DD239203A5 - PROCESS FOR THE PREPARATION OF NITROGEN DERIVATIVES OF BETA-LAPACHONE AND ITS ANALOGUE - Google Patents

Abstract

Described is a process for the preparation of compounds of the formula wherein R1 and R2 independently of one another are hydrogen, lower alkyl or aryl or taken together lower alkylene, one of the radicals R3 and R4 represents the group NR (Ia), wherein R is the group -O-Ra (I b) and Ra are hydrogen, lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R is the group -N (Rb) -Rc (I c) and Rb and Rc independently of one another are hydrogen or lower alkyl or one of Rb and Rc is hydrogen and the other the In which X is oxo and Rd is lower alkoxy, di-lower alkylamino-lower alkyl, tri-lower alkylammonio-lower alkyl, lower alkyleneamino-lower alkyl, oxo-lower alkylene-lower alkyl, thian-lower alkyleneamino-lower alkyl optionally substituted by lower alkyl aza-substituted azan-lower alkyleneamino-lower alkyl or pyridinio-lower alkyl or X is oxo or thioxo and Rd is amino, or both Rb and Rc taken together are lower alkylene, oxanoweralkyl en, thianethylene or optionally substituted by lower alkyl aza-substituted Azaniederalkylen, and the other of the two radicals R3 and R4 have the same meanings or oxo and the ring A has no further substituents or additionally substituted by lower alkyl, lower alkoxy and / or halogen, and Salts of such compounds with salt-forming properties. The novel compounds are effective in retrovirus-induced mouse Rauscher leukemia and therefore can be used therapeutically, for example, in the control of immune diseases or autoimmune diseases also caused by retroviruses.

Description

^s v \ A.

wherein one of R _x and Ry is oxo and a ther oxo or dieGruppe = NR (I a) represents and Ri and R ₂ and the ring A in the formula II and R in the group I a is the above-given meanings , with a compound of formula H ₂ NR (III), wherein R has the meaning given above, and, if desired, converted a compound obtained in another compound of the invention and / or, if desired, a salt obtained in the free compound or in another salt, or salting a resulting free compound with salt-forming groups and / or converting a compound obtained into a pharmaceutical preparation.

2. The method according to item 1 for the preparation of compounds of formula I, wherein R _{1 is} hydrogen or lower alkyl, R _{2 is} hydrogen, lower alkyl or phenyl, one of R ₃ and R _{4 represents} the group = NR (Ia), wherein R is the Group -OR, (I b) and R, hydrogen, lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R is the group -N (Rb) -Re (Ic) and Rb and R _{0 are} independently hydrogen or lower alkyl or one of R _b and R _{0 is} hydrogen and the other radical of the group -C (=) - R <j, where X is oxo and R _{d is} lower alkoxy, di-lower alkylamino lower alkyl, tri-lower alkylammonio-lower alkyl, lower alkyleneamino-lower alkyl, 4-morpholinoloweralkyl, 4-loweralkyMpiperazinoloweralkyl or pyridinio-lower alkyl or X Oxo or thioxo and Rd Amino mean or mean, or both radicals R _b and R _{0 taken} together are lower alkylene, 3-oxa-1,5-pentylene or 3-lower alkyl-3-aza-1,5-pentylene, and the other of the two radicals R ₃ and R ₄ for Ox o, and ring A has no further substituents or is additionally substituted by lower alkyl, lower alkoxy or halogen, where radicals denoted by lower * contain 1 or 2 carbon atoms, lower alkylene radicals contain 4 or 5 carbon atoms, and halogen has an atomic number of at most 35, and pharmaceutically acceptable salts of such compounds having salt-forming properties, characterized in that reacting a compound (II), wherein R _x and R _{y is} oxo, with an appropriately substituted compound (III)

3. The method according to item 1 for the preparation of compounds of formula I, wherein R _{1 is} hydrogen or lower alkyl and R _{2 is} lower alkyl or phenyl, R _{3 represents} a group of formula = NR (I a), wherein R is the group -OR , (I b) and R _{a is} lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R is the group -N (Rb) -R ₀ (I c) one of the radicals R _b and R _{c is} hydrogen and the other radical is the group -C (= X) - R _{d is} where X is oxo and thioxo and R _{d is} amino or both radicals R _b and R _{c taken} together are lower alkylene, 3-oxa-1,5-pentylene or 3-lower alkyl-3-aza-1,5-pentylene, and R _{4 is} oxo, wherein radicals designated "lower" contain 1 or 2 carbon atoms, lower alkylene radicals contain 4 or 5 carbon atoms, and pharmaceutically acceptable salts of such compounds having salt-forming properties, characterized by reacting a compound (II) wherein R is _x and R _{y are} oxo, with a correspondingly substituted compound (III).

4. Process according to point t for the preparation of compounds of the formula I in which R _{1 is} hydrogen or methyl and R _{2 is} methyl or phenyl, R _{3 is} the group = NR (Ia) and R is the group -N (R _b ) R _{c represents} (I c), wherein one of the radicals R _b and R _{c is} hydrogen and the other radical is the group -C (= X) -R _d (Id), wherein X is oxo and Rd is amino, wherein with "lower" designated radicals in the first line, furthermore also contain two carbon atoms, characterized in that one reacts a compound (II), wherein R _x and Ry are oxo, with an appropriately substituted compound (III )-

5. Vet ^ _{hrenzurHereteHungvon2>} 2-dimethyl-3,44lihydro * 2H-naphtho [1 ^ -b] pyran-5,6-Clion-6-semicarbazone according to item 1, characterized in that one / reacting 3-lapachone with semicarbazide hydrochloride ,

6. A process for the preparation of 2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione-6-thiosemicarbazone according to item 1, characterized in that 0- Lapachon with thiosemicarbazide.

