AU594943B2 - Heterocyclic disulfides and their use as immunodulators - Google Patents
Heterocyclic disulfides and their use as immunodulators Download PDFInfo
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- AU594943B2 AU594943B2 AU54605/86A AU5460586A AU594943B2 AU 594943 B2 AU594943 B2 AU 594943B2 AU 54605/86 A AU54605/86 A AU 54605/86A AU 5460586 A AU5460586 A AU 5460586A AU 594943 B2 AU594943 B2 AU 594943B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/36—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 i
J
u COMPLETE SPECIFICATION
(ORIGINAL)
LdC la ss Application Number: L 6
CS/
Lodged: Int. Class Complete Specification Lodged: Accepted: Published: Priority 4 A1.01 Related Art: 7:' Name of Applicant: HOECHST AKTIENGESELLSCHAFT Address of Applicant: 'Actual Inventor: A (ddress for Service St 4 45 Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany KLAUS FLEISCHMANN, WALTER DURCKHEIMER, JURGEN BLUMBACH, MICHAEL LIMBERT, HANS-ULRICH SCHORLEMMER, GERHARD DICKNEITE, HANS-HARALD SEDLACEK EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: HETEROCYCLIC DISULFIDES AND THEIR USE AS IMMUNOMODULATORS The following statement is a full description of this invention, including the best method of performing it known to US 1.
-la- HOECHST AKTIENGESELLSCHAFT HOE 85/F 042 Dr.Ka/Fr Heterocyclic disulfides and their use as immunomodulators It is known that the defense mechanisms of the living body, which are briefly termed the humoral immunity and cellular immunity, cooperate to neutralize and eliminate foreign bodies which may give rise to pathogenetic changes and be injurious, principally microorganisms or neoplastic cells.
Immunological investigations have shown that there are connections between a decrease in immunological activity provoked by internal or external factors and an increase in the infectious or tumorous diseases. In addition, other diseases arise owing to changes in the functioning at* of the immune system. These include, for example, autoimmune diseases or disorders caused by immJne complexes.
S Thus, there has for a long time been a search for immuno- 15 stimulants, that is to say substances which are able to modify the immunological activity of the recipient, preferably to increase it, and which allow, by reason of their high efficacy and good tolerability, wide use to support the body's defenses. Examples which have been S 20 tested for their stimulation of immunity are BCG and C.
parvum, as well as extracts of M. tuberculosis and of the Brucellae.
However, at the concentrations at which these substances Sare used they produce marked side effects such as, for example, local granulomas to varying extents. The lack A of knowledge of the exact nature of these substances makes it difficult to carry out a systematic investigation with reasonable reproducibility of the clinical results. Thus, in this connection there is a requirement for new immunostimulants which are chemically defined substances and have low toxicity, such as, for example, bestatin which is an immunostimulant of low molecular weight, is undergoing intensive investigation at present and is, in general, a 2 scientific reference substance.
It has now been found, surprisingly, that the compounds according to the invention have a potent immunostimuLating and immunorestorative action, as is expressed, for example, in the DTH reaction on sheep erythrocytes, in the activation of mononuclear phagocytes and in a pronounced CSF activity. These immunostimulating effects can also be observed, for example, in an increase in the power of resistance to infections. Furthermore, the compounds according to the invention have, surprisingly, cytostatic activity, for example against B16 melanoma of the mouse.
The present invention thus describes a class of substances which have immunopharmacological and cytostatic activity, are chemically defined, have low toxicity and are, as such S 15 or combined with other active compounds, valuable medicaments. The compounds according to the invention have a
LD
50 value above 1,000 mg/kg on intravenous injection in mice. The effective immunomodulatory and cytostatic amount for vertebrates, preferably warm-blooded mammals is in the range from about 0,5 to about 100 mg/kg of body weight for each parenteral or oral dose, and this shows no toxic side effects and is thus very well suited for the treatment of diseases of the immune system.
o af Thus the present invention relates to the use of compounds of the general formula I Het-S-S-Het (I) i for immunostimulation, immunorestoration and cytostatic treatment and to the use of these compounds for the preparation of a medicament to be used for this purpose.
The invention also relates to pharmaceutical agents for immunostimulation, immunorestoration and cytostatic treatment, which contain a compound of the general formula I, ,t .I i
I
-3and to the use of a pharmaceutical agent of this type for the medical indication mentioned.
In the compounds of the general formula I, Het represents an optionally substituted 5- or 6-membered heterocycle.
The heterocycle can contain, for example, 1 4 heteroatoms, in particular N, where appropriate in combination with S or 0.
The following fundamental ring systems may be mentioned as examples of Het: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and benzo-fused derivatives, such as benzoxazolyl, benzothiazolyl and benzito be entirely or partially hydrogenated, such as, for example, dihydrotriazinyl.
The preferred ring systems have 5 members and one sulfur or oxygen atom and 1 or 2 nitrogen atoms, such as thiazolyl, in particular 2-thiazoy and 5-thiazolyl, 1,3,4- I 20 thiadiazolyl, in particular 1,3,4-thiadiazol-5-yL, oxadiazolyl, such as 1,3,4-oxadiazol-5-yl. Other preferred ring L I systems have 5 members and 1 to 4, in particular 2 to 4, nitrogen atoms such as, for example, imidazolyl, preferably 2-imidazolyl, triazolyl, preferably 1,3,4-triazol-5yl and 1,2,4-triazol-5-yl. Benzo-fused derivatives are I also preferred, in particular benzoxazol-2-yl, benzothiazol-2-y and benzimidazol-2-yl.
Other suitable and preferred ring systems have 6 members and 1 to 3, preferably 1 or 2, nitrogen atoms, such as, for example, pyridyl, preferably 2-pyridyL, 3-pyridy and 4-pyridyL, pyrimidyl, preferably 2-pyrimidy and 4-pyrimidyl, triazinyl, preferably 1,2,4-triazin-3-yl, and and 4,5-dihydro-1,2,4-triazin-3-yL.
