NO854712L - NITROGEN DERIVATIVES OF OXO COMPOUNDS. - Google Patents

Description

The present invention relates to nitrogen derivatives of oxo compounds as well as their preparation, further pharmaceutical preparations containing such compounds and the use of the latter as pharmacologically active substances.

First and foremost, the present invention relates to compounds of the formula

where R^ and F^ independently of each other stand for hydrogen, lower alkyl or aryl or together mean lower alkylene,

one of the residues R^ and R^ stands for the group =N-R (Ia), where R is the group -O-R (Ib) and R stands for hydrogen, lower-

cl cl

alkyl, carboxyl lower alkyl or lower alkoxycarbonyl lower alkyl or R represents the group -N(R^)-R (Ic) and R and Rc independently represent hydrogen or lower alkyl or one of the residues R^ and Rc represents hydrogen and the other residue represents the group -C( =X)-R^, where X

stands for oxo and R^ stands for lower alkoxy, diloweralkylaminoloweralkyl, triloweralkylammonioloweralkyl, loweralkyleneaminoloweralkyl, oxalaverealkylammonioloweralkyl, thialaverealkyleneaminoloweralkyl, optionally with lower alkyl aza-substituted azaloweralkyleneaminoloweralkyl or pyridiniolaloweralkyl or X stands for oxo or thioxo and R^ stands for amino, or both residues R^ and R ^ together means lower alkyl, oxala lower alkyl, thiala lower alkyl or optionally with lower alkyl aza-substituted aza lower alkyl, and the other of the two residues R^ and R^ have the same meaning or stand for oxo and the ring A has no further substituents or is additionally substituted with lower alkyl , lower alkoxy and/or halogen,

as well as salts of such compounds with salt-forming properties.

Above and below, organic residues and compounds designated by "lower" contain up to and including 7, preferably up to and including 4, and primarily 1 or 2 carbon atoms. Lower alkylene residues preferably contain 4 or 5 carbon atoms.

Lower alkyl primarily means methyl and ethyl, but can

also stand for n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, further for n-pentyl, n-hexyl and n-heptyl.

Aryl is primarily monocyclic, carbocyclic aryl, e.g. optionally substituted phenyl, where the substituents can be, among other things, lower alkyl, lower alkoxy or halogen.

Lower oxy is in particular methoxy or ethoxy, further n-propoxy, isopropoxy, n-butoxy or isobutoxy and n-pentyloxy.

Halogen preferably means halogen with an atomic number on it

at most 35, i.e. fluorine, chlorine or bromine.

The lower alkylene is e.g. 1,4-butylene, 1,5-pentylene or 1,6-hexylene.

Carboxyl lower alkyl is primarily carboxymethyl and 2-carboxyethyl as well as 3-carboxy-n-propyl.

Lower oxycarbonyl lower alkyl is first and prepared methoxy- or ethoxycarbonylmethyl and 2-methoxy- or 2-ethoxycarbonylethyl.

Lower alkylaminolower alkyl is preferably dimethylamino-, diethylamino-, di-n-propylamino- or N-ethyl-N-methylamino-methyl and 2-dimethylaminoethyl.

Trilower alkylammonio lower alkyl is preferably N-di-ethyl-N-methylammonio- or trimethylammoniomethyl and 2-trimethylammonioethyl.

Lower alkylene amino lower alkyl is preferably 1-pyrrolidino-methyl, 2-(1-pyrrolidino)ethyl, 1-piperidinomethyl, 2-(1-piperidino)ethyl, 1-hexahydroazepinomethyl and 2-(1-hexahydroazepino)ethyl.

Oxalavereaalkyleneamino and thialaverealkyleneaminolower alkyl are preferably 4-morpholino- and 4-thiomorpholinomethyl as well as 2-(4-morpholino)- and 2-(4-thiomorpholino)-ethyl.

Optionally with lower alkyl aza-substituted aza lower alkylene amino lower alkyl is preferably 1-piperazinomethyl, 2-(1-piperazino)ethyl, 4-methyl- or 4-ethyl-1-piperazinomethyl as well as 4-methyl- or 4-ethyl-2-(1-piperazino) ) ethyl.

Pyridino lower alkyl ] is preferably pyridinomethyl and 2-pyridinoethyl.

Oxalaverealkylene and thialaverealkylene are in particular 3-oxa-1,5-pentylene and 3-thia-1,5-pentylene respectively.

Optionally with alverealkyl substituted azalaverealkylene

is e.g. 3-zaa-1,5-pentylene or 3-methyl-3-aza-1,5-pentylene.

Preferably, in the compounds of formula I, only one means

of the residues R^ and R4, primarily the residue R^, the group of formula Ia, while the other residue stands for oxo.

