MC1710A1 - NITROGEN COMPOUNDS OF OXO DERIVATIVES - Google Patents

Description

1

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

Firstly, the invention relates to compounds of formula

1(1 *

I to II I ^ / \ / \

k,1

ri" ^rz

(I),

where R1 and R2' independently represent a hydrogen, a lower alkyl, or an aryl, or, taken together, a lower alkylene; one of the radicals R3 and R4 represents the group =N-R(la), where R represents the group -O-Ra(Ib) and Ra represents a hydrogen, a lower alkyl, a lower carboxyalkyl, or a lower alkoxycarbonyl-lower alkyl; or R represents the group -l(Rb)-Rc(le), and Rb and Rc independently represent a hydrogen or a lower alkyl; or one of the radicals Rb and Rc represents a hydrogen and the other radical represents the group -C(=X)-Rd, where X represents an oxo and Rd represents a lower alkyl, a lower dialcoyl-lower aminoalkyl, a lower trialcoyl-lower ammonioalkyl, or a lower alkylene-aminoalkyl lower, a lower oxaal-coylene-lower ammonio-alcohol, a lower thiaalcoylene-lower amino-alcohol, a lower azaalcoylene-lower amino-alcohol possibly substituted at aza by a lower alkyl or a lower pyridinio-alcohol

20 or X represents an oxo or a thioxo and Rd represents an amino, or the two radicals Rb and Rc taken together represent a lower alkoylene, a lower oxaalkoylene, a lower thiaalkoylene or a lower azaalkoylene possibly substituted in aza by a lower alkoylene, and the other of the two radicals R3 and R4 has the same meanings or represents an oxo and 25 the nucleus A has no other substituents or is further substituted by one or more substituents selected from lower alkoylenes, lower alkoxys and halogens, as well as salts of such compounds having salifying properties.

2

Above and below, the radicals and organic compounds designated as "lower" contain up to and including 7 carbon atoms, preferably up to and including 4, and primarily 1 or 2. Lower alkoylene radicals preferably contain 4 or 5 carbon atoms.

5. Lower alkyl groups primarily represent methyl and ethyl groups,

but can also represent n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, or even n-pentyl, n-hexyl and n-heptyl.

Aryl is primarily a monocyclic aryl, carbocyclic, e.g. a phenyl possibly substituted, and the substituents may be ^ among others lower alkyl, lower alkoxy or halogen.

In particular, lower alkoxy is methoxy or ethoxy, or n-propoxy, isopropoxy, n-butoxy or isobutoxy, as well as n-pentyloxy.

Halogen preferably represents a halogen having an atomic number of at most 35, i.e. fluorine, chlorine or bromine. 15 Lower alkoxylene is e.g. 1,4-butylene, 1,5-pentylene or 1,6-hexylene.

Inferior carboxyalkyl is primarily carboxymethyl and 2-carboxyethyl as well as 3-carboxy-n-propyl.

Lower alkoxy-lower carbonyl alcohol is primarily 20-methoxy- or ethoxycarbonylmethyl and 2-methoxy- or 2-ethoxycarbonylethyl.

Lower dialcoyl-lower aminoalcoyl is preferably dimethylamino-, diethylamino-, di-n-propylamino- or N-ethyl-IM-methylamino-methyl and 2-dimethylaminoethyl.

Lower trialcoyl ammoniacyl is preferably 25l-diethyl-N-methyl-ammonio- or trimethylammoniomethyl and 2-trimethylammonio-ethyl.

Lower amino alcohols are preferably 1-pyrrolidinomethyl, 2-(1-pyrrolidino)ethyl, 1-piperidinomethyl, 2-(1-piperidino)ethyl, 1-hexahydroazepinomethyl, and 2-(1-hexahydroazepino)ethyl. Lower amino alcohols are preferably 4-morpholino- and 4-thiomorpholinomethyl, as well as 2-(4-morpholino)- and 2-(4-thiomorpholino)ethyl.

Azaalcoylene lower aminoalcoyl possibly substituted in aza by a lower alcoyl is preferably 1-piperazino-35 methyl, 2-(1-piperazino)ethyl, 4-methyl- or 4-ethyl-1-piperazinomethyl as well as 4-methyl- or 4-ethyl-2-(1-piperazino)ethyl.

I

3

Lower pyridinioalkoyl is preferably pyridiniomethyl and 2-pyridinioethyl.

Lower oxaalcoylene and lower thiaalcoylene are in particular 3-oxa-1,5-pentylene or, depending on the case, 3-thia-1,5-pentylene. Lower azaalcoylene, possibly substituted by a lower alkyl, is e.g. 3-aza-1,5-pentylene or 3-methyl-3-aza-1,5-pentylene.

Preferably, in compounds of formula I, only one of the radicals R3 and R4, primarily the radical R3, represents the group of formula la, while the other represents an oxo.

10

Salts of compounds of formula I having salificating properties are first and foremost pharmaceutically acceptable salts, p.

e.g., acid addition salts of such compounds with basic groups, such as addition salts with inorganic acids, e.g., hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids,

15

such as carboxylic or sulfonic acids, e.g., acetic, maleic, fumaric, malic, oxalic, tartaric, citric, methanesulfonic, or p-toluenesulfonic acids. Quaternary nitrogen compounds where the Rd radical represents a lower trialcoyl-ammonium or lower pyridinioalkoyl are preferably in the form of pharmaceutical quaternary salts.

20 (

acceptable, where e.g. the anion is derived from an inorganic acid, such as a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid.

