DE19947297A1 - Cyclic biphenyls, processes for their preparation and their use as medicines - Google Patents

Abstract

The invention relates to compounds of general formula (I), wherein the radicals R independently represent a hydroxy group, a hydrogen atom, a halogen atom, a pseudohalogen, a substituent, an optionally substituted alkyl radical, alkenyl radical, alkynyl radical, aralkyl radical, aralkenyl radical, aralkynyl radical, cycloalkyl radical, cycloalkenyl radical, cycloalkynyl radical, cycloaralkyl radical, cycloaralkenyl radical, cycloaralkynyl radical, aryl radical, alkoxy radical or a heterocyclic ring, and the radicals R' and R , independent of one another, represent usual radicals of the amine component or isocyanide component of the Ugi reaction. The invention also relates to the use of the inventive compounds or pharmaceutical compositions for treating or preventing gastrointestinal, immunological, neurological, ocular, psychological, renal-urological and respiratory defective functions, as well as cancer, tumors and infections.

Description

The present invention relates to new biphenyls, they ent pharmaceutical compositions containing, their preparation and use, especially as a tumor and cancer resolving, antibacterial, gastrointestinally effective, immune modulating, neurologically effective, ocularly effective, psy chopharmacological, renal-urologically effective and the Re medication to improve spiration.

It was the object of the present invention to create new effects to provide substances that improve or complete mental effect in the prophylaxis or therapy of gastro intestinal, immunological, neurological, ocular, mental, renal-urological, respiratory malfunction and have cancer and tumors and infections.

It was another object of the present invention to create new ones To provide active ingredients that an improved or com have complementary effects as antibiotics.

This invention relates to cyclic biphenyls of the general formula (I)

wherein the radicals R independently represent a hydroxy group, a hydrogen atom, a halogen atom, a pseudohalogen, a substituent, an optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl -, Cycloaralkyl-, Cycloaralkenyl- Cycloaralkinyl-, Aryl-, Alkoxy, or a heterocyclic ring, and
the radicals R 'and R ", independently of one another, are conventional radicals of the amine or isocyanide component of the Ugi reaction.

The radicals R are, independently of one another, an optionally substituted alkoxy, a hydroxyl group, an amide, a sulfonamide, a hydrogen atom, a halogen atom, a pseudohalogen,
more preferably a hydrogen atom, a hydroxy group, an alkoxy group, fluorine or chlorine,
most preferably a hydroxy group, an alkoxy group, a hydrogen atom or fluorine.

The radicals R 'and R "are preferably independent of one another the usual residues of the amine or isocyanide component the Ugi reaction, such as B. hydrogen atoms, unsubstituted or preferably substituted alkyl radicals or unsubstituted ized or preferably substituted aryl radicals.  