Salts of the compounds of formula I with salt-forming properties are primarily pharmaceutically usable salts, e.g. acid addition salts of compounds with basic groups, such as addition salts with inorganic acids, e.g. hydrochloric acid, sulfuric acid or phosphoric acid, or organic

acids, such as carboxylic or sulphonic acids, e.g. vinegar-,

maleic, fumaric, malic, oxalic, tartaric, citric, methanesulfonic or p-toluenesulfonic acid. Quaternary nitrogen compounds, where the residue R stands for trilower alkylammonio or pyridiniolower alkyl, are preferably available in the form of pharmaceutically usable quaternary salts, where e.g. the anion is derived from an inorganic acid, such as a hydrohalide acid, e.g. hydrochloric, hydrobromic or hydroiodic acid.

It is believed that the compounds of the present invention are "prodrugs" that inhibit the reverse transcriptase of an enzyme characteristic of retroviruses (or onconarviruses),

as RNS tumor and leukemia viruses; retroviruses require this enzyme for the natural replication cycle (Baltimore, Nature, vol. 226, p. 1209 (1970); and Temin and Mizutani,

Nature, vol. 226, p. 1211 (1970)).

The inhibitory effect on the reverse transcriptase and virus replication can be determined using in vivo assays. The compounds of formula I have in animal experiments certain neoplastic diseases, which are induced by RNS tumor viruses, or where RNS tumor viruses can be detected,

a strong business. They e.g. extend the average survival time of mice after infection with Rausch leukemia virus (RLV, an RNS tumor virus).

In the experiments with Rausch leukemia 4 Q (NIH), female mice of the strain Balb/c (28-34 days old) are infected with 0.2 ml of a 10-fold diluted (Hanks solution) virus suspension of splenic material from mice infected 4 - 6 weeks earlier.

In an experiment, 15 animals are treated either with the test compound or as a control group, with placebo continuously per

us. The first application takes place 30 minutes before the infection, further applications once a day and five times a week during four weeks. The criterion for the effect is the extension of the survival time. While in the control animals from 28 days after the infection it was possible to find

a leukemia with leukemic blood cells in an amount of more than 50,000/mm<3> and the animals began to die, the survival time of the female mice treated with 125 mg/kg p.o.

of the test substance significantly. It constitutes e.g. for 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-semi-carbazone by 20-fold p.o. administration to female mice of the strain balb/c in an amount of 12 5 mg/kg (10 animals per group) 53.5 days, compared to the survival time of the control animals of 26.0 days (p <^0.01 Cox test).

The pharmacological action of the compound according to the present invention is accompanied by good tolerability.

E.g. is the maximum tolerated dose for the above-mentioned 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-semicarbazone in mice at a single p.o.- and i.p. administration and subsequent 7-day observation period over. 2500 mg/kg.

The detection of diseases that are caused by retroviruses builds e.g. on the following observations: The detection of type C retroviruses and their formation by reverse transcriptase in humans occurs first in a T-cell leukemia; the virus is called human T-cell leukemia virus (HTLV-I).

In other T-cell leukemias and lymphomas, the same viruses and a similar retrovirus (HTLV-II) have been found (Gallo, "Cancer Surveys" (ed. Franks, Wyke and Weiss), vol. 3, pp. 113-160 (Oxford Univ. Press, 1984)). Finally, a similar virus has also been isolated in connection with AIDS (Acquired Immune Deficiency Syndrome) (Gottlieb et al., Morbid. Mortal. Weekly Rep., vol. 30, p. 25 (1981); Friedman-Kien et al. , Morbid. Mortal. Weekly Rep., vol. 30, p. 305 (1981); Gottlieb et al., New Engl. J. Med., vol. 305, p. 1425 (1981); Masur, New Engl. J . Med., vol. 305, p. 1431 (1981); Siegal et al., New Engl. J. Med., vol. 305, p. 1439 (1981); "CDC Task

Force on Kaspoi<1>s Sarcoma and Opportunistic Infections", New Engl. J. Med., vol. 306, p. 248 (1982)); this was designated HTLV-III (Essex et al., Science, vol. 220, p. 859 (1983), Gelmann et al., vol. 220, p. 862 (1983); Gallo et al., Science, vol. 220, p. 865 (1983); Gallo, "Cancer Surveys", vol. 3, p. 113 (1984); Barré-Sinoussi et al., Science, vol. 220, p. 868 (1983); Hirsch and Levy, "Viruses in Human Malignancy and AIDS", ASCO/AACR Symposium , May 1984, Toronto).

These retroviruses belonging to the HTLV family need the reverse transcriptase for the formation of a double-stranded DNA (provirus), which "integrates" into the cell genome and can lead to malignant transformation (Strayer and Gillespie,

"The Nature and Organization of Retroviral Genes in Animal Cells", Virology Monographs, vol. 17 (Springer Ed., 1980)).