7. A process for the preparation of 2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione-6- (2-dimethylaminoacetylhydrazone) and salts thereof according to item 1, characterized in that reacting / 3-lapachone with Ν, Ν-Dimethylglycinhydrazid.

8. A process for the preparation of 2,2-dimethyl-3,4-dihydro-2H-naphthoI1-b] pyran-5,6-dione-6- (2-trimethylammonioacetylhydrazone) according to item 1, characterized in that 3-lapachone with Trimethylarnmonioacetylhydrazidhydrochlorid

9. A process for the preparation of 2,2-dimethyl-3,4-dihydro-2H-naphtho [1 ^ -b] pyran-5,6-dione-6- (2-pyridinioacetylhydrazone) according to item 1, characterized in that man / 3-lapachone with 1- (2-hydrazino-2-oxoethyl) -pyridiniochlorid.

Field of application of the invention

The present invention relates to a process for the preparation of novel nitrogen derivatives of beta-lapachone and analogues thereof and to pharmaceutical preparations containing these nitrogen compounds. The compounds which can be prepared according to the invention are distinguished by inhibitory action on reverse transcriptase and virus replication and can therefore be used for combating immune and autoimmune diseases.

Characteristic of the known technical solutions

Beta-lapachone (2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione) and analogs thereof and their inhibitory action on the enzyme reverse transcriptase are known, see K Schaffpѳg-Saba et al., J. Med. Chem. 1984, 27, 990-994. By inhibiting the reverse transcriptase, the formation of retroviruses of the HTLV family is influenced. Certain types of leukemia are induced by HTLV-I and HTLV-II retroviruses. However, after induction of malignant, leukemic or lymphatic neoplasms by HTLV-l and HTLV-II retroviruses, a decrease of retroviruses of this type occurs, so that the effect of inhibiting reverse transcriptase described for the known compounds is only prophylactic, for example to prevent Leukemia can be used.

Object of the invention

The aim of the invention is the provision of novel compounds with action on reverse transcriptase, which are both prophylactically and therapeutically usable. Since in certain immune diseases such as AIDS (Acquired Immune Deficiency Syndrome) the enzyme reverse transcriptase and retroviruses type HTLV-III are detectable throughout the course of the disease, compounds with reverse transcriptase activity should be therapeutically suitable for controlling these immune disorders.

Explanation of the essence of the invention

The invention has for its object to provide novel compounds with action on reverse transcriptase and methods for their preparation.

According to the invention, novel compounds of the formula

VA Λ ^(Ι>

K, ¹

wherein R ₁ and R _{2 are} independently hydrogen, lower alkyl or aryl or taken together lower alkylene, one of R ₃ and R _{4 represents} the group = NR (Ia), wherein R is the group -OR. (I b) and R, hydrogen, lower alkyl "carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R represents the group -N (R 1) -R ,; (Ic) and R ₁ , and R _c independently of one another are hydrogen or lower alkyl or one of the radicals R _b and Rc is hydrogen and the other radical is the group-C (EX) -R,! represents wherein XOXO and rVNiederalkoxy, Diniederalkylaminoniederalkyl, Triniederalkylammonioniederalkyl'Niederalkylenaminoniederalkyl, Oxaniederalkylenammonioniederalkyl, Thianiederalkylenaminoniederalkyl, optionally substituted by lower aza-substituted Azaniederalkylenaminoniederalkyl or Pyridinioniederalkyl or X is oxo or thioxo and Rd amino, or two radicals R _b and R _c taken together are lower alkylene, Oxaniederalkylen, thia-lower alkylene or optionally by lower alkyl aza-substituted AzaniederalkyleYi, and the other of the two radicals R ₃ and R _{4 has the} same meanings or oxo and the ring A has no weathering substituents or additionally substituted by lower alkyl, lower alkoxy and / or halogen, and salts of these compounds having salt-forming properties and pharmaceutical preparations containing these compounds.

The above organic radicals and compounds referred to as "lower" include, up to and including 7,

preferably up to and including 4, and primarily 1 or 2 carbon atoms. Lower alkylene radicals preferably contain 4 or 5 carbon atoms.

Lower alkyl means in the first place · methyl and ethyl, but may also be n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl,

furthermore represent n-pentyl, n-hexyl and n-heptyl.

Aryl is primarily monocyclic, carbocyclic aryl, ζ. B. optionally substituted phenyl, wherein substituents

et al Lower alkyl, lower alkoxy or halogen.

In particular, lower alkoxy is methoxy or ethoxy, furthermore n-propoxy, isopropoxy, n-butoxy or isobutoxy, and n-

Pentyloxy.