Throughout the description and claims, the term "alkyl" may be used e.g. B. represent a C _1-50 alkyl group, preferably a C _1-12 alkyl group, preferably a C _1-6 alkyl group; so an alkyl group z. B. be a methyl, ethyl, propyl, isopropyl or butyl group;
is the expression "alk" z. B. defined in the term "alkoxy" as "alkyl";
are "aromatics" or "aryls" or corresponding residues such. B. substituted or unsubstituted phenyl, benzyl, naphthyl, biphenyl or anthracene groups or aromatic heterocycles with 5 or 6 ring atoms;
is the expression "Ar" z. B. in the terms "aralkyl" etc. and "cycloaralkyl" etc. as defined "aryl";
the expression "alkenyl" can e.g. B. represent a C _2-10 alkenyl group, preferably a C _2-6 alkenyl group, which has the double bond (s) at any position and can be unsubstituted or substituted;
the term "alkynyl" can e.g. B. represent a C _2-10 alkynyl group, preferably a C _2-6 alkynyl group, which has the triple bond (s) at any point and can be unsubstituted or substituted;
the term "cycloalkyl" can e.g. B. represent an optionally substituted carbocycle with 3 to 20 carbon atoms, preferably with 5 to 15 carbon atoms and more preferably with 5 or 6 carbon atoms, which has no multiple bond in the carbocycle;
the term "cycloalkenyl" z. B. represent an optionally substituted carbocycle with 3 to 20 carbon atoms, preferably with 5 to 15 carbon atoms and more preferably with 5 or 6 carbon atoms, which has at least one double bond in the carbocycle;
the term "cycloalkynyl" can e.g. B. represent an optionally substituted carbocycle with 3 to 20 carbon atoms, preferably with 5 to 15 carbon atoms and more preferably with 9 or 10 carbon atoms, which has at least one triple bond in the carbocycle;
can the term "alkoxy" z. B. a group of the formula -O- alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-cycloal kenyl, -O-cycloalkynyl, -O-aryl,
can the expression "heteroaroyl" z. B. 5-6-membered heterocyclic aromatic heterocycles with 1, 2 or 3 hetero atoms such as. B. substituted (as defined below) pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imi dazole, oxazole, thiazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole , 1,2,5-oxadiazole, 1,2,5-thiadiazole, tetra zole, pyridine, pyrylium, thiapyrylium, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1, 3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, indole, coumarone, thionaphthene, carbazole, bibenzofuran, dibenzothiophene, 1H -Indazole, indoxazole, benzo [d] isothiazole, anthranil, benzimidazole, benzoxazole, benzothiazole, benzotriazole, quinoline, isoquinoline, benzopyrylium, thiabenzopyrylium, acri din, benzo [g] quinoline, benzo [g] isoquinoline, benzo [cinoline] noline, cinnoline, phthalazine, quinazoline, quinoxaline, phenazine, benzo [g] cinnoline, benzo [g] quinazoline, benzo [g] quinoxaline, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine , 1,8-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, 1,7-phenanthroline, 1,8-phenanthroline, 1,9-phenane throline, 1,10-phenanthroline, I. ndolizine, 4H-quinolizine, carolin, ergoline, purine, pteridine, alloxazine, flavin, mean;
the term "substituted" or substituent can be defined as follows: -H, -OH, -R _a , -O-alkyl, -O-aryl, -O-hetero aroyl, -O-heterocycle, -NH ₂ , -NO ₂ , -CN, -N ₃ , -CNR _a NR _b R _c , -NR _a R _b , NR _a R _b R _c ⁺ , fluorine, chlorine, bromine, a-, b-, to w-amino acid ester, - NR _a COR _b , -NR _a COXR _b (X = -O, -NR, -PO _0.2.3.4 R, -SO _0.1.2.4 R, -NR _a NR _b R _c ), -COR _a , -COOR _a , -OCOOR _a , -CONR _a R _b , -OCONR _a R _b , -NRCCONR _a R _b , -R _a -OR _b , -R _c -NR _a R _b , -R _a - SR _b , -R _a -SOR _b , -R _a -S (O) ₂ -R _b , -OR _a -OR _b , -NR _a R _b -OR _c , -SO ₂ R _a , -SO _{1.2 , 3,4} R _a -OR _b , -COR _a -OR _b , -COOR _a -OR _b , -OCOR _a -OR _b , -OCOOR _a -OR _b , -NR _b COR _a -OR _b , -CONR _a R _b -OR _c , -OCONR _a R _b -OR _c , -NR _c CONR _a R _b -OR _d , -NR _a COR _b -OR _c , -OR _a -SR _b , -NR _a R _b -SR _c , -SO1,2,3,4R _a -SR _b , -COR _a -SR _b , -OCOR _a -SR _b , -OCOR _a -SR _b , NR _a COR _b -SR _c , -CONR _a R _b -SR _c , -NR _a CONR _b R _c -SR _d , -OR _a -NR _b R _c , -NR _a R _b -NR _c R _d , -SO _1,2,3,4 R _b -NR _b R _c , -COR _a -NR _b R _c , -COOR _a -NR _b R _c , -OCOR _a -NR _b R _c , -OCOOR _a -NR _b R _c , -NR _a CONR _b R _c -NR _d , -NR _a COOR _b -NR _c R _d , -OCONR _a R _b -NR _c R _d , -NR _a CONR _b R _c -NHR _d , -NR _a COOR _b -NR _c R _d , -POOR _a OR _b , -NR _c POOR _a OR _b ,
where R _a , R _b , R _c and R _{d are} independently defined as above alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, heterocycle, ARalkyl, aralkenyl or perhaloalkyl and where R _a , R _b , R _c and R _d may be substituted, but the substituents of R _a , R _b , R _c and R _d are preferably unsubstituted;
the term "ring" can represent an aromatic, a cycloalkyl, cycloalkenyl, cycloalkynyl or heterocyclic ring.