It is assumed that the compounds of the invention are drug precursors for the inhibition of reverse transcriptase, a characteristic enzyme.

OC

than retroviruses (or onconarviruses), such as tumor and leukemia RNA viruses; retroviruses need this enzyme for their natural replication cycle (Baltimore, Nature, Vol. 226, p.1209 (1970); and Temin and Mizutani, Nature, Vol. 226, p. 1211 (1970)).

□The inhibitory action on reverse transcriptase 30 and viral replication can be established using in vivo experimental devices. Thus, compounds of formula I exhibit high efficacy in animal experiments in certain neoplastic diseases caused by RNA tumor viruses, or where ARIM tumor viruses can be detected. For example, they prolong the average survival time of mice 35 after infection with Rausch leukemia virus (RLV, RNA tumor virus).

4

In experiments with Rausch leukemia 4 Q (NIH), Balb/c mice (aged 20 to 34 days) are infected with 0.2 ml of a ten-fold diluted viral suspension (Hank's solution) made from spleen material of mice infected 4 to 6 weeks earlier. In one experiment, 15 animals are treated every 5 times with either the experimental compound or, as controls, with a placebo, continuously by oral administration. The first administration is given 30 minutes before infection, with subsequent administrations once daily and 5 times weekly for 4 weeks. The criterion for efficacy is the prolongation of survival time. While in control animals, leukemia with leukemic blood cells exceeding 50 OOD/mm3 can be found as early as 28 days after infection, and the animals begin to die, the... The survival time of female mice treated with 125 mg/kg p. o. of the experimental substance is significantly increased. For example, for 2,2-dimethyl-3,4-dihydra-2H-naphthoZT,2-^^pyran-5,6-dione-6-semicarbazone with 20 p. o. administrations to female Balb/c mice of 125 mg/kg each time (10 animals per group) is 53.5 days, compared with the survival time of 26.0 days of the control animals (P < 0.01 Cox test).

The pharmacological efficacy of the compounds of the invention is accompanied by good compatibility. Thus, the maximum tolerated dose for the 2,2-dimethyl-3,4-dihydro-2H-naphthoZT12-b7pyrane-5,6-dione-6-semicarbazone mentioned above in mice is high after oral and intraperitoneal administration.

then an observation period of 7 days at more than 2500 mg/kg.

The identification of diseases caused by retroviruses is based, for example, on the following discoveries: the identification of type C retroviruses and their reverse transcriptase formation in humans first occurred in a T-cell leukemia; the virus was named "Human T-cell leukemia virus" (HTLV-I). It has also been identified in other T-cell leukemias and lymphomas.

'n we found the same viruses and an analogous retrovirus (HTLV-II)(Gallo, Cancer Surveys (Dir. publ. Franks, LJyke and LJeiss), Vol. 3, p. 113-160 (Dxford Univ.

Press, 1984). Finally, a virus of this type has also been isolated in connection with AIDS (Acquired Immunodeficiency Syndrome) (Gottlieb et al., Morbid. Mortal. ileekly Rep., Vol. 30, p. 25, (1981); Friedman-Kien et al., Morbid.

;r

Deadly. UJeekly Rep., Vol. 30, p. 305 (1981); Gottlieb et al., New Engl. J.Med.,

5

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 Tosk Force on Kaspoi's Sarcoma and Opportunistic Infections, New Engl. J. Med., Vol. 306, p. 248 (1982)); this one has been described as HTLV-III (Essex et al., Science, Vol. 220, p.

5,859 (1983), Gelmann et al., Vol. 220, p. 862 (1983); Gallo et al., Science,

Flight. 220, p. 865 (1983); Gallo, Cancer Surveys, Vol. 3 p. 113 (1984); Barré-Sinoussi et al., Science Vol. 220, 868 (1983); Hirsch and Levy, Viruses in Human Malignancy and AIDS, ASCO/AACR Symposium, May 1984, Toronto).

These retroviruses belonging to the HTLV family require the

10

reverse transcriptase for the formation of double-stranded DNA (provirus),

which is "integrated" into the cell's 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 retroviruses induce leukemic, lymphatic, or malignant tumors, leading to a decrease in reverse transcriptase and HTLV-I and -II viruses, and the secondary oncogenes induced by these viruses direct the replication of malignant cells, HTLV-III virus and reverse transcriptase can be detected in AIDS not only in the early stages but also throughout the entire course of the disease. The developing infection and the destruction of immunocompetent T helper cell function ultimately lead to immune system collapse with a fatal outcome. It must be admitted that inhibition of reverse transcriptase and viral replication in the positive detection of the enzymatic and viral antigen (Beardsley, Nature, 25 Vol. 311, p. 195 (1984)) influences the course of the disease in at-risk patients, e.g., homosexuals. In the induction of leukemias and lymphomas by retroviruses (HTLV-I and HTLV-II), as well as possibly also in retrovirus-induced sarcomas or breast carcinomas, a prophylactic application should, on the other hand, be possible, insofar as one can assume easy and widespread diagnostic identification of these at-risk patients.

□n has also found in connection with non-A and non-B hepatitis reverse transcriptase as a specific enzyme in association with viral particles (Seto et al., Lancet, p. 941 (1984)).

Therefore, the compounds in this application can be applied to the prophylaxis and treatment of diseases where reverse transcriptase is present.

