MMP and various inhibitors. The propeptide forms a smaller separation region comprising an extended peptide that occupies the active site and three α-helices. The catalytic region in all these structures contains two Zn ²⁺ ions, namely “structural” zinc ions and “catalyst” zinc ions. The side chains of the three histidine residues of the consensus sequence HEXXHXXGXXH coordinate the "catalyst" zinc ion. The fourth ligand of the "catalyst" zinc in the inhibited enzyme is the coordination of an inhibitor such as hydroxysamate or carboxylate; In proMMP propeptides this is the thiol group of the cysteine residue.

Correspondingly, the thiol-based collagenase inhibitors thus far proposed are typically peptidic structures comprising amino acids such as cysteine or cysteine and their design was based on the binding mode of the substrate, more recently. It is a cysteine containing propeptide.

Muller et al. Have recently disclosed a new class of MMP inhibitors derived from cysteine in a nonpeptidic fashion (Biol. Chem. 378 , 1475-1480 (1997)). Several cysteine derivatives are disclosed herein as intermediates for preparing the final cystine derivatives, but the pharmaceutical use of these cystine derivatives is not disclosed or anticipated.

Surprisingly, the present applicant has found that similar disulfide compounds, ie cystine derivatives, are very active in vivo. Indeed these inhibitors have no activity against matrix metalloproteases (ie Ki> 10 μM). However, activity can be demonstrated in matrix metalloproteases involved in diseases such as tumor growth and metastasis. In fact, these compounds are superior to the inhibitors cited in Muller et al.

Subject of the invention are the non-peptidic cystine derivatives of formula I, their pharmaceutically acceptable salts and their optically active forms and pharmaceutically acceptable carriers:

Wherein R ₁ and R ₃ may be the same or different and represent a hydrogen, aromatic or non-aromatic carbocyclic or heterocyclic ring or a C _1-15 straight or branched chain saturated or unsaturated alkyl group, which is capable of Optionally substituted with an aromatic or non-aromatic carbocyclic or heterocyclic ring),

R ₂ and R ₄ may be the same or different and are hydrogen or a C _1-15 straight or branched chain, saturated or unsaturated alkyl group, which may be heteroatomic and substituted by aromatic or non-aromatic carbocyclic or heterocyclic ring. Is selected from

A is a valence bond or a -CO-, -SO _2- , -NHCO-, -NHCS- or -O-CO- group).

With respect to formula (I), R ₁ or / and R _y is C _1-15 selected from methyl, ethyl, propyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. Branched saturated or unsaturated alkyl groups, vinyl groups and the like, as well as the corresponding alkynyl groups such as acetylene.

Carbocyclic aromatics or non-aromatics, alone or as substituents of the above alkyl groups, are C ₃ -C ₆ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or phenyl, naphthyl, fluorenyl, fluoreno C ₆ -C ₁₄ carbocyclic aromatic substituents such as nil or anthranyl, or heterocyclic non-aromatic substituents such as pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, or pyrrolyl, pyridinyl, And heterocyclic aromatic substituents such as furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, furinyl, indolyl, quinolyl, carbazolyl.

Carbocyclic aromatic or non-aromatic ring systems are halogen, for example, each heterocyclic -, nitro -, hydroxy -, C ₁ ~C ₆ alkyl -, C ₁ ~C ₆ alkoxy-, amino-, mercapto- Optionally substituted one or several times by a carboxyl-, cyano-, benzoyl-, phenoxy-, or methylsulfonyl group.

The alkyl group may be interrupted by a heteroatom, preferably O, N, S.

A preferably represents -CO-, -SO ₂ -and -O-CO- groups.

When A represents -CO-, the R ₁ and R ₃ groups are preferably selected from the following residues:

Hydrogen, C ₁ -C ₆ -alkyl, fluorenyl, fluorenyl, phenyl, benzyl or styryl, whereby the phenyl ring is selected from chloro, methyl, ethyl, methoxy, phenoxy, benzoyl or methylsulfonyl Can be substituted.

