DE3510134A1 - 1H, 7H-PYRAZOLO (1,5-A) PYRIMIDINE-7-ON DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

FARMITALIA CARLO ERBA S.p.Α., MILAN / ITALY

1H, 7H-pyrazole o / T, 5-a / pyrimidin-7-one derivatives, processes for their preparation and medicaments which contain them

The invention relates to new 1H, 7H ~ pyrazolo / 1, 5-a / -pyrimidin-7-one derivatives, a process for their manufacture and medicaments containing them.

According to the invention, compounds of the general Formula (I)

0
1

made available, in which mean:

^R 1

(a) C.g-alkyl or benzyl;

(b) pyridyl which is unsubstituted or substituted by C.g-alkyl;

(c) Phenyl that is unsubstituted or by one or more substituents selected from halogen, trihalomethyl, C, _g -alkyl, C. --alkoxy, hydroxy, formyloxy, C__ ₍ --alkanoyloxy, nitro, amino, formylamino and C__ _fi -alkanoylamino, is substituted;

R ₀

(a) pyridyl or

(b) phenyl, which is unsubstituted or substituted by one or more substituents selected from halogen, trihalomethyl, nitro, C _1, .- alkoxy and C _{1 c} - alkyl;

I — D I — 0

R _{3 is} hydrogen or C, g-alkyl, which is unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, C 1, -alkoxy, formyloxy, C ₂ _ _g -alkanoyloxy and the ~ ^N \ _R ^ -Group, in which each R _c and R, - independently of one another hydrogen,

D. D.

C _1- alkyl, phenyl or benzyl or R ₅ and R _fi together with the nitrogen atom

which they are bound, a heterocyclic ring selected from N-imidazolyl, hexahydro-N-azepinyl, N-pyrrolidinyl, N-piperazinyl, piperidino, thiomorpholino and morpholino, form, each of the heterocyclic rings being unsubstituted or substituted by

₁₆

R. hydrogen, halogen, C, _g -alkyl, hydroxy, Cg-alkoxy, C ₃ _.- alkenoyloxy, formyloxy or C ₂ _g-alkanoyloxy;

as well as pharmaceutically acceptable salts thereof.

The invention also includes metabolites and metabolite precursors of the compounds of the formula (I) and all possible isomers of the compounds of the formula (I), e.g., optical isomers or mixtures thereof.

The alkyl, alkoxy, alkanoyloxy and alkanoylamino groups can be straight-chain or branched groups.

A halogen atom is, for example, chlorine, bromine or fluorine and preferably chlorine or fluorine.

A trihalomethyl group is preferably a trifluoromethyl group.
30th

A C1, alkanoyloxy group is, for example

Acetoxy, propionyloxy, butyryloxy or valeryloxy, but preferably acetoxy.

A C ₁ _, - alkyl group is preferably a C ₁ alkyl group, in particular methyl, ethyl, propyl or t-butyl.

A C ₁ alkoxy group is preferably C ₁ alkoxy, in particular methoxy, ethoxy, propoxy or butoxy. 10

A C1, -alkanoylamino group is, for example Acetylamino, propionylamino, butyrylamino or valerylamino, preferably acetylamino.

If R. and / or R _{3 is} phenyl with the aforementioned substituents or R_ is C _1- , -alkyl with the aforementioned substituents, then one, two or three substituents are preferably present.

If R .. means a C., alkyl group, this is for example Methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, but preferably methyl, Ethyl, propyl or t-butyl.

If R _{1 is} a pyridyl group which _{is substituted by a C 1-} , -alkyl group, then the alkyl group is, for example, methyl, ethyl or propyl, preferably methyl.

If R ₁ and / or R- represent a phenyl ring which is substituted in the aforementioned manner, then

the phenyl ring is preferably substituted by one or two substituents selected from halogen, nitro-trifluoromethyl, C 1-4 alkyl and C 1-4 alkoxy.
5

If R- and / or R _{4 is} an unsubstituted C 1-6 alkyl group, then these radicals are, for example, methyl, ethyl, propyl, isopropyl or butyl, preferably methyl, ethyl, propyl or isopropyl.