Halogen is preferably halogen having an atomic number of at most 35, d. H. Fluorine, chlorine or bromine. Lower alkylene is e.g. 1,4-butylene, 1,5-pentylene or 1,6-hexylene. Carboxyniederalkyl is primarily carboxymethyl and 2-carboxyethyl and 3-carboxy-n-propyl. Lower alkoxycarbonyl-lower alkyl is primarily methoxy or di-lower alkylamino-lower alkyl is preferred Dimethylamino, diethylamino, di-n-oropylamino or N-ethyl-N-methylaminomethyl and 2-dimethylaminoethyl. Triniederalkylammonioniederalkyl is preferably IM diethyl-N-methyl-ammonio or trimethylammoniomethyl and

2-trimethylammonioethyl.

Lower alkyleneamino-lower alkyl is preferably 1-pyrrolidinomethyl, 2- (1-pyrrolidino) ethyl, 1-piperidinomethyl, 2- (1- Piperidinolethyl, 1-hexahydroazepinomethyl and 2- (1-hexahydroazepino) ethyl. Oxaniederalkylenamino- and Thianiederaikylenaminoniederalkyl are preferably 4-morpholino and A- Thiomorphotinomethyl and 2- (4-morpholino) - and 2- (4-thiomorpholino) -ethyl. Optionally lower-alkyl aza-substituted azan-lower alkyleneamino-lower alkyl is preferably 1- Piperazinomethyl, 2- (1-piperazino) ethyl, 4-methyl or 4-ethyl-i-piperazinomethyl and 4-methyl or 4-ethyl-2- (1-

piperazino) ethyl.

Pyridinio-lower alkyl is preferably pyridiniomethyl and 2-pyridinioethyl. Oxaniederalkylen and Thianiederalkylen are in particular 3-oxa-1,5-pentylene and 3-thia-1,5-pentylene. Optionally substituted by lower alkyl Azaniederalkylen is z. 3-aza-1,5-pentylene or 3-methyl-3-aza-1,5-

pentylene.

In the compounds of the formula I, preferably only one of the radicals R ₃ and R ₄ , in the first instance the radical R ₃ , means the group

of the formula I a, while the other radical is oxo.

Salts of compounds of the formula I having salt-forming properties are primarily pharmaceutically acceptable salts _{and the like}

z. B. acid addition salts of such compounds with basic groups, such as addition salts with inorganic acids,

z. For example, hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as carboxylic or sulfonic acids, eg. Vinegar,

Maleic, fumaric, malic, oxalic, tartaric, citric, methanesulfonic or p-toluenesulfonic acid. Quaternary nitrogen compounds,

in which the radical Rd is tri-lower alkylammonium or Pyridinioniederalkyl, are preferably in the form of pharmaceutically acceptable quaternary salts in which z. B. the anion of an inorganic acid, such as a

Hydrohalic acid, z. As hydrochloric, hydrobromic or hydroiodic acid is derived. The compounds of the present invention are believed to be prodrugs for inhibiting reverse transcriptase

are one of retroviruses (or oncopnarviruses), such as RNA tumor and leukemia viruses, characteristic of the enzyme; Retro viruses require 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 effect on reverse transcriptase and viral replication can be assessed by in vivo assays

be determined. Thus, in animal experiments, compounds of the formula I have a strong activity in certain neoplastic diseases caused by RNA tumor viruses or in which RNA tumor viruses are detectable

Effectiveness You extend z. B. the mean survival time of mice after infection with Rauscher Leukemia Virus (RLV,

an RNA tumor virus).

In the experiments with Rauscher leukemia 4Q (NIH) female Balb / c mice (28 to 34 days old) with 0.2 ml of a

diluted tenfold (Hanks solution) virus suspension of spleen material from 4-6 weeks previously infected infected mice.

In one experiment, 15 animals are continuously per os either with the test compound or as controls with placebo

treated. The first administration is 30 minutes before the infection, further administrations daily once and five times a week for 4 weeks. The criterion for the effect is the extension of the survival time. While at the

Control animals from 28 days after infection found a leukemia with leukemic blood cells of over 50,000 / mm ³

and the animals begin to die, the survival time of 125 mg / kg p. o. the test substance treated female mice significantly extended. It is z. B. for the 2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione-6-semicarbazone at 20 times p. o. administration to female Balb / c mice of 125 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 activity of the compounds of the present invention is accompanied by a good one Compatibility So 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 after a single p. o.- and i. p.-administration and subsequent 7 days

Observation period over 2 500mg / kg. The detection of diseases caused by retroviruses is based z. B. on the following findings: The Detection of type C retroviruses and their formation of reverse transcriptase in humans was first performed in a T-cell leukemia; the virus was called human T-cell leukaemic virus (HTLV-I). For other T-cell leukemia and

The same viruses and a similar retrovirus (HTLV-II) were found (GaIIo, Cancer Surveys [Ed.