r. The Het radical can be substituted, examples of suitable substituents being the following: Straight-chain and branched alkyl groups having 1 6, preferably 1 3 carbon atoms, such as, for example, methyl, ethyl, n- or i-propyl, n- or tert.-butyl, preferably methyl, which can, where appropriate, in turn be substituted by halogen, such as, for example, chlorine or bromine, hydroxyl, alkoxy having 1 4 carbon atoms, such as, for example, methoxy or ethoxy, amino, alkylamino or dialkylamino having 1 4 carbon atoms in each alkyl radical, such as, for example, methylamino, ethylamino, dimethylamino and diethylamino, mercapto, alkylthio having 1 4 carbon atoms, such as, for example, methylthio and ethylthio, alkoxycarbonyl having 1 4 carbon atoms in the alkyl moiety, such as, for example, methoxycarbonyl and ethoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl having 1 4 carbon atoms per alkyl moiety, such as, for example, N-methylaminocarbonyL and N-ethylti aminocarbonyl or N,N-dimethylaminocarbonyl and N,N- If r diethylaminocarbonyL, carboxyl, sulfo, phospho, aryl, such as, for example, phenyl, halogen, such as, for example, chlorine or bromine, hydroxyL, oxo, oxido, alkoxy having 1 4 carbon atoms, such as, for example, methoxy or ethoxy, amino, alkylamino or dialkylamino having 1 4 carbon atoms per alkyl moiety, such as, for example, methylamino, ethylamino, dimethylamino or diethylamino, or acylamino, where acyl may represent the radical of an aliphatic mono- or dicarboxylic acid having 2 5 carbon atoms, such as, for example, acetyl, propionyl, 3 carboxypropionyl, 4 carboxybutyryl preferably acetyl, alkyLthio, alkenyithio and alkynylthio having 1 4 carbon atoms in the alkyL moiety and 2 4 carbon atoms in the alkenyl and alkynyl moiety, such as, for example, methylthio, ethylthio, vinylthio, allylthio, ethynylthio or propynylthio, which can optionally be substituted by carboxyL, sulfo, phospho, 1H-tetrazo-5-yL or aminocarbonyL, aLkenyl having 2 4 carbon atoms, such as, for example, vinyL or allyL, which can be optionalLy substituted by halogen such as, for exampLe, chLorine or bromine, hydroxyl, aLkoxy having 1 4 carbon atoms, such as, for example, methoxy or ethoxy, alkoxycarbonyL having 1 4 carbon atoms in the aLkyt moiety, such as, for exampLe, methoxycarbonyl or ethoxycarbony, aminocarbonyl, N-alkyLaminocarbonyL, N,N-diaLkyLaminocarbonyl having 1 4 carbon atoms per alkyl moiety, such as, for example, N-methylaminocarbonyl and N-ethyLaminocarbonyL or N,N-dimethyLaminocarbonyL and N,N-diethylaminocarbonyL, carboxyL, suLfo, phospho, Scarboxyl or alkoxycarbonyl having 1 4 carbon atoms in the aLkyL moiety, such as, for example, methoxycarbonyl or ethoxycarbonyl.
Within the general formuLa I, the use according to the invention also covers new compounds.
Accordingly, the present invention also relates to new Lowmolecular weight heterocyclic disulfides of the general formula I' Het'-S-S-Het' in which Het' represents a 5-membered ring system having one sulfur and 1 or 2 nitrogen atoms or having 1 3 nitrogen
I
-6atoms, such as, for example, thiazoyl, in particular 2thiazolyl and 5-thiazolyl, 1,3,4-thiadiazoy, in particular 1,3,4-thiadiazol-5-yL, imidazolyl, in particular 2-imidazolyl, and triazolyl, in particular 1,2,4-triazoL- 5-yL. Benzo-fused derivatives are also preferred, in particular benzothiazol-2-y and benzimidazol-2-yl.
Het' can also represent a 6-membered ring system having 1 to 3 nitrogen atoms, such as, for example, pyridyl, preferably 2-pyridyl, pyrimidyl, preferably 2-pyrimidyl, and triazinyl, preferably 1,2,4-triazin-3-yL, it also being possible for the ring systems to be entirely or partiaLly hydrogenated, such as, for example, dihydrotriazinyl.
The radical Het' can be substituted, examples of suitable substituents being the foLLowing: Straight-chain and branched alkyl groups having 1 6, preferably 1 3 carbon atoms, such as, for example, methyl, ethyl, n- or i-propyl, n- or tert.-butyl, preferably methyl, which can, where appropriate, in turn be substituted by halogen, such as, for example, chlorine or bromine, hydroxyl, aLkoxy having 1 4 carbon atoms, such as, for example, Kj methoxy or ethoxy, amino, alkylamino or dialkylamino having 1 4 carbon atoms in each aLkyL radicaL, such as, for example, methylamino, ethylamino, dimethylamino and diethylamino, mercapto, alkylthio having 1 4 carbon atoms, such as, for example, methylthio and ethylthio, alkoxycarbonyl having 1 4 carbon atoms in the alkyl moiety, such as, for example, methoxycarbonyl and ethoxycarbonyL, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl having 1 4 carbon atoms per aLkyl moiety, such as, for example, N-methylaminocarbonyL and N-ethylaminocarbonyL or N,N-dimethylaminocarbonyl and N,N- .1 i I_ 7diethyLaminocarbonyL, carboxyL, sulfo, phospho, aryl, such as, for example phenyL, halogen, such as, for example, chlorine or bromine, hydroxyl, oxo, oxido, alkoxy having 1 4 carbon atoms, such as, for example, methoxy or ethoxy, amino, alkylamino or dialkylamino having 1 4 carbon atoms per aLkyl moiety, such as, for exampLe, methylamino, ethylamino, dimethylamino or diethylamino, or acylamino, where acyL may represent the radical of an aliphatic mono- or dicarboxylic acid having 2 5 carbon atoms, such as, for example, acetyL, propionyL, 3 carboxypropionyl, 4 carboxybutyryl, preferably acetyl, alkylthio, alkenylthio and alkynylthio having 1 4 carbon atoms in the alkyl moiety and 2 4 carbon atoms in fill *ta, the alkenyl and alkynyl moiety, such as, for example, I methylthio, ethyLthio, vinylthio, allyLthio, ethynyl- 8444 4 thio or propynylthio, which can optionally be substituted by carboxyl, sulfo, phospho, 1H-tetrazo-5-yL or aminocarbonyL, alkenyl having 2 4 carbon atoms, such as, for example, vinyl or allyl, which can be optionally substituted by #4#8 8 halogen such as, for example, chlorine or bromine, hydroxyl, alkoxy having 1 4 carbon atoms, such as, for example, 8 4 methoxy or ethoxy, alkoxycarbonyl having 1 4 carbon atoms in the alkyl moiety, such as, for example, methoxycarbonyl or ethoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyL having 1 4 carbon atoms per alkyl moiety, such as, for example, N-methylaminorarbonyL and N-ethylaminocarbonyl or N,N-dimethylaminocarbonyl and N,N-diethyLaminocarbonyI,' carboxyl, sulfo, phospho, carboxyl or alkoxycarbonyl having 1 4 carbon atoms in the alkyl moiety, such as, for example, methoxycarbonyl or ethoxycarbonyl.
8 The heterocycLes Het and Het' can be substituted once or several times, for example once to three times, in the manner described above. However, preference is given to heterocycles Het and Het' which carry one or 2 substituents in the heterocyclic ring or in the carbocyclic ring which is fused on. Those which are particularly preferred are ones in which at least one of these substituents carries an acid group, in particular a carboxyl group such as, for example carboxyalkyl or carboxyalkylthio.
Preference is also given to heterocycles Het and Het' which carry in the heterocyclic moiety or in the fused-on carbocyclic ring one or two substituents, at least one of which is a directly bonded acid group such as, for example, carboxyl or hydroxyl.
If the substituents on the heterocycle Het and Het', such as, for example, alkyl, alkenyl, alkylthio, alkenylthio or alkynylthio, are further substituted in the manner described above, then they can also carry more than one substituent, for example 1 3 other substituents. However, single substitution is preferred.
4 Where the compounds of the formulae I and I' carry acid groups they can also be in the form of their physiologically tolerated salts, for example as alkali metal and alkaline earth metal salts such as, preferably, the Na, K, Ca or Mg salts or, for example, ammonium salts or substi- S tuted ammonium salts such as, for example, NH 4 ethanolammonium, diethanolammonium, trialkylammonium, such as, 3 for example, triethylammonium, tetraalkylammonium, or salts with basic amino acids such as, for example, lysine or arginine.