If R- is a C ₁ - alkyl group which is substituted by one or more halogen atoms, then this radical is preferably a C .. - alkyl group which is substituted by one to three chlorine or fluorine atoms.

If R_ is a C, _g -alkyl group which is substituted by one or more C, -alkoxy groups, then this radical is preferably a C, ^ -alkyl group which is substituted by one to three C, ₂ -alkoxy groups.

If R. is a halogen atom, this is a chlorine, bromine or fluorine atom, but preferably chlorine or Bromine.

R. represents a C ₁ _g alkoxy group, this is for example methoxy, ethoxy, propoxy, isopropoxy or butoxy, but preferably methoxy, ethoxy or propoxy.

If one of the two radicals R ₁ - and R 1, which can be identical or different, is a C 1 -C alkyl group, then this radical is, for example, methyl, ethyl, propyl, isopropyl or butyl, preferably methyl, ethyl, propyl or isopropyl.

If R _c and R, together with the nitrogen atom to which they are bonded, form a heterocyclic ring of the aforementioned type and this ring is _{substituted by C 1} , -alkyl, then the alkyl group is preferably C ... -alkyl and in particular methyl or Ethyl.

Preferred compounds according to the invention are those of the formula (I) in which:

^R 1

(a ¹ ) C. .. alkyl or benzyl; 20th

(b ') pyridyl which is unsubstituted or substituted by methyl,

(c ¹ ) phenyl which is unsubstituted or substituted by one or two substituents selected from halogen, trifluoromethyl, C ₁ -C alkyl, C 1 -C alkoxy, nitro, amino, formylamino and C ₂ -C alkanoylamino;

R _{2 is} phenyl which is unsubstituted or substituted by one or two substituents selected from chlorine, fluorine, trifluoromethyl, nitro, C., -alkyl and C ₁ ,. -Alkoxy;

R _{3 is} hydrogen or C -C -alkyl, unsubstituted or substituted by one to three substituents selected from chlorine, fluorine, hydroxy, C, -C -alkoxy, formyloxy, C ₂ _g-alkanoyioxy and the -NC ^ -. ⁵ group, in which R _K and R-- each independently

Kg Db

gig of one another are hydrogen, C _{.. -alkyl or t} phenyl or R ₅ and R _fi together with the nitrogen atom to which they are bonded form a heterocyclic ring selected from N-imidazolyl, hexahydro-N-azepinyl, N-pyrro - ■ lidinyl, N-piperazinyl, piperidino, morpholino and thiomorpholino, each of the heterocyclic rings is unsubstituted or substituted by C ₁ _-j-alkyl;

R _{4 is} hydrogen, halogen, C _1- . -Alkyl, hydroxy, C. -Alkoxy, C ₃ _ -alkenyloxy or C ₂ _ -alkanoyloxy;

as well as the pharmaceutically acceptable salts thereof.

Compounds according to the invention are even more preferred of formula (I), in which: 30

JbIDlYES

- 18 -

(a ") C,. -alkyl, benzyl or pyridyl,

(b ") phenyl which is unsubstituted or substituted by one or two substituents, selected from chlorine, fluorine, trifluoromethyl, methyl, C, «-alkoxy, nitro, amino, Fo'rmylamino and C 1-4 alkanoylamino;

R_ phenyl, which is unsubstituted or substituted by one or two substituents selected from halogen, trifluoromethyl, nitro, C ₁ alkyl. C and _n-alkoxy.

