Derived nitrogenized compounds oxo, proceeded of preparation and pharmaceutical compositions comprising them.

The present invention relates to nitrogen-containing oxo compounds as well as their preparation, and even as pharmaceutical formulations containing such compounds and the application thereof as pharmaceutical active substances.

Primarily the invention relates to compounds of formula

The s/e VBE1 VBE1

ii has the II ii

Π \ / \

■' the L^]

The RT,

vBE1/

IR

(I-),

where r1 and r2 ' represent independently of one another represent hydrogen, lower alkyl or aryl or, taken together, a lower alkylene, one of the radicals r3 and Ra represents the group by n-r=(the), wherein R is the group - (lb) d the Ra and Ra represents a hydrogen, a lower alkyl, a carboxyalkyl or a lower alkoxycarbonyl-lower lower alkyl or R represents the group - L-L \ α (RBs)- RC-(the) and RB and RC are independently of each other hydrogen or lower alkyl or one of the radicals

■Rb and Rc represents hydrogen and the other radical is the group

The c - (=the X) - DR, wherein X represents oxo and Rd is lower alkoxy,

a lower dialkyl lower-aminoalkyl, a trialkyl inferior trimethylammonioethyl methacrylate lower alkyl, a lower alkylene-lower aminoalkyl, a oxaalcoylene inferior-ammonio lower alkyl, a lower thiaalcoylene lower-aminoalkyl, a azaalcoylene lower-aminoalkyl optionally substituted lower in aza-by a lower alkyl or a lower pyridinioalcoyle or X represents oxo or thioxo and Rd represents an amino, or both radicals Rb and Rc taken together represent a lower alkylene, a lower oxaalcoylene, a thiaalcoylene azaalcoylene lower or an optionally substituted lower in aza-by a lower alkyl, and the other of

two radicals r3 and Ra has the same meanings or represents an oxo and

the core has has not further substituents or is further substituted by a

one or more substituents selected from lower alkyl, lower alkoxy and halogen, as well as salts of such compounds having properties salificatrices.

Above as below the radicals and organic compounds designated "lower" contain up to 7 carbon atoms ranging, preferably up to 4 inclusive, and firstly 1 or 2. Lower alkylene radicals preferably contain 5 or has carbon atoms.

Lower alkyl primarily represents methyl and ethyl, but may also represent n-propyl, isopcopyle, n-butyl, isobutyl or tert-butyl, or n-pentyl, n-hexyl and n-heptyl.

Aryl is primarily a monocyclic aryl, carbocyclic,

e.g.. an optionally substituted phenyl, and the substituents may be inter alia lower alkyl, lower alkoxy at halogen.

Lower alkoxy is especially methoxy or ethoxy, or the n-butoxy, isopropoxy group, n-butoxy or isobutoxyethyl and n pentylaxy.

Halogen is preferably halogen having an atomic number of at most 35, it is to say the fluorine, chlorine or bromine.

Lower alkylene is e.g.. the 1.4-butylene, the 1.5-pentylene or 1.6-hexylene.

Lower carboxyalkyl is firstly carboxymêthyle

and 2 ethyl acrylate and 3 carboxy-n-propyl.

Lower alkoxy-carbonylalcoyle lower is first methoxy - or ethoxycarbonylmethyl and 2-methoxy - or 2 a-ethoxycarbonylethyl.

Lower dialkyl lower-aminoalkyl is preferably dimethylamino -, diethylamino -, di-n-propylamino - or n-ethyl-n-méthylaminométhyle and 2-dimethylaminoethyl.

Trialkyl inférieurammonioalcoyle lower is preferably n-diethyl-n-methyl trimethylammonioethyl triméthylammoniométhyle ee.t - or 2 a-trimethylammonioethyl.

Lower alkylene is preferably inférieuraminaalcoyle 1 a-pyrrolidinométhyle, 2 - (1 a-of pyrrolidino) ethyl, 1 a-pipéridinométhyle, 2 - (1-piperidino) ethyl, 2 - and 1 a-hexahydroazépinométhyle (1 a-hexahydraazépino) ethyl,

□ xaalcoylene lower alkylamino lower-aminoalkyl thiaalcoylene - and are preferably less than 4 a-morphalino - and 4 a-thiamorpholinométhyle and 2 - (4 morpholino) - 2 and - (4 a-thiomorpholino) - ethyl.

Azaalcoylene inférieuraminoalcoyle optionally substituted lower in an aza by lower alkyl is preferably 1 to-pipérazinométhyle, 2 - (1-piperazino) ethyl, 4-methyl - or 4-ethyl-L-pipérazinométhyle and 4-methyl - or 4 ethyl 2 - (1 a-pipérazina) ethyl.

Is preferably lower Pyridinioalcoyle pyridiniomethyl

and 2 a-pyridinioéthyle.

□ xaalcoylene lower ec. thiaalcaylene lower are especially 3 a-oxa 1.5-pentylene or wetting 3-thia 1.5-pentylene.