When A represents -SO _2- , the R ₁ and R ₃ groups are preferably selected from the following residues:

Methyl, ethyl, toluolyl or phenyl.

When A represents -O-CO-, the R ₁ and R ₃ groups are preferably selected from the following residues:

Benzyl or phenyl, optionally substituted by halogen.

R ₂ and R ₄ are preferably selected from the following residues:

Phenethyl, phenylmethyl, phenylcyclopropyl, morpholinoethyl, morpholinopropyl, cyclohexylethyl, pyridylethyl, imidazolylethyl, indolylethyl or 4-chlorophenylethyl, whereby the phenyl moiety is halogen , Methyl or methoxy group.

Also subject of the invention are the novel compounds of formula I, their pharmaceutically acceptable salts and their optically active forms:

[Formula I]

Wherein R ₁ and R ₃ may be the same or different and represent a hydrogen, aromatic or non-aromatic carbocyclic or heterocyclic ring or a C _1-15 straight or branched chain saturated or unsaturated alkyl group (which may be heteroatomic and Optionally substituted with an aromatic or non-aromatic carbocyclic or heterocyclic ring),

R ₂ and R ₄ may be the same or different and are hydrogen or a C _1-15 straight or branched chain, saturated or unsaturated alkyl group (heteroatom intercalable and substituted with aromatic or non-aromatic carbocyclic or heterocyclic ring) ),

A is a valence bond or a -CO-, -SO _2- , -NHCO-, -NHCS- or -O-CO- group

Conditionally, when R ₂ and R ₄ are benzyl, R ₁ -A and R ₃ -A cannot be formyl, C ₁ -C ₁₀ alkylcarbonyl, benzoyl, toluenesulfonyl or benzyloxycarbonyl,

When R ₁ -A and R ₃ -A are benzyloxycarbonyl, R ₂ and R ₄ are pyridylmethyl, phenylethyl, 4-hydroxyphenylethyl, 4-chlorophenylethyl, phenylpropyl or indolylethylyl Can not).

Compounds of formula I can be prepared using traditional methods of peptide chemistry.

Cystine or a carboxy protected derivative thereof is acylated with an activated carboxylic acid such as acid chloride or sulfonic acid, an active ester such as N-hydroxysuccinimide or a hydroxy benzotriazole ester. These activated esters can be prepared in situ using an activator such as carbodiimide or N, N'-carbonyldiimidazole and then subjected to amidation of the carboxy group of cystine using the method of peptide chemistry. .

Another preparation begins with carboxy protected cystine and reacts with activated acids, isocyanates, isothiocyanates. After decomposition of the protecting group, the carboxyl functional groups may be amidated as disclosed above. Useful protecting groups are known in peptide chemistry, such as methyl, ethyl, benzyl or p-tert. Butylester. Alkyl esters are decomposed by alkaline hydrolysis and benzyl esters are decomposed by HBr in acetic acid. tert.Butyl esters are broken down into strong organic acids such as trifluoro acetic acid.

Compounds of the present invention are related diseases in which rheumatoid arthritis and collagenase activity are contributing factors, such as corneal ulcer, osteoporosis, periodontitis, Paget's disease, gingivitis, tumor infiltration, dystrophic bullous epidermal detachment, systemic ulcer, skin ulcer It is pharmaceutically useful for the treatment of diseases such as stomach ulcers. These compounds are used for the treatment of rheumatoid arthritis (primary chronic polyarthritis, PCP), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis, Sjogren's syndrome (RA + dry syndrome), nodular polyarteritis and related vasculities, such as , Wegener's granulomatosis, giant cell arteritis, Goodpasture syndrome, irritable vasculitis, polymyositis and dermatitis, progressive systemic sclerosis, M. It is particularly useful for the treatment of M.Bechterew, Reiter syndrome (arthritis + urethritis + conjunctivitis), mixed connective tissue disease (Sharp syndrome), and ankylosing spondylitis (M.Bechterew).

The compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for this route and at a dose effective for the intended treatment. Therapeutically effective doses of the compounds of the present invention necessary to prevent or arrest the progression of the disease state are readily established by one of ordinary skill in the art.

Accordingly, the present invention contains one or more non-toxic pharmaceutically acceptable carriers and / or adjuvant (hereinafter referred to as "carrier material"), if necessary, in combination with other active ingredients, containing one or more compositions of the present invention. A class of novel pharmaceutical compositions is provided. The compounds and compositions can be administered, for example, intravenously, intraperitoneally, subcutaneously, intramuscularly or topically.

For all administrations, the pharmaceutical composition may be in the form of a tablet, capsule, suspension or liquid, for example. Pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of active ingredient. Examples of such dosage units are tablets or capsules. Suitable daily dosages for mammals can vary widely depending on the condition of the patient and other factors. However, dosages of about 0.1 to 300 mg / kg body weight, in particular about 1 to 30 mg / kg body weight, will be appropriate. The active ingredient can also be administered by injection.

Dosage regimens for treating disease states with the compounds and / or compositions of the invention are selected according to a variety of factors, including the patient's disease type, age, weight, sex and medical condition. It can vary widely depending on the severity of the infection and the role of administration and the particular compound introduced.

For therapeutic purposes, the compounds of the present invention are generally combined with one or more adjuvant appropriate for the parenchymal route of administration. When taken, the compounds are lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sodium salts of calcium and sulfuric acid, gelatin, acacia, It may be mixed with sodium alginate, polyvinyl-pyrrolidone and / or polyvinyl alcohol, thus tableted or encapsulated for easy administration. Alternatively, the compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other adjuvant and dosage forms are well known in the pharmaceutical art. Of course, the appropriate dosage in any given example depends on its species, including the nature and severity of the condition to be treated, the route of administration and the size of the stray animal and any individual specific constitution.

Representative carriers, diluents and adjuvant include, for example, water, lactose, gelatin starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, waseline and the like. Pharmaceutical compositions may be prepared in solid form such as granules, powders or suppositories, or in liquid form such as solutions, suspensions or emulsions. Pharmaceutical compositions may incorporate conventional pharmaceutical adjuvant such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like.

For use in the treatment of rheumatoid arthritis, the compounds of the present invention may be administered by any convenient route, preferably in the form of a pharmaceutical composition suitable for this route and in a dose effective for the intended treatment. In the treatment of arthritis, it can be easily administered by the oral route or by injection into the joints into the joint lesion.

As pointed out, the dose administered and treatment regimen will depend, for example, on the disease, its severity, the patient to be treated and its response to the treatment, and can therefore vary widely.

The following compounds are synthesized analogously to Muller et al. (Biol. Chem. 378 , 1475-1480 (1997)). The following compounds are the subject of the present invention and are novel:

1) 2-formylamino-3- (2-formylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

2) 2-acetylamino-3- (2-acetylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

3) 2-propanoylamino-3- (2-propanoylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

4) 2-hexanoylamino-3- (2-hexanoylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

5) 2-Penacetylamino-3- (2-Penacetylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

6) 2-cinnamoylamino-3- (2-cinnamoylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

7) 2-Benzoylamino-3- (2-benzoylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

8) 2- (4-Chloro-benzoyl) amino-3- (2- (4-chlor-benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

9) 2- (4-Methyl-benzoyl) amino-3- (2- (4-methyl-benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

10) 2- (4-methoxy-benzoyl) amino-3- (2- (4-methoxy-benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

11) 2-Methylsulfonylamino-3- (2-methylsulfonylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

12) 2-ethylsulfonylamino-3- (2-ethylsulfonylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

13) 2-benzylsulfonylamino-3- (2-benzylsulfonylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

14) 2-Benzenesulfonylamino-3- (2-benzenesulfonylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

15) 2-Toluolsulfonylamino-3- (2-toluolsulfonylamino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