While after the induction of malignant leukaemia, lymphatic or tumorous neoplasms caused by retroviruses a reduction of the reverse transcriptase can be demonstrated and the virus HTLV-I and -II and secondary oncogenes induced by these viruses control the replication of malignant cells, the virus HTLV-III and the reverse transcriptase in AIDS is not only detectable in the early stage, but throughout the course of the disease. The ongoing infection and dysfunction of immunocompetent T-helper cells eventually leads to a breakdown of the immune system with fatal outcome. It must be assumed that an inhibition of the reverse transcriptase and virus replication by positive enzyme and virus antigen detection (Beardsley, Nature, vol. 311, p. 195 (1984) in risk patients, e.g. homosexuals, can influence the disease process. In the induction of leukemia and lymphomas by retroviruses (HTLV-

I and HTLV-II), as well as possibly also in the sarcomas and mammary carcinomas induced by retroviruses, on the other hand, a prophylactic application should be possible, if a simple and widely applicable diagnostic treatment of such risk patients can be carried out. Also in the context of non-A and non-B hepatitis, the reverse transcriptase as a specific enzyme has been found together with virus particles (Seto et al., Lancet, p. 941 (1984)).

The compounds according to the present invention can therefore be used for prophylaxis and therapy in diseases where the reverse transcriptase is important, above all in malignant diseases which are caused by type C retroviruses or where these are a contributing cause, but also find use in certain immune diseases and autoimmune diseases. Tumor diseases primarily include leukaemia, lymphomas and lymphosarcomas caused by retroviruses, as well as osteosarcomas and mammary carcinomas. The compounds according to the invention are also particularly suitable for relapse prophylaxis after surgical therapy, radiation therapy and cytostatic or antimetabolic chemotherapy. AIDS can be mentioned as an immune disease, and systemic lupus erythematosus as an autoimmune disease, where, according to recent results, RNS tumor viruses also seem to play an important role (Dennman, Med., Biol., vol. 53,

pp. 61 (1975); Panem et al., New England J. Med., vol. 295, 470 (1976)).

The invention relates in particular to compounds of formula I where R^ stands for hydrogen or lower alkyl, R2 stands for hydrogen, lower alkyl or phenyl, one of the residues R^pg R^, preferably R^, stands for the group =N-R (Ia), where R stands for the group -O-R (Ib) and R stands for hydrogen, lower-a a

alkyl, carboxyl lower alkyl or lower alkoxycarbonyl lower alkyl or R represents the group -N(R^)-R (Ic) and R and Rc independently represent hydrogen or lower alkyl or one of the residues R^ and Rc represents hydrogen and the other residue represents the group -C(= X)-R^, where X stands for oxo and R^ for lower alkoxy, diloweralkylaminoloweralkyl, triloweralkylammonioloweralkyl, loweralkyleneaminoloweralkyl, 4-morpholinoloweralkyl, 4-loweralkyl-1-piperazineloweralkyl or pyridinolloweralkyl or X stands for oxo or thiooxo and R, amino, or both residues R and Rc together mean lower alkylene, 3-oxa-1,5-pentylene or 3-lower alkyl-3-aza-1,5-pentylene, and the other of the residues R^ and R^, preferably R^, stands for oxo , and the ring A has no additional substituents or is i

additionally substituted with lower alkyl, lower alkoxy or halogen, where residues denoted by "lower" preferably contain 1 or 2 carbon atoms, lower alkylene residues contain 4 or 5 carbon atoms, and halogen has an atomic number of at most 35, and salts, especially pharmaceutically usable salts , of such compounds with salt-forming properties.

The invention primarily relates to compounds of

mel I where R, stands for hydrogen or lower alkyl and R2

for lower alkyl or phenyl, R^ is a group of the formula =N-R (Ia), where R stands for the group -O-R a (Ib) and R is for lower alkyl, carboxyl lower alkyl or lower alkoxycarbonyl lower alkyl or R stands for the group -N(R^)- R

(Ic) one of the residues R^ and Rc stands for hydrogen and the other residue for the group -C(=X)-R^, where X stands for oxo or thioxo and R^ stands for amino, or both residues R^ and Rc together mean 3 -oxa-1,5-pentylene or 3-lower alkyl-3-aza-1,5-pentylene, and R^ stands for oxo, and the ring A has no further substituents, where residues denoted by "lower" preferably contain 1 or 2 carbon atoms, lower alkylene residues containing 4 or 5 carbon atoms, and salts, especially pharmaceutically useful salts, of such compounds with salt-forming properties.

The invention primarily relates to compounds of

mel I, where R^ stands for hydrogen or lower alkyl, e.g. methyl, and R2 stands for lower alkyl, e.g. methyl or phenyl,

R-j stands for the group =N-R (Ia) and R stands for the group -N(Rj3)-R (Ic), where one of the residues R^ and Rcer is hydrogen and the other residue is the group -C(=X)-R^( Id), where X stands for oxo and R^ stands for amino, where residues are denoted by "lower"

primarily contains one or two carbon atoms.