Lower azaalcoylene optionally substituted by lower alkyl is e.g.. 3 aza-1.5-pentylene or 3 methyl-3 aza-1.5-pentylene.

Preferably, in the compounds of formula I, only one of the radicals r3 and Of Rh, firstly the radical r3, represents the group of formula la, while the other represents the AXA.

The salts of the compounds of the formula I having properties are primarily salificatrices pharmaceutically acceptable salts, P-.

the ex. acid addition salts of such compounds with basic groups, such as the addition salts with inorganic acids, e.g.. hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, such as carboxylic or sulfonic acids, e.g.. acetic acids, maleic, fumaric, malic, oxalic, tartaric, citric, methanesulfonic or P-toluenesulfonic acid. The quaternary nitrogen compounds where the radical Rd is a trialkyl - or lower trimethylammonioethyl pyridinioalcoyle lower

preferably take the form of pharmaceutically acceptable quaternary salts, 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 believed that the compounds of 1 'invention are percurseurs drug for 1' inhibition of reverse transcriptase, an enzyme characteristic retroviruses (or onconarvirus), RNA viruses as tumors and leucé crumb; retroviruses need of this enzyme for their replication cycle natural (in Baltimore, in nature, flight. 226, p. 1209 (1970); and TeminMizutani and, in nature, flight. 226, e. 1211 (1970)).

□ n can establish the action of inhibiting the reverse transcriptase and viral replication using in vivo experimental devices. Thus the compounds of formula I possess a high efficiency in experiments in animals in certain neoplastic diseases which are caused by tumor viruses MRA, or wherein the CN can evidence of RNA tumor viruses. They lengthen e.g.. the mean survival of mouse after infection with leukemia virus Rausch has (VLANs, tumor viruses

rNA).

In the experiments with leukemia of Rausch has 4 Q-(nih batteries) is infected of Balb/cc.ç (aged 28 to 34 days of) with 0.2 ml of a viral suspension diluted ten times (Hank's solution) from material of mouse spleen 4 to 6 weeks previously infected. In an experiment is treated in each case 15 animals with either the experimental compound, either as controls with a placebo, and is arranged orally. The first administration is performed 30 minutes prior to infection, other administration 1 times a day and 5 times a week for 4 weeks. As a criterion for the action

used by prolonging the duration of survival. While in animals...

controls may be found from 28 days after infection leukemia with leukemic blood cells to more than 50 OQO/NORM³ and that the:

animals begin to death, the ' survival time female mouse treated with 125 mg/kg of substance P O experimental elongates significantly. E.g. it rises. for the 2.2-dimethyl-3.4 to-willwill dihydra-to-2h-to-naphtozï, 2 a-tjfpyrane-to-ss.é dione and welfare-to-semicarbazone'semicarbazone' with 20 shots P O to Balb/c-female of 125 mg/kg in each case (10 animals per group) to 53.5 days, to be compared with the time of survival of 26.0 days control animals (P-^ 0.01 Cox testing).

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-to-naphtozï, 2 a-b7pyrane and 5.6 and Diana-a 6 a-semicarbazane mentioned above in mice rises after administration w,₀ . and ii.p.

then an observation period of 7 days to more than 2500 mg/kg body weight.

The highlighting of diseases that are caused by retroviruses is based e.g.. on the following findings: the revealing of the retroviruses c and their formation of reverse transcriptase in humans occurs at first in a T cell leukemia; the virus has been called "the human tert-Glial cell leukaemia viruses" (virus human T cell leukemia) (cancer cells). In other leukemias and lymphomas T cells a similar set, virus and retrovirus-like (with HTLV-II) (Friedman, diagnoses of cancer (benzoylacetanilide dir. fine colle. Franks as, Wyke and Weiss), v. 3, P 113 - 160 (the Oxford Mlev.

Press assembly, 1984)). Finally also isolated a virus of this type in connection with damage of aids (Muir cfimmuno-to-specify icience acquired) (Gottlieb and al,Morbid. Morbid. Tri rep, v. 30, 25 P, (1981); Friedmann-Fujian et, Morbid. Morbid. Tri rep, v. 30, ρ. 305 (1981); Gottlieb and al, JAMA nu. J Med., flight. 305, ' p (1981) 1425; making and, JAMA nu. J Med., flight. 305, p ' 1431 (1981); Siegal et, JAMA nu. J Med., flight. 305, e. 1439 (1981); CDCs Task Force Kaspoi's sarcoma and non-Opportunistic infection, JAMA ^ nu. J Med., flight. 306, e. 248 (1982));

it has been described as to HTLV-III(Essex and al, forensic science, flight. 220, p-.

859 (1983), Gelmann et, flight. 220, p (1983) 862; Gallo and al, forensic science, flight. 220, p (1983) 865; Friedman, of cancer diagnoses, v. 3 w. 113 (1984); Barred-to-sinoussi and al, science and flight. 220, 868 (1983); To negotiated and Levy, Microbiology independence in human Malignancy NDA sida, perforation/BCAA Symposia, ' May 1984, in Toronto).