16) 2-formylamino-3- (2-formylamino-2-phenylmethylcarbamoyl-ethyldisulfanyl) -N-phenylmethyl-propionamide

17) 2-formylamino-3- (2-formylamino-2- (2-phenylcyclopropyl) -carbamoyl-ethyldisulfanyl) -N- (2-phenylcyclopropyl) -propionamide

18) 2-formylamino-3- (2-formylamino-2-morpholinoethylcarbamoyl-ethyldisulfanyl) -N-morpholinoethyl-propionamide

19) 2-formylamino-3- (2-formylamino-2-cyclohexylethylcarbamoyl-ethyldisulfanyl) -N-cyclohexylethyl-propionamide

Example 1

2- (4-Chloro-benzoyl) amino-3- (2- (4-chlor-benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

1) N, N'-di-tert.butoxycarbonyl-L-cystine-bis-phenethylamide

N, N'-di tert.Butyloxycarbonyl-L-cystine (2.2 g) is dissolved in tetrahydrofuran (120 mL) and N-hydroxybenzotriazole (1.35 g), O- (benzotriazole- 1-yl) -N, N, N ', N'-tetramethyluronium-tetrafluoroborate (4.27 g), di-isopropylethylamine (3.37 mL) and phenethylamine (1.38 mL) . The mixture is stirred at room temperature for 4 hours and left without stirring overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in dichloromethane and the organic phase is washed twice with NaHSO ₄ solution. Solids precipitate in the biphasic solvent mixture. The precipitate is filtered off and the organic phase is washed three times with NaHCO ₃ solution and water. The filtrate was concentrated and the residue was combined with the previously isolated precipitate to yield 3.18 g (98%) of the title compound.

R _f silica gel = 0.66 (dichloromethane / methanol 95: 5), m / e [M + H] = 647

1.L-cystine-bis-phenethylamide

The product (3.18 g) obtained by the above procedure is dissolved in dichloromethane (30 mL) and trifluoro-acetic acid (8.16 mL). The mixture is left at room temperature overnight, concentrated and neutralized with a solution of NaHCO ₃ in water. The precipitate was filtered off and washed with water to afford 1.22 g of the title compound.

R _f silica gel = 0.4 (dichloromethane / methanol 9: 1)

3. 2- (4-Chloro-benzoyl) amino-3- (2- (4-chlor-benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide

4-chlorobenzoic acid (156.5 mg) is dissolved in tetrahydrofuran (10 ml) and 1-hydroxybenzotriazole (135 mg), O- (benzotriazol-1-yl) as a solution in 10 ml tetrahydrofuran. -N, N, N ', N'-tetramethyluronium-tetrafluoroborate (389 mg), di-isopropylethylamine (342 μL) and L-cystine-bis-phenethylamide (223 mg) Process. The reaction mixture is stirred for 24 hours. The precipitate was filtered off, washed with tetrahydrofuran and dried to give 280 mg (77%) of the title compound.

TLC: R _f silica gel = 0.7 (dichloromethane / methanol 95: 5)

Example 2

The compounds in the following table were synthesized using an example procedure.

