ZA200103605B - Cystine derivatives as therapeutic agents for matrix metalloprotease related diseases. - Google Patents

Cystine derivatives as therapeutic agents for matrix metalloprotease related diseases. Download PDF

Info

Publication number
ZA200103605B
ZA200103605B ZA200103605A ZA200103605A ZA200103605B ZA 200103605 B ZA200103605 B ZA 200103605B ZA 200103605 A ZA200103605 A ZA 200103605A ZA 200103605 A ZA200103605 A ZA 200103605A ZA 200103605 B ZA200103605 B ZA 200103605B
Authority
ZA
South Africa
Prior art keywords
formula
aromatic
compound
medicament
diseases
Prior art date
Application number
ZA200103605A
Inventor
Frank Grams
Hans-Willi Krell
Herbert Leinert
Gerd Zimmermann
Original Assignee
Roche Diagnostics Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Roche Diagnostics Gmbh filed Critical Roche Diagnostics Gmbh
Publication of ZA200103605B publication Critical patent/ZA200103605B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Description

© WO 0027378 PCT/EP99/08460
CA
CYSTINE DERIVATIVES AS THERAPEUTIC AGENTS FOR MATRIX
METALLOPROTEASE RELATED DISEASES
The invention relates to the use of compounds of formula I as pharmaceuticals and the use of such pharmaceuticals as drugs to treat diseases such as tumor growth and metastasis, inflammatory diseases like osteo- and rheumatoid arthritis, osteoporosis, multiple sclerosis, periodontitis, restenosis, diseases caused by bacteria such as meningitis, sun-induced skin aging and Alzheimers disease.
The family of matrix metalloproteases (MMPs) has become a major target for drug design, since these enzymes are involved in tissue remodeling and connective tissue turnover, and thus in several diseases where (i) rapid extracellular matrix degradation is . taking place, e.g. during congestive heart failure and extravasion of highly metastatic tumor cells, or (ii) slow extracellular matrix degradation is occurring, e.g. . artherosclerotic lesion formation and rupture, cartilage matrix loss in osteoarthritis, bone matrix degradation in osteoporosis, gingival degradation in periodontal disease, matrix remodeling and deposition in Alzheimer plaque formation and rheumatoid arthritis.
The MMP family currently includes seventeen members, thirteen of which are secreted from the cells in a soluble form and four members are membrane-bound enzymes. The
MMPs are zinc dependent and calcium requiring enzymes which are inhibited by one of the members of the tissue inhibitor of metalloproteinase (TIMP) family. Synthetic inhibitors of this class of enzymes have been developed as hydroxamates, N- carboxyalkyl derivatives, phosphonamidates and phosphinates as well as by using thiol groups as ligands for the active-site zinc atom.
Y A i" 3D-structures of the complexes between the catalytic domains of MMPs and various inhibitors have been published as well as the structure of the proenzyme of MMP-3 with an N-terminal propeptide of about 80 residues. The propeptide forms a separate smaller domain that contains three a-helices and an extended peptide that occupies the active site. The catalytic domain in all these structures contains two 7n%t lons, i.e. a "structural" zinc ion and a "catalytic" zinc ion. The "catalytic" zink ion is coordinated by the side chains of three histidyl residues of the consensus sequence HEXXHXXGXXH.
The fourth ligand of the "catalytic" zink in the inhibited enzymes is a coordinating group of the inhibitors like the hydroxamate or carboxylate; in the pro-MMP propeptide itis the thiol group of the cysteine residue.
Correspondingly, the thiol-based collagenase inhibitors, proposed so far, are generally of peptidic structure containing cysteine or cysteine-like amino acids and their design was based on the binding mode of the substrate and more recently, of the cysteine- containing propeptide.
Recently Miller et al. (Biol. Chem 378, 1475-1480 (1997)) described a new class of