Wyke and Weiss}, Vol. % S. 113-160 [Oxford UnIv. Press, 1984]). Finally, such a virus was also in Connection with AIDS (Acquired Immune Deficiency Syndromel Diseases isolated (Gottlieb et al .. Morbid. Mortal. Weekly Rep., Vol. 30, p. 28, [1981]; Friedman-Kien et al .. Morbid. Mortal. Weekly Rep., Vol. 30, p.305 <198iy, · Gottlieb et al., New Engt. J. Med., Vol. 305, p. 1425 (198T); Masur, New Engt. J. Mod., Vol. 305.5.143t Ц98T]; Siegal et al. New Engl. J. Med., Vol. 305, p. 1439 [1981]; CDC Taks Force on Kaspoi'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]; Galoo et al., Science, Vol 2202, p.865 [1983]; GaIIo, Cancer Surveys, vol. 3 p. 113 [1984]; Barre-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 HTLV family-owned retroviruses require reverse transcriptase for the formation of a double-stranded DNA (provirus), which is "integrated" into the cell genome and results in malignant transformation (Strayer and Gillespie), The Nature and Organization of Retroviral Genes in Animal Cells, Virology Monographs, Vol. 17 [Springer Ed., 1980]). Whereas retroviruses can detect a decrease in reverse transcriptase and the virus HTLV-I and -Il after the induction of malignant leukemic, lymphatic or tumorous neoplasms, and Secondary, these viruses induced oncogenes control the replication of malignant cells, the virus HTLV-III and the reverse transcriptase in AIDS not only in the early stages, but throughout the disease is detectable.The ongoing infection and dysfunction of immunocompetent T helper cells leads finally, the collapse of the immune system with fatal outcome. It can be assumed that e Ine inhibition of reverse transcriptase and virus replication with positive enzyme and virus antigen detection (Beardsley, Nature, Vol. 311, p. 195 [1984] in high-risk patients, eg. In the induction of leukemias and lymphomas by retroviruses (HTLV-I and HTLV-II), as may be the case with retrovirus-induced sarcomas or breast cancers, prophylactic use should be possible provided that it is light and broad available diagnostic detection of such high-risk patients can be assumed. Also in the context of non-A and non-B hepatitis, reverse transcriptase has been found to be a specific enzyme in association with virus particles (Seto et al. Lancet, p. 941 [1984]). The compounds of the present application can therefore be used for the prophylaxis and therapy of diseases in which the reverse transcriptase is important, especially of malignancies caused or co-caused by type C retroviruses, but also of certain immune diseases and autoimmune diseases. Tumor diseases primarily include retrovirus-induced leukemias, lymphomas and lymphosarcomas, as well as osteosarcomas and breast cancers. The compounds of the invention are also particularly suitable for the prophylaxis of recurrence after surgical therapy, radiotherapy or cytostatic or antimetabolic chemotherapy. As an immune disease is AIDS, as an autoimmune disease systemic lupus erythematosus called in which according to recent findings RNA tumor viruses also seem 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 the formula I in which R _{1 is} hydrogen or lower alkyl, R _{2 is} hydrogen, lower alkyl or phenyl, one of the radicals R ₃ and R ₄ , preferably R ₃ , represents the group = NR (Ia), where R is the group -OR, (I b) and R _{1 are} hydrogen, lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R is GrUDDe-N (Rb) -Ac (Ic) and R _b and R _{1 are} independently hydrogen or lower alkyl or one of R _b and R _{c is} hydrogen and the other radical is the group-C (= X) -R _d , where X is oxo and R _{d is} lower alkoxy, diniederafamino-lower-alkyi, tri-lower-alkylammonio-lower alkyl, lower-alkyleneamino-lower alkyl, morpholinone-lower alkyl, 4-lower-alkyl-piperazinone-lower alkyl or pyridinio-lower alkyl, or X is oxo or thioxo and R _d Amino, or both radicals R _b and R _{c taken} together are lower alkylene, 3-oxa-1,5-pentylene or 3-lower alkyl-3-aza-1,5-pentylene, and the other of the two radicals R ₃ and R ₄ , preferably R ₄ , is oxo, and ring A has no further substituents or is additionally substituted by lower alkyl, lower alkoxy or halogen, wherein radicals designated by "lower" preferably contain 1 or 2 carbon atoms, lower alkylene radicals contain 4 or 5 carbon atoms, and halogen has an atomic number of has at most 35, and salts, especially pharmaceutically acceptable salts, of such compounds having salt-forming properties.

The invention relates in the first place to compounds of the formula I in which R _{1 is} hydrogen or lower alkyl and R _{2 is} lower alkyl or phenyl, R _{3 is} a group of the formula = NR (I a), where R is the group -OR, (I b) and R, lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R the group-N (Rb) -R ₀ (ic) one of the radicals Rb and R _{c represents} hydrogen and the other radical represents the group -C (= X) -R _d , wherein X is oxo or thioxo and R _{1 is} amino or both radicals R _b and R _{c taken} together are lower alkylene, 3-oxa-1,5-pentylene or 3-lower alkyl-3-aza-1,5-pentylene, and R ₄ is oxo, and the ring A has no further substituents, wherein radicals designated "lower * preferably contain 1 or 2 carbon atoms, lower alkylene radicals contain 4 or 5 carbon atoms, and salts, especially pharmaceutically acceptable salts, of such compounds having salt-forming properties.