number Chemical name TLC R _f value silica gel One 2- (butanoyl) amino-3- (2- (butanoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.5 dichloromethane / methanol 95: 5 2 2- (4-Methylbenzoyl) amino-3- (4-methylbenzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.7dichloromethane / methanol 95: 5 3 2-((3-benzoyl) -benzoyl) amino-3- (3-benzoyl) -benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.7dichloromethane / methanol 95: 5 4 2-((Fluoren-1-yl-carbonyl) amino-3- (3-benzoyl) -benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -phenethyl-propionamide 0.75 dichloromethane / methanol 95: 5 5 2-((Fluorenone-1-yl-carbonyl) amino-3- (3-benzoyl) -benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.5 dichloromethane / methanol 95: 5 6 2- (pentanoyl) amino-3- (pentanoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.65 dichloromethane / methanol 95: 5 7 2- (4-ethyl-biphenyl-1-yl-carbonyl) amino-3- (4-ethyl-bi) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.65 dichloromethane / methanol 95: 5 8 2- (3,4-Dichloro-benzoyl) amino-3- (3,4-dichlorobenzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.8 dichloromethane / methanol 95: 5 9 2- (4-phenoxy-benzoyl) amino-3- (4-phenoxy-benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.8 dichloromethane / methanol 95: 5 10 2- (4-toluenesulfonyl) amino-3- (4-toluenesulfonyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.56 dichloromethane / methanol 95: 5 11 2- (propionyl) amino-3- (propionyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.4dichloromethane / methanol 95: 5 12 2- (4-methylsulfonyl-benzoyl) amino-3- (4-methylsulfonyl-benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.31 dichloromethane / methanol 95: 5 13 2- (4-Chloro-phenylacetyl) amino-3- (4-chloro-phenylacetyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.8 dichloromethane / methanol 90:10 14 2- (4-Methyl-cinnamoyl) amino-3- (4-methyl-cinnamoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.3 dichloromethane / methanol 95: 5 15 2- (4-Methyl-phenylacetyl) amino-3- (4-methyl-phenylacetyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.37 dichloromethane / methanol 95: 5 16 2- (4-methoxy-benzoyl) amino-3- (4-methoxy-benzoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.65 dichloromethane / methanol 95: 5 17 2- (4-methoxy-cinnamoyl) amino-3- (4-methoxy-cinnamoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.67 dichloromethane / methanol 95: 5 18 2- (4-Chloro-cinnamoyl) amino-3- (4-chloro-cinnamoyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.58 dichloromethane / methanol 95: 5 19 2- (acetyl) amino-3- (acetyl) amino-2-phenethylcarbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.25 dichloromethane / methanol 95: 5

Example 3

2- (benzyloxycarbonyl) amino-3- (2- (benzyloxycarbonyl) amino-2-hexylcarbamoyl-ethyldisulfanyl) -N-hexyl-propionamide

Di-benzyloxycarbonyl-L-cystine (508 mg) was dissolved in tetrahydrofuran (25 mL) and 1-hydroxybenzotriazole (270 mg), O- (benzotriazol-1-yl) -N Treat with, N, N ', N'-tetramethyluronium-tetrafluoroborate (777 mg) and di-isopropylethylamine (0.68 mL). The mixture is stirred for 10 minutes and n-hexylamine (0.29 mL) is added. After stirring overnight, the reaction mixture is concentrated. The residue is dissolved in ethyl acetate and washed twice with NaHSO ₄ solution, NaHCO ₃ solution and water. The organic phase is dried and concentrated. The residue is triturated with isohexane to afford 550 mg (77%) of the title compound.

R _f (silica gel) = 0.3 (dichloromethane / methanol 97: 3)

Example 4

The compounds in the following table were synthesized using an example procedure.

number Chemical name TLC R _f value silica gel One 2- (benzyloxy-carbonyl) amino-3- (benzyloxycarbonyl) -amino-2-4-fluoro-phenethylcarbamoyl-ethyldisulfanyl) -N-4-fluoro-phenethyl- Propionamide 0.72 dichloromethane / methanol 97: 3 2 2- (benzyloxy-carbonyl) amino-3- (benzyloxycarbonyl) -amino-2-3,4-dimethoxy-phenethylcarbamoyl-ethyldisulfanyl) -N-3,4-dimethoxy -Phenethyl-propionamide 0.3 dichloromethane / methanol 97: 3 3 2- (benzyloxy-carbonyl) amino-3- (benzyloxycarbonyl) -amino-2-morpholino-propylcarbamoyl-ethyldisulfanyl) -N-morpholino-propyl-propionamide 0.4dichloromethane / methanol 95: 5 4 2- (benzyloxy-carbonyl) amino-3- (benzyloxycarbonyl) -amino-2-4-imidazolyl-ethylcarbamoyl-ethyldisulfanyl) -N-4-imidazolyl-ethyl- Propionamide 0.6dichloromethane / methanol 80:20 5 2- (benzyloxy-carbonyl) amino-3- (benzyloxycarbonyl) -amino-2-4-chloro-phenethylcarbamoyl-ethyldisulfanyl) -N- (4-chloro-phenethyl)- Propionamide 0.77 dichloromethane / methanol 97: 3 6 2- (benzyloxy-carbonyl) amino-3- (benzyloxycarbonyl) -amino-2- (3-indolyl-ethyl) -carbamoyl-ethyldisulfanyl) -N- (3-indolyl- Ethyl) -propionamide 0.6dichloromethane / methanol / condensed ammonia 16: 4: 0.1 7 2- (benzyloxy-carbonyl) amino-3- (benzyloxycarbonyl) -amino-2-phenethyl-carbamoyl-ethyldisulfanyl) -N-phenethyl-propionamide 0.45 dichloromethane / methanol 98: 2