MMP inhibitors which were derived from cysteine in a non-peptidic manner. :
Some cysteine derivatives are disclosed therein as intermediates to prepare the final uystin detivatives but no pharmaceutical use of theses systine derivatives ic disclosed or predicted.
Surprisingly we now have found that similar disulfide compounds, i.e. cystine derivatives are highly active in vivo. In fact these inhibitors are not active against matrix metalloproteases (i. e. Ki > 10uM). However, activity can be demonstrated in matrix metalloprotease related diseases like tumor growth and metastasis. Indeed these compounds are better than the inhibitors cited in the paper of Miiller et al.
© WO 00/27378 PCT/EP99/08460
ETE I
< A
Cd
Subject of the present invention are nonpeptidic cystine derivatives of the general formula I i
Ri_ Ny H _R,
S
I. (1) ~AL ~~ H..
Rs A N™g,
O wherein
R, and R, may be the same or different and are selected from hydrogen, an aromatic or non-aromatic carbocyclic or heterocyclic ring or a linear or branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms which can be interrupted by a hetero atom and which can be substituted by an aromatic or non-aromatic carbocyclic or heterocyclic ring. } R, and R, may be the same or different and are selected from hydrogen, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms which can be interrupted by a hetero atom and which can be substituted by an aromatic or non- aromatic carbocyclic or heterocyclic ring and
A is a valency bond or a-CO-, -S0O,-, -NHCO-, -NHCS- or —-O-CO-group their pharmacologically acceptable salts and optically active forms thereof and pharmaceutically acceptable carriers.
With respect to formula I R, or/and R, represent a branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms selected from methyl, ethyl, propyl, n-butyl, tert-
WO (0127378 PCT/EP99/08460 [A I 2 A . la Bh butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc., vinyl, etc. as well as the corresponding alkinyl groups e. g. acetylene.
The carbocyclic aromatic or non aromatic alone or as substituents for said alkyl groups are selected from C;-C, cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or C,-C,, carbocyclic aromatic substituents such as phenyl, naphthyl, fluorenyl, fluorenonyl or anthranyl, or heterocyclic non aromatic substituents such as pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, or heterocyclic aromatic substituents such as pyrrolyl, pyrdinyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, purinyl, indolyl, quinolyl, carbazolyl.
The carbocyclic aromatic or non aromatic ring systems respectively heterocycles can optionally be substituted once or several times for example by halogen-, nitro-, hydroxy-, C,-C, alkyl-, C,-C, alkoxy-, amino-, mercapto-, carboxyl-, cyano-, benzoyl, phenoxy or methylsulfonyl groups.
The alkyl group can be interrupted by a heteroatom, preferably by O, N, S.
A preferably denotes the group —CO-, -SO,- and —-O-CO-.
If A denotes —CO-, the groups R, and R, are preferably selected from the following residues: hydrogen, C,-C,-alkyl, fluorenyl, fluorenonyl, phenyl, benzyl or styryl whereby the phenyl rings may be substituted by chloro, methyl, ethyl, methoxy, phenoxy, benzoyl or methylsulfonyl.
If Adenotes -SO,-, R, and R, are preferably selected from the following residues: methyl, ethyl, toluolyl or phenyl.
% nL
A
If A denotes —O-CO-, R, and R, are preferably selected from the following residues: benzyl or phenyl optionally substituted by halogen. 5 R, and R, are preferably selected from the following residues: phenethyl, phenylmethyl, phenylcyclopropyl, morpholinoethyl, morpholinopropyl, cyclohexylethyl, pyridylethyl, imidazolylethyl, indolylethyl or 4-chlorophenylethyl whereby the phenyl moities can be substituted by halogen, methyl or methoxy groups.
Subject of the invention are also new compounds of formula I qo