The invention particularly relates to compounds of the formula I, wherein R _{1 is} hydrogen or lower alkyl, for. For example, methyl, and R _{2 is} lower alkyl, for example methyl, or phenyl, R _{3 is} the group = NR (Ia) and R is the group -N (R _b ) -R _c (Ic), wherein one of the radicals Rb and Rc is hydrogen and the other radical is the group -C (= X) -R _d (Id) wherein X is oxo and R _{d is} amino, wherein radicals designated "lower" contain primarily one, and also two carbon atoms The compounds of the present invention are prepared by methods known per se, for example by dissolving a compound of the formula

IAI I

Äs

wherein one of the groups R _x and Ry is oxo and the other oxo or the group = NR (la), and R ₁ and R ₂ and the ring A in the formula Jl and R in the group I a have the meanings given above have reacted with a compound of the formula H ₂ NR (III) wherein R has the meaning given above, and, if desired, converting a compound obtained into another compound of the invention and / or, if desired, a salt obtained in the free Connection or

into a different salt, or salting a resulting free compound with salt-forming groups and / or processing a resulting compound into a pharmaceutical preparation.

The starting materials used are preferably compounds of the formula II in which both radicals R _x and R _{y are} oxo

stand. The compounds of formula III can in free form or in the form of acid addition salts, such as salts with inorganic acids, eg. For example, 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 a Alkali Metal Lower Alkanoates, e.g. Sodium acetate, and / or one, preferably polar, diluent, such as one Lower alkanols, e.g. As ethanol, a cyclic ether, z. For example, tetrahydrofuran or dioxane, or an amide, for. B. Dimethylformamide, with cooling, at room temperature or preferably with heating, for. In one Temperature interval of about 10 ⁰ C and about 120 ⁰ C, preferably 50 ⁰ C and about 100 ⁰ C, if necessary, in one

closed vessel under pressure and / or кг an inert gas atmosphere.

Obtained compounds can be converted into other compounds of the invention, such. B. those of the formula I with

a group of the formula -C (= X) -R _d (I d) wherein R _{4 is} a di-lower alkylamino lower 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 having a tri-lower alkylammonium lower alkyl group R _d . According to the invention available salts of compounds of formula I can in known manner, for. B. Acid addition salts by treatment with a suitable base are converted into the free compounds. quaternary Salts can be г. B. by treating with a suitable acid or anion exchange ^ into another quaternary Salt be transferred. Compounds of formula I with salt-forming properties can, for. B. by treating with a Acid or a suitable ion exchanger can be converted into the desired salts. The starting materials of the formulas II and III used in the above process are known or, if they are new, in

be prepared in a known manner.

The present invention also relates to pharmaceutical preparations containing as active ingredients one of the inventive Contain connections. Both pharmaceutical preparations according to the invention are those for enteral,

such as oral or rectal or parenteral, e.g. I. v., i. m. or rectal, administration. The preparations contain the active ingredient alone or preferably together with a pharmaceutically acceptable carrier material. The dosage of the active ingredient depends on the species to be treated, its age and individual condition, as well as the mode of administration.

The pharmaceutical preparations contain from about 5% to about 95% of the active ingredient, with single-dose Preferably, dosage forms of from about 20% to about 90% and non-unit dosage forms of administration are preferred

from about 5% to about 20% active ingredient.

Pharmaceutical preparations according to the invention in dosage unit form, such as dragees, tablets, capsules, suppositories or Ampoules containing from about 0.05 g to about 1.5 g, preferably from about 0.1 g to about 1.0 g of the active ingredient. The pharmaceutical preparations of the present invention are prepared in a manner known per se, e.g. by means of conventional Mixing, granulating, coating solution or lyophilization process prepared. So you can get pharmaceuticals

for oral administration, by combining the active ingredient with one or more solid excipients, optionally granulating a mixture as obtained, and optionally, if desired, the mixture or granules

Addition of additional excipients, processed into tablets or dragee cores. Suitable carriers are in particular fillers, such as sugars, for. Lactose, sucrose, mannitol or sorbitol, Cellulose preparations and / or calcium phosphates, eg. Tricalcium phosphate or calcium hydrogen phosphate, further Binders such as starches, e.g. Corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, Sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as those listed above

starch, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as

Sodium alginate. Additional aids are primarily flow regulators and lubricants, for. For example, silica, talc, Stearic acid or salt thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, optionally gastric juice-resistant coatings, where u. a.

concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as

Acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. The tablets or dragee coatings

For example, dyes or pigments, e.g. To identify or label different doses of the active ingredient.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules

from gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can be the active ingredient in the form of a

Granules, z. B. in admixture with fillers, such as corn starch, binders and / or lubricants, such as talc or Magnesium stearate, and optionally stabilizers included. In soft capsules, the active ingredient is preferably in

suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, dissolved or suspended, in which case stabilizers may be added.

Other oral forms of administration are for. B. in the usual way prepared syrups containing the active ingredient z. B. in suspended form

and in a concentration of about 5% to 20%, preferably about 10% or in a similar concentration, the z. For example

Measuring 5 or 10ml gives a suitable single dose included. Furthermore, z. B. also powdery or

liquid concentrates for the preparation of shakes, ζ. B. in Müch, into consideration. Such concentrates can also be found in

Be packed single dose amounts. As rectally applicable pharmaceutical preparations come z. B. Suppositories into consideration, which consists of a combination

consist of the active ingredient with a suppository base. As suppository base are z. As natural or synthetic triglycerides, paraffins, polyethylene glycols or higher alkenols. Furthermore, gelatin rectal capsules consisting of a combination of the active ingredient with a matrix may also be used; For example, liquid triglycerides, polyethylene glycols or paraffins may be used as the basic material.