Claims (4)

A pharmaceutical composition containing a non-peptidic cystine derivative of Formula I, a pharmaceutically acceptable salt thereof and its optically active form and a pharmaceutically acceptable carrier: [Formula I] Wherein R ₁ and R ₃ may be the same or different and represent a hydrogen, aromatic or non-aromatic carbocyclic or heterocyclic ring or a C _1-15 straight or branched chain saturated or unsaturated alkyl group (which may be heteroatomic and Optionally substituted with an aromatic or non-aromatic carbocyclic or heterocyclic ring), R ₂ and R ₄ may be the same or different and may be a C _1-15 straight or branched chain, saturated or unsaturated alkyl group, which may be _{interrupted by} a hetero atom and substituted with an aromatic or non-aromatic carbocyclic or heterocyclic ring. Is selected from, A is a valence bond or a -CO-, -SO _2- , -NHCO-, -NHCS- or -O-CO- group). Active ingredient for the treatment of diseases selected from inflammatory diseases such as tumor growth and metastasis, osteoarthritis and rheumatoid arthritis, osteoporosis, multiple sclerosis, periodontitis, restenosis, meningitis, sun-derived skin aging and Alzheimer's disease Use of a compound according to formula (I) of claim 1 for the preparation of a medicament containing a compound of formula (I). For the treatment of inflammatory diseases such as tumor growth and metastasis, osteoarthritis and rheumatoid arthritis, diseases caused by bacteria such as osteoporosis, multiple sclerosis, periodontitis, restenosis, meningitis, sun aging skin and MMP-related diseases such as Alzheimer's disease Use of a compound according to formula I of claim 1 for the preparation of a medicament containing a compound of formula I as active ingredient. Novel compounds of formula (I), their pharmaceutically acceptable salts and their optically active forms: [Formula I] Wherein R ₁ and R ₃ may be the same or different and represent a hydrogen, aromatic or non-aromatic carbocyclic or heterocyclic ring or a C _1-15 straight or branched chain saturated or unsaturated alkyl group (which may be heteroatomic and Optionally substituted with an aromatic or non-aromatic carbocyclic or heterocyclic ring), R ₂ and R ₄ may be the same or different and are hydrogen or a C _1-15 straight or branched chain, saturated or unsaturated alkyl group, which may be heteroatomic and substituted by aromatic or non-aromatic carbocyclic or heterocyclic ring. Is selected from A is a valence bond or a -CO-, -SO _2- , -NHCO-, -NHCS- or -O-CO- group Conditionally, when R ₂ and R ₄ are benzyl, R ₁ -A and R ₃ -A cannot be formyl, C ₁ -C ₁₀ alkylcarbonyl, benzoyl, toluenesulfonyl or benzyloxycarbonyl, When R ₁ -A and R ₃ -A are benzyloxycarbonyl, R ₂ and R ₄ are pyridylmethyl, phenylethyl, 4-hydroxyphenylethyl, 4-chlorophenylethyl, phenylpropyl or indolylethylyl Can not).