The invention also relates to a process for the preparation of the compounds, according to the invention, of the formula I'.
iL_~ ~i 9 The process according to the invention comprises conversion of a compound of the formula II Het'-SH
(II)
I 4
S*
0 0 0 0 0 o o o 0 0 0 6 orirE( in which Het' has the meaning detailed above, by reaction with an oxidizing agent, into the compounds according to the invention and, where appropriate, conversion of the abovementioned substituents, according to the invention, of Het' into others of the abovementioned substituents, according to the invention, of Het'.
Examples of suitable oxidizing agents which may be mentioned are oxygen, hydrogen peroxide, where appropriate with addition of iron salts such as, for example, Mohr's salt, or with the addition of bases such as, for example, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate, organic peracids such as, for example, peracetic acid, perbenzoic acid or m-chloroperbenzoic acid, elementary iodine or bromine, where appropriate with the addition of bases such as, for example, sodium hydroxide or potassium hydroxide, FeCL 3 or 20 K 3 (Fe(CN) 6 The oxidizing agents which may be mentioned as preferred are: oxygen, hydrogen peroxide, organic peracids such as, for example, peracetic acid, perbenzoic acid and m-chloroperbenzoic acid, and elementary iodine. The oxidation is 25 preferably carried out in water or an organic solvent such as, for example, methanol, ethanol, isopropanol, ethyl acetate and halogenated hydrocarbons such as, for example, dichloromethane and chloroform. It is also possible to use a mixture of these solvents. When working with oxygen, hydrogen peroxide and peracids, the use of solvents which are known to be able to form explosive peroxides, such as, for example, ether, tetrahydrofuran, dioxane and acetone, methyl ethyl ketone, isopropanol, etc. should be avoided.
d 1 I ;Lnr~
I
10 The compounds according to the invention can also be prepared by reaction of a compound of the formula III Het'-X (III) in which Het' has the meaning detailed above, and X represents a reactive leaving group such as halogen, preferably chlorine or bromine, such as -OS0 2 R, R preferably meaning methyl, trifluoromethyl, phenyl, tolyl or naphthyl, or such as -OPO(OR' 2 R' preferably meaning phenyl, with Me 2
S
2 Me representing an alkali metal, preferably sodium, and, where appropriate, conversion of the abovementioned substituents, according to the invention, of Het' into others of the abovementioned substituents, according to the invention, of Het'.
Furthermore, the compounds according to the invention can be prepared by reaction of a compound of the formula IV Het'SSO 2 Me (IV) j in which Het' and Me have the meanings detailed above, with iodine in an aqueous medium and, where appropriate, Sconversion of the abovementioned substituents, according I 20 to the invention, of Het' into others of the abovementioned substituents, according to the invention, of Het'.
The reaction can be carried out in a temperature range between about -40 0 C and the boiling point of the solvent or mixture of solvents, preferably between about -100C and about +400C..
It is quite generally possible to convert by processes known from the literature the substituents contained in the heterocycle Het' in the disulfides of the 4ormula I' into other substituents according to the invention. Thus, for example, an alkoxycarbonyl or aminocarbonyl group can be converted by hydrolysis, or in the case of the amino- 11 carbonyl group also by nitrosation, into a free carboxyl group.
The active compound can be administered alone or combined with one or more, preferably one other medicament having favorable effects on infections, caused, for example, by bacteria, fungi, or viruses, and on tumorous diseases.
According to the. invention, the active compounds can be administered both parenterally and orally. Suitable for parenteral administration are solutions or suspensions of the active compound in a pharmaceutically tolerated vector, preferably a vegetable oil such as, for example, peanut oil or sesame oil, and alcoholic solutions of the active compound, for example, in ethanol, propanediol or glycerol or in mixtures of the abovementioned solvents.
To prepare aqueous solutions, the active compound is preferably used in the form of physiologically tolerated salts which are soluble in water. It is possible for the formulations to contain the customary auxiliaries and excipients. Examples of these are fillers, emulsifiers, lubricants and buffers and flavor-modifying agents.
IIn the text which follows, the action of the compounds on the immune response of the mouse and their immunostimulant activities in various in vivo standard methods are illustrated by way of example. The various test methods employed are known to be particularly well suited for the assessment of immunostimulants and their quality of action.
Experiment 1 Effect on the cellular immunological reaction, of the delayed type, to sheep erythrocytes (delayed type hypersensitivity, DTH) Either 106 or 10 red blood cells from sheep were administered intravenously to each animal in groups of 5 female NMRI mice weighing 18 20 g. Sheep erythrocytes are I I~i_ 12 regarded in immunology as a standard test substance (antigen) for the induction of cellular and humoral immune reactions. In particular, this test provides information about the functioning of the T-cell-dependent component (Thelper cells) of the immune system. The test substance obtained as in exemplary embodiment 8 4-methyl-2-thiazolyl) disulfide) was administered intraperitoneally (2x/day) in the concentrations 20 mg/kg, 30 mg/kg and mg/kg in physiological saline solution on days -1 and 0. After 5 days, each animal received 2 x 10 sheep erythrocytes injected into the underside of the foot and, 24 hours later, the swelling of the foot was measured.
The foot swelling is induced by a skin reaction of the delayed type (delayed type hypersensitivity, DTH) and is, as is known to the expert, a measure of the cellular immune response (Collins, F.M. and Mackaness, J.
Immunol. 101, 830-845, 1968). The results compiled in Table 1 illustrate that there is an increase in the cellular immune response owing to the administration of the substance obtained according to the invention, for example after immunization with 106 sheep erythrocytes. A maximum stimulation can be observed in this experimental design on administration of 30 mg/kg test substance.
Table 1 Immunization of mice with sheep erythrocytres-action on the cellular immune response (DTH reaction) 2x/day i.p. administration foot swelling with P0 6 S' on days -2 -1 and 0 of 10 erythrocytes S* 30 PBS* 24.3 1.3 mg/kg 28.3 6.7 Test substance 30 mg/kg 36.5 mg/kg 31.4 T 8.7 PBS phosphate-buffered saline (NaCI:8,000 mg/l, KCI: 200 mg/l, Na 2
HPO
4 .2H20: 1,440 mg/l,
KH
2 P0 4 :200 mg/l q_ t 13 Experiment 2 Effect on the stimulation of non-specific immunity activation of mononuclear phagocytes This entailed investigation of the effect of the test substance obtained as in exemplary embodiment 8 on the stimulation of peritoneal macrophages in 6-8 week-old NMRI mice.
Female mice received the test substance in parenteral or oral doses of 25 mg/kg, 50 mg/kg, 100 mg/kg and 200 mg/kg.
Buffered saline solution was administered to a control group. The mice were sacrificed three days after the injections, and the peritoneal macrophages of the animals were examined for their state of activation. The secretion of the lysosomal enzymes (B-galactosidase, 0-glucuronidase, and N-acetyl-a-D-glucosaminidase) was determined as one measure of macrophage activation. In addition, it was possible to examine the pinocytosis in comparable macrophage cultures by the uptake of colloidal gold (198Au) as is known to the expert. The Level of oxidative metabolism in macrophages is taken as another measure of their state of activation. This activity is measured with the assistance of a biolumate by determination of the chemiluminescence.
For this purpose, either 3 x 106 macrophages were cultured with 1 ml of TC 199 culture medium in Petri dishes of diameter 30 mm or 10 macrophages were cultured with 100 pl of medium in round-bottomed polyethylene tubes (for determination of the chemiluminescence), with 5% CO 2 and at 370C.