For parenteral administration, e.g. Suspensions of compounds of the present invention, such as

corresponding oily injection suspensions, taking into consideration suitable lipophilic solvents or vehicles such as fatty oils, e.g. As sesame oil, or synthetic fatty acid esters, eg. As ethyl oleate or triglycerides, used, or it is suitable

aqueous injection suspensions, which viscosity-increasing substances, eg. As sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers.

Particularly suitable for parenteral administration are liposome dispersions with compounds of the formula I. The liposome end preparations are composed of at least two lipid components, e.g. As phosphatidylserine and phosphatidylethanolamine or phosphatidylserine and phosphatidylcholine, which encapsulate compounds (I). For the preparation of the üposomendispersion suitable for one lipid component phosphatidylserine of natural origin with different or identical Cw-Qa-Alkanovlresten, z. As n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-Octadecanoyt, or Сю-Сго-Аккопоу I resten, _z . в. 9-cis-dodecenoyl, 9-cis-tetradecenoyl-S-cis-hexadecenoyl, 6-cis, 6-trans, 9-cis, 9-trans or 11-iso-octadecenoyl or 9-cis-lcosenoyl, z. B. bovine brain phosphatidylserine, or synthetic phosphatidylserine with identical Сю-См-АккопоуІresten, z. Sodium-1-di-O-cis-octadecenyl-S-sn-phosphatidyl-MS) serine, and for the other lipid component phosphatidylcholine of natural origin having different or identical Cio-Cjo alkanoyl residues, e.g. B. phosphatidylcholine from the hen's egg or from soybean oil, synthetic phosphatidylcholine with identical Cm-CM-alkanoyl, z. Dimyristoyl, distearoyl or dipalmitoylphosphatidylcholine, or synthetic phosphatidylcholine with a Сю-См-АІкапоуІ- ^and a do-C ^ AIkenoylrest, z. B. 1 -n-hexadecanoyl-2- (9-cisoctadecenoyD-S-sn-phosphatidylcholine.

The üposomendispersion can be prepared by, for example, a lyophilisate from the lipid components and the compound (I) prepared according to the method described in German Offenlegungsschrift 2818655, preferably after dissolving the lipid components and the active ingredient in tert-butanol, and stripping off the solvent at temperatures Below -20 ⁰ C, and this lyophilisate dispersed in an isotonic buffer solution. The dispersion is carried out by shaking (vortex mixer) or stirring 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 method is suitable when Irpophile or in organic solvents, eg. As tert-butanol, soluble compounds (I) can be used. In the case of water-soluble compounds (I), a lyophilizate is prepared only from the lipid components and dispersed in an aqueous phase containing the dissolved compound (I).

The invention also relates to a method for the treatment of diseases in which, as described above, the reverse transcriptase of importance, characterized in that one administers a prophylactically or therapeutically effective amount of a compound according to the invention are used primarily the above said pharmaceutical preparations comprising administering to a warm-blooded animal of about 70 kg weight a daily dose of from about 0.1 g to about 5 g, preferably from about 0.5 g to about 1.5 g, of a compound of the present invention. The following examples illustrate the present invention; Temperatures are given in degrees centigrade.

Embodiment Example 1

"N-5, e-dion-e-seinicarbazon

A solution of 6.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho- [1,2-bl-pyran-5,6-dione (/ 9-lapachone) in 200 ml of a 1: 1 Mixture of ethanol and water is prepared by heating to 70 ° and the solution with 2.03g sodium acetate and 2.76g semicarbazide hydrochloride added. The resulting yellow suspension is stirred for 3 hours at 80 °, cooled to 10 ° and filtered. The filter residue is washed with 100 ml of water and in 1000 ml of acetone, wherein this is only partially soluble, boiled and filtered the mixture. The title compound available from the filtrate melts at 249-253 ° (with decomposition). Another amount of the desired compound is not soluble in the indicated amount of acetone and contained in the filter residue. Additional material can be obtained from the mother liquor.

Example 2:

2,2-DimethyM, 44-tliyl-iro-2H-naphtho [1-bl-pyran-5-e-dione-6-thiosemicarbazone A mixture of 15 g of 2-dimethyl-3A <lihydro-2H-naphtho [1,2- b] pyran-5,6-dione (/ 3-lapachone), 15.8 g thiosemicarbazide and 15.8 g of sodium acetate in 500 ml of a 1: 1 mixture of ethanol and water is refluxed for 4 hours and then cooled to room temperature , The reddish precipitate is filtered off, the residue washed with water, dried for 16 hours at 70 ° under reduced pressure and then recrystallized from 3000 ml of acetone with concentration to half volume and washed with diethyl ether. The title compound melts at 249-250 °. An additional amount of the desired product can be isolated from the mother liquor.

Example 3: W-Dlmethyi-3> 4Hhydro-2H-naphthoyl-b] pyran-5, e-dione-e- (2-dimethylaminoacetylhydrazone) hydrochloride A suspension of 7.2 g of 2,2-dimethyl-3,4 -dihydro-2H-naphtho [1,2-b] pyran-5,6-dione (/ 3-lapachone) and 6.1 g of N, N-dimethylglycine hydrazide hydrochloride in 70 ml of acetic acid is stirred for 10 minutes at a bath temperature of 100 ° C heated. The solvent is removed under reduced pressure, and the residue is dissolved in hot dimethylformamide. On cooling, Sieb forms an orange-red, crystalline precipitate, which is dried at 9O ⁰ C under high vacuum. This gives the title compound which melts at 185 ^° C. (with decomposition).