R ~ ~H ~ R, 1—A Y N i
Ss 0) ~ Al H SL " A "R, . Oo wherein
R, and R, may be the same or different and are selected from hydrogen, an aromatic or non-aromatic carbocyclic or heterocyclic ring or a linear or branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms which can be interrupted by a hetero atom and which can be substituted by an aromatic or non-aromatic carbocyclic or heterocyclic ring.
R, and R, may be the same or different and are selected from hydrogen, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms which can be interrupted by a hetero atom and which can be substituted by an aromatic or non- aromatic carbocyclic or heterocyclic ring and
TRE & 6
A
A is a valency bond or a-CO-, -S0O,-, -NHCO-, -NHCS- or —O-CO-group with the proviso that if R, and R, are benzyl, R;-A and Rs-A cannot be formyl, C,-C,, alkylcarbonyl, benzoyl, toluenesulfonyl or benzyloxycarbonyl, and if R,-A and R,-A are benzyloxycarbonyl, R, and R, cannot be pyridylmethyl, phenylethyl, 4-hydroxyphenylethyl, 4-chlorophenylethyl, phenylpropyl or indolylethyl their pharmacologically acceptable salts and optically active forms thereof.
The compounds of formula I can be prepared using classical methods of peptide chemistry.
Acylation of cystine or its carboxy protected derivatives with activated carboxylic or sulfonic acids like acid chlorides, active esters like N-hydroxysuccinimid or hydroxy . benzotriazol esters. These activated esters may be prepared in situ using activating agents like carbodiimides or N,N’-carbonyldiimidazole followed by amidation of the . carboxy group of the cystine using the methods of peptide chemistry.
Auother method of preparation starts with carboxy protected cystine and reacting it with activated acids, isocyanates, isothiocyanates. After the cleavage of the protecting group the carboxylic function can be amidated as described above. Useful protecting groups are known from peptide chemistry e.g. methyl, ethyl, benzyl or p-tert.butylesters. Alkyl esters are cleaved by alkaline hydrolysis, benzyl esters by HBr in acetic acid. Tert.butyl esters are cleaved with strong organic acids like trifluoro acetic acid.
The compounds of the present invention are pharmacologically useful in the treatment of rheumatoid arthritis and related diseases in which collagenolytic activity is a contributing factor, such as, for example, corneal ulceration, osteoporosis, periodontitis,
Paget's disease, gingivitis, tumor invasion, dystrophic epidermolysis, bullosa, systemic
© WO 0027378 PCT/EP99/08460 ) A 4 ulceration, epidermal ulceration, gastric ulceration, and the like. These compounds are particularly useful in the treatment of rheumatoid arthritis (primary chronic polyarthritis,
PCP), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis, Sjégren’s syndrome (RA + sicca syndrome), polyarteritis nodosa and related vasculities, e. g. Wegener’s granulomatosis, giant-cell arteritis, Goodpasture’s syndrome, hypersensitiveness angiitis, polymyositis and dermatomyositis, progressive system sclerosis, M. Bechterew, Reiter syndrome (arthritis + urethritis + conjunctivitis), mixed connective tissue disease (Sharp’s syndrome), spondylitis ankylopoetica (M.
Bechterew).
The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route and in dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art.
Accordingly, the invention provides a class of novel pharmaceutical compositions ) comprising one or more compounds of the present invention, in association with one or more non-toxic pharmaceutically acceptable carriers and/or adjuvants (collectively referred to herein as “carrier materials”) and, if desired, other active ingredients. the compounds and compositions may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