The term "heterocyclic ring" or "heterocycle" can e.g. B. a cycloalkyl, cycloalkenyl, cycloalkynyl or aromatic ring, which in addition to carbon atoms 1, 2, Contains 3 or 4 N, S or O atoms, being 5- or 6-membered Some rings are preferred which contain 1 or 2 N atoms.

The compounds of the invention are a sequence Ugi reaction and oxidative phenol coupling synthesized. Isocyanides, with substituted benzaldehydes, with substituted benzoic acids and substituted primary Amines converted to the corresponding α-aminoacylamides and then with a suitable oxidizing agent Performs phenol coupling to the biarylene.

The Ugi reaction is based on the four component condensate tion (Isocyanide Chemistry, (I. Ugi, ed.), Wiley, New York, 1971; I. Ugi, R. Karl, in: Comprehensive Organic Synthesis), (B. M. Trost, C. H. Heathcock (ed.), Vol. II, 1083-1109, Pergamon Press, New York 1991). React in this reaction  the four starting components isocyanide, oxo compound (aldehydes or ketones), amine-like compounds (e.g. ammonia, pri mary amines, secondary amines, hydrazine and derivatives, Hy droxylamine and derivatives) and suitable acid components (e.g. carboxylic acids, carbonic acid monoesters, water, thiosul fat, selenium hydrogen, hydrochloric acid, cyan acid, thiocyanic acid) to uniform products whose zen trales basic structure essentially by the nature of the acid compo depends on. Remarkably, the remains of the individual components without loss of reactivity Limits can be varied. So react sterically demanding full or small, aromatic, heteroaromatic as well aliphatic or heterocyclic, electron-withdrawing or electron-donating educts equally in the Ugi Reak tion. Related isocyanide based MCR's are the Passerini reaction (I. Ugi in, Isocyanide Chemistry, (I. Ugi, ed.), Wiley, New York, 1971), and a number of He terocycle syntheses (S. Marcaccini, T. Torroba, OPPI, 143.).

For example, the amine component is reacted with the oxo component, the acid component and an appropriately substituted amine-protected isocyanoamine component. Advantageously, the equivalent of each of the four different components is put together and thus brought to reaction. The amine and the oxo components must also be precondensed to give Schiff's base. Aprotic polar such as non-polar and protic polar are suitable as solvents. There are especially protic and protic polar solvents such. B. alcohols such as water, methanol, ethanol, propanol, ethylene glycol, glycerol, trifluoroethanol and apro table polar solvents such as. B. pyridine, N-methylmor pholine, methylene chloride, chloroform, dimethylformamide, dimethyl sulfoxide, acetonitrile, ethylene glycol dimethyl ether or mixtures thereof, such as. B. ethylene glycol dimethyl ether / glycerol or the Schiffbasenbildung promoting Lö solvent such as trimethyl orthoformate. Acylation catalysts such as. B. pyridine or 4-dimethylaminopyridine prove to promote the reaction in the Ugi reaction. Lewis acids such as ZnCl ₂ , TiCl ₄ , ZrCp ₂ Cl ₂ etc. also prove to promote the reaction in the Ugi reaction. The reaction temperature can be -20 ° C and + 100 ° C, but preferably 10-40 ° C. The reaction time is seconds to several days depending on the reactivity of the components. The Ugi reaction is advantageously carried out in a concentrated manner, ie the concentrations of the individual components are 0.1 M to 4 M.

Oxidative phenol couplings are known per se, cf. e.g. B. Franck, B., Tietze, LF, Angewandte Chemie 1967, 79, 815f. Suitable oxidizing agents can be all common oxidizing agents, preferably FeCl ₃ , K ₃ [Fe (CN) ₆ ], hypervalent iodine compounds and their polymer-bound forms.