6

is important, especially for malignant diseases caused or co-caused by type C retroviruses, but also for certain immune and autoimmune diseases. Among tumor diseases, leukemias, lymphomas, and lymphosarcomas caused by retroviruses should be mentioned first, as well as osteosarcomas and breast carcinomas. The compounds of the invention are also particularly suitable for prophylaxis of recurrence after surgical treatment, radiation therapy, or cytostatic or antimetabolic chemotherapy. AIDS can be mentioned as an immune disease, and systemic lupus erythematosus as an autoimmune disease, where, according to new discoveries, tumor RNA viruses also appear to play an important role (Dennman, Med. Biol., Vol. 53, p. 61 (1975); Panem et al., New England J. Med., Vol. 295, 470 (1976)).

The invention relates in particular to compounds of formula I where R1 represents a hydrogen or a lower alkyl group, R2 represents a hydrogen, a lower alkyl group, or a phenyl group, one of the radicals R3 and R4, preferably R3, represents the =N-R group (Ia), where R represents the -ORa group (Ib) and Ra represents a hydrogen, a lower alkyl group, a lower carboxy-alkyl group, or a lower alkoxycarbonyl-lower alkyl group, or R represents the -N(Rb)-Rc group (Ie), and Rb and Rc independently represent a hydrogen or a lower alkyl group, or one of the radicals Rb and Rc represents a hydrogen group and the other radical the -C(=X)-Rd group, where X represents an oxo group and Rd represents a lower alkyl group, a lower dialcoyl-lower amino-alkyl group, a lower trialcoyl-lower ammonio-alkyl group, or an alkoylene group. lower-aminoalkoyl, a lower 4-morpholinoalkoyl, a lower 4-alkoyl-1-piperazinoalkoyl or a lower pyridinioalkoyl, or X represents an oxo or a thioxo and Rd represents an amino,

or the two radicals Rb and Rc taken together represent a lower alkoylene, a 3-oxa-1,5-pentylene or a lower 3-alkoyl-3-aza-1,5-pentylene, and the other of the two radicals R3 and R4, preferably R4, represents an oxo, 3q and the A nucleus has no other substituents or is further substituted by one or more substituents selected from lower alkoylene, lower alkoxy or halogen, and the radicals described known as "lower" preferably contain 1 or 2 carbon atoms, the lower alkoylene radicals contain 4 or 5 carbon atoms, and halogen has an atomic number of at most 35, and the salts, especially the 35 pharmaceutically acceptable salts, of such compounds having salifying properties.

7

The invention relates primarily to compounds of formula I where R1 represents a hydrogen or a lower alkyl group and R2 represents a lower alkyl group or a phenyl group, R3 represents a group of formula =N-R (Ia), where R represents the -O-Ra group (Ib) and Ra represents a lower alkyl group, a lower carboxyalkyl group, or a lower alkoxycarbonyl-lower alkyl group, or R represents the -i\](Rb)-Rc group (Ie), one of the radicals Rb and Rc represents a hydrogen group and the other radical represents the -C(=X)-Rd group, where X represents an oxo or thioxo group and Rd represents an amino group, or the two radicals Rb and Rc taken together represent a lower alkyl group, a 3-oxa-1,5-pentylene group, or a lower 3-alkyl-3-aza-1,5-pentylene group, and R4 represents an oxo group, and the nucleus A has no other substituents, where the radicals described as "lower" preferably contain 1 or 2 carbon atoms, the lower U alkoylene radicals or 5 carbon atoms, and salts, especially pharmaceutically acceptable salts, of such compounds 15 having salifying properties.

The invention relates particularly to compounds of formula I where R1 represents a hydrogen or a lower alkyl group, e.g., methyl, and R2 represents a lower alkyl group, e.g., methyl, or a phenyl group, R3 represents the =N-R(la) group and R represents the -l\'(Rb)-Rc(le) group, where one of the radicals Rb 20 and Rc represents a hydrogen and the other radical represents the group

-C(=X)-Rd (Id) , where X represents an oxo and Rd represents an amino, where the radicals described as "lower" contain firstly one, or even two carbon atoms.

□n prepares the compounds of the invention according to known processes, e.g. by reacting a compound of formula

Ifx

./\y\A

1 A II I , s

(II)'

6 i \ /

R'

where one of the groups Rx and Ry represents an oxo group and the other represents an oxo group or the group =I\I-R (la), and R1 and R2 as well as the nucleus A in formula II and R in group la have the meanings given above, with a compound of formula H2N-R (III), where R has the meaning given above, and,

if desired, by transforming a compound obtained into another compound according to the invention and/or, if desired, by transforming a salt obtained into the free compound or into another salt or by transforming a free compound

I

obtained having salt-forming groups in a salt.

Preferably, starting materials are compounds of formula n where the two radicals Rx and Ry represent an oxo group. Compounds of formula III can be used in free form or as salts of addition to acids, such as salts with inorganic acids, e.g. hydrochloric acid or sulfuric acid, or with organic acids.

The reaction is carried out in a known manner, preferably in the presence of a base, such as a lower alkali metal alkanoate, e.g. sodium acetate, and/or a diluent, preferably polar, such as a lower alkanool, e.g. ethanol, a cyclic ether, e.g. tetrahydrofuran or dioxane, or an amide, e.g. dimethylformamide, cooling, e.g. in a temperature range of about 10°C to about 120°C, preferably 50°C to about 100°C, if necessary in a closed, pressurized container and/or in an inert gas atmosphere.