For all administrations, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit contained in a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose from about 0.1 to 300 mg/kg body weight, particularly from about 1 to 30 mg/kg body weight may be appropriate. The active ingredient may also be administered by injection.
The dose regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex and medical conditions of the patient. Severity of the infection and the role of administration and the particular compound employed and thus may vary widely.
For therapeutic purposes, the compounds of the invention are ordinarily combined with one ore more adjuvants appropriate to the indicated route of administation. If per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl ester, talc, stearic acid, magnesium stearat, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatine, acacia, sodium alginate, polyvinyl-pyrrolidone and/or polyvinyl alcohol, and thus tabletted or encapsulated for convenient administration. Alternatively, the compounds may be : dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cotton seed oil, peanut oil, sesam oil, benzyl alcohol, sodium chloride and/or various buffers. Other : adjuvants and modes of administration are well and widely known in the pharmaceutical art. Appropriate dosages in any given instance. of course, depend upon the nature and severity of the condition treated, the route of administration and the species of mammal involved, including its size and any individual idiosyncracies.
Representative carriers, dilutions and adjuvants include, for example, water, lactose, gelatine starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petroleum gelly, etc. The pharmaceutical compositions may be made up in a solid form, such as granules, powders or suppositories, or in liquid form, such as solutions, suspensions or emulsions. The pharmaceutical compositions may be subjected to conventional pharmaceutical adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
© WO 00127378 PCT/EP99/08460
For use in the treatment of rheumatoid arthritis, the compounds of this invention can be administered by any convenient route, preferably in the form of a pharmaceutical composition adapted to such route and in a dose effective for the intended treatment. In the treatment of arthritis, administration may be conveniently be by the oral route or by injection intra-articularly into the affected joint.
As indicated, the dose administered and the treatment regimen will be dependent, for example, on the disease, the severity thereof, on the patient being treated and his response to treatment and, therefore, may be widely varied.
The following compounds are synthezised in analogy to Miller et al. (Biol. Chem. 378, 1475-1480 (1997)).They are new and subject of the invention: 1) 2-Formylamino-3-(2-formylamino-2-phenethylcarbamoyl-ethyldisulfanyl)-N- x phenethyl-propionamide . 2) 2-Acetylamino-3-(2-acetylamino-2-phenethylcarbamoyl-ethyldisulfanyl)-N- phenethyl-propionamide 3) 2-Propanoylamino-3-(2-propanoylamino-2-phenethylcarbamoy]l- ethyldisulfanyl)-N-phenethyl-propionamide 4) 2-Hexanoylamino-3-(2-hexanoylamino-2-phenethylcarbamoyl-ethyldisulfanyl)-
N-phenethyl-propionamide 5) 2-Phenacetylamino-3-(2-phenacetylamino-2-phenethylcarbamoyl- ethyldisulfanyl)-N-phenethyl-propionamide
LL
Jo ’ 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-Chlor-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- phenethylcarbamoy]l-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-phenethylcarbamoyi- 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)- V-phenethyl-propionamide
© WO 00/27378 PCT/EP99/08460 . A 1 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
LIES . . =,
Experimental part
Example 1 2-(4-Chlor-benzoyl)amino-3-(2-(4-chlor-benzoyl)amino-2-phenethylcarbamoyl- ethyldisulfanyl)-N-phenethyl-propionamide 1) N,N’-Di-tert.butoxycarbonyl-L-cystin-bis-phenethylamide N,N’-Di tert.butyloxycarbonyl-L-cystin (2.2 g) is dissolved in tetrahydrofurane (120 ml) and treated with N-hydroxybenzotriazole (1.35 g), O-(benzotriazole-1-yl)-