Said retroviruses belonging to the HTLV family require reverse transcriptase double stranded DNA (proviruses), which is "integrated" in the genome of the cell and can lead to malignant transformatio (Strayer and Shipp, tea type methods and practices retrovirus gene in-animals cells involved, Virology Audiovisuals, flight 17 (Springer with Ed., 1980)).

While following induction of neoplasias leukemic, lymphatic or malignant tumor by retroviruses can carry a decrease of reverse transcriptase. the HTLV-I and - II and that oncogene induced side these viruses direct replication of malignant cells, can carry the HTLV-III virus - and reverse transcriptase in aids not only at the early stage, but also during the entire course of the disease. Infection that develops and the destruction of the function of immunocompetent T helper cell line finally

the breakdown of the immune system with fatal outcome. Must be allowed that a - inhibition of reverse transcriptase and viral replication in highlighting positively the enzyme and a viral antigen (Beardsley, in nature, flight. 3.11, e. 195 (1984) influences the course of the disease in patients at risk, e.g.. the homosexuals. In the induction of leukemia and lymphoma by retroviruses (HTLV-I and HTLV 1i) and âventuellement also in sarcomas or mammary carcinomas induced by retroviruses, a prophylactic application must however be possible, in the. since it can be assumed a census diagnostic easy and widely scattered from these patients at risk.

It has also been found in connection with hepatitis non-A - naan and

B the reverse transcriptase as specific enzyme in combination with viral particles (Seto and al, the Lancet, P (1984) 941).

Can thus be applied the compounds of the present application

the prophylaxis and treatment of. diseases have reached reverse transcriptase

is important, especially malignant diseases caused or co-caused by retroviruses type c, but also of certain immune or autoimmune diseases. As tumor diseases also mentions primarily leukemias, lymphomas and lymphosarcomas caused by retroviruses, as well as bone and breast carcinomas. The compounds of the invention are also useful for prophylaxis of recurrence after surgical treatment, radiation treatment or chemotherapy cytostatic or antimetabolic. As immune disease aids there can be mentioned, and as autoimmune disease web ' systemic lupus erythematosus,

where according to recent discoveries the RNA tumor viruses appear to also play an important role (Dennman, Med., Biol., flight. 53, 61 p (1975); Panem

et, nu NewEngland J Med., flight. =295, 470 (1976)).

The invention relates especially to compounds of formula

I where r1 - represents a hydrogen or a lower alkyl, r2 represents a hydrogen, a lower alkyl or phenyl, one of the radicals r3 and A RU,

preferably r3, represents the group by n-r=(the), wherein R represents the group

- (Lb) O the Ra and Ra represents a hydrogen, a lower alkyl, a lower carboxyalkyl or a lower alkoxycarbonyl-alkyl lower or R represents the group - D (RBs)- RC-(the) and RB and RC are independently of each other hydrogen or lower alkyl - or one of the radicals.

Rb and Rc represents hydrogen and the other of the group - C. (=the X) - rd.,

wherein X represents an oxo and Rd represents a lower alkoxy, a lower dialkyl inferior-aminoalkyl, a trialkyl-lower ammanioalcoyle lower, a lower alkylene-lower aminoalkyl, a 4 a-marphalinoalcoyle lower, a 4-alkyl lower L-pipérazinbalcoylëpyridinioalcoyle lower or a lower or X is oxo or URIs thioxooxazolidinones and Rd represents an amino,

or the two radicals Rb and Rc taken together represent a lower alkylene, a 3 a-oxa 1.5-pentylene or 3-alkyl-lower 3 aza-~pentylène 1.5, and the other of the two radicals r3 r4 and, preferably r4, represents an oxo,

and the core has has not further substituents or is further substituted by a or of substituents selected from lower alkyl, lower alkoxy or halogen, and the radicals described as "lower" contain of preferably 1 or 2 atoms of carbon, lower alkylene radicals contain 4 or 5 carbon atoms, and halogen with an atomic number ofat most 35, and the salts, in particular the salts pharmaceutiquemsnt acceptable, such compounds having properties salificatrices.

L-.' invention especially relates to the compounds of formula

I where r1 represents a hydrogen or a lower alkyl and r2 represents

a lower alkyl or phenyl, r3, represents a group of formula

- (The) n-R, wherein R is the group - O the Ra and Ra (lb) represents lower alkyl, lower alkoxycarbonyl or a carboxyalkyl-lower alcayle lower or R represents the group - D (RBs)- RC-(the), one of the radicals to RB

and RC is hydrogen and the other radical represents the group

The c - (" the X) - DR, wherein X represents oxo or thioxooxazolidinones and Rd. represents amino or both radicals Rb and Rc taken together represent a lower alkylene,

a 3 a-oxa 1.5-pentylene or 3 a-aIcoyle inferior-3 aza-1.5-pentylene, and

A RU represents an oxo, and the core has has not. other substituents, where the radicals described, as "lower" 1 or 2 preferably contain atoms

•carbon, lower alkylene radicals U. 5 or more carbon atoms, and

the sels,-especially the pharmaceutically acceptable salts, such compounds having properties salificatrices.

