DE4313118A1 - Use of 1,2,3,4-tetrahydroisoquinoline derivatives as antimycotics - Google Patents

Abstract

Published without abstract.

Description

The invention relates to the use of 1,2,3,4-tetrahydroisoquinoline derivatives as antifungals.

In the publications DE-A 34 33 553 and EP 180 850 A2 (HOE 86 / F 060) are different bis- and triazoles or cyclopropane derivatives as antifungals and fungicides are described, but their effects and tolerability are not entirely are satisfactory.

There was therefore a need for further antifungal agents Compounds with improved effectiveness and tolerability.

Surprisingly, an excellent effectiveness of 1,2,3,4- Determine tetrahydroisoquinoline derivatives as antifungals.

These have the following formula I:

in which mean:
X is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₃-C₁₂) cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl,
Y is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₃-C₁₂) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl,
Z is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₃-C₂₁) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl, or a protective group customary in peptide chemistry.

Preferred is the use of compounds I in which either X or Y Are hydrogen.

Just as suitable as the compounds I themselves are the pharmacological ones compatible salts of these compounds of formula I.

Unless expressly stated otherwise, aryl means phenyl, benzyl or Naphthyl.

Heteroaryl is understood in particular to be residues which differ from phenyl or Derive naphthyl in which one or more CH groups have been replaced by N. and / or in which at least two neighboring CH groups (with formation of a five-membered aromatic ring) are replaced by S, NH or O. Of further one or both atoms of the condensation site can be bicyclic Residues (as in indolizinyl) are N atoms.

Heteroaryl is especially furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, Triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, Pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, Quinoxalinyl, quinazolinyl, cinnolinyl.

Protecting groups mean, for example, fluorenylmethoxycarbonyl (FMOC), tert.- Butyloxycarbonyl (Boc), H-CO (FOR), 1- (Dimethoxyphenyl) -1-  methylethyloxycarbonyl (DDZ), methylsulfonylethyloxycarbonyl (MSP), o- Nitrophenylsulfenyl (NPS), phenylacetyl (PAC), trifluoroacetyl (TFA), tosyl (TOS), Benzyloxycarbonyl (Z), adamantyloxycarbonyl (ADOC), isoborneyloxycarbonyl (IBC), trichloroacetoxy etc.

The 1,2,3,4-tetrahydroisoquinoline derivatives have a suitable Substitution pattern at least one asymmetric carbon atom on and can occur in these cases as enantiomers or diastereomers. The The invention includes both the use of the individual enantiomeric or Diastereomers as well as their mixtures.

For the preparation of the compounds of formula I used according to the invention the procedures according to European laid-open specification 496 369 applied to compounds of formula I with additional Substituents as defined for X, Y and Z. The type of manufacture is limited but not to the procedures mentioned there, but other, processes known from the literature of organic chemistry can also be used.

The compounds of formula I used according to the invention and their pharmaceutically acceptable salts have antimicrobial, especially strong antifungal effects. They have a broad spectrum of activity in vitro, especially against the fungi Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis, Candida albicans, Aspergillus niger and the protozoan Trichonomas vaginalis, which is not a limitation of the list represents germs being fought, but only has an explanatory character.

The compounds are very effective in vitro against skin fungi, such as. B. Trichophyton mentagrophytes, Microsporum canis, Epidermophyton floccosum; against mold, such as B. Aspergillus niger or against yeasts, such as. B. Candida albicans, C. tropicalis, Candida glabrata and Trichosporon cutaneum or  against protozoa such as Trichomonas vaginalis or T. fetus. Some of them are too effective against gram-positive and / or gram-negative bacteria.

Also in vivo, e.g. B. in the experimental kidney candidiasis of the mouse, have Compounds after oral or parenteral use are very good systemic effect, e.g. B. against Candida albicans. Here, in particular Exoenzyme system of the yeast Candida albicans influenced in such a way that the Pathogenicity of the pathogen drops significantly. There is also a very good effect against various pathogens of skin mycoses (e.g. Trichophyton mentagrophytes) on guinea pigs after oral, parenteral or local application.