After incubation for one hour, the cultures were washed to remove floating cells. The chemiluminescence (tube culture) was then determined directly, whereas the Petri dishes were incubated for a further 24 hours at 37 0 C and then the enzyme and pinocytosis activities in the cultures were determined. The following results were obtained.
I
L-~~W;cr-clr~1 reT1 14 Table 2 Action on the oxidative metabolism in mouse peritoneal macrophages (chemiluminescence in RLU*/15 minutes).
1 x administration intraperitoneal oral
PBS
Test 25 mg/kg substance 50 mg/kg 100 mg/kg 200 mg/kg 2.97 i 0.28 x 105 7.87 0.28 x 105 9.72 i 0.82 x 105 12.85 2.37 x 105 24.40 7 3.39 x 105 3.65 0.81 x 105 6.41 0.42 x 105 8.99 0.39 x 105 11.85 0.92 x 105 15.60 i 1.98 x 105 *RLU relative light units t *i 4 *1 o i *o 4
I
acn t 44 i Both parenteral and oral treatment of NMRI mice with the test substance prepared as in Example 8 stimulate macrophage activity and thus have an immunity-stimulating action. Thus, the oxidative metabolism of macrophages, with the generation of oxygen radicals and the measurable light associated with this, is markedly raised. At dosages of 25 mg/kg upwards, there is a dose-dependent increase in the macrophage activity with both parenteral 20 and oral administration.
It can be seen from Table 3 that macrophages from control mice release only small amounts of lysosomal enzymes (Bglucuronidase, 8-galactosidase and N-acetyl-B-D-glucosaminidase) into the culture supernatant. Mononuclear 25 phagocytes from mice which have been treated parenterally or orally with the test substance for 72 hours secrete markedly more of the abovementioned acid hydrolases (B-Glu, O-Gal and N-Ac-Glu), and thus show a dose-effect curve which demonstrates a superiority over the controls for all the enzymes measured. It is evident that the test substance has a stimulant action on macrophage activity and contributes to an increase in enzyme release.
eA 15 Table 3 Effect of the test substance on the release of the lysosomal hydroLase enzymes from mouse peritoneal macrophages.
1 x a-GLu -Gal N-Ac-GLu Administration mU/mL mU/ml mU/ml PBS 755/ 484 1306/ 1702 1238/1168 mg/kg 1001/ 897 2584/ 4917 2786/1947 Test 50 mg/kg 1370/1133 11058/ 9179 3315/2862 substance 100 mg/kg 1791/1593 17596/13195 4305/3676 200 mg/kg 2136/1886 22351/17357 6548/5621 0 00 0 0 ao 0 0000 09 00 0 00 0 o o e o 000 a S000 0 00 0 0 0 0 00 0 0 o o o oo 0 0 0 0 0 o a 0 4 The quantitative determination of the pinocytosis activity of mononuclear phagocytes was carried out by the method of Davies et al. (Davies, ALLison, A.C. and Haswell, 15 Biochem. Biophys. Res. Com. 52, 627, 1973). Radio- 198 active colloidal gold (198Au) with a particle size of 20 nm and a specific activity of 4-12 mCi/mg of Au was used for this. The results in Table 4 illustrate the effect of the test substance obtained as in Example 8 on 20 the efficiency of endocytosis. The pinocytosis of colloidal gold (19Au) by mouse peritoneal macrophages from animals treated with the compound according to the invention is significantly and dose-dependently higher than by macrophages from untreated animals.
Table 4 The effect of the test substance on the efficiency of pinocytosis of mouse macrophages.
1 x administration of intraperitoneal oral PBS 0.286 x 10 cpm 0.198 x 103 cpm 25 mg/kg 0.341 0.272 Test 50 mg/kg 0.396 0.358 substance 100 mg/kg 0.462 0.416 200 mg/kg 0.587 0.506 .r in. k. 16 Experiment 3 Increase in the resistance of Balb/c mice to infection with Candida albicans a) Prophylactic treatment: BaLb/c mice were treated intraperitoneaLLy with the test substance (compound of exemplary embodiment 8) at a dose of 2 x 60 mg/kg/day for 4 days. 24 hours after the last administration of the test substance, these animals and the control animals, which had received administrations of physiological saline solution in the same volumes and time intervals, are infected intravenously with Candida albicans (5 x 105 CFU/mouse). The relevant mean survival times can be calculated from the death rate after the infection. 50% of the animals in the control group die after 9.7 days, while the group treated with the test substance showed a mean survival time of 16.1 days. With the selected administration regimen and with these doses (prophylactic administration), the test substance induces a significant increase in the resistance of the Balb/c mouse to Candida albicans.
t t Table *I Mean survival times after C. albicans infection (5 x 105 CFU) Substance Mean Confidence limits 2 x 60 mg/kg/ survival day i.p. time (days) 95% 99% SPBS 9.7 8.4-10.6 7.8-10.9 Test substance 16.1 14.8-17.4 14.4-17.8 b) Therapeutic treatment: For the therapeutic treatment of a chronic Candida albicans infection, female Balb/c mice (15/group) were infected intravenously on day 0 with Candida albicans (1 x 105 1~ 17 17 CFU/mouse). After the infection had taken place, the animals were treated intraperitoneally on each of 8 consecutive days (days 3 10) with 60 mg/kg of the test substance (compound of exemplary embodiment The control animals received injections of physiological saline solution. Urine was collected from the animals on days 8, 14 and 21, and the organism count was determined. On day the animals were sacrificed and the organism count and the formation of necroses in the kidneys were uetermined.
Table 6 shows that the test substance on therapeutic administration markedly reduces all the parameters of chronic Candida albicans infection (organism count in the urine and kidneys and formation of necroses) and thus exerts a therapeutic effect on the disease. Whereas organisms are detectable in the urine of a high percentage of the control animals, there is a significant reduction in the organism count in the treated animals.
In addition, the treatment reduces the colonization of the kidneys by the organism from 63% to 27% with, at the same time, a reduction in the formation of necroses from 87% to S. Table 6 Therapeutic treatment of a chronic Candida albicans infection (1 x 105 CFU) 0 0 4 o ac 0 0 Substance Animals with Kidneys with Necrotic mg/kg positive findings positive kidneys i.p. organism Sfindings Day 3-10 Day 8 Day 14 Day 21 Day 30 Day PBS 4/15 8/15 10/15 19/30 26/30 (87%) Test 1/15 1/15 4/15 8/30 3/30 substance 4 I 18 Experiment 4 Stimulation of the DTH reaction by the compounds according to the invention NMRI mice were treated with the substances according to the invention as described in experiment 1.
The DTH reaction was checked as a test to determine the immunostimulation.
Table 7 shows the relative activity of the test substance, related to the compound from Example 8 whose maximal activation corresponds to 100% (difference between control and stimulation). It can be seen from the table that the DTH reaction in the animals pretreated with the test substances is more pronounced than in the corresponding control animals.
Table 7 Compound from Dose Administration DTH reaction Example No. (mg/kg) (SRBC) 2 20 1 x i.p. day 0 88% 5 200 61% 6 100 100% S 8 100 100% 10 112% 12 100 96% 13 200 147% 25 14 100 118% Experiment Stimulation of macrophage activity by the compounds according to the invention NMRI mice were treated with the compounds according to the invention as described in experiment 2.
ii Y R 'i r.
r i 19 The macrophage function (chemiluminescence and enzyme activity) was checked as a test to determine the immunostimulation.