The compounds according to the present invention are produced

by methods known per se, e.g. by converting a compound of the formula

where one of the groups R and R stands for oxo and the other stands for oxo or the group =N-R (Ia), and R^ and R2 as well as the ring A in formula II and R in group Ia have the meanings indicated above, with a compound of the formula r^N-R (III), where R has the meaning given above, and,

if desired, transfers a manufactured compound into another compound according to the invention and/or, if desired, transfers to a manufactured salt to the free compound or to another salt or transfers a manufactured free compound with salt-forming groups to a salt.

Compounds of formula II are preferably used as starting materials where both residues R and R stand for oxo. The compounds of formula III can be used in free form or in the form of acid addition salts, such as salts with inorganic acids, e.g. hydrochloric or sulfuric acid, or organic acids.

The reaction is carried out in a manner known per se, preferably in the presence of a base, such as an alkali metal lower alkanoate, e.g. sodium acetate, and/or a preferably polar diluent, such as a lower alkanol, e.g. ethanol,

a cyclic ether, e.g. tetrahydrofuran or dioxane or an amide, e.g. dimethylformamide, under cooling, at room temperature or preferably by heating, e.g. to a temperature in the range from approx. 10°C to approx. 120°C, preferably 50°C to approx. 100°C, if necessary in a closed container under pressure and/or in an atmosphere of inert gas.

Made connections can be transferred to other connections

see according to the invention, e.g. compounds of formula I

with a group of formula -C(=X)-Rd(Id), where R^ represents a dilower alkylaminolower alkyl group, by treatment with a reactive ester of a lower alkanol such as a lower alkyl halide, e.g. -chloride, -bromide or -iodide, in compounds with a trilower alkylaminolower alkyl group R^.

Salts of compounds of formula I which can be prepared according to the invention can be transferred to the free compounds in a manner known per se, e.g. acid addition salts by treatment with a suitable base. Quaternary salts can e.g. by treatment with a suitable acid or an anion exchanger is transferred to another quaternary salt. Compounds of formula I with salt-forming properties can be transferred to the desired salts, e.g. by treatment with an acid or a suitable ion exchanger.

The starting materials of the formulas II and III used in the above process are known, or can, if they are new, be prepared by methods known per se.

The present invention further relates to pharmaceutical preparations which, as active substance, contain compounds according to the invention. The pharmaceutical preparations according to the invention are preparations for enteral use, such as oral or parenteral, e.g. i.v., i.m. or rectal administration. The preparations contain the active substance alone or preferably together with a pharmaceutical carrier material. The dosage of the active substance depends on the object of treatment, its age and individual condition, as well as on the method of administration.

The pharmaceutical preparations contain from approx. 5% to approx. 95% of the active substance, where single-dose delivery forms preferably show from approx. 20% to approx. 90% and non-single-dose delivery forms preferably exhibit approx. 5% to approx. 20% active ingredient.

Pharmaceutical preparations according to the invention in unit dose forms, such as dragées, tablets, capsules, suppositories or ampoules, contain from approx. 0.05 g to approx. 1.5 g, preferably from approx. 0.1 g to approx. 1.0 g of the active substance.

The pharmaceutical preparations according to the present invention are prepared in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. Pharmaceutical preparations for oral use can be obtained by mixing the active substance with one or more solid carriers, optionally granulating a prepared mixture and processing the mixture or granulate, if desired, possibly after the addition of additional excipients, into tablets or dragee cores.

Suitable carriers are especially fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starches, e.g. corn, wheat, rice or potato starch, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or, if desired, explosives, such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, as sodium alginate. Further aids are primarily flow regulators and lubricants, such as e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.

Dragon cores are equipped with suitable, possibly gastric juice-resistant, coatings, where, among other things, concentrated sugar solutions are used, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragee coatings may have added dyes or pigments, e.g. for identification or to

specify different doses of active substance.

Other oral pharmaceutical preparations that can be used are capsules made of gelatin, as well as soft, closed capsules made of gelatin and a plasticizer, such as glycerin or sorbitol. The stick capsules can contain the active substance in the form of a granule, e.g. in a mixture with fillers, such as corn starch, binders and/or lubricants, such as talc or magnesium stearate, and possibly stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, where stabilizers may be added.

Further oral delivery forms are e.g. syrups prepared in the usual way that contain the active substance, e.g. in suspended form and in a concentration of approx. 5%

to 20%, preferably approx. 10% or a similar concentration, such as measuring out 5 or 10 ml gives a suitable single dose. Furthermore, e.g. also powdery or liquid concentrates for preparing shake mixes, e.g. milkshake, considering. Such concentrates can also be packaged in single-dose quantities.

As rectally applicable pharmaceutical preparations, e.g. suppositories in consideration, these consist of a combination of the active substance with a suppository base.