As indication areas in human medicine, for example become:

Dermatomycosis and systemic mycosis caused by Trichophyton mentagrophytes and other types of Trichophyton, microspore, Epidermophyton floccosum, and biphasic fungi are caused. In particular, deep mycoses are the caused by Candida albicans, favorably influenced, since this one Penetration of the fungi into the host cell is prevented or made more difficult.

Indications in veterinary medicine can include the following:

All dermatomycoses and systemic mycoses, especially those caused by the pathogen mentioned above.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients one or contain several active substances or which consist of one or more according to the invention Active ingredients used exist and methods for producing them Preparations.  

Non-toxic, inert pharmaceutically suitable excipients include solid, semi-solid or liquid diluents, fillers or formulation aids to understand every kind.

An inhibitor for the different phospholipases from Candida albicans must are present in sufficient concentrations in the patient wherever the fungus can colonize the parenchyma. This fact presupposes that the corresponding substances must be administered in a concentration that has previously been shown to be effective in animal experiments.

In the severe clinical pictures of deep candidiasis there are Patients mostly in a very poor general condition. High fever and other diseases are usually encountered. With the dosage specifications must be between the prophylactic dose and the therapy in the proven Infection case can be distinguished. Prophylaxis can be of a better kind General condition of the patient is assumed to be an oral Allows administration. Here tablets, solutions, gels or Dry juice are used. For shapes with proven depths Candidiasis must often be assumed to be a regulated oral Intake of the active ingredients is not always guaranteed. Then come for this parenteral use forms in question. In exceptional cases, you can also contact one subcutaneous administration.

For example, tablets, coated tablets, capsules, Pills, aqueous solutions, suspensions and emulsions, optionally sterile injectable solutions, non-aqueous emulsions, suspensions and solutions, Ointments, creams, pastes, lotions, sprays etc. into consideration.

The prophylactically and therapeutically active compounds are in the above listed pharmaceutical preparations preferably in a Concentration from about 0.1 to 99.5, in particular from about 0.5 to 95 wt .-% of Total mixture must be present.  

The pharmaceutical preparations listed above can in addition to Active ingredients used according to the invention also other pharmaceutical Contain active ingredients.

The pharmaceutical preparations listed above are produced in customarily by known methods, e.g. B. by mixing the active ingredient or of the active ingredients with the carrier or carriers.

The present invention includes the use of the active ingredients and of pharmaceutical preparations containing one or more active ingredients in of human and veterinary medicine for the prevention, improvement and / or healing of diseases mentioned above.

The active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally.

In general, it has been found in both human and veterinary medicine proven to be advantageous in the active ingredient (s) used according to the invention in Total amounts of at least about 0.05, preferably 0.1, in particular 0.5 mg / kg body weight up to at most about 200, preferably up to 100, in particular up to 10 mg / kg body weight per 24 hours, if necessary in the form of several To administer individual doses to achieve the desired results. The Total amount is in 1 to 8, preferably in 1 to 3, single doses at low However, mycoses are administered over much longer periods (up to 6 weeks).

However, it may be necessary to deviate from the doses mentioned depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of Preparation and application of the drug as well as the period or Interval within which the administration takes place. In some cases it can be sufficient with less than the above amount of active ingredient get along, while in other cases the amount of active ingredient mentioned above  must be exceeded. The determination of the optimum required in each case Dosage and type of application of the active ingredients can be determined by any specialist of his specialist knowledge easily.

The active ingredients listed in Tables A-E below are as Substance examples listed in EP-OS 496 369 A1.

Test methods Method: HC 710 In vitro efficacy: fungi - microtiter test fungi execution

The test is carried out as a microtitration test (microtitration plate, U-shape, 96 wells).

The test preparation (10 mg) is dissolved in a suitable solvent (10 ml Aqua dist., or 1 ml organic solvent + 9 ml distilled water).