The invention relates to the compounds of the formula I wherein r1 represents hydrogen or lower alkyl, P ' an ex. methyl ., r2 represents lower alkyl, e.g. methyl, or-phenyl, r3 represents the group by n-r=(the) and R represents the group - - VI (RBs)- RC-(the), wherein RB is one-to-radicals -

and RC is hydrogen and the other radical-represents the group

The c - (=the X) - DR (IDs), oùoù.x represents an oxo and ' Rçi represents an amino, where the radicals described^- as ' "lower"^- in contain. first. place a, or two carbon atoms.

Is, prepares the carrier compounds of the invention - according to des-..procédés known, e.g.. by, react^- a compound of formula. , •

wherein one of Rx and Ry represents an oxo. and the other is

oxo or the group=by n-r (the), and ri and r2 as well as the core has the formula

R in group II and the have the significances given above, with a compound of formula (II) h21m - r, wherein R has the meaning given above, and,

if desired, converting a resulting compound into another compound according to the invention and/or, if desired, converting a resulting salt into

the free compound or another salt or by converting a resulting free compound having a salt forming groups.

As starting materials are preferably used compounds of formula n where the two radicals Rx and Ry represent 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 acid or sulfuric acid, or organic acids.

The reaction is carried out in known manner, preferably in the presence of a base, such as an alkali metal lower alkanoate, P-.

the ex. sodium acetate, and/or a diluent, preferably polar, as of a lower alkanol, e.g.. ethanol, a cyclic ether, e.g._; tetrahydrofuran or dioxane, or an amide, e.g.. dimethylformamide, by cooling, e.g.. in a temperature range of from about to about 12d °C 1q °C, preferably 50 °c to about 100 °c, if necessary in a closed vessel and/or pressurized. in an inert gas atmosphere.

The obtained compounds can be transformed into other

. compounds, of the invention, e. g. as well. those of-formula I with a group of the formula - C. (=the X) - DR (IDs), where Rd is lower dialkyl lower-aminoalkyl group, by treatment with a reactive ester of a lower alkanol, as a lower alkyl halide, e.g.. chloride, bromide or iodide, in compounds having an inferior-ammonioalcoyle lower trialkyl group

DR.

Salts of compounds of formula I can be obtained as that year

the method may be transformed, in known manner, e.g.. the acid addition salts by treatment with a suitable base, in the free compounds.

The quaternary salts can be transformed e.g.. by treatment with a suitable acid or an anion exchanger in another quaternary salt.

The compounds of the formula I having properties e.g. salificatrices convertable. by treatment with an acid or an appropriate ion exchanger in the desired salts.

The starting materials. formulae II and III used in the above process are known or can, if they are new, be prepared in a known manner.

The invention also relates to preparations showed ' pharmaceutical which contain as active ingredient one of the compounds according to the invention. As for the pharmaceutical preparations according to the invention these are those for enteral, such as oral or rectal, or parenteral, E.P.' X-. iV, ii.m. The preparations contain the active substance alone or preferably with a pharmaceutically acceptable carrier. The dosage of the active substance depends on the species to be treated, the age and the individual state, - as well as the mode of application.

The pharmaceutical preparations contain about 5%

to about 95 c/o of active substance, and the single dose administration forms preferably have from about 20% to about 90% and the application forms to single dose not have preferably about 5% to about 20% of active substance.

The pharmaceutical preparations of the invention in unit dosage form, such as pills, tablets, caplets, suppositories or ampoules, contain from about 0.05 g to about 1.5 grams, 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 conventional methods of mixing, granulating, sugar-coating, dissolving or lyophilizing; this permits preparations' pharmaceutical for oral application by combining the active compound with one or more solid carriers, if desired granulating a mixture obtained, and processing the blend or wetting the granulate, if desired, optionally after addition of additives, additional, in tablets or dragee cores.

. The relevant carriers are in particular the fillers, such as sugars, e.g.. lactose, sucrose, mannitol ' or sorbitol, cellulose preparations and/or calcium phosphates, e.g.. tricalcium phosphate or. the phosphated, acid - - of the calcium ', or binders, such as starches, e. g... of corn starch, wheat, rice or potato, the méthylcellulcse, the hydroxypropylméthylcellulase, carboxymethylcellulose sadistic and/or polyvinylpyrrolidone, and/or, if. desired, solvents, as the ' starches mentioned above, still the carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. The additional additives are primarily the viscosity regulators and lubricants, e.g..

the silicic acid, talc, stearic acid or salts thereof, such as stearate

magnesium or calcium, and/or polyethylene glycol.

Dragee cores are provided with suitable coatings ., -.

optionally resistant - gastric juice; and used inter alia of sugar solutions concentrated-which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol/stored characteristics or titanium dioxide, lacquer solutions in suitable solvents or solvent mixtures or, for preparing coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as

acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.

May be added to the ' tablets or dragee coatings, dyes -^: or pigments, e.g.. to identify or characterization of different doses of active ingredient.