As a suppository base material, e.g. natural or synthetic triglycerides, paraffins, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used, which consist of a combination of the active substance with a base mass; as base material comes e.g. liquid triglycerides, polyethylene glycols or para-

veneer on speech.

For parenteral administration, e.g. suspensions of compounds according to the present invention in consideration, as corresponding oily injection suspensions, where suitable lipophilic solvents or carriers are used, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglyceride, or you can also use aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilizers.

Liposome dispersions with compounds of formula I are particularly suitable for parenteral administration. The liposome dispersions are formed from at least two lipid components, e.g. phosphatidylserine and phosphatidylethanolamine or phosphatidylserine and phosphatidylcholine, which encapsulate the compounds (I).

For the preparation of the liposome dispersion, phosphatidylserine of natural origin with different or identical C-^-C^ Q-alkanoyl residues is suitable as the one lipid component, e.g. n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl, or C10-C20-alkenoyl residues, e.g. 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl, 6-cis-, 6-trans-, 9-cis-, 9-trans- or 11-cis-octadecenoyl or 9-cis-icosenoyl e.g. phosphatidylserine from ox brain, or synthetic f phosphatidylserine with identical C]_q~C2o~alkenoyl residues, e.g. sodium-1,2-di-(9-cis-octadekenoyl)-3-sn-phosphatidyl-(S)-serine, and as the second lipid component phosphatidylcholine of natural origin with different or identical C^Q-C^-alkanoyl residues, e.g. e.g. phosphatidylcholine from chicken eggs or soybean oil, synthetic phosphatidylcholine with identical C^Q-C^g-alkanoyl residues, e.g. dimyristoyl, distearoyl or dipalmitoyl phosphatidylcholine, or synthetic phosphatidylcholine with a C10-C20 alkanoyl and a C10-C20 alkenoyl residue, e.g. l-n-hexadecanoyl-2-(9-cis-octadecanoyl)-3-sn-phosphatidylcholine

The liposome dispersion can be prepared by, for example, preparing a lyophilisate of the lipid components and compound (I) according to the method described in German explanatory document 28 18 655, preferably after dissolving the lipid component and the active substance in tert-butanol,

and removing the solvent at temperatures below -20°C, and dispersing this lyophilisate in an isotonic buffer solution. The dispersion takes place by shaking (Vortex mixer) or stirring the aqueous phase. The liposome dispersion can then be enriched by centrifugation and/or gel filtration or separated by extrusion through a straight-pore filter.

This method is suitable when lipophilic, or in organic solvents such as tert-butanol, soluble compounds (I). In the case of water-soluble compounds (I), a lyophilisate is prepared only of the lipid component and this is dispersed in an aqueous phase containing the dissolved compound (I).

The invention further relates to a method for treating diseases where, as mentioned above, the reverse transcriptase is important, characterized by adding a prophylactically or therapeutically effective amount of a compound according to the invention. In this way, one primarily uses the above-mentioned pharmaceutical preparations where one adds a warm-blooded individual of approx. 70 kg body weight a daily dose of approx. 0.1 g to approx. 5 g, preferably approx. 0.5 g to approx. 1.5 g of a compound according to the present invention.

The following examples illustrate the present invention; the temperatures are given in °C.

Example 1

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1. 2- b] pyran- 5, 6- dione- 6-semicarbazone

A solution of 6.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-1,2-b]pyran-5,6-dione (6-lapacone) in 200 ml of a 1:1- mixture of ethanol and water is prepared by heating to 70° and the solution is mixed with 2.03 g of sodium acetate and 2.76 g of semicarbazide hydrogen chloride. The yellow suspension that forms is stirred for 3 hours at 80°, cooled to 10° and filtered. The filter residue is washed with 100 ml of water and in 100 ml of acetone,

in which it is only partially soluble, boil and mix

the thing is filtered. The title connection obtained from file-

the funnel melts at 249-253° (on decomposition). A further quantity of the desired compound is not dissol-

equal to the specified amount of acetone and is found in the filter residue. Additional material can be recovered from the mother liquor.

Example 2 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-thiosemicarbazone

A mixture of 15 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]-pyran-5,6-dione (6-lapacon), 15.8 g of thiosemicarbazide and 15.8 g of sodium acetate in 500 ml of a 1:1 mixture of ethanol and water is heated for 4 hours under reflux and cooled there-

after to room temperature. The reddish precipitate is filtered off, the residue is washed with water, dried for 16 hours at 70° under reduced pressure and then recrystallized from 3000 ml of acetone under evaporation to half the volume and washed with diethyl ether. The title compound produced melts at 249-250°. A further quantity of the desired pro-

the duct can be isolated from the mother liquor.