N,N,N’, N’-tetramethyluronium-tetrafluoroborat (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 over night without stirring. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and the organic phase washed two times with NaHSO,-solution. A solid precipitated from the biphasic solvent mixture.
The precipitate was filtered and the organic phase washed three times with NaHCO, solution and water. The filtrate was concentrated and the residue combined with the previously isolated precipitate to yield 3.18 g (98 %) of the title compound. R;silica gel = 0.66 (dichloromethane/methanol 95:5), m/e [M+H] = 647 1. L-Cystin-bis-phenethylamide
The product obtained by the above procedure (3.18 g) was dissolved in dichloromethane (30 ml) and trifluoro-acetic acid (8.16 ml). The mixture was kept at room temperature overnight , concentrated and neutralized with a solution of NaHCO, in water. The . precipitate was filtered and washed with water to yield 1.22 g of the title compound.
R; silica gel = 0.4 (dichloromethane/methanol 9:1) 3. 2-(4-Chlor-benzoyl)amino-3-(2-(4-chlor-benzoyfiiiifis-2-phistietiy ca bauioyt- ethyldisulfanyl)-N-phenethyl-propionamide 4-Chlorobenzoic acid (156.5 mg) was dissolved in tetrahydrofurane (10 ml) and treated with 1-hydroxybenzotriazole (135 mg), O-(benzotriazole-1-yl)-N,N,N’ N’- tetramethyluronium-tetrafluoroborat (389 mg), di- isopropylethylamine (342 pl) and L- cystin-bis-phenethylamide (223 mg) as a solution in 10 ml tetrahydrofurane. The reaction mixture was stirred for 24 hours. The precipitate was filtered washed with tetrahydrofurane and dried to yield 280 mg (77%) of the title compound.
TLC: Rf silica gel = 0.7 (dichloromethane/methanol 95:5)
© WO 0027378 PCT/EP99/08460 13 >
IB
~ | :
Example 2
The compounds in the following table were synthesized using the procedure from exampled 5
Numbe | Chemical Name TLC R; value 1 2-(Butanoyl)amino-3-(2-( butanoyl)amino-2- 0.5 phenethylcarbamoyl-ethyldisulfanyl)-N-phenethyl- dichlormethane/methanol 95:5 propionamide 2 2-(4-Methylbenzoyl)amino-3-(4- 0.7 methylbenzoyl)amino-2-phenethylcarbamoyl- dichlormethane/methanol 95:5 ethyldisulfanyl)-N-phenethyl-propionamide . 3 2-((3-Benzoyl)-benzoyl)amino-3-(3-benzoyl)- 0.7 benzoyl)amino-2-phenethylcarbamoyl- dichlormethane/methanol 95:5
Ea — 4 2-((Fluoren-1-yl-carbonyl)amino-3-(3-benzoyl)- 0.75 } benzoyl)amino-2-phenethylcarbamoyl- dichlormethane/methanol 95:5 ethyldisulfanyl)- phenethyl-propionamide 5 2-((Fluorenon-1-yl-carbonyl)amino-3-(3-benzoyi)- 0.5 benzoyl)amino-2-phenethylcarbamoyl- dichlormethane/methanol 95:5 co ethyldisulfanyl)-N-phenethyl-propionamide comctincua 155 2-(Pentanoyl)amino-3-( pentanoyl)amino-2- 0.65 ] phenethylcarbamoyl-ethyldisulfanyl)-N-phenethyl- dichlormethane/methanol 95:5 propionamide } 7 2-(4-Ethyl-biphenyl-1-yl-carbonyl)amino-3-(4-Ethyl- | 0.65 bi)amino-2-phenethylcarbamoyl-ethyldisulfanyl)-N- | dichlormethane/methanol 95:5 phenethyl-propionamide 2-(3,4-Dichloro-benzoyl)amino-3-( 3,4-dichloro- 0.8 benzoyl)amino-2-phenethylcarbamoyl- dichlormethane/methanol 95:5 ethyldisulfanyl)-N-phenethyl-propionamide 2-(4-Phenoxy-benzoyl)amino-3-( 4-phenoxy- 0.8 benzoyl)amino-2-phenethylcarbamoyl- dichlormethane/methanol 95:5 ethyldisulfanyl)-N-phenethyl-propionamide 2-(4-Toluenesulfonyl)amino-3-(4- 0.56 toluenesulfonyl)amino-2-phenethylcarbamoyl- dichlormethane/methanol 95:5 ethyldisulfanyl)-N-phenethyl-propionamide 11 2-(Propionyl)amino-3-(propionyl)amino-2- 0.4 phenethylcarbamoyl-ethyldisulfanyl)-N-phenethyl- dichlormethane/methanol 95:5 propionamide 12 2-(4-Methylsulfonyl-benzoyl)amino-3-(4- 0.31 methylsulfonyl-benzoyl)amino-2- dichlormethane/methanol 95:5 phenethylcarbamoyl-ethyldisulfanyl)-N-phenethyl- propionamide
Loa nATE Tm @i rs in
Sei ADL