Other preparations, pharmaceutical applicable by

oral are gelatin capsules as well as the closed capsules' soft made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain, the substance actiyèsous. the form of a granule, e.g.. mixed with fillers, as. corn starch, binders and/or dice lubricants, such as talcum. or stearate, of.' magnesium, and. optionally stabilizers. In soft capsules, the above active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, oil. liquid paraffin or the palyêthylèneglycols, and also can be added stabilizers.

■other forms of oral application e.g. sont.p... the.syrups prepared in the usual manner, which contain the. an active material. soussous.fo.rite suspended and at a concentration of about 5% to 20%, preferably about 10% or

at a concentration like, e.g. which gives. when measuring 5 or 1q

a suitable unit dose per ml. Further P-it may also be considered.

the ex. powdered concentrates at liquid for preparing liquids' whipped ("smoothies"), e.g.. in the milk. Such concentrates can also be packed in unit doses.

As preparations of pharmacy rectally applicable also mentions e.g.. the suppositories which consist of a combination of the active ingredient with a suppository base. As suppository base e.g. may be used. the natural or synthetic triglycerides, paraffin, the polyêthylèneglycols₀ u-higher alkanols.

In addition may also be used gelatin rectal capsules which consist of a combination of the active compound with a carrier;

as products for e.g. carriers there can be mentioned. liquid triglycerides, the polyêthylèneglycols or paraffins.

For parenteral administration e.g. also mentions. the suspensions of compounds of the invention, as the corresponding oily injectable suspensions, and using solvents or suitable lipophilic vehicles, such as fatty oils, e.g. · ρ.. sesame oil, or synthetic fatty acid esters, e.g.. ethyl oleate or triglycerides, or can employ aqueous injectable suspensions. lifting body contain viscosity, e.g.. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally stabilizers.

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

For preparing the liposome dispersion might be used for the lipid component. phosphatidylserine of natural origin with alkanoyl radicals' ClO ' c20 to different or identical, e.g.. n dodêcanoyle, or n-tetradecanoyl, n hexadecanoyl or n-octadecanoyl, or alkenoyl radicals in c10 to c20, e.g.. 9 cis-dodécénoyle, 9 cis-tétradêcênoyle, 9 cis-hexadécénoyle, 6 cis--, 6 trans -, 9 cis--, 9 trans - or 11-cis octadécénpyle or 9 cis-icosénoyle, e.g.. beef brain phosphatidylserine, or synthetic phosphatidylserine with ' alkenoyl radicals in c10 to c2q identical, e.g.. the 1.2 di - (9 cis-octadecenoyl) - 3 Sn-phosphatidyl - (O)- serine sodium, and for the other lipid component phosphatidylcholine of natural origin with alkanoyl radicals c10 c20 to different at identical, e.g.-a chicken egg phosphatidylcholine soybean oil had, synthetic phosphatidylcholine with alkanoyl radicals in. To ClO: ç2q. identical, -, .

e.g.. the ' dimyristoylphosphatidyl -, panel-.distéaroyl -^: or dipalmitoylphosphatidylcholine, or synthetic phosphatidylcholine with a ' çiü alkanoyl moiety. to.

CZD and a radical alkenoyl in c10 to c20, e.g. '-a 1 n-hexadecanoyl-a 2 - (9 -' cis octadecenoyl) - 3 Sn-phosphatidyl choline.

□ n can prepare the liposome dispersion by preparing e.g. a lyophilisate from components-lipid of the compound (I-) and according to the method described in Patent published in Germany in the № Β 1b 655 2, preferably after dissolution of the lipid components 5 and active substance in tert-butanol, and removal of the solvent

at temperatures below - z0°, and dispersing the lyophilisate in an isotonic buffer solution. The dispersion is carried out by shaking (swirl mixer) or by stirring the aqueous phase. Then may enrich the liposome dispersion by centrifugation and/or the separating by filtration

^ on gel or extrusion through filters to straight pores.

This method is suitable when using compounds (I-) lipophilic or starch soluble in organic solvents, e.g.. tert-butanol for compounds (I-) water-soluble a lyophilisate prepared from only lipid components and is dispersed in an aqueous phase

⁵ which contains the compound (I-) dissolved.

•also disclosed is a method of treating diseases in which, as mentioned above, the reverse transcriptase is important, characterized in administering a prophylactically or therapeutically effective amount of a compound according to the invention. Is

1 uses here first the pharmaceutical preparations mentioned above, and the method comprises administering to a warm-blooded animal weighing about 70 kg d is a daily dose from about 0.1 g to about 5 grams, preferably about 1.5 g to about■0.5 g of a compound of the invention.

The following examples further specify the invention; the temperatures are indicated in degrees Celsius.

The invention also relates, as new industrial products, the compounds obtained by implementing the method defined above; these products are however not protected by this patent for their uses in therapy.