Example 3

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2- b] pyran- 5, 6- dione- 6-( 2- dimethylaminoacetylhydrazone)- hydrogen chloride

A suspension of 7.2 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-fl , 2-b ]pyran-5 , 6-dione (6-lapacone) and 6.1 g of N,N- dimethylglycine-hydrazide-hydrogen chloride id in 70 ml of acetic acid is heated for 10 minutes to a bath temperature of 100°. The solvent is removed under reduced pressure, and the residue is dissolved in hot dimethylformamide. On cooling, an orange-red, crystalline precipitate forms, which is dried at 90° under high vacuum.

In this way, the title compound is obtained which melts

at 185° (during decomposition).

Example 4

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2- b] pyran- 5, 6- dione- 6-( 2- trimethylammonioacetylhydrazone)- chloride

A mixture of 7.2 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]-pyran-5,6-dione (6-lapacone) and 6.72 g of trimethylammonioacetyl hydrazide -chloride in 50 ml of acetic acid is heated for 10 minutes to 100° and then evaporated to dryness under reduced pressure. The oily product produced is crystallized by repeated treatment with 1,2-dimethoxyethane. The crystalline material is filtered off, dissolved in ethanol and the solution is diluted with the same amount of acetic acid ethyl ester. On cooling to 0°, the title compound is formed in the form of an orange-coloured, crystalline precipitate, which melts at 210° (during decomposition).

Example 5

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2- b] pyran- 5, 6-dione- 6-( 2- pyridinedioacetylhydrazone)- chloride

A suspension of 7.2 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]-pyran-5,6-dione (6-lapacone) and 7.5 g of 1-( 2-hydrazino-2-oxo-ethyl)-pyridine dichloride in 50 ml of acetic acid is heated for 10 minutes to 100° and then evaporated to dryness under reduced pressure. The oily product produced is crystallized by repeated treatment with 1,2-dimethoxyethane. The crystalline material is filtered off and crystallized from isopropanol and then from acetonitrile. The title compound produced is obtained in the form of sesquihydrate and decomposes at 225°.

Example 6

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2-b] pyran- 5, 6- dione-6- oxime

A solution of 2.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-1,2-b]pyran-5,6-dione (6-lapacon) in 125 ml of ethanol and 4.2 ml triethylamine is mixed with 1.73 g of hydroxylamine hydrogen chloride. The reaction solution is stirred for 6 hours at 25°C and cooled to 5°. The crystals are filtered off, washed with water and dried. The title compound produced has a melting point of 169-171°.

Example 7

2, 2- dimethyl- 3, 4- dihydro- 2N- naphtho[ 1, 2-b] pyran- 5, 6-dione-6- methoxy

A solution of 2.49 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-fl,2-b]pyran-5,6-dione (6-lapacon) in 155 ml of ethanol and 21 ml of water is mixed with 4.22 g of sodium acetate and 4.3 g of methylhydroxylamine hydrogen chloride. The reaction solution is heated for 4 hours under reflux and cooled to 5°. The crystals are filtered off, washed with water, dried and recrystallized from heptane. The title compound obtained has a melting point of 79-80°.

Example 8

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2-b] pyran- 5, 6- quinone-6- ethoxime

A solution of 2.49 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-1,2-b]pyan-5,6-dione (6-lapacon) in 150 ml of ethanol and 20 ml of water is mixed with 4.22 g of sodium acetate and 5.0 g of ethyl hydroxylamine hydrogen chloride. The reaction solution is heated for 4 hours under reflux and then evaporated to dryness. The residue is dissolved in methylene chloride and the organic phase is washed twice with water. The organic phase is dried, evaporated to dryness and the residue crystallized from hexane. The title compound obtained melts at 72-73°.

Example 9

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2-b] pyran- 5, 6-dione- 6-ethoxycarbonylmethyl oxime

A solution of 2.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b]pyran-5,6-dione (B-lapacon) in 1000 ml of ethanol is mixed with 10 g of O -carboxymethylhydroxylamine hemihydrogen chloride and stirred for 2 hours at room temperature, whereby the solution turns orange to yellow. The solution is evaporated to dryness, the residue is dissolved in methylene chloride and washed twice with sodium bicarbonate solution. The organic phase is then washed twice with dilute HCl and once with water, dried and evaporated. From the residue crystallized from ether/petroleum ether, the title compound is obtained in the form of yellow needles, melting point 93-95°.

Example 10

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2-b] pyran- 5, 6- dione- 6- carboxynrethyl oxime

A solution of 1.56 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-fl,2-b]pyran-5,6-dione (B-lapacon) in 30 ml of THF is mixed with 0.78 g O-carboxymethylhydroxylamine hemihydrogen chloride, dissolved in 8 ml THF-P^O (1:1), and stirred for 8 hours at room temperature. The solution is evaporated to dryness, the residue is dissolved in methanolic chloride and washed twice with dilute HCl and once with E2 O. The organic phase is dried and evaporated. The residue is slurried in 120 ml of hot ether and heated under reflux, whereby the title compound is obtained as yellow crystals with a melting point of 165-167°.