Claims (13)

bal * & « Patent Claims
1. A pharmaceutically composition containing non peptidic cystine derivatives of the general formula I R \ ! Ro 1 A” y ss S s m id Al N.- Rs ve N R, O wherein R, and R, may be the same or different and are selected from hydrogen, an aromatic or non-aromatic carbocyclic or heterocyclic ring or a linear or branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms which can be interrupted by a hetero ) atom and which can be substituted by an aromatic or non-aromatic carbocyclic or heterocyclic ring. R,and R, may be the same or different and are selected from hydrogen, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms which can be interrupted by a hetero atom and which can be substituted by an aromatic or non- aromatic carbocyclic or heterocyclic ring and A is a valency bond or a-CO-, -SO,-, -NHCO-, -NHCS- or ~O-CO-group their pharmacologically acceptable salts and optically active forms thereof and pharmaceutically acceptable carriers.
AMENDED SHEET ba) WO 0027378 PCT/EP99/08460
2. 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 for treatment of diseases selected from tumor growth and metastasis, inflammatory diseases like osteo- and rheumatoid arthritis, osteoporosis, multiple sclerosis, periodonititis, restenosis, diseases caused by bactena such as meningitis, sun- induced skin aging and Alzheimers disease.
3. Use of compound according to formula I of claim 1 for the preparation of a medicament containing a compound of formula I as active ingredient for the treatment of MMP-related diseases such as tumor growth and metastasis, inflammatory diseases like osteo- and rheumatoid arthritis, osteoporosis, multiple sclerosis, periodontitis, restenosis, diseases caused by bacteria such as meningitis, sun-induced skin aging and Alzheimers disease.
4. Compounds of formula I ol R ~~ H - R,
1. A a H I m SAL Ho wherein R, and R, may be the same or different and are selected from hydrogen, an aromatic or non-aromatic carbocyclic or heterocyclic nng or a linear or branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms which can be interrupted by a hetero atom and which can be substituted by an aromatic or non-aromatic carbocyclic or heterocyclic ring.
h WO 00/27378 AMENDED SHEET PCT/EPI95/08460 Rand R, may be the same or different and are selected from hydrogen, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms which can be interrupted by a hetero atom and which can be substituted by an aromatic or non- aromatic carbocyclic or heterocyclic ring and A is a valency bond or a-CO-, -SO,-, -NHCO-, -NHCS- or —O-CO-group with the proviso that if R, and R, are benzyl, R,-A and R,-A cannot be formyl, Ci-Cyo alkylcarbonyl, benzoyl, toluenesulfonyl or benzyloxycarbonyl, and if R,-A and R;,-A are benzyloxycarbonyl, R, and R, cannot be pyridylmethyl, phenylethyl, 4-hydroxyphenylethyl, 4-chlorophenylethyl, phenylpropyl or indolylethyl and their pharmacologically acceptable salts and optically active forms thereof.
5. Compounds of formula I as claimed in claim 4, specifically as hereinbefore described and exemplified.
6. Compounds of formula I including any new and inventive integer or combination of integers, substantially as herein described.
7. A medicament as claimed in claim 1, substantially as hereinbefore described and exemplified.
8. A medicament including any new and inventive integer or combination of integers, substantially as herein described.
9. Use of a compound of formula I as claimed in either of claim 2 or 3, substantially as hereinbefore described and exemplified.
AMENDED SHEET
10. Use of a compound of formula I including any new and inventive integer or combination of integers, substantially as herein described.
11. A compound of formula I or the medicament comprising thereof as claimed in any one of claims 1 and 4 to 8 whenever supplied with instructions for the use thereof in treatment of diseases selected from tumor growth and metastasis, inflammatory diseases like osteo- and rheumatoid arthritis, osteoporosis, multiple sclerosis, periodonititis, restenosis, diseases caused by bacteris such as meningitis, sun-iduced skinaging andAlzheimers disease.
12. A compound of formula I or the medicament comprising thereof as claimed in claim 11 when the instructions are in printed or written form.
13. A compound of formula I or the medicament comprising thereof as claimed in claim 12 supplied in a package or container having the said instructions provided therein or thereon.
ZA200103605A 1998-11-06 2001-05-04 Cystine derivatives as therapeutic agents for matrix metalloprotease related diseases. ZA200103605B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP98121073 1998-11-06