Example 1: 2.2-dimethyl-3.4 dihydro-2h-naphtho/liter, 2 a-b7pyrane and 5.6-to-dione 6 a-semicarbazone linkage

□ b is prepared by heating a solution of 6.0 to 70° g of 2.2-dimethyl-3.4 dihydro-2h-to-naphnaph.to/î, 2 a-b7-pyran-to-5.6 dione (β-lapachone in) in 200 ml of a 1:1 mixture of ethanol and ee.au and mixing the solution with 2.03 g of sodium acetate and 2.76 g of semicarbazide hydrochloride. The mixture is stirred 3 hr to 80° yellow suspension which forms, is cooled to 10° and filtering. The filtration residue is washed with 100 ml of water and is boiled

In 1000 ml of acetone•, as it. that is soluble only in part, and is. filter, the mixture. The compound of the titrenbtenu from the filtrate melts at 269 - 253 degrees (with decomposition). An additional quantity of the desired compound is not soluble in the indicated amount of acetone and is obtainable in the filtration residue. There can be obtained a further quantity of material from

•from the mother liquor;

Example 2: 2.2 to-dimétdimét.hyl-to-3.6 dihydro-2h-naphtho/L-, 2~b7pyrane and 5.6-to-diohe and 6 a-thiosemicarbazone for..

Is heated during 4 Irau refluxing a mixture of 15 g of 2, 2 -

•dimétbyl and 3.4 to-dihydrb-to-2. H haphto2T, 2 a-b7pyrane and 5.6 dione (13 a-lapachone in), '/. 15', 8 g of thiosémicarbazidè. and 15.8 g of sodium in 500 ml açétàte a 1:1 mixture of ethanol and eaupuis is cooled to room temperature (AEG). The precipitate is separated by filtration reddish, ' the residue is washed with water, dried for 16 H at 70° under reduced pressure then recristailise. from 3000 ml of acetone with concentration to half the volume and onon.lave with the title compound. diéthylétheri resulting melts at 2.49 - 250 degrees. Can be isolated from the mother liquor a further quantity of the desired product.

Example 3: hydrochloride 2.2-to-dirnéthyl-to-3 ,' 6 a-dihydr'dihydr' o-to-2HTnaphto/T-, 2 a-b7pyrane and 5.6-to-dione 6 - (Z diméthyiaminoacétylhydrazane)

Is heated during 10 minutes at a bath temperature of

A suspension of 7.2 grams 100° de 2.2-dimethyl-3.4 to-willwill dihydra-to-2h-naphtho - / î, 2 a-b7

, pyran-to-5.6 dione (β-the apachone) and 6.1 g of L-VBE1 is L, n Dimethylgly-NICE hydrazide in 70 ml of acetic acid. The solvent is removed under reduced pressure, and the residue is dissolved in dimethylformamide (Vilsmeier) hot. Upon.

cooling a precipitate red-orange crystalline, that.

dry 9q ° under a high vacuum. This gives the title compound, that melts 185° (with decomposition).

Example 4: chloride 2.2-dimethyl-3.4 dihydro-2h-naphtho./ T-, 2 a-b7pyrane-a 5.6 - - dione 6 (2 a-triméthylammonioacétylhydrazone)

Is heated during 10 minutes to 100° a mixture of 7.2 g of 2.2-dimethyl-3.4 dihydro-2h-naphtho_{the I} 7^,ï, 2 a-tl7pyrane and 5.6 dione (β-lapachone in)

and 6.72 g of chloride in 50 ml of acetic acid triméthylammonioacétylhydrazide then concentrate to dryness at reduced pressure. The oily product obtained is crystallized by treating it several times with 1.2 to-diméthoxyêthane. Removed by filtration the crystalline material, is dissolved in ethanol and the solution is diluted with the same amount of ethyl acetate.

Upon cooling to 0°-form of the title compound as an orange colored crystalline precipitate, which melts at 210° (with decomposition).

Example 5: chloride 2.2-dimethyl-3.4 dihydro-2h-naphtho/î, 2 a-b7pyrane-a 5.6 - dione 6 - (2 a-pyridinioacétylhydrazone)

Is heated during 10 minutes to a suspension of 100°

7.2 g of 2_I 2-dimethyl-3.4 dihydro-2h-naphtho/3.2 and b7pyrane and 5.6 dione (β-lapachone in) and 7.5 g of 1 - (2 a-hydrazino moiety and 2 a-oxoethyl) in 50 ml acetic acid pyridiniochlorure then concentrate to dryness at reduced pressure. The oily product obtained is crystallized by treating it several times with 1.2 to-dimethoxyethane. Removed by filtration and the crystalline material is crystallized from isopropanol and then from acetonitrile. Obtained the title compound thus prepared as sesquihydrate and it decomposes to

225°.

Example 6: 2.2-dimethyl-3.4 dihydro-2h-to-naphtha/1.2 to-b7pyrane and 5.6-to-dione 6 oxime

A solution of 2, d-g of 2.2-dimethyl-3.4 dihydro-2h-naphtho/liter, 2 - ^ 7pyrane and 5.6 dione (β-lapachone in) in 125 ml of ethanol and

4.2 ml of triethylamine with 1.73 g of hydroxylamine hydrochloride. Agitated

the reaction solution during 6 - H at 25 °c and is cooled to 5°. Crystals are filtered with a filter funnel, washed with water and dried. The title compound obtained has a melting point of 169 - 171 degrees.