Example 4:

2,2-Dimethyl-3,4-dihydro-2H-naphtho [1 ^ -b] pyran-5,6-dione-6- (2-trimethylammonium acetylhydrazone) chloride A mixture of 7.2 g of 2,2-dimethyl 3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione (/ 3-lapachone) and 6.72 g trimethylammonioaceryihydrazide chloride in 50 mL acetic acid is heated at 100X for 10 minutes and then evaporated to dryness under reduced pressure. The resulting oily product is crystallized by repeated treatment with 1,2-dimetfeoxyäthan. The crystalline material is filtered off, dissolved in ethanol and the solution is diluted with the same amount of ethyl acetate. Upon cooling to OX, the title compound forms in the form of an orange, krisTarWnen precipitate, which melts on 21OX (with decomposition).

Beispiels-

2-Dimethyl-3,4-dihydro-2H-naphtho-1-b-pyran-5,6-dione (2-pyridinioacetylhydrazone) chloride A suspension of 7.2 g of 2,2-dimethyl 3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione (/ 3-lapachone) and 7.5 g of 1- (2-hydrazino-2-oxoethyl) -pyridiniochloride in 50 ml of acetic acid is heated for 10 minutes at 100 ⁰ C and then evaporated to dryness under reduced pressure. The resulting oily product 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 thus prepared is obtained as sesquihydrate and decomposes at 225 ⁰ C.

Examples: 2,2-dimethyl-3,4-dihydro-2H-naphtho-l1,2-b] pyran-5,6-dione-6-oxime

A solution of 2.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-bJ-pyran-5,6-dione (/ 3-lapachone) in 125 ml of ethanol and 4.2 ml of triethylamine is treated with 1.73 g of hydroxylamine hydrochloride. The reaction solution is cooled for 6 hours at 25 ° C and at 5 ° C. The crystals are filtered off with suction, washed with water and dried. The title compound obtained has a melting point of 169-171 ⁰ C.

Example 7: 2 ^ -dimethyl-3,44-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione-6-methoxime

A solution of 2.49 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione (/ 3-lapachone) in 155 ml of ethanol and 21 ml of water added with 4.22 g of sodium acetate and 4.3 g of methylhydroxylamine hydrochloride. The reaction solution is refluxed for 4 hours and cooled to 5 ° C. The crystals are filtered with suction, washed with water, dried and recrystallized from heptane. The title compound obtained has a melting point of 79-80 ° C.

Examples: 2 ^ -dimethyl-3,4-dihydro-2H-naphtho {1 ^ -b} pyran-S, 6-quinone-6-ethoxime

A solution of 2.49 g of 2,2-ditmethyl-3,4-dihydro-2H-naphthof1,2-b] pyran-5,6-dione (β) -lapachone) in 150 ml of ethanol and 20 ml of water is designated 4, 22g sodium acetate and 5.0g Äthylhydroxylaminhydrochlorid added. The reaction solution is refluxed for 4 hours 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 is crystallized from hexane. The title compound obtained melts at 72-73 ⁰ C.

Example 9: 2,2-Dimethyl-3,4-hydroxy-2H-naprrotho [1,2-b] pyran-5,6-dione-6-ethoxycarbonylmethyloxime A solution of 2.0 g of 2,2-dimethyl-3 , 4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione (/ 3-lapachone) in 1000 ml of ethanol is treated with 10 g of O-carboxymethylhydroxylamine hemihydrochloride and stirred for 2 hours at room temperature, the Solution from orange to yellow colors. The solution is evaporated to dryness, the residue dissolved in methylene chloride and washed twice with sodium bicarbonate solution. The organic phase is then washed twice with dil. HCl and once with water, dried and evaporated. The title compound in yellow needles crystallizes from the residue from ether / petroleum ether. Melting point 93-95 ⁰ C.

Example 10: 2,2-Oimethyl-3,4-dihydro-2H-naphtho (1'-b] pyran-5, e-dione-6-carboxymethyloxime A solution of 1.56 g of 2,2-dimethyl-3,4 -dihydro-2H-naphtho [1,2-b] pyran-5,6-dione (/ 3-lapachone) in 30 ml of THF is treated with 0.78 g of O-carboxymethylhydroxylamine hemihydrochloride dissolved in 8 ml of THF-H ₂ O (1: 1). The solution is evaporated to dryness, the residue is dissolved in methylene chloride and washed twice with dilute HCl and once with H ₂ The organic phase is dried and evaporated The residue is dissolved in 120 ml slurried and refluxed to warm ether, whereby the title compound as yellow crystals with a melting point of 165-167 ° C is obtained.

Example IT 2-Dimethyl-3A <lihydro-2H-naphtho {1-b-p] pyran-5, e-dione-6-carboxymethyloxime-sodium salt 1 g of 2,2-dimethyl-3,4-dihydro-2H- naphthot1,2-b] pyran-5,6-dione-6- (carboxymethyl) -oxm is dissolved in about 20 ml of dioxane and treated with equimolar amount of 1N sodium hydroxide solution. The clear solution is freeze-dried to give the title compound as a yellow powder.