The compounds obtained can be transformed into other compounds of the invention, such as e.g. those of formula I with a group of formula -C(=X)-Rd (Id), where Rd represents a lower dialcoyl-lower aminoalkyl group, by treatment with a reactive ester of a lower alkanol, such as a lower alkyl halide, e.g. chloride, bromide or iodide, into compounds having a lower trialcoyl-lower ammonioalkyl group Rd.

The salts of compounds of formula I that can be obtained by the process can be transformed in a known way, e.g. the addition salts of acids by treatment with a suitable base, into the free compounds.

Quaternary salts can be transformed, for example, by treatment with a suitable acid or an anion exchanger into another quaternary salt. Compounds of formula I having salt-forming properties can be transformed, for example, by treatment with a suitable acid or an ion exchanger into the desired salts.

The starting products of formulas II and III used in the above process are known or, if new, can be prepared in a known way.

9

The present invention also relates to pharmaceutical preparations containing one of the compounds according to the invention as their active substance. The pharmaceutical preparations according to the invention are those for enteral administration, such as oral or rectal administration, or parenteral administration, e.g., intravenous or intramuscular administration. The preparations contain the active substance alone or, preferably, with a pharmaceutically acceptable carrier. The dosage of the active substance depends on the species being treated, the age and individual condition, as well as the method of administration.

Pharmaceutical preparations contain from about 5% to about 95% of the active substance, and single-dose application forms preferably contain from about 20% to about 90% and non-single-dose application forms preferably contain from about 5% to about 20% of the active substance.

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

The pharmaceutical preparations of the invention are prepared in a conventional manner, e.g., by means of conventional processes of mixing, granulation, coating, dissolving, or freeze-drying. Pharmaceutical preparations for oral administration can thus be obtained by combining the active substance with one or more solid carriers, optionally granulating the resulting mixture, and transforming the mixture or, as the case may be, the granules, if desired, possibly after the addition of further additives, into tablets or coated tablet cores.

Suitable carriers include, in particular, fillers such as sugars, e.g., lactose, sucrose, mannitol, or sorbitol; cellulose preparations and/or calcium phosphates, e.g., tricalcium phosphate or calcium phosphate rock; or binders such as starches, e.g., corn, wheat, rice, or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone; and/or, if desired, solvents such as the starches mentioned above, or carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid, or one of its salts, such as sodium alginate. Additional additives include, primarily, viscosity regulators and lubricants, e.g.

w

10

silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate, and/or polyethylene glycol.

The dragee cores are coated with appropriate materials, possibly resistant to gastric juices, and contain, among other things, concentrated sugar solutions which may also contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, etc.

and/or titanium dioxide, lacquer solutions in suitable solvents or solvent mixtures or, for preparing coatings resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.

□Colorants or pigments may be added to tablets or coatings of dragees, e.g. for the purpose of identifying or characterizing different doses of active substance.

Other pharmaceutical preparations suitable for oral administration include gelatin capsules and softgel capsules made of gelatin and a plasticizer, such as glycerin or sorbitol. Capsules may contain the active substance in granular form, e.g., mixed with fillers, such as corn starch, binders and/or lubricants, such as talc or magnesium stearate, and possibly stabilizers. In softgel capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil, or liquid polyethylene glycols, and stabilizers may also be added.

Other forms of oral administration include, for example, syrups prepared in the usual way, which contain the active substance in suspension form and at a concentration of approximately 5% to 20%, preferably approximately 10%, or at a similar concentration, which gives, for example, an appropriate unit dose when 5 or 10 ml is measured. In addition, one can also consider...

Examples include powdered or liquid concentrates for preparing whipped drinks ("shakes"), e.g., in milk. Such concentrates can also be packaged in unit doses.

Examples of rectal pharmaceutical preparations include suppositories, which consist of a combination of the active substance with a suppository excipient. Natural or synthetic triglycerides can be used as suppository excipients.

11

ticks, paraffins, polyethylene glycols or higher alkanols. In addition, rectal gelatin capsules, which consist of a combination of the active substance with an excipient, can also be used;

Examples of excipient products include liquid triglycerides, polyethylene glycols, and paraffins.

For parenteral administration, mention should be made, e.g., of suspensions of compounds of the invention, such as the corresponding oily injectable suspensions, and appropriate lipophilic solvents or vehicles are used, such as fatty oils, e.g. sesame oil, or esters of synthetic fatty acids, e.g. ethyl oleate or triglycerides,

or aqueous injectable suspensions containing viscosity-raising agents, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and possibly also stabilizers, can be used.

For parenteral administration, liposome dispersions with formula I compounds can be used in particular. Liposome dispersions are formed of at least two lipid components, e.g. phosphatidylserine and phosphatidylethanolamine or phosphatidylserine and phosphatidylcholine, which encapsulate the (I) compounds.

To prepare the liposome dispersion, the lipid component can be prepared using naturally occurring phosphatidylserine with different or identical C10-C20 alkanoyl radicals, e.g. n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl, or C10-C2D alkenoyl radicals, 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 beef brain, or synthetic phosphatidylserine with identical C10-C20 alkenoyl radicals, e.g. 1,2-di-(9-cis-octadecenoyl)-3-sn-phosphatidyl-(S)-serine sodium, and for the other lipid component, naturally occurring phosphatidylcholine with different or identical C10-C20 alkanoyl radicals, e.g., phosphatidylcholine from chicken egg or soybean oil, synthetic phosphatidylcholine with identical C10-C20 alkanoyl radicals, e.g., dimyristoyl-, distearoyl- or dipalmitoylphosphatidylcholine,

: or synthetic phosphatidylcholine with an alcanoyl radical at C10 to C20 and an alkenoyl radical at C10 to C20, e.g. 1-n-hexadecanoyl-2-(9-cis-octadecenoyl)-3-sn-phosphatidylcholine.