R _{3 is} hydrogen or C, ₄ ~ alkyl, unsubstituted or substituted by one to three substituents selected from halogen, hydroxy, C ₁ --alkoxy, formyloxy, C "_. -Alkanoyloxy and the -N-CTp ^ · group , in which R ₁ - and R _{fi are} each, independently of one another, hydrogen or C. .. -alkyl

or R _c and R, together with the nitrogen atom, Db-.

to which they are bound, a heterocyclic see Form ring selected from unsubstituted N-imidazolyl, unsubstituted hexahydro-N-azepinyl, unsubstituted N-pyrrolidinyl, N-piperazinyl that is unsubstituted or substituted is by C. - alkyl, piperidino and morpholino, which are each unsubstituted or are substituted by methyl, and unsubstituted thiomorpholino;

Ϊ: iS? EiCTtD

. R. is hydrogen, halogen, C, alkyl, hydroxy, C, - alkoxy, allyloxy or C ₂ _ ₄ ~ alkanoyloxy;

as well as pharmaceutically acceptable salts thereof. 5

Examples of pharmaceutically acceptable salts are salts of inorganic acids, e.g. of nitric acid, Hydrochloric acid, hydrobromic acid and sulfuric acid, as well as salts of organic acids, e.g. of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, methanesulfonic acid and ethanesulfonic acid.

Examples of particularly preferred according to the invention Connections are:

1,2-Diphenyl-5-methyl-1H, 7H-pyrazolo / T, 5-a7 ~ pyrimidin-7-one,

1,2-diphenyl-5-trifluoromethyl-1H, 7H-pyrazolo- / T, 5-a7pyrimidine-7-σn;

1,2-diphenyl-1H, 7H-pyrazolo / T, 5-a7pyrimidin-7-one;

5-methyl-1- (4-methyl-phenyl) -2-phenyl-1H, 7Jl - pyrazolo / T, 5-a7-pyrimidin-7-one;

5-methyl-1 (4-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one;

1- (4-chloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one;

1- (3-chloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one;

1- (4-fluoro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a / pyrimidin-7-one;

5-methyl-2-phenyl-1- (3-trifluoromethyl-phenyl) -1H, 7H-pyrazolo / ^: f, 5-a7-pyrimidin-7-one;

1 -Benzyl-5-methyl-2-phenyl-1H, 7H-pyrazolo / ^: T, 5-a7-pyrimidin-7-one;

1-t-Butyl-5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7 ~ pyrimidin-7-one;

1 _/ 5-dimethyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one;

5-methyl-2-phenyl-1 (2-pyridyl) -IH 1 H -pyrazolo- / 1,5-a7-pyrimidin-7-one; 20th

5-methyl-2-phenyl-1 - (3-pyridyl) -1H, 7H-pyrazolo- / T, 5-a7pyrimidin-7-one;

1,2-bis (3-chloro-phenyl) -5-methyl-iH, 7H-pyrazolo- / T _/ 5-a7pyrimidin-7-one;

1- (3-chloro-phenyl) -2- (4-methoxyphenyl) -5-methyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one;

1,2-diphenyl-5,6-dimethyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one;

6-chloro-1,2-diphenyl-5-methyl-1H, 7H-pyrazolo- / T, 5-a7pyrimidin-7-one;

1 ^ -Diphenyl-O-methoxy-S-methyl-IH ^ H-pyrazolo / 1, S-j

1,2-diphenyl-6-ethoxy-5-methyl-1H, 7H-pyrazolo- / T, 5-a7pyrimidin-7-one;

5- (N, N-diethylamino-methyl) -1,2-diphenyl-1H, 7H-pyrazolo / T, 5-a7pyrimidin-7-one;

1,2-diphenyl-5- (pyrrolidin-1-yl-methyl) -1H, 7H-pyrazolo / T , 5-a / pyrimidin-7-one; 15th

1,2-diphenyl-5- (imidazol-1-yl-methyl) -1H, 7H-pyrazolo / 1,5-a / pyrimidin-7-one;

1 ^ -diphenyl-S-methoxymethyl-IH ^ H-pyrazolo- / T _f 5-a7pyrimidin-7-one;

as well as pharmaceutically acceptable salts thereof.