Example 7: 2.2-dimethyl-3.4 dihydro-2HmâphtQ/T-; 2 a-t37pyrane and 5.6-to-'diane-a' 6 a-méthoxime

GnRH mixture 2.49 g of each solution 2.2-to-dimêthyl-to-3.4 dihydro-2h-to-naphto£f, 2 a-b7pyrane and 5.6-to-Diana. (β-lapachone in) in. 155 ml, 'd ' 21 ml ethanol and water with 4.22 g of sodium acetate and 4.3 g of hydrochloride mâthyl hydroxyl amine. one heats the reaction solution at reflux for

4 h and is cooled to 5°. GnRH filter the crystals with a filter funnel, washed with water, dried and recrystallized from heptane. The title compound obtained has a Pf of 79 - 80 degrees.

EXAMPLE 8: 2.2-dimethyl-3.4 to-willwill dihydra-to-2h-naphtho/T-, 2 a-jJ7pyrane and 5.6-to-quinone-a 6 a-éthoxime

GnRH mixture a solution of 2.49 g of 2.2-dimethyl-3.4 dihydro-2h-to-naphtoZT, 2 a-b7pyrane and 5.6 dione (β-lapachone in) in 150 ml of ethanol and 20 ml of water with 4.22 g of sodium acetate and 5.0 g of ethylhydroxylamine hydrochloride. GnRH heats the reaction solution at reflux for

4 hr then concentrate to dryness. The residue is dissolved in methylene chloride and washed 2 times the organic phase with water. The organic phase is dried, concentrated to dryness and crystallizing the residue from hexane. The title compound obtained melts at 72 - 73 degrees.

' Example 9: 2.2-dimethyl-3.4 to-willwill dihydra-to-2h-to-naphtozî, .2 a-b7pyrane and 5.6-to-dione 6 a-éthoxycarbonylmêthyloxime

A solution of 2.0 g of 2.2 to-dimêthyl-to-3.4 dihydro-2h-to-naphto£T, 2 a-ti7pyrane and 5.6 dione. (Β-lapachone in) in 1000 ml of ethanol with 10 g of hémichlorhydrate Q-carboxyméthylhydroxylamine and mixture is stirred 2 hr to Ta, and the solution changes from orange to yellow. The solution is concentrated to dryness, is dissolved. the residue in methylene chloride and washed 2 times with a sodium bicarbonate solution. Then washed.

2 times the organic phase with diluted HCl and 1 times with water, dried and concentrated. From the residue crystallizes from ether/petroleum ether the title compound as yellow needles. FP 93 - 95 degrees.

Example 10: 2.2-dimethyl-3.4 dihydro-2h-naphtho/ï, 2 a-b7pyrane and 5.6-to-dione 6 a-carboxymethyloxime

Mixing a solution key 1.56 g of 2.2-dimethyl-3.4 dihydro-2h-to-naphtoZT, 2 a-b7pyrane and 5.6 dione (13 a-lapachone in) in 30 ml of THF with 0.78 g of hémichlorhydrate Q-carboxyméthylhydroxylamine, dissolved in

8 ml THF-h20 (1:1), and the mixture is stirred 8 hr to Ta. The solution is concentrated to dryness, the residue is dissolved in methylene chloride and washed 2 times with diluted HCl and 1 times with h20. The organic phase is dried

and is concentrated. The residue is suspended in 120 ml of ether hot

and is heated to reflux, and obtained the title compound as yellow crystals FW 165 - 167 degrees.

Example 11: sodium salt of 2.2-dimethyl-3.4 dihydro-2h-naphtho_J The £F., 2 a-b7pyrane and 5.6-to-dione 6 a-carboxymethyloxime

1 G of dissolved 2.2-dimethyl-3.4 dihydro-2h-to-naphto£î, 2 a-tj7-pyran-to-5.6-to-dione 6 - (carboxymethyl) - oxime in about 20 ml of dioxane and mixed with an equimolar amount of sodium hydroxide solution 1 MI. The clear solution is freeze-dried, giving the title compound as a yellow powder.

Example 12: 2.2-dimethyl-3.4 dihydro-to ZH-to-naphtOj/liter, 2 a-jj7pyrane and 5.6-to-dione 6 a-éthoxycarbonylhydrazone

A solution of 2.0 g of 2.2-dimethyl-3.4 dihydro-2h-to-naphto£f, 2 a-£7pyrane and 5.6 dione (13 a-lapachone in) in 100 ml of ethanol and

20 ml water with 0.75 g of sodium acetate and 4.8 g of hydrazinecarboxylic acid ethyl ester and heating at reflux for 50 hr. The reaction mixture is concentrated, the residue is dissolved in methylene chloride

and washed 2 times with water. The organic phase is dried, concentrated

and chromatography the residue on 100 g of silica gel. The polymeric compound of the title is obtained in the form of yellow crystals and with a m.p. of 90 - 95 degrees.