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□The liposome dispersion can be prepared by preparing, for example, a lyophilized product from the lipid components and compound (I)

according to the process described in patent application published in Germany under No. 28 18 655, preferably after dissolving the lipid components and the active substance in tert-butanol, and removing the solvent at temperatures below -20°C, and dispersing this lyophilized powder in an isotonic buffer solution. Dispersion is carried out by shaking (vortex mixer) or by agitating the aqueous phase. The liposome dispersion can then be enriched by centrifugation and/or separated by gel filtration or extrusion through straight-pore filters.

This process is suitable when using lipophilic compounds (I) or, where applicable, compounds soluble in organic solvents, e.g., tert-butanol. For water-soluble compounds (I), a lyophilized powder is prepared from only the lipid components and dispersed in an aqueous phase containing the dissolved compound (I).

• The invention also relates to a method for treating diseases in which, as stated above, reverse transcriptase is important, characterized in that a prophylactically or therapeutically effective amount of a compound according to the invention is administered. Firstly, the pharmaceutical preparations mentioned above are used, and a homeothermic individual weighing approximately 70 kg is administered a daily dose of approximately 0.1 g to approximately 5 g, preferably approximately 0.5 g to approximately 1.5 g, of a compound of the invention.

The following examples illustrate the invention; temperatures are given in degrees Celsius.

The invention also relates, as novel industrial products, to the compounds obtained by implementing the process defined above; however, these products are not protected by this patent for their therapeutic uses.

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EXAMPLE 1: 2,2-dimethyl-3,4-dihydro-2H-naphtho/l ,2-b/pyrane-5,6-dione-6-semicarbazone

A solution of 6.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho/1,2-β7-pyran-5,6-dione (β-lapachone) is prepared by heating 6.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho/1,2-β7-pyran-5,6-dione in 200 mL of a 1:1 mixture of ethanol and water to 70°C. This solution is then mixed with 2.03 g of sodium acetate and 2.76 g of semicarbazide hydrochloride. The resulting yellow suspension is stirred for 3 h at 80°C, cooled to 10°C, and filtered. The filter residue is washed with 100 mL of water and boiled in 1000 mL of acetone, in which the acetone is only partially soluble. The mixture is then filtered. The compound of the titer obtained from the filtrate melts at 249–253°C.

(with decomposition). An additional quantity of the desired compound is not soluble in the stated amount of acetone and is obtained in the filtration residue. An additional quantity of the substance can be obtained from the mother liquor.

EXAMPLE 2: 2,2-dimethyl-3,4-dihydro-2H-naphtho/l ,2-b7pyran-5,6-dione-6-thiosemicarbazone

□n heats for 4 h under reflux a mixture of 15 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho/T,2-b7pyran-5,6-dione (B-lapachone),

15.8 g of thiosemicarbazide and 15.8 g of sodium acetate are dissolved in 500 mL of a 1:1 mixture of ethanol and water, then cooled to room temperature (TA). The reddish precipitate is separated by filtration, the residue is washed with water, dried for 16 h at 70°C under reduced pressure, and then recrystallized from 3000 mL of acetone at half volume concentration and washed with diethyl ether. The compound of the concentration thus obtained melts at 249–250°C. An additional quantity of the desired product can be isolated from the mother liquor.

EXAMPLE 3: 2,2-Dimethyl-3,4-Dihydro-2H-naphtho/T,2-β7pyran-5,6-dione-6-(2-dimethylaminoacetylhydrazone) hydrochloride

A suspension of 7.2 g of 2,2-dimethyl-3,4-dihydro-2H-naphthoZ1,2-b7-,pyran-5,6-dione (B-lapachone) and 6.1 g of N,N-dimethylglycine-hydrazide hydrochloride is heated in 70 mL of acetic acid for 10 minutes at a bath temperature of 100°C. The solvent is removed under reduced pressure, and the residue is dissolved in hot dimethylformamide (DMF). Upon cooling, a red-orange crystalline precipitate forms, which is

H

It is dried at 90° under a high vacuum. This yields the compound of the titration, which melts at 185° (with decomposition).

EXAMPLE 4: 2,2-Dimethyl-3,4-dihydro-2H-naphtho/T,2-b/pyrane-5,6-dione-6-(2-trimethylammonioacetylhydrazone) chloride

5. Heat a mixture of 7.2 g of

2,2-dimethyl-3,4-dihydro-2H-naphtho/T,2-ti7pyran-5,6-dione (B-lapachone)

and 6.72 g of trimethylammonioacetylhydrazide chloride in 50 mL of acetic acid, then concentrated to dryness under reduced pressure. The resulting oily product is crystallized by treating it several times with 1,2-dimethoxy-10 ethane. The crystalline material is separated by filtration, dissolved in ethanol, and the solution is diluted with an equal amount of ethyl acetate.

Upon cooling to 0°, the compound of the titration forms in the form of an orange crystalline precipitate, which melts at 210° (with decomposition).