Table 8 shows the relative activity of the test substances, related to the compound from Example 8 whose maximal activation (difference between control and stimulation) corresponds to 100%. It can be seen from the table that in comparison with macrophages from untreated animals, the chemiluminescence reaction of these cells was also greatly 1" stimulated by all the test substances, and their content of lysosomal enzymes was markedly raised.
Table 8 Compound from Example No.
(100 mg/kg i.p.) 1 2 6 8 Macrophage activity Chemiluminescence Exocytosis t bi ii I I 30% 72% 37% 26% 100% 66% 39% 81% 97% 48% 53% 33% 100% 21% 54% 77% 93% Experiment 6 Stimulation of the defense against infection by Candida albicans by prophylactic administration of the compounds according to the invention Balb/c mice were treated with the compounds according to the invention as described in experiment 3a.
As Table 9 shows, the mean survival time of the mice after C.albicans infection increases significantly compared with an untreated control group.
Table 9 Example Dose Relative prolongation of the No. (mg/kg) mean survival times 1 x i.p. day after infection 1 1 144 2 1 123 10 142 6 10 145 8 1 130 10 135 12 10 205 14 10 107 *Mean survival time of the control group 100 Experiment 7 Effect on the stimulation of defense against the 816 melanoma tumor Primary tumor growth was induced with 2 x 105 live 816 melanoma cells in female C5781/6 mice (10 animals/group) weighing 18 20 g. After development of a particular tumor size (0.65 cm in diameter), the primary tumor was removed. The untreated animals then died of metastases in the Lung. After the tumor induction, the animals were treated intraperitoneally on days 3, 5, 7, 9, 11 and 13 after amputation of the primary tumor with 50, 100 and 200 mg/kg of the test substance obtained as in Example 8.
The relevant mean survival times can be calculated f'rom the death rate after amputation of the primary tum,pr owing to the development of pulmonary metastases. Acco{ding to this, 50% of the animals in the control group die' after 26 days. The groups treated with the test substance showed i tr Ci ti L C
C
21 (cf. Table 10) a significant increase in the mean survival time to 43, 40 and 35 days with the appropriate dosages.
Table Therapeutic treatment of 816 melanoma tumor Administration 6 x i.p. (mg/kg) Mean survival time day 3, 5, 7, 9, 11, 13 (days) PBS 26 43 Test substance 100 200 Experiment 8 Effect on formation of bone marrow colonies This examined the effect of the test substance obtained as in Example 8 on the stimulation of bone marrow colonies in 6 8 week-old B2D2F1 mice. Female mice received the test substance intraperitoneally in the doses 2.5 and .mg/kg. The animals were sacrificed one day later, and the l, bone marrow cells were isolated and cultured by generally known methods (Metcalf, Immunology 21, 427, 1971 and o 20 Stanley et al., J. Exp. Med. 143, 631, 1979). As is customary, L-cell supernatant was used as CSF source (colony stimulating factor) for the development of the bone marrow colonies. The colonies were counted 8 days t after the start of culturing. As can be seen in Table 11, a single dose of 2.5 or 5 mg of the test substance results in a marked increase in the formation of bone marrow cell colonies both with and without addition of CSF (colony stimulating factor) in vitro.
1 22 Table 11 In vivo-effect on the formation of bone marrow colonies Test substance 1 x i.p. (mg/kg)
PBS
Test 2.5 substance 5.0 Number of bone marrow colonies (day 8) with CSF without CSF *41 6 94 11 163 8 0 24 2 44 The examples which follow illustrate the invention but do not restrict it.
Example 1 Bis(3-hydroxy-1-phenyl-1,2,4-triazol-5-yl) disulfide 2.9 g (15 mmol) of 3-hydroxy-1-phenyl-5-mercapto-1,2,4triazole are initially introduced into 100 ml of methanol and, at room temperature, 3.2 ml (33 mmol) of 35% strength hydrogen peroxide in methanol are added dropwise. The solution initially turns yellow and, after 20 min, the new compound slowly precipitates out. After 4 hours, the precipitate is filtered off with suction, washed 5' with methanol and dried.
Yield 2.1 g 72% of theory.
Melting point: 232 0 C decomposition H t NMR (d 6 -DMSO) 6 11.58 ppm, s, 2H, OH 7.38 ppm, m, 10H, aromat. H -23 Example 2: Bis(5-carboxybenzimidazoL-2-yL dlisuLfidle Preparation in analogy to ExampLe 1 -from 2-mercaptobenzimiic acid Yield 70% of theory Melting point 235 -8 0
C
NMR (d 6 -DMSO) 6=9.4 ppm, dl, NH 7.4 8.4 ppm, m, aromat. H Example 3: Bis(3-carboxy-2-pyridyL) dlisuLfidle Preparation in analogy to Example 1 from 2-mercaptopyridine-3-carboxyLic acid Yield: 56% of theory *Melting point: 206 0
C
N MR (d 6 -DMSO) 6=8.55 ppm, q, 2H 8.22 ppm, q, 2H 7.53 ppm, q, 2H nyLmethyL-4-methyL-1,3-thiazoL-2-yL dlisuLfidle Preparation in analogy to Example o m methyl -2-me rca pt 0-4 -methyl-i, 3-t h ia z Ie YiA' 92 1 24- -Met t int 200 2030oC NMR (d 6 -DMSO) =6 7 d4HNH 3.62 S, 4H, C 21 Exam Le Bis[4-(2-chLoroaLLyL)-6-hydroxy-5-oxo-4,5-dihydro-1,2,4t r iaz in-3-y L] dlisulfidle 2.2 g of 4-(2-chLoroaLLyL)-6-hydroxy-3-mercapto-5-oxo- 4,5-dihydro-1,2,4-triazine were dlissolved in 25 ml of methanol and, at room temperature, 0.86 mL of 35Z H 2 0 2 was added dropwise,. and the mixture was then stirred for 1 hour during which the product crystallized out. It was filtered off with suction, washed with methanol and dried in air.
Y ie Ld 1 .2 g Melting point: 204 50C~ (decomposition) NMR Cd 6 -DMSO) =12.7 ppm (br. OH) ppm (dld, =CH 2 4.8 ppm CH 2
N)
I1 9 Z0 Example 6: Bis (6-hvdroxv--2-methyL-5-oxo-2,5-dihydro-1,24-triaz in- 3-yL) dlisuLfidle 1.59 g of 6-hydroxy-3-mercapto-2-methyL-5-oxo-2,5-dihydro- 1,2,4-triazine were dissolved in 30 ml of methanol and, at room temperature, 0.43 ml of 35% H 2 0 2 was added dropwise, and the mixture was then stirred for 30 minutes. The solution was clarified with charcoal, evaporated to dryness in ii ii
I
Bt 25 a rotary evaporator, and the residue was triturated with ice-water. The precipitate was filtered off, washed with ice-water, dried in air, suspended in methanol, filtered off, washed with a little methanol, and dried in vacuo.
Yield 0.8 g Melting point: 220 0 C (decomposition) NMR (d 6 -DMSO) 6 3.87 ppm CH 3 Example 7: Bis(6-hydroxy-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3yl) disulfide 3.7 g of 6-hydroxy-3-mercapto-4-methyl-5-oxo-4,5-dihydro- 1,2,4-triazine were dissolved in 400 ml of methanol and 38 ml of H 2 0. At room temperature, ml of 35% H 2 0 2 were added dropwise. After stirring the mixture for 30 minutes, it was concentrated to 100 ml, and the precipitate was filtered off with suction and dried.