Example 12: 2-Dimethyldimethyl-3,4-dihydro-2H-naprrotho [1'-b] pyran-5,6-dione-6-ethoxycarbonylhydrazone A solution of 2.0 g of 2,2-dimethyl-3,4- dihydro-2H-naphtho [1,2-b] pyran 5,6-dione (/ 3-lapachoin) in 100 ml of ethanol and 20 ml of water is treated with 0.75 g of sodium acetate and 4.8 g of hydrazinecarboxylic acid ethyl ester and heated under reflux for 50 hours , The reaction mixture is eigeengt, the residue dissolved in methylene chloride and washed twice with water. The organic phase is dried, evaporated and the residue chromatographed on 100g silica gel. It is obtained in the form of yellow crystals having a melting point of 90-95 ⁰ C the title compound.

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 10000 "tablets):

2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b] -

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

Wheat starch 790.00 g

Stearic acid 30.00 g

Magnesium stearate 30.00 g

Talc 400.00 g

The active ingredient is uniformly wetted with gelatinized wheat starch obtained by mixing 500 g of wheat starch with about 1300 ml of demineralized water and an additional 600 ml of demineralized water, kneaded to a slightly plastic mass and forced through a 3 mm mesh sieve. The granules are then dried and beaten again through a sieve. To the granules dry and uniform granule size, magnesium stearate, stearic acid, talc and the remainder of the wheat starch are mixed, and the resulting mixture is compressed 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 5000ml): 2,2-dimethyl-3-dihydro-2H-naphthol [1,2-b]

pyran-5,6-dione-6-semicarbazone 500.00 g

Propylene glycol 500.00 g

Hydroxypropylmethylcellulose 25.00 g

Citric acid 5.00 g

Saccharin sodium 2.50 g

4-hydroxybenzoic acid methyl ester 6.00 g

Propyl 4-hydroxybenzoate 1.50 g

Raspberry flavor 5.00g

70% aqueous sorbitol solution 1250 ml

demineralised water q.s.

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

Example 15: Capsules containing in each case 300 mg of 2,2-dimethyl-3- _f 4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione-6-semicarbazone can be prepared as follows:

Composition (for 10000 capsules) 2,2-Dimethyl-3,4-dithydro-2H-naphtho [1,2-b] -

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

Magnesium stearate 100.00 g

The active ingredient is mixed with the magnesium stearate and each filled 0.31 g of the mixture by means of an encapsulation machine in hard gelatin capsules.

Example 16: An aqueous suspension for injection (for intramuscular administration) containing 1.0 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione-6 semicarbazone per 5 ml, can be prepared as follows:

Suspension medium:

Sodium salt of carboxymethylcellulose 0.10% Mixture of sodium hydrogen phosphate and Disodium hydrogen phosphate 0.15% sodium chloride 0.75% Sodium salt of the S-alkylmercuric thiosalicylic acid (thiomersal) 0.02% 1,2-propylene glycol 20.00% Distilled water ad 100.00%

The sterile 2,2-dimethyl-3,4-dihydro-2H-naphtho {1,2-b] pyran-5,6-dione-6-semicarbazone active ingredient is processed under antimicrobial conditions with the suspension medium to provide a sterile medium Suspension, which receives 1, Og of the active ingredient in 5 ml.

Example 17: An aqueous suspension for injection (for intramuscular administration) containing 0.75 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho [1,2-b] pyran-5,6-dione-6 semicarbazone per 5ml, can be prepared as follows:

Suspension medium:

Sodium chloride 0.90%

Sodium salt of S-ethylmercuric acid

thiosalicylic acid (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 ingredient is processed under antimicrobial conditions with the suspension medium so as to obtain a sterile suspension containing 0.75 g of active ingredient in 5 ml.

Claims (1)

1. Process for the preparation of compounds of the formula I. I ³ алл wherein R ₁ and R _{2 are} independently hydrogen, lower alkyl or aryl or taken together lower alkylene, one of R ₃ and R _{4 represents} the group = NR (I a), wherein R is the group -OR, (I b) and R _{a is} hydrogen , Lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R is the group -N (R _b ) -R _c (Ic) and R _b and R _c are each independently hydrogen or lower alkyl or one of R _b and R _{c is} hydrogen and the other group is C (^ = X) -R (J wherein X is oxo and Rd is lower alkoxy, di-lower alkylamino lower alkyl, tri-lower alkyiarepmonone-lower alkyl, lower alkyleneamino-lower alkyl, oxo-lower alkylene-lower alkyl, thian-lower alkyleneamino-lower alkyl, optionally lower alkyl aza-substituted azan-lower alkyleneamino-lower alkyl or pyridinio-lower alkyl or X is oxo or thioxo and R _{d is} amino, or both radicals R _b and R _{c taken} together lower alkylene, Oxaniederalkylen, Thianiederalkyfen or optionally by lower alkyl mean aza-substituted Azaniederalkylen, and the other of the two radicals R 3 and R ₄ has the same meanings or is oxo and the ring A has no further substituents or is additionally substituted by lower alkyl, lower alkoxy and / or halogen, and salts of salt-forming of such compounds with Properties, characterized in that a compound of the formula