EXAMPLE 5: 2,2-Dimethyl-3,4-Dihydro-2H-naphtho/i,2-β7pyran-15 5,6-dione-6-(2-pyridinioacetylhydrazone) chloride

A suspension of 7.2 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho(II)pyrane-5,6-dione (13-lapachone) and 7.5 g of 1-(2-hydrazino-2-oxoethyl)pyridiniochloride is heated for 10 minutes at 100°C in 50 mL of acetic acid and then concentrated to dryness under reduced pressure. The resulting oily product is crystallized by treating it several times with 1,2-dimethoxyethane. The crystalline material is separated by filtration and crystallized from isopropanol and then from acetonitrile. The compound thus prepared is obtained as its sesquihydrate and decomposes at 225°C.

25 EXAMPLE 6: 2,2-dimethyl-3,4-dihydro-2H-naphtho/1,2-β7pyran-5,6-dione-6-oxime

A solution of 2.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho/1,2-γ7pyran-5,6-dione (I3-lapachone) in 125 mL of ethanol and 4.2 mL of triethylamine is mixed with 1.73 g of hydroxylamine hydrochloride. The reaction solution is stirred for 30°C for 6 h at 25°C and cooled to 5°C. The crystals are filtered through a filter funnel, washed with water, and dried. The compound of the titer obtained has a melting point of 169–171°C.

15

EXAMPLE 7: 2,2-dimethyl-3,4-dihydro-2H-naphtho/TI2-b7pyran-5,6-dione-6-methoxime

A solution of 2.49 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho/J,2-β7pyran-5,6-dione (13-lapachone) is mixed in 155 mL of ethanol and 521 mL of water with 4.22 g of sodium acetate and 4.3 g of methylhydroxylamine hydrochloride. The reaction solution is heated under reflux for 4 h and cooled to 5°C. The crystals are filtered using a filtering funnel.

It is washed with water, dried, and recrystallized from heptane. The compound obtained has a Pf of 79-80°.

EXAMPLE 8: 2,2-dimethyl-3,4-dihydro-2H-naphtho/T,2-tyrpyran-5,6-quinone-6-ethoxime

A solution of 2.49 g of 2,2-dimethyl-3,4-dihydro-2H-naphthoZJ,2-β7"pyran-5,6-dione (β-lapachone) 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-5-hydroxylamine hydrochloride. The reaction solution is heated under reflux for

After 4 hours, the mixture is concentrated to dryness. The residue is dissolved in methylene chloride, and the organic phase is washed twice with water. The organic phase is dried, the mixture is concentrated to dryness, and the residue is crystallized from hexane. The compound of the obtained concentration melts at 72-73°C.

EXAMPLE 9: 2,2-dimethyl-3,4-dihydro-2H-naphthoZi,2-β7pyran-5,6-dione-6-ethoxycarbonylmethyloxime

A solution of 2,2-dimethyl-3,4-dihydro-2H-naphtho£T,2-ji7pyran-5,6-dione (β-lapachone) is mixed in 1000 mL of ethanol with 10 g of O-carboxymethylhydroxylamine hemihydrochloride and stirred for 5 to 2 hours at room temperature. The solution changes color from orange to yellow. The solution is concentrated 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 concentrated. The compound with a yellow needle count is crystallized from the residue using petroleum ether/oil ether. Pf 93-95°.

16

EXAMPLE 10: 2,2-dimethyl-3,4-dihydro-2H-naphtho/1,2-β7pyran-5,6-dione-6-carboxymethyloxime

A solution of 1.56 g of 2,2-dimethyl-3,4-dihydro-2H-naphthoZT,2-β7pyran-5,6-dione (β-lapachone) is mixed in 30 ml of THF with 0.78 g of O-carboxymethylhydroxylamine hemihydrochloride, dissolved in

8 mL of THF-H2O (1:1) are stirred for 8 h at room temperature. The solution is concentrated to dryness, the residue is dissolved in methylene chloride, and the mixture is washed twice with dilute HCl and once with H2C. The organic phase is dried and concentrated. The residue is suspended in 120 mL of hot ether and heated under reflux, yielding the compound as yellow crystals with a boiling point of 165-167°.

EXAMPLE 11: Sodium salt of 2,2-dimethyl-3,4-dihydro-2H-naphthofloxacin,2-β7pyran-5,6-dione-6-carboxymethyloxime

□n dissolves 1 g of 2,2-dimethyl-3,4-dihydro-2H-naphthoZjT,2-b7-

15

pyrane-5,6-dione-6-(carboxymethyl)-oxime in about 20 ml of dioxane and mixed with an equimolar amount of 1 N sodium hydroxide solution. The clear solution is lyophilized, and the compound of titration is obtained in the form of a yellow powder.

EXAMPLE 12: 2,2-dimethyl-3,4-dihydro-2H-naphtho/i,2-b7pyran-5,6-dione-6-

20

ethoxycarbonylhydrazone

A solution of 2,2-dimethyl-3,4-dihydro-2H-naphtho£T,2-17pyran-5,6-dione (β-lapachone) in 100 mL of ethanol and 20 mL of water is mixed with 0.75 g of sodium acetate and 4.8 g of ethyl ester of hydrazinecarboxylic acid and heated under reflux for 50 h. The reaction mixture is concentrated, the residue is dissolved in methylene chloride, and washed twice with water. The organic phase is dried, the residue is concentrated, and chromatographed on 100 g of silica gel. The compound is obtained as yellow crystals with a Pf of 90–95°.