Publications (1)

Publication Number Publication Date
ZA200103605B true ZA200103605B (en) 2001-12-11

Family

ID=8232930

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA200103605A ZA200103605B (en) 1998-11-06 2001-05-04 Cystine derivatives as therapeutic agents for matrix metalloprotease related diseases.

Country Status (11)

Country Link
EP (1) EP1143960A2 (en)
JP (1) JP2002529404A (en)
KR (1) KR20010100983A (en)
CN (1) CN1346272A (en)
AR (1) AR025135A1 (en)
AU (1) AU1379600A (en)
BR (1) BR9915127A (en)
CA (1) CA2348946A1 (en)
TR (1) TR200101222T2 (en)
WO (1) WO2000027378A2 (en)
ZA (1) ZA200103605B (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2346700A1 (en) 1998-10-09 2000-04-20 Ajinomoto Co., Inc. Cysteine derivatives
JP2002226457A (en) * 2001-02-02 2002-08-14 Ajinomoto Co Inc New cystine derivative and inflammation factor activation inhibitor
US7723328B2 (en) 2005-04-15 2010-05-25 The University Of North Carolina At Chapel Hill Methods of facilitating cell survival using neurotrophin mimetics
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US9271986B2 (en) 2009-11-12 2016-03-01 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10137097B2 (en) 2015-06-08 2018-11-27 Osaka Prefecture University Public Corporation Non-peptidic GAPDH aggregation inhibitor

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1478002A (en) * 1975-02-12 1977-06-29 Ecnpk Biolog I Mediko Biolog P Pharmaceutical composition having anti-tumour activity

Also Published As

Publication number Publication date
TR200101222T2 (en) 2001-12-21
JP2002529404A (en) 2002-09-10
CN1346272A (en) 2002-04-24
AU1379600A (en) 2000-05-29
EP1143960A2 (en) 2001-10-17
AR025135A1 (en) 2002-11-13
CA2348946A1 (en) 2000-05-18
WO2000027378A2 (en) 2000-05-18
KR20010100983A (en) 2001-11-14
BR9915127A (en) 2001-07-31
WO2000027378A3 (en) 2001-09-20

Similar Documents

Publication Publication Date Title
KR100352316B1 (en) Sulfonylamino substituted hydroxamic acid derivatives as metalloprotease inhibitors
RU2126791C1 (en) Derivatives of hydroxamic acid, method of their synthesis and pharmaceutical or veterinary composition based on said
Levy et al. Matrix metalloproteinase inhibitors: a structure− activity study
EP0934267B1 (en) Alpha-amino sulfonyl hydroxamic acids as matrix metalloproteinase inhibitors
US5932579A (en) Collagenase-1 and stromelysin-1 inhibitors, pharmaceutical compositions comprising same and methods of their use
US5859061A (en) Bis-sulfonamides hydroxamic acids as MMP inhibitors
KR20000035925A (en) Phosphinic acid amides as matrix metalloprotease inhibitors
US5872146A (en) Mercapto alkyl peptidyl compounds having MMP and TNF inhibitory activity
CA2102890A1 (en) Substituted n-carboxyalkylpeptidyl derivatives as antidegenerative active agents
EP0826000B1 (en) Peptide compounds which inhibit metalloproteinase and tnf liberation and their therapeutic uses
HRP970474A2 (en) Compounds for and a method of inhibiting matrix metalloproteinases
US5190937A (en) Lactam derivatives
CA2289094A1 (en) New cysteine derivatives, processes for their production, and pharmaceuticals containing them
WO1992006966A1 (en) N-(2-alkyl-3-mercaptoglutaryl)-amino-diaza cycloalkanone derivatives and their use as collagenase inhibitors
ZA200103605B (en) Cystine derivatives as therapeutic agents for matrix metalloprotease related diseases.
JP2001509790A (en) Metalloproteinase inhibitors
JP2000508639A (en) Peptidyl compounds having MMP and TNF inhibitory activity
CA2351321A1 (en) Hydrazine derivatives
CA2274889A1 (en) Bis-sulfonomides hydroxamic acids as mmp inhibitors
MXPA99010180A (en) New cysteine derivatives, processes for their production, and pharmaceuticals containing them
WO1994014765A1 (en) Cyclohexylsulfonyl-acrylic acid and its derivatives, pharmaceutical compositions containing them and process for preparing same