The new compounds of the invention and the fiction contemporary pharmaceutical composition can be used for therapy or prophylaxis of tumor or cancer diseases become. They can also be used as antibiotics.

They can be used locally or systemically. Systemic application means e.g. B. one in travenous, intrapleural, intraperitoneal, rectal or oral application or irrigation of body cavities and Bladder. Local application means e.g. B. the  subcutaneous, intracutaneous, intratumoral, peritumoral applications tion, e.g. B. in the form of solutions for injection, syringes for injection ions, creams, lotions, gels and ointments.

The active substances according to the invention have systemic and with local application a dose-dependent effect. The The dose of the active compounds according to the invention is therapeu use in the order of 0.1 to 100 mg / kg Body weight, preferably from 2 to 40 mg / kg body weight important. In individual cases, the dosage can be larger or less than specified above.

The active compounds according to the invention can be - according to the individual clinical picture - in one Formulation can be applied, such as plasters, ointments, Pa plasters, creams, soluble powders, emulsions, powders, suspensions and injection solutions.

The active compounds according to the invention can be exemplified in ei ner solution for injection with the help of Solubilizers in diluted physiologically acceptable Bases dissolved and more physiologically compatible by adding Acids in an injectable form from pH 6 to 8, ins special 6.9 to 7.5 are brought.

Exemplary physiologically compatible bases can Hy hydroxides, bicarbonates, carbonates of alkali and earth alkali metals, especially potassium, sodium and calcium his.  

Exemplary physiologically acceptable acids can Lactic acid, citric acid, tartaric acid, oxalic acid, malic acid, Acetic acid, formic acid, benzoic acid, salicylic acid, salt acid, sulfuric acid or phosphoric acid.

In the formulation of the active ingredients according to the invention - the can be used alone or in groups Auxiliaries are added. Such non-toxic and pharmaceutically suitable excipients can be solid, semi-solid or liquid carriers, emulsifying or dispersing be middle. The concentration of the active ingredient according to the invention substances is between 1 and 90 wt .-%, preferably 5 to 50% by weight.

The dosage units of the active substances according to the invention can consist of 1, 2, 3 or 4 single doo sen or 1/2, 1/3 or 1/4 of a single dose. A single Dose preferably contains the amount of active ingredient an application is administered and usually one whole, half or third or even one Quarter corresponds to a daily dose.

Creams, pastes, ointments and gels can be added to the or the Active substances customary carriers known to the person skilled in the art for example waxes, paraffins, starches, vegetable and tie Organic fats, cellulose derivatives, tragacanth, silica, valley cum, zinc oxide, bentonite, silicone, polyethylene glycol.

Sprays and powders can besides the active ingredient (s) che carriers known to the person skilled in the art, such as milk sugar, Talc, silica, aluminum hydroxide, calcium silicate or  Contain polyamide powder or mixtures thereof. Sprays can additional blowing agents, for example chlorofluorocarbon contain substances.

Suppositories can be customary in addition to the active ingredient (s) carriers known to the person skilled in the art, such as polyethylene glycols, Contain fats or mixtures thereof.

The present invention also relates to antibodies perkonjugate from one or more tumor-specific anti body and one or more active ingredient according to the invention fen, under tumor-specific physiological conditions the tumor environment or the tumor interior are split off can. These antibody conjugates can ver in liposomes be gripped.

Local application of the active ingredients according to the invention can done by micromachines.

The active compounds according to the invention can be better in order to achieve them rer locally relevant drug concentrations and esp be tolerated in liposomes.

So far for the treatment of the tumor disease or for that General condition of the patient or his relatives of Can be used simultaneously or with a time delay Combinations with other active ingredients that serve the patient be administered.

The present invention also includes the use of the described active ingredients and pharmaceutical preparation  conditions containing one or more active substances act of atypical tissues in humans and farm animals, the prevent the normal biological functions from running or to disturb.