17

EXAMPLE 13: Tablets containing 500 mg of 2,2-dimethyl-3,4-dihydro-2H-naphtho/T,2-β7pyran-5,6-dione-6-semicarbazone can be prepared as follows: Composition (for 10,000 tablets): , 2,2-dimethyl-3,4-dihydro-2H-naphtho/T,2-β7-

5 pyran-5,6-dione-6-semicarbazone 5000.00g

Wheat starch 790.00 g Stearic acid 30.00 g Magnesium stearate 30.00 g

Talc 400.00 g

10. The active substance is regularly moistened with gelled wheat starch, which has been obtained by diluting 500 g of wheat starch with approximately 1300 ml of demineralized water, and then with another 600 ml of demineralized water. This mixture is kneaded to form a slightly plastic mass and passed through a sieve with a mesh size of approximately 3 mm. The resulting granules are then dried and passed through another sieve. Magnesium stearate, stearic acid, talc, and the remaining wheat starch are mixed into the dried granules, and the resulting mixture is compressed to form tablets.

EXAMPLE 14: A 10% suspension containing 2,2-dimethyl- can be prepared

20 3,4-dihydro-2H-naphtho/T,2-y7pyran-5,6-dione-6-semicarbazone as follows: Composition (per 5000 ml):

2,2-dimethyl-3,4-dihydro-2H-naphtho/J,2-b7-

pyran-5,6-dione-6-semicarbazone

500.00 g

Propylene glycol

500.00 g

25

Hydroxypropylmethylcellulose

25.00 g

Citric acid

5.00 g

sodium saccharin

2.50 g

4-Hydroxybenzoic acid methyl ester

6.00 g

Propyl ester of 4-hydroxybenzoic acid

1.50 g

30

Raspberry flavor

5.00 g

70% aqueous sorbitol solution

1250 ml

Demineralized water q.s.

18

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

EXAMPLE 15: Capsules containing 300 mg of 2,2-dimethyl-3,4-dihydro-2H-naphtho2i,2-S7pyran-5,6-dione-6-semicarbazone can be prepared as follows:

15 Composition (for 10,000 capsules):

2,2-dimethyl-3,4-dihydro-2H-naphtho/T,2-b7-

pyran-5,6-dione-6-semicarbazone 3000.00 g

Magnesium stearate 100.00 g

The active substance is mixed with magnesium stearate 20 and 0.31 g of the mixture is poured each time using an encapsulator into hard gelatin capsules.

EXAMPLE 16: An aqueous injectable suspension (for intramuscular administration) containing 1.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphthofloxacin,2-S7pyran-5,6-dione-6-semicarbazone can be prepared per 5 ml as follows: 25 Suspension medium:

Sodium salt of carboxymethylcellulose 0.10%

Mixture of sodium acid phosphate and disodium acid phosphate 0.15%

Sodium chloride 0.75%

30 Sodium salt of S-ethylmercury-

thiosalicylic (Thiomersal) 0.02%

1,2-Propylene glycol 20.00%

Distilled water q.s.p. 100.00%

19

□n treats the sterile active substance 2,2-dimethyl-3,4-dihydro-2H-naphtho /i,2-b7pyran-5,6-dione-6-semicarbazone under antimicrobial conditions with the suspension medium so as to obtain a sterile suspension which contains 1.0 g of active substance in 5 ml.

EXAMPLE 17: An aqueous injectable suspension (for intramuscular administration) containing 0.75 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho/T,2-b7pyran-5,6-dione-6-semicarbazone per 5 ml can be prepared as follows:

Suspension medium:

Sodium chloride 0.90%

Sodium salt of S-ethylmercury-

thiosalicylic (Thiomersal) 0.02%

Polyoxyethylene(20)sorbitan monostearate

(molecular weight: 1311.7 g; Tween 60©) 0.75 /

Sodium salt of carboxymethylcellulose 0.50 /

The sterile active substance is transformed under antimicrobial conditions with the suspension medium to obtain a sterile suspension which contains 0.75 g of active substance in 5 ml.

20

Claims (9)