The compounds according to the invention can be prepared by

(a) a compound of the general formula (II)

R..OC

(ID

wherein R .., R ₂ , R and R. have the meanings given in claim 1 and R _{7 is} a nucleophilic group which is cleaved from the carbon atom to which it is bonded during the cyclization of the compound of the formula (II) can be, or a salt thereof cyclized,

10 15 20

(b) a compound of the general formula (III)

COOH

(HI)

in which R ₁ and R "have the meanings given in claim 1 and R" is hydrogen or unsubstituted C 1 -alkyl, to give compounds of the formula (I) in which R 1 is hydrogen or unsubstituted C ₁ -alkyl

ι —ο

and R. are hydrogen, decarboxylated, or

25 30

(c) a compound of the general formula (IV)

R -

(IV)

- 23 -

thermally cyclized, in which R ₁ and R _{2 have} the meanings given in claim, R _{R has} the meaning given above and each of the radicals Rg and R _1n independently of one another is C _1-6 -AlCyI, to obtain compounds of the formula (I) , where R_ is hydrogen or unsubstituted C a pharmaceutically acceptable salt thereof and / or, if desired, a free compound of the formula (I) is prepared from a salt thereof and / or, if desired, an isomer mixture is separated into the individual isomers.

If R_ is a nucleophilic group of those previously described Kind is, for example, hydroxy, TrI- (C.) Alkyl-silyloxy or C.g-alkoxy.

The compounds of the formula (II) can also be in the tautomeric formula (Ha)

(Ha) K -N N

I Ii c

R ₇ OC
\ N / ' V
H /
\ R-N V
^Xr 3

are reproduced, in which R ₁ , R, R, R. and R_ have the meanings given above.

Preferred salts of the compounds of the formula (II) are, for example, those with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid and sulfuric acid. The cyclization of a compound of formula (II) can, for example, by treating with an acidic condensing agent such as polyphosphoric acid (alone or in the presence of phosphorus oxychloride), sulfuric acid, hydrochloric acid, methanesulfonic acid or p-toluenesulfonic acid, at a temperature in the range of preferably about 50 to about 150 ⁰ C can be carried out. The reaction can be carried out in an organic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, benzene, toluene, xylene, ethylene glycol monomethyl ether. or dichloroethane, but it is preferably carried out in the absence of a solvent.

Alternatively, the cyclization of a compound of the formula (II) can be carried out by heating the compound to a temperature in the range from about 150 to about 350 ^° C. and preferably between 200 and 300 ^° C. in an inert, high-boiling, organic solvent such as diphenyl ether , or heated in the absence of a solvent.

The decarboxylation of a compound of the formula (III) can be carried out, for example, by heating

in a solvent such as quinoline, in the presence of copper powder at a temperature between and 200 ^° C. or alternatively by melting them in the presence of CuO at a temperature in the range between 200 and 300 ^{° C.}

The thermal cyclization of a compound of formula (IV) can be carried out, for example, by melting or, alternatively, by heating in an inert solvent such as nitrobenzene, diethyl phthalate, mineral oil, diphenyl ether or Dowtherm A (eutectic mixture of diphenyl and diphenyl ether) at a temperature in the range of 200 to 300 ⁰ C and preferably between 230 and 270 ⁰ C.

A compound of the formula (I) can be converted into another compound of the formula (I) in a known manner. For example, free hydroxyl groups can be etherified by reaction with a suitable alkyl halide in the presence of a base such as NaOH, KOH, Na ₃ CO ₃ , NaH, NaNH ₃ , sodium methoxide, K-CO-. or sodium hydroxide in a solvent selected from, for example, methanol, ethanol, dioxane, acetone, dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran, water and mixtures thereof, at temperatures in the range from preferably about 0 to about 150 ^° C.

Furthermore, the etherified hydroxyl groups can be converted into free hydroxyl groups, for example by

Treat with pyridine hydrochloride or with a strong acid such as HCl, HBr and HJ, or with a Lewis acid such as AlCl ₃ or BBr ₃ .

Furthermore, for example, a nitro group can be converted into an amino group, for example by treating with tin chloride in concentrated hydrochloric acid and, if necessary, using an organic cosolvent such as acetic acid, dioxane, tetrahydrofuran, and the temperature varying ^{in the range from room temperature to about 100 ° C.} .