Examples

1. 6,7-dihydro-2,10,11-trihydroxy-1,3-dimethoxy-7-oxo-N-6- bis (phenylmethyl) -5H-dibenz [c, e] azepine-5-carboxamide

[M + H] +. Found ISP-TOF-MS: 509.579 [M + H] +; 532.2932 [M + Na] +.

2. 6-Cyclopropyl-N- (1,1-dimethylethyl) -6,7-dihydro-2,10,11-trihydroxy-1,3-dimethoxy-7-oxo-H-dibenz [c, e] azepine 5-carboxamide

[M + H] +. Found ISP-TOF-MS: 425.501 [M + H] +; 447.481 [M + Na] +.

Claims (10)

1. Compounds of the general formula (I)
wherein the radicals R independently a hydroxy group, a hydrogen atom, a halogen atom, a pseudohalogen, a substituent, an optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl -, Cycloaralkyl-, Cycloaralkenyl- Cycloaralkinyl-, Aryl-, Alkoxy, or a he terocyclic ring, and
the radicals R 'and R ", independently of one another, are conventional radicals of the amine or isocyanide component of the Ugi reaction. 2. Compounds according to claim 1, characterized in that the radicals R independently of one another are an alkoxy or Hy droxy group, an amide, sulfonamide, a hydrogen atom, a Halogen atom or a pseudohalogen. 3. Compounds according to one of the preceding claims, since characterized in that the radicals R 'and R "independently  from each other a hydrogen atom, a substituted alkyl, or are a substituted aryl radical. 4. Pharmaceutical composition containing at least one Connection according to one of the preceding claims if in combination with conventional carriers and / or Contains adjuvants. 5. Pharmaceutical composition according to claim 4, which as Plasters, ointment, paste, cream, soluble powder, emulsion, Powder, suspension or solution for injection is formulated. 6. Pharmaceutical composition according to one of the claims 4 or 5, the at least one tumor-specific antibody contains. 7. Pharmaceutical composition according to one of the claims 4 to 6, wherein the active ingredients and optionally the tu morse-specific antibodies are packaged in liposomes. 8. Use of the compounds or pharmaceutical co Settings according to one of the preceding claims for The therapy or prophylaxis of gastrointestinal, immunological human, neurological, ocular, psychological, renal-urological respiratory disorders, cancer and tumors and Infections. 9. Use according to claim 8, characterized in that the tumor or cancerous diseases benign and malignant tumors solid or cystic in nature, adenomas, cyst adenomas, Papillomas, adenocarcinomas, cirrhosis adenocarcinomas  Type, basal cell carcinoma, sarcoma, fibrosarcoma, liposar coma, lymphosarcoma, rhabdomyosarcoma, myxosarcoma, chon drosarcomas, reticular sarcomas, Hodgkin's disease, embryonic Tumors, neuroblastomas, nephroblastomas, teratomas, adamintomas, Retroblastomas, haemangiomas, chordomas, odontomas, Craniopharyngomas, Hamartomas, Lymphoangiomas, Exostoses, New rofibrantosis, melanomas, lymphomas, hepatoblastomas, mammary caries zinoma, cervical carcinoma, choriocarcinoma, adenoacantoma, an droblastomas, leiomyomas, arrhenoblastomas, sertoli cell tumors, Theca and granulosa cell tumors, germinomas and seminomas, Ovarian and vulvar cancers, bladder and prostate cancers nome tumors caused by schistosomiasis, astro cytomas, ependymogliomas, glioblastomas, medulloblastomas, oli godendrogliomas, spongioblastomas, meningiomas, tumors of the Swan vaginal cells, pinealomas, hemangioblastomas, Osteoclastomas, Ewings tumors, multiple myelomas, mxcosis fungoides, Burkitt tumors, leukemia, acute and chronic lymphocytic leukemia, acute and chronic granulocytes leukemia, acute and chronic monocyte leukemia, strain Cell leukaemias, basaliomas, fibromas, fibroids, and those in egg Access to local injection during surgery metastases of all types of tumors. 10. Use according to one of claims 8 or 9, characterized characterized in that the compounds or pharmaceutical Compositions can be used locally or systemically.