The microtiter plate is prepared as follows: The wells (2 rows / stem) with 50 µ neopeptone dextrose broth each (12- Channel pipette). In addition, a row / strain is used for yeast and mold 50 µl each of Yeast Nitrogen Base / well loaded. In the wells of the first Then add 50 µl of preparation solution in a row, mix and dilute Transfer of 50 µl in a 1: 2 ratio further. Then everyone Wells inoculated with 150 µl standardized germ suspension (yeast: 1 × 103 germs / ml suspension; Skin and mold: 1.6 × 10⁵ germs / ml Suspension), the total volume is 200 µl per well.

A growth control (inoculated, not medicated), a solvent control (inoculated, not medicated, containing solvents like medicated series) and a zero control (not inoculated, not medicated) is carried out.  

After 5 days of incubation at 30 ° C, a photometric evaluation is carried out. The Measured values obtained are checked visually (macroscopically and microscopically) and corrected if necessary.

The following criteria are used to assess the antifungal effect:

• a) Photometric measurement results (matrix method)
• b) growth, microscopic assessment
• c) growth, microscopic assessment (reversing microscope, bright field, Magnification 64 x).

Method: HC 040 Microtiter test (MTT): protozoa execution

The test is carried out as a microtitration test.

The test preparation (10 mg) is in a suitable solvent (Ag. Dest. 10 ml or organic solvent 1 ml + Ag. least 9 ml) dissolved.

The standardized pathogen suspensions are used to prepare the inoculation diluted:

• - Suspension with Trichomonas vaginalis (48 h culture Thioglycolate / broth) in a ratio of 1: 5 with medium TTY-SB (Tryptose Tripticase Yeast extract-SB)
• - the suspension with the amoeba Entamoeba histolytica (48 h culture TP-S-1 medium without vitam. - see Diamond, J. Parasitology, 54, 1047-1056 [1968]) in the ratio 1: 2 (10 ml Entamoeba histolytica- Culture + 9 ml TP-S-1 medium without vitamin + 1 ml Crithidia species- Culture).

The microtitration plates are prepared as follows:  

For each preparation concentration, 2 rows of 8 wells with 50 µl medium are used filled for Trich.vag .: TTY-SB medium with 200 i.E. Penicillin-G sodium and others Streptomycin sulfate for Ent.hist .: TPS-1 medium without vitamin mixture.

50 µl of preparation solution are added to the first well of each row, mixed and by transferring 50 µl to the following well geometric dilution series in the ratio 1: 2 created. Then the Inoculation with 150 µl ready-to-use germ suspension per well (= 2.5-3 × 10³ trichomonads or 1 × 10³ amoeba with 2.4 × 10³ Crithidien / well).

A growth control (inoculated, not medicated), a solvent control (inoculated, with solvent like medicated series) and a zero control (not inoculated, not medicated) are carried along.

After 48 or 72 h incubation at 37 ° C compared to growth and Solvent controls evaluated microscopically.

The following criteria are used to assess the effectiveness on protozoa:

• a) morphological changes in the pathogen (microscopic)
• b) Microscopic growth (semi-quantitative; findings 0.1-4).

With unclear results, as well as preventing growth at the lowest Follow-up trials are used to prepare the preparation concentration.  

Table A

Table B

Table C.

Table D

Table E

Claims (3)

1. Use of a compound of formula I. in which mean:
X is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₁-C₁₂) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl,
Y is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₁-C₁₂) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl,
Z is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₁-C₁₂) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl, or a protective group customary in peptide chemistry
for the manufacture of a medicament for the treatment of mycoses. 2. Use according to claim 1, characterized in that in formula I mean:
X hydrogen,
Y is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₁-C₁₂) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl,
Z is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₁-C₁₂) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl, or a protective group customary in peptide chemistry. 3. Use according to claim 1, characterized in that in formula I mean:
X is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₁-C₁₂) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl,
Y hydrogen,
Z is hydrogen, hydroxycarbonyl, (C₁-C₁₂) alkyloxycarbonyl, (C₁-C₁₂) - cycloalkyloxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₆-C₁₂) - heteroaryloxycarbonyl, or a protective group customary in peptide chemistry.