Yield 1.5 g Melting point: 237 0
C
NMR (CF 3
CO
2 6 3.67 ppm s, 2H, OH 3.8 ppm, s, 6H, CH 3 Example 8: Bis(5-carboxymethyl-4-methyl-2-thiazolyl) disulfide 23.62 g of 5-carboxymethyl-4-methyl-2-mercaptothiazole were dissolved in 1 4 41a t t a C 1 E1 I tcr~ L- E9 CYIIPrYLlbllCln~C~~ 1 26 250 ml of methanol, and the mixture was filtered off and, while cooling in a water bath, 12.5 ml of 35% H 2 0 2 were added slowly. The mixture was then stirred in the water bath for 30 minutes and at room temperature for 2 hours. After filtration and washing with methanol, 22.8 g of the title compound were isolated.
Melting point: 162 0
C
NMR (CF 3
CO
2 2.6 ppm, s, 6H, CH 3 4.2 ppm, s, 4H, CH 2 Example 9: Bis(5-carboxymethyl-1,3-thiazol-2-yl) disulfide 0.88 g of 2-mercapto-1,3-thiazol-5-ylacetic acid is dissolved in about 10 ml of methanol and, while stirring at room temperature, ml of 33% H 2 0 2 solution is added. After 0.5 h, the suspension of crystals was cooled, filtered, and the residue from filtration was dried. Yield 0.6 g 2 of decomposition point 150 0 C. Comparison by thin-layer chromatography on Merck silica gel Splates shows reaction complete (Rf: 0.3; mobile phase: ethyl acetate: 65, ethanol: 25, water: formic acid: 1) i Example Bis(4-carboxymethyl-1,3-thiazol-2-yl) disulfide When 1.75 g of 4-carboxymethyl-2-mercaptothiazole is reacted in analogy to Example 8, then 0.95 g of the title compound is obtained.
rr -i n~r~s 27 Melting point: 163 5 0
C
NMR (DMSO-d 6 6 3.7 ppm, s, 4H, CH 2 7.6 ppm, s, 2H, CH 9.4 ppm, s, 2H, CO 2
H
Example 11 Bis(2-carboxymethylthio-1,3,4-thiadiazol-5-yl) disulfide 1.4 g of 2-mercapto-1,3,4-thiadiazoL-5-ylthioacetic acid are dissolved in 10 mL of methanol and, while cooling in ice, 0.65 ml of 35% H 2 0 2 is added dropwise. The mixture is then stirred at room temperature for 1 hour and filtered. The crystals are washed with a little methanol and are dried in vacuo.
I
r% w irr-~ Yield: 1.3 g Melting point: 179 0 C (decomposition) NMR (DMSO-d 6 6 13 ppm, broad, CO 2 4.2 ppm, s, CH 2 Example 12: Bis(5-carboxy-1,3-thiazol-2-yl) disulfide t2 I i C u I 21 g of 2-mercaptothiazole-5-carboxylic acid are dissolved in 100 ml of methanoL by warming gently. While cooling in ice, 10.7 ml of 35% H 2 0 2 are added slowly, and the mixture is then stirred at room temperature for 45 minutes.
The solid is filtered off with suction, washed with methanol and dried in vacuo.
-ra?
E
a, 28 Yield 21.5 g Melting point: 280 0 C (decomposition) NMR (DMSO-d 6 6 8.48 ppm, s, thiazole-H iI
I
Example 13: Bis(5-carboxy-4-methyl-2-thiazolyl) disulfide 1.75 g (10 mmol) of 4-methyL-2-mercaptothiazole-5carboxyLic acid are suspended in mL of methanoL and, while cooling in ice, 0.86 ml of 35% H 2 0 2 is added. The solution is then 0 stirred at 0°C for 1/2 hour and at room temperature for 1 hour. The crystals which have formed are filtered off with suction, washed with a Little methanol and dried in vacuo.
Yield 1.52 g, melting point: 240 10C (decomposition) NMR (DMSO-d 6 6 2.6 ppm, s, CH 3 Example 14: Bis(4-carboxymethyl-5-methyl-2-thiazolyl) disulfide St t Stage 1 Methyl 4-bromopropionylacetate 22 g of methyl propionylacetate are dissolved in g of CH 2
CL
2 and 8.7 mL of Br2 in mL of CH 2
CL
2 are added dropwise. The mixture is then stirred at room temperature for 1 1/4 h, a further 0.66 mL of Br2 in
I
ml Ii ,1 Ii ii ii I l i
II
-1 29 of CH 2
CI
2 is added, and the mixture is stirred for a further 1 1/4 h.
It is washed with ml of H 2 0 each time, mL of saturated NaHCO 3 and mL of H20 each time, dried over Na 2
SO
4 and evaporated. 38.6 g of oil are obtained.
3 1 2 x 50 x 20 x 50 Stage 2 Methyl 2-mercapto-5-methyl-4-thiazolyLacetate 30.1 g 80 ml 24 g of the oil from stage 1, dissolved in of ethanol, are added dropwise to a solution of of freshly prepared ammonium dithiocarbamate in 200 ml of ethanol and 200 ml of H 2 0 at room temperature. The mixture is then stirred for 2 1/2 h and ml of trifluoroacetic acid are added. After having been stirred for 1 hour, the mixture is evaporated to dryness and 200 ml of CHCI 3
/H
2 0 are added. After two further washings with H 2 0, the solution is dried over Na2SO 4 and evaporated. The solid residue is suspended in ether and filtered off.
t
L
Yield 8.9 g Melting point: 149 C (decomposition) NMR (d 6 -DMSO): 6= 11 ppm, broad, SH 3.7 ppm, s, OCH 3 ppm, s, CH 2 2.1 ppm, s, CH 3 30 Stage 3 2 -Mercapto-5-methyl-4-thiazolylacetic acid 1.98 g of stage 2 were dissolved, with warming in ml of methanol. The solution was then stirred at room temperature for 40 min, mL of H 2 0 were added, and the mixture was acidified to pH 1.0 with concentrated HCL. After stirring for 1 h while cooling in ice, the solid was filtered off with suction and washed with ice-water until-free of chloride. Drying in vacuo over P205 produced 1.67 g.
NMR (d 6 -DMSO): 6 13.9 ppm, broad, CO 2
H
ppm, s, CH 2 2.08 ppm, s, CH 3 15 Stage 4 Bis(4-carboxymethyl-5-methyl-2-thiazolyl) disulfide !1 430 mg of stage 3 were suspended in I 20 ml of methanol and dissolved by heating. At room temperature 'j 0.25 ml of 35% H 2 0 2 was added dropwise, and the mixture was then stirred for 1 h. After having been concentrated to about 5 ml, the mixture was filtered, and the solid was washed with a little ice-cold Smethanol.
Yield: 280 mg NMR (d 6 -DMSO): 6 3.65 ppm, s, CH 2 2.37 ppm, s, CH 3 31 Example Bis(5-carboxymethyL-1,3-thiazoL-2-yL disuLfide 0.8 g of 2 -mercapto-5-carboxymethyl-1,3-thiazole were dissolved in 10 mL of methanol and, while stirring, 0.5 ml of 33% strength H 2 0 2 solution was added dropwise. The mixture was allowed to stir overnight, and the product which had crystallized out was filtered off.