DEMANDS 1. Process for preparing a compound of formula I /s /" ' A " ' d) \s\/\ where R1 and R2' independently represent a hydrogen, a lower alkyl, or an aryl, or, taken together, a lower alkoylene; one of the radicals R3 and R4 represents the group =N-R(la), where R represents the group -Q-Ra(Ib) and Ra represents a hydrogen, a lower alkyl, a lower carboxyalcohol, or a lower alkoxycarbonyl-lower alkyl; or R represents the group -N(Rb)-Rc(le), and Rb and Rc independently represent a hydrogen or a lower alkyl; or one of the radicals Rb and Rc represents a hydrogen and the other radical represents the group -C(=X)-Rd, where X represents an oxo and Rd represents a lower alkoxy, a lower dialcoyl-lower aminoalcoyl, a lower trialcoyl-lower ammonioalcoyl, a lower alkoylene-lower aminoalcoyl, a lower oxaalcoylene-lower ammonioalcoyl, a lower thiaalcoylene-lower aminoalcoyl, a lower azaalcoylene-lower aminoalcoyl possibly substituted at aza by a lower alcoyl or a lower pyridinioalcoyl, or X represents an oxo or a thioxo and Rd represents an amino, or the two radicals Rb and Rc taken together represent a lower alcoylene, a lower oxaalcoylene, a lower thiaalcoylene or a lower azaalcoylene possibly substituted at aza by a lower alcoyl, and the other of the two radicals R3 and Rh has the same meanings or represents an oxo and the nucleus A has no other substituents or is further substituted by one or more substituents selected from lower alcoyl, lower alkoxy and halogen, as well as salts of such compounds having salifying properties, 21 characterized in that a compound of formula is reacted Hx y\/\A 1 a n i ,TT, \/s/s (II)' N •' • *x/! where one of the groups Rx and Ry represents an oxo and the other represents an oxo or the group -N-R (la), and R1 and R2 as well as the nucleus A in formula ii and R in the grouped la have the meanings given above, with a compound of formula H2N-R (III), where R has the meaning given above, and, if desired, in that a compound obtained is transformed into another compound according to the invention and/or, if desired, in that a salt obtained is transformed into the free compound or into another salt or in that a free compound obtained with salt-forming groups is transformed into a salt. 2. A process according to claim 1 for preparing compounds of formula I where R1 represents a hydrogen or a lower alkyl, R2 represents a hydrogen, a lower alkyl, or a phenyl, one of the radicals R3 and Rk represents the =N-R group (la), where R represents the -O-Ra group (Ib) and Ra represents a hydrogen, a lower alkyl, a lower carboxyalkyl, or a lower alkoxycarbonyl-lower alkyl, or R represents the -N(Rb)-Rc group (le), and Rb and Rc independently represent a hydrogen or a lower alkyl, or one of the radicals Rb and Rc represents • one hydrogen and the other radical represents the group -C(=X)-Rd, where X represents an oxo and Rd a lower alkoxy, a lower dialcoyl-lower aminoalcoyl, a lower trialcoyl-lower ammonioalcoyl, a lower alkoylene-lower aminoalcoyl, a lower 4-morpholinoalcoyl, a lower 4-alcoyl-1-piperazinoalcoyl, or a lower pyridinioalcoyl; or X represents an oxo or a thioxo and Rd represents an amino; or the two radicals Rb and Rc taken together represent a lower alkoylene, a 3-oxa-1,5-pentylene, or a lower 3-alcoyl-3-aza-1,5-pentylene, and the other of the two radicals R3 and R4 represents an oxo, and the nucleus A has no other substituents or is further substituted by one or more substituents 22 chosen from lower alkyl, lower alkoxy or halogen, the radicals described as "lower" containing 1 or 2 carbon atoms, the lower alkoylene radicals 4 or 5 carbon atoms, and halogen having an atomic number of at most 35, and pharmaceutically acceptable salts of such compounds having salifying properties, characterized in that a compound (II), where Rx and Ry represent an oxo, is reacted with a correspondingly substituted compound (III). 3. A process according to claim 1 for preparing compounds of formula I, wherein R1 represents a hydrogen or a lower alkyl and R2 represents a lower alkyl or a phenyl, R3 represents a group of formula =N-R(la), where R represents the -O-Ra group (Ib) and Ra represents a lower alkyl, a lower carboxyalkyl, or a lower alkoxycarbonyl-lower alkyl, or R represents the -N(Rb)-Rc group (le), one of the Rb radicals and Rc represents a hydrogen and the other radical represents the group -C(=X)-Rd, where X represents an oxo and a thioxo and Rd represents an amino or the two radicals Rb and Rc taken together represent a lower alkoylene, a 3-oxa-1,5-pentylene or a lower 3-alkoyl-3-aza-1,5-pentylene, and R4 represents an oxo, where the radicals described as "lower" contain 1 or 2 carbon atoms, the lower alkoylene radicals 4 or 5 carbon atoms, and pharmaceutically acceptable salts of such compounds having salificating properties, characterized in that a compound (II), where Rx and Ry represent an oxo, is reacted with a correspondingly substituted compound (III). 4. A process according to claim 1 for preparing compounds of formula I, where R1 represents a hydrogen or a methyl, and R2 represents a methyl or a phenyl, R3 represents the =N-R group (la) and R the -N(Rb)-Rc group (le), where one of the radicals Rb and Rc represents a hydrogen and the other radical the -C(=X)-Rd group (Id), where X represents an oxo and Rd represents an amino, where the radicals described as "lower" contain in the first place one, or even two, carbon atoms, characterized in that a compound (II), where Rx and Ry represent an oxo, is reacted with a correspondingly substituted compound (III). 23 10 5. .Process for the preparation of 2,2-dimethyl-3,4-dihydro-2H-naphtho/1,2-β7pyrane-5,6-dione-6-semicarbazone according to claim 1, characterized in that β-lapachone is reacted with semicarbazide hydrochloride. 6. Process for preparing 2,2-dimethyl-3,4-dihydro-2H-naphthoZÎ,2-b7pyrane-5,6-dione-6-semicarbazone according to claim 1, characterized in that B-lapachone is reacted with thiosemicarbazide. 7. Process for preparing 2,2-dimethyl-3,4-dihydro-2H-naphtho/3,2-b7pyrane-5,6-dione-6-(2-dimethylaminoacetylhydrazone) and its salts according to claim 1, characterized in that B-lapachone is reacted with 1,1-dimethyl-glycinhydrazide. 8. Process for preparing 2,2-dimethyl-3,4-dihydro-2H-naphtho/T,2-b7pyrane-5,6-dione-6-(2-trimethylammonioacetylhydrazone) according to claim 1, characterized in that B-lapachone is reacted with trimethylammonioacetylhydrazide hydrochloride. 9. Process for preparing 2,2-dimethyl-314-dihydro-2H-naphthoZT,2-b7pyrane-5,6-dione-6-(2-pyridinioacetylhydrazone) according to claim 1, characterized in that B-lapachone is reacted with 1-(2-hydrazino-2-oxoethyl)-pyridiniochloride. VCfW qi <no l~S o i CIBA GEIGY AG BY PROXY naked Is