Example 11

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2-b] pyran- 5, 6-dione- 6-carboxymethyloxime- sodium salt 1 g 2,2-dimethyl-3,4-dihydro-2H -naphtho[1,2-b]pyran-5,6-dione-6-(carboxymethyl)-oxime is dissolved in approx. 20 ml of dioxane and mix with an equimolar amount of IN caustic soda. The clear solution is freeze-dried, whereby the title compound is obtained as a yellow powder.

Example 12

2, 2- dimethyl- 3, 4- dihydro- 2H- naphtho[ 1, 2-b] pyran- 5, 6-dione-6- ethoxycarbonylhydrazone

A solution of 2.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-fl , 2-b ]pyran-5 , 6-dione (B-lapacon) in 100 ml of ethanol and 20

ml of water is mixed with 0.75 g of sodium acetate and 4.8 g of hydrazine-carbonic acid ethyl ester and heated for 50 hours under reflux. The reaction mixture is evaporated, the residue is dissolved in methylene chloride and washed twice with water. The organic phase is dried, evaporated and the residue is chromatographed on 100 g of silica gel. The title compound is obtained in the form of yellow crystals with a melting point of 90-95°.

Example 13

Tablets containing 500 mg of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-semicarbazone can be prepared as follows:

Composition (for 10,000 tablets):

The active ingredient is moistened uniformly with paste of wheat starch, which is produced by stirring 500 g of wheat starch for approx. 1300 ml of demineralized water, and with a further 600 ml of demineralized water, are crushed to a weak plastic mass and run through a sieve with a mesh size of approx. 3 mm. The granulate is then dried and driven through the sieve again. The dried granulate which has been brought to a uniform grain size is mixed with the magnesium stearate, the stearic acid, the talc and the rest of the wheat starch, and the resulting mixture is pressed into tablets.

Example 14

A 10% suspension containing 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-semicarbazone can be prepared as follows:

Composition (for 5000 ml):

A suspension of the active substance in 250 g of propylene glycol and 1250 ml of demineralized water is ground in a colloid mill. The fine suspension, with an average particle size for the active substance of less than 10 µm, is dispersed in a solution of the hydroxypropylmethylcellulose, citric acid and saccharin sodium in 1250 ml of demineralized water and in the sorbitol solution. While stirring, a solution of the 4-hydroxybenzoic acid methyl ester and the 4-hydroxybenzoic acid propyl ester in 250 g of propylene glycol and raspberry aroma is added to this suspension. After adding demineralized water to a volume of 5000 ml, a suspension containing 500 mg of active substance in 5 ml is obtained.

Example 15

Capsules, each containing 300 mg of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-semicarbazone, can be prepared as follows:

Composition (for 10,000 capsules):

The active substance is mixed with the magnesium stearate and a quantity of 0.31 g of the mixture is filled by means of an encapsulation machine into hard gelatin capsules.

Example 16

An aqueous injection suspension (tor intramuscular administration) containing 1.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-fl ,2-b]pyran-5,6-dione-6-semicarbazone per 5 ml can be prepared as follows:

Suspension medium:

The sterile active substance 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-semicarbazone is processed under antimicrobial conditions with the suspension medium in such a way that one obtains a sterile suspension containing 1.0 g of active substance in 5 ml.

Example 17

An aqueous injection suspension (for intramuscular administration) containing 0.75 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-fl , 2-b ]pyran-5 , 6-dione-6-semicarbazone per 5 ml can be prepared as follows:

Suspension medium:

The sterile active substance is processed under antimicrobial conditions with the suspension medium in such a way that a sterile suspension containing 0.75 g of active substance in 5 ml is obtained.

Claims (9)