Yield 0.6 g of melting point 150 0 C (decomposition), homogeneous by thin-layer chromatography (Rf 0.3; silica gel; mobile phase: ethyl acetate/ ethanol/water/formic acid (60:25:15:1) IR (KBr disk): v 1710 cm (COOH).
1 H-NMR (d 6 -DMSO): a (ppm): 3.8 CH 2 -thiazole, 2H) 7.6 thiazole-4H, 1H).
thoxycarbonyLmethyl-1,3-thiazo-2-yL) disulfide g of 2- rcapto-5-methoxycarbonymethyL-1,3-thiazoLe was dissoLt ed in 5 ml of methanol and, while stirring, 0. ml of 33% strength H 2 0 2 solution was added dropwi The mixture was allowed to stir overnight, and e product which had crystal- Lized out was fiLtered o f. 0.3 g of melting point 72oC, homogeneous by in-ayer chromatography on silica gel using ethy acetate as the mobile phase (Rf 0.8).
I-c-- IR (KBr disk): -r 1v 1735 cm (COOCH3)- 6 1 2 32 3.7 C00 13, 3H), H 0 T fhTr+a4H- Example 17: Bis(4-carboxy-1,3-thiazol-5-yl) disuLfide 5 g of bis(4-methoxycarbonyL-1,3-thiazol-5-yl) disulfide were suspended in 100 mL of methanoL. To this was added a solution of 1.5 g of NaOH in mL of H 2 0, and the mixture was heated under reflux for 1 h. After the solution had been cooled, methanol was removed in a rotary evaporator, the aqueous phase was extracted once with a little ethyl acetate and acidified with 2 NHCL solution. The product was fiLtered off, dried and recrystallized from ethyl acetate. 2 g of melting point 154 0 C were obtained.
ii ii IR (XIr disk): v 1680 cm-1 (COOH) 1 H-NMR (d 6 -DMSO): (ppm), 8.6 s, thiazoLe-2H).
H-NMR (d6-DMSO): 6 (ppm), 8.6 thiazole-2H).
*r Et I 45 o 455 b Examples 18 to 22 were synthesized as described in Example 1.
Bis(5-acet L~amino-1,3-thiazoL-2-yL disulfide 1H-NMR (d 6
DM
2.16 ppm 6H, 7.56 ppm 2H, thiazoe-H), 11.6 ppm (br s, 2H, -NH-) Example 19: Bis(5-acetyLamino-1,3,4-thiadiazoL-2-yL disulfide 1H-NMR (d 6
DMSO):
6 2. s iPPKi
TV
-ce 333 ExampLe BisC5-glutaromonoamido-1,3-th iazol-2-yL dlisuLfidle 1H-NMR (c1 6
DS)
B 5 =1.6 2.6 ppm Cm, 12H, six CH 2 groups), 7.50 ppm Cs, 2H, thiazoLe-H), 12.63 ppm Cbr s, 2H, 13.05 ppm Cbr s, 2H, -C0 2
H)
ExampLe 21: Bis(5-succinomonoamido-1,3-thiazoL-2-yL dlisulfidle 1H-NMR (cd 6
DMSO):
6 2.4 2.7 ppm Cm, 8H, -CH 2 7.50 ppm Cs, 2H, thiazoLe-H), 12.66 ppm Cbr s, 2H, 13.15 ppm Cbr s, 2H, -CO 2
H)
Example 22: BisE5-C2-carboxyethyL)-4-methyL-1,3-thiazoL-2-yLJ D dlisulf ide 1H-NMR (cd 6
DMSO):
=2.27 ppm Cs, 6H, -CH 3 2.55 ppm (Cd, 4H, thiazole-
CH
2 2.96 ppm Ct, 4H, CH 2 -C0 2 ExampLe 23: B isE 5-carboxymethyL-6-hydroxy-4-methyL )-2-pyr imidinylI disuLf ide 4 g of 5-carboxymethyL-6-hydroxy-2-mercapto-4-methyLpyri- K midline were dissolved in 200 ml of 1 molar sodium bicarbonate solution and, while cooling in ice, 10 mL of
H
2 0 2 were added dropwise. The mixture was stirred at room temperature for 4 h and, while cooling in ice, was acidified to pH 2.0 with 1 N HCL. The precipitate was filtered off with suction and provided, after drying, g of the titLe compound.
Melting point 331 OC (cdecomposition), IR 1630, 1700 cm1 6 2.5 ppm Cs, 6H, -CH 3 3.26 ppm, Cs, 4H, -CH 2
Claims (4)
1. A disulfide of the formula I' Het' S S -Het' in which both Het' radicals are the same and Het' represents a heterocyclic ring system selected from the group consisting of thiazolyl, 1,3,4-thiadiazolyl, triazolyl, triazinyl and partially hydrogenated triazinyl, and wherein said Het' is substituted by: C -C -alkyl, which may be unsubstituted or substituted by halogen, hydroxyl, C -C 4 -alkoxy, mercapto, C -C -alkylthio, C -C -alkoxy-carbonyl, aminocarbonyl or carboxyl; phenyl, halogen; hydroxy; oxo; C -C 4 -alkoxy; C -C-acylamino wherein acyl is the radical of an aliphatic mono- or dicarboxylic acid; C -C 4 -alkylthio, C 2 -C 4 -alkenylthio or C 2 -C 4 -alkynylthio, wherein said C -C -alkylthio, C -C 4 -alkenylthio or C -C -alkynylthio may be unsubstituted or substituted by carboxyl; C 2 -C 4 alkenyl which may be unsubstituted or substituted by halogen, hydroxyl, C -C -alkoxy, C -C 4 -a lkoxy-carbonyl or rcarboxyl; carboxyl; or C -C -alkoxy-carbonyl, wherein at least one of the above-defined substituents of St Het' is or carries carboxyl or hydroxyl.
2. The use of disulfides of the general formula I' Het'-S-S-Het' in which Het' is as defined in claim 1 for the preparation of a medicament for immunostimulation, immunorestoration and cytostatic treatment. A' t 0 35
3. A pharmaceutical agent for immunostimulation, immunorestoration and cytostatic treatment, containing a compound of the formula I' in adjunct with suitably inert pharmaceutical carrier or excipients.