Example 13: may be prepared tablets containing 500 mg of 2.2-dimethyl-3.4 dihydro-2h-naphtho/T-, 2 a-b7pyrane and 5.6-to-dione 6 a-semicarbazone linkage as follows:

The composition (for 10,000 tablets):,

2.2-to-diméthy] and 3.4 dihydro-2h-naphtho/R., 2 a-ti7-pyran-to-5.6-to-dione 6 a-semicarbazone linkage 5000.00_grams

Wheat starch 790.00 grams stearic acid 30.00 30.00 grams magnesium stearate 400.00 grams of talc grams

The active substance is moistened uniformly with wheat starch gel, which was obtained by stirring of 500 g of wheat starch with about 1300 ml of deionized water, and still with 600 ml of demineralized water, is massaged to give a slightly plastic mass and passed through a sieve of about 3 mm mesh. The granulate is then dried again and made to pass through a sieve. At dried and granulated to a uniform added by mixing magnesium stearate, stearic acid, talc and the remainder of the wheat starch, and the resulting mixture is compressed into tablets.

Example 14: a slurry can be prepared containing the 10% to 2.2-dimethyl-3.4 dihydro-2h-naphtho/T-, 2 a-ti7pyrane and 5.6-to-dione 6 a-semicarbazone linkage as follows:

The composition (5000 ml for):

2.2 a-dimethyl 3.4 dihydro-2h-to-naphtoZT, 2 a-ti7-pyran-to-5.6-to-dione 6 a-semicarbazone linkage 500.00 grams propylene glycol 500.00 grams hydroxypropylmethylcellulose 25.00 grams citric acid 5.00 grams sodium saccharin 2.50 grams acid methyl ester * 6.00 g of 4-hydroxybenzoic acid propyl ester 4-hydroxybenzoic 1.50 grams raspberry flavor 5.00 g aqueous sorbitol 70% 1250 ml demineralized water Q.S..

□ n-ground in a colloid mill a suspension of the active substance in z50 g propylene glycol and 1250 ml of deionized water, DNs disperses the fine suspension, with an average particle size of the active substance less than 10 .Ym, in a solution LED ' hydroxypropylmethylcellulose, citric acid and saccharin sadistic in 1250 ml of deionized water and in the sorbitol solution. While cooling to the suspension is added a solution of the methyl ester 4-hydroxybenzoic acid propyl ester 4-hydroxybenzoic in 250 g propylene glycol and raspberry flavor. After that has been completed with demineralized water to a volume of 5000 ml forms a suspension, which contains

500 mg of the active substance in 5 ml.

Example 15: can be prepared capsules each containing 300 mg of 2.2 - dimethyl-3.4 dihydro-2h-to-naphta.zï, 2 a-tj7pyrane and 5.6-to-dione 6 a-semicarbazone linkage, as follows ':

The composition (10,000 for capsule):

2.2 - dimethyl-3.4 dihydro-to ZH-naphtho./ a T, Z ti7 -pyran-to-5.6-to-dione 6 a-semicarbazone linkage 3000.00 grams magnesium stearate 100.00 grams

The active substance is mixed with the magnesium stearate

each case is poured and 0.31 g of the mixture using a encapsuleuse in hard gelatin capsules.

Example 16: can be prepared an aqueous injectable suspension (for intramuscular administration), containing 1.0 g of 2.2-dimethyl 3, ^ - dihydro 2h-to-naphto£r, 2 a-t57pyrane and 5.6-to-dione 6 a-semicarbazone linkage for 5 ml as follows:

0.10% Sodium salt of carboxymethyl cellulose sodium acid phosphate mixture

0.15 disodium acid and phosphate % Sodium chloride 0.75 %

Sodium salt of acid s-éthylmercuri -

thiosalicylic (to thiomersal) 0.02 % 1.2-to-propylene glycol 20.00 %

Distilled water q.s. 100.00 %

one processes the active substance 2.2-dimethyl 3 ,i dihydro-2h-naphtho/i, z-to-b7pyrane and 5.6-to-dione 6 a-semicarbazone linkage antimicrobial sterile conditions with the suspending medium so as to obtain a sterile suspension containing 1.0 g of active substance in 5 ml.

Example 17: can be prepared an aqueous injectable suspension (for intramuscular administration) containing 0.75 g of 2.2-dimethyl-3.6 dihydro-2h-naphtho/T-, 2 a-b7pyrane and 5.6-to-dione 6 a-semicarbazone linkage for 5 ml as follows:

Sodium chloride 0.90 % Sodium salt of acid s-éthylmercuri -

thiosalicylic (to thiomersal) 0.02 %

(20) Polyoxyethylene sorbitan mono

(molecular weight: 1311.7 grams; the Tween 60 ©) 0.75% sodium salt of carboxymethyl cellulose 0.50 %

Is converted into the active substance sterile antimicrobial under conditions with the suspending medium so as to obtain a sterile SiON is hung that contains 0.75 g of active ingredient in 5 ml.