1. Process for the preparation of compounds of formula (I) where R, and R2 independently of each other stand for hydrogen, lower alkyl or aryl or together stand for lower alkylene, one of the residues R^ and R4 stands for the group =N-R (Ia), where R stands for the group -O-R cl (Ib) and Rcl stands for hydrogen, lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl lower alkyl or R stands for the group -N(R^)-Rc (Ic) and Rb and Rc stand independently of each other for hydrogen or lower alkyl or one of the residues Rfa and Rc stands for hydrogen and the other the rest represents the group -C(=X)-R^ , where X stands for oxo and R^ for lower alkoxy, dilower alkylaminolower alkyl, trilower alkylammoniolower alkyl, lower alkyleneaminolower alkyl, oxalaverealkyleneammoniolower alkyl, thialaverealkyleneaminoloweralkyl, optionally with loweralkyl aza-substituted azaloweralkyleneaminoloweralkyl or pyridinolaverealkyl or X stands for oxo or thio and R^ for amino, or both residues R^ and Rc together stand for lower alkylene, oxalave alkylene, thia lower alkylene or optionally with lower alkyl aza-substituted azalower alkylene, and the other of the residues R^ and R^ has the same meaning or means oxo and the ring A contains no further substituents or additionally substituted with lower alkyl, lower alkoxy and/or halogen, as well as salts of such compounds with salt-forming properties, characterized by reacting a compound of the formula where one of the groups R and R stands for oxo and the other stands for oxo or the group =N-R (Ia), and R^ and R^ as well as the ring A in formula II and R in group Ia have the meanings indicated above, with a compound of the formula r^ N-R (III), where R has the above meaning, and if desired, transfers a prepared compound to another compound according to the invention and/or, if desired, transfers a prepared salt to the free compound or to another salt or transfers a produced free compound with salt-forming groups to a salt. 2. Process according to claim 1 for the preparation of compounds of formula I, where R^ stands for hydrogen or lower alkyl, R^ for hydrogen, lower alkyl or phenyl, one of the residues R^ and R^ stands for the group =N-R (Ia), where R stands for the group -O-R (Ib) and R stands for hydrogen, lower- a a alkyl, carboxyl lower alkyl or lower alkoxycarbonyl lower alkyl or R stands for the group -N(R^)-R (Ic) and Rk and Rc independently mean hydrogen or lower alkyl or one of the residues R^ and Rc stands for hydrogen and the other residue for the group - C{~ X)- R^, where X stands for oxo and R^ for lower alkoxy, diloweralkylaminoloweralkyl, triloweralkylammonioloweralkyl, loweralkyleneaminoloweralkyl, 4-morpholinoloweralkyl, 4-loweralkyl-1-piperazinoloweralkyl or pyridinolloweralkyl or X stands for oxo or thioxo and R^ for amino, or both residues R^ and Rc together mean lower alkylene, 3-oxa-1,5-pentylene or 3-lower alkyl-3-aza-1,5-pentylene, and the other of the residues R-, and R4 stands for oxo , and the ring A contains no additional substituents or is additionally substituted with lower alkyl, lower alkoxy, or halogen, where residues denoted by "lower" contain 1 or 2 carbon atoms, lower alkylene residues contain 4 or 5 carbon atoms, and halogen has an atom number of no more than 35, and pharmaceutically usable salts of such compounds with salt-forming properties, characterized by reacting a compound (II) where R x and ^ R stand for oxo with a correspondingly substituted compound (III). 3. Method according to claim 1 for the preparation of compounds of formula (I), where R^ stands for hydrogen or lower alkyl and R2 for lower alkyl or phenyl, R^ stands for a group of the formula =N-R (Ia), where R is the group -O-R a (Ib) and R 3. are lower alkyl, carboxyl lower alkyl or lower alkoxycarbonyl lower alkyl or R is the group -N(Rj _) )-R (Ic), one of the residues Rfa and Rc is hydrogen and the other residue is the group -C(=X)- R^ , where X is oxo or thioxo and R^ is amino, or both residues R^ and Rc together represent lower alkylene, 3-oxa-1,5-pentylene or 3-lower alkyl-3-aza-1,5-pentylene , and R4 stands for oxo, where residues denoted by "lower" contain 1 or 2 carbon atoms, lower alkylene residues contain 4 or 5 carbon atoms, and pharmaceutically usable salts of such compounds with salt-forming properties, characterized by reacting a compound (II) , where R^ and R y stand for oxo, with a correspondingly substituted compound (III) . 4. Process according to claim 1 for the preparation of compounds of formula (I), where R^ stands for hydrogen or methyl, and R^ stands for methyl or phenyl, R^ is the group =N-R (Ia) and R is the group -NfR^-R (Ic), where one of the residues R^ and Rc is hydrogen and the other residue is the group -C(=X)-R^ (I d), where X stands for oxo and R^ for amino, where residues denoted by "lower" primarily contain one, but also two carbon atoms, characterized by reacting a compound (II), where R x and R Y stand for oxo, with a correspondingly substituted compound (III). 5. Process for the preparation of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-semicarbazone according to claim 1, characterized in that 6 -lapakone is reacted with semicarbazide -hydrogen chloride. 6. Process for the production of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-thiosemicarbazone according to claim 1, characterized in that 6-lapazone is reacted with thiosemicarbazide. 7. Process for the production of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-(2-dimethylaminoacetyl-hydrazone) and salts thereof according to claim 1, characterized by reacting 6-lapakone with N,N-dimethylglycine hydrazide. 8. Process for the production of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6-(2-trimethylammonioacetyl-hydrazone) according to claim 1, characterized in that 6-lapakone is reacted with trimethylammonioacetylhydrazine hydrogen chloride. 9. Process for the preparation of 2,2-dimethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione-6(2-pyridinioacetylhydrazone) according to claim 1, characterized in that one reacts 6 -lapakone with 1-(2-hydrazino-2-oxoethyl)-pyridine chloride.