4. A method of immunorestoration, immunostimulation and cytostatic treatment comprising administering to a patient requiring immunorestoration, immunostimulation and/or cytostatic treatment an effective amount of a compound of the formula or of an agent as claimed in claim 3. A process for the preparation of the disulfides of a the general formula which comprises a) conversion of a compound of the formula II Het'-SH (II) in which Het' has the previous meaning, into a compound of the formula I' by reaction with oxidizing agent, or b) reaction of a compound of the formula III Het'-X (III) in which Het' has the previous meaning, and X represents a reactive group which can be easily eliminated, with Me 2 S 2 Me representing an alkali metal, or c) reaction of a compound of the formula IV Het'-S-SO2Me (IV) S in which Het' and Me have the previous meanings, with iodine in an aqueous medium. t DATED this 12th day of December, 1989 SHOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS, 2nd Floor, "The Atrium", 290 Burwood Roag, Hawthorn, Victoria, 3122, AUSTRALIA. DBM:KJS:bc(EK):(1.11) 36 c) reaction of a compound of the formula IV Het'-S-SO 2 Me (IV) in which Het' and Me have the previous meanings, with iodine in an aqueous medium and, where appropriate, in the compounds of the formula I' obtained according to b) or c) conversion of a substituent of the heterocycle Het' in a manner known per se into another substituent of Het'. DATED this 17th day of March 1989 HOECHST AKTIENGESELLSCHAFT EDWD. WATERS SONS, Patent Attorneys Queen Street MELBOURNE. VIC. 3000 AUSTRALIA DBM:KJS:bc (1.11) i i H 1t t1t
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3508666 | 1985-03-12 | ||
| DE19853508666 DE3508666A1 (en) | 1985-03-12 | 1985-03-12 | HETEROCYCLIC DISULFIDES AND THEIR USE AS IMMUNO MODULATORS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5460586A AU5460586A (en) | 1986-10-16 |
| AU594943B2 true AU594943B2 (en) | 1990-03-22 |
Family
ID=6264871
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU54605/86A Ceased AU594943B2 (en) | 1985-03-12 | 1986-03-11 | Heterocyclic disulfides and their use as immunodulators |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0194571B1 (en) |
| JP (1) | JPH0751572B2 (en) |
| KR (1) | KR940001773B1 (en) |
| AR (1) | AR245113A1 (en) |
| AT (1) | ATE58293T1 (en) |
| AU (1) | AU594943B2 (en) |
| DE (2) | DE3508666A1 (en) |
| DK (1) | DK165181C (en) |
| ES (3) | ES8801506A1 (en) |
| FI (1) | FI860980A (en) |
| GR (1) | GR860649B (en) |
| HU (1) | HU201742B (en) |
| IE (1) | IE58729B1 (en) |
| IL (1) | IL78091A (en) |
| NO (1) | NO168357C (en) |
| NZ (1) | NZ215424A (en) |
| PH (1) | PH22275A (en) |
| PT (1) | PT82166B (en) |
| ZA (1) | ZA861780B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3915094A1 (en) | 1989-05-09 | 1991-01-10 | Hoechst Ag | PROCESS FOR THE PREPARATION OF 2-MERCAPTO-4-METHYL-1,3-THIAZOL-5-YL-ACETIC ACID AND THEIR ESTERS |
| TW252112B (en) * | 1993-08-19 | 1995-07-21 | Pfizer | |
| DE10055219A1 (en) | 2000-11-08 | 2002-05-29 | Bayer Ag | Process for the preparation of dithiazolyl disulfides |
| EP1383499B1 (en) | 2001-01-10 | 2013-03-06 | The GRASSETTI Family Trust | Method of immunomodulation using thione-forming disulfides |
| DE102005004472A1 (en) * | 2005-01-31 | 2006-08-10 | Rhein Chemie Rheinau Gmbh | Process for the preparation of bis-DMTD |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4152439A (en) * | 1978-01-12 | 1979-05-01 | Davide R. Grassetti | Stimulant and antidepressant agents |
| US4378364A (en) * | 1970-05-05 | 1983-03-29 | Grassetti Davide R | Postoperative treatment of carcinoma patients |
| AU5461186A (en) * | 1985-03-11 | 1986-10-16 | Richter Gedeon Vegyeszeti Gyar Rt. | 5-substituted benz-imidazole derivatives |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR5680M (en) * | 1966-08-19 | 1968-01-08 | ||
| IL36587A (en) * | 1970-05-05 | 1977-10-31 | Grassetti D | Compositions containing pyridine derivatives and their use in a method of modifying cellular surface reactions |
| GB1365943A (en) * | 1970-09-16 | 1974-09-04 | Gaf Corp | Metalworking additive and composition and process for making the same |
| GB1327467A (en) * | 1970-10-12 | 1973-08-22 | Merck & Co Inc | Pharmaceutical compositions for inhibiting indoleamine- n-methyl transferase |
| FR2403798A1 (en) * | 1977-09-22 | 1979-04-20 | Rorer Inc William H | SYNERGIC COMPOSITIONS BASED ON BIS (2-PYRIDYL-1-OXIDE) DISULPHIDE AND THEIR USE FOR THEIR ANTI-INFLAMMATORY ACTIVITY |
| DE2944225A1 (en) * | 1979-11-02 | 1981-05-07 | Akzo Gmbh, 5600 Wuppertal | METHOD FOR PRODUCING DITHIAZOL DISULFIDES |
| US4451471A (en) * | 1981-03-18 | 1984-05-29 | Ciba-Geigy Corporation | Certain 2,4,5-tri-substituted thiazoles, pharmaceutical compositions containing same and methods of using same |
| DE3118128A1 (en) * | 1981-05-07 | 1982-12-02 | Bayer Ag, 5090 Leverkusen | Use of disulphides as lipoxygenase inhibitors and pharmaceutical compositions containing these |
| EP0077630B1 (en) * | 1981-10-21 | 1985-04-17 | Beecham Group Plc | Topical antimicrobial compositions |
-
1985
- 1985-03-12 DE DE19853508666 patent/DE3508666A1/en not_active Withdrawn
-
1986
- 1986-03-05 AT AT86102901T patent/ATE58293T1/en not_active IP Right Cessation
- 1986-03-05 DE DE8686102901T patent/DE3675561D1/en not_active Expired - Fee Related
- 1986-03-05 EP EP86102901A patent/EP0194571B1/en not_active Expired - Lifetime
- 1986-03-07 AR AR86303344A patent/AR245113A1/en active
- 1986-03-10 NZ NZ215424A patent/NZ215424A/en unknown
- 1986-03-10 IL IL78091A patent/IL78091A/en not_active IP Right Cessation
- 1986-03-10 FI FI860980A patent/FI860980A/en not_active Application Discontinuation
- 1986-03-10 PH PH33495A patent/PH22275A/en unknown
- 1986-03-10 DK DK108786A patent/DK165181C/en active
- 1986-03-10 ES ES552840A patent/ES8801506A1/en not_active Expired
- 1986-03-10 GR GR860649A patent/GR860649B/en unknown
- 1986-03-10 HU HU861011A patent/HU201742B/en not_active IP Right Cessation
- 1986-03-11 NO NO860908A patent/NO168357C/en unknown
- 1986-03-11 ZA ZA861780A patent/ZA861780B/en unknown
- 1986-03-11 AU AU54605/86A patent/AU594943B2/en not_active Ceased
- 1986-03-11 PT PT82166A patent/PT82166B/en not_active IP Right Cessation
- 1986-03-11 JP JP61051594A patent/JPH0751572B2/en not_active Expired - Lifetime
- 1986-03-11 IE IE63086A patent/IE58729B1/en not_active IP Right Cessation
- 1986-03-12 KR KR1019860001768A patent/KR940001773B1/en not_active IP Right Cessation
-
1987
- 1987-07-07 ES ES557614A patent/ES8801624A1/en not_active Expired
- 1987-07-07 ES ES557615A patent/ES8801625A1/en not_active Expired
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4378364A (en) * | 1970-05-05 | 1983-03-29 | Grassetti Davide R | Postoperative treatment of carcinoma patients |
| US4152439A (en) * | 1978-01-12 | 1979-05-01 | Davide R. Grassetti | Stimulant and antidepressant agents |
| AU5461186A (en) * | 1985-03-11 | 1986-10-16 | Richter Gedeon Vegyeszeti Gyar Rt. | 5-substituted benz-imidazole derivatives |
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