An amino or hydroxy group can be converted into a formylamino, C "_ _g -alkanoylamino or C__ _fi -alkanoyloxy group, for example by reaction with formic acid or with the corresponding alkanoyl anhydride without a solvent or in an organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, with one usually in the presence of a base such as pyridine or triethylamine, and operates the temperature between 0 and about 100 ⁰ C.

A compound of the formula (I) in which R _{4 is} hydrogen can be converted into a compound of the formula (I) in which R is chlorine or bromine by treatment with a suitable halogenating agent, such as chlorine, succinimide or bromosuccinimide, SO ₂ Cl ₃ or pyridinium bromide perbromide, with temperatures in the range from 0 to 100 ⁰ C

works and used, for example, as solvent CCl ₄ or dichloroethane in the reaction with SO ₂ Cl ₂ , pyridine in the reaction with pyridinium bromide perbromide, and benzene in the reaction with a halogen succinimide.

A compound of the formula (I) in which R-, a C, - alkyl group which is substituted by a halogen atom can be converted into a compound of the formula (I) in which R ^ is a C, - alkyl group, which is substituted by a group -Nc ^ 5, in which R ₁ . and R, which have the meanings given above, can be converted by converting a compound of the formula HN <T_5, in which R _c and R _c are as previously given

Kg DO

Have meanings, in an organic solvent such as methyl ethyl ketone, toluene, xylene, dimethylformamide, Dimethylacetam.id, at a temperature between 20 and 150 ⁰ C implemented.

The salt formation, if desired, of a compound of the formula (I), as well as the conversion of an alkene into the free acid and the separation of isomer mixtures into the individual isomers, can be done according to customary methods. For example, you can have a mix of the optical Isomers into the individual isomers by salt formation with optically active bases or acids and then Separate fractional crystallization.

The compounds of the formula (II) can be prepared by, for example, a compound of the formula (V)

- 28 -

(V)

wherein R ₁ and R _{2 have} the meanings given above, or a salt thereof with a compound of the formula (VI)

wherein R ₃ , R- and R _{7 have} the meanings given above and R _{11 is} a reactive group selected from, preferably, hydroxy, amino, C * _fi -alkoxy or tri- (C _1-6 ) alkyl-silyloxy.

Preferred salts of a compound of the formula (V) are, for example, those with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid.

The reaction between a compound of the formula (V) and a compound of the formula (VI) can be carried out, for example, by heating in a solvent such as dioxane, toluene, xylene, acetonitrile, C 1 -C 4 -alkyl alcohol, acetic acid, dimethylformamide, dimethylacetamide, diphenyl ether or in the absence of solvents, at a temperature ranging between room temperature .and 200 ⁰ C.

Preferably, when R _{11 is} hydroxy, the reaction between a compound of the formula (V) and a compound of the formula (VI) in the presence of an acidic condensing agent such as polyphosphoric acid, methanesulfonic acid, p-toluenesulfonic acid or acetic acid, under the same experimental conditions as previously indicated for the cyclization of the compound of formula (II).

Under these special conditions, one can react a compound of formula (V) with carry out a compound of the formula (VI) until a compound of the formula (I) has been obtained without that one has to isolate the intermediate of the formula (II) formed during the reaction.

The compounds of the formula (III) can be prepared, for example, by a compound of Formula (VII)

(VII) 25

wherein R ₁ , R ~ and R _{3 have} the meanings given above and R ₁ - cyano or an esterified carboxy group or a tri- (C ₁ _g) alkyl-silyloxycarbonyl group, hydrolyzed, for example by treatment with a mineral acid such as HCl, HBr . HJ, in water

or in acetic acid or in dioxane or mixtures thereof at a temperature in the range between room temperature and about 120 ^° C.

The compounds of the formula (IV) can be prepared by, for example, a compound of the formula (V) with a mixture of the compound of the formula (VIII)

R ₈ -C (OR ₁₃ ) ₃ (VIII)

wherein R _{0 has} the meaning given above and ο

R C .._ means g-alkyl, and a compound of Formula (IX)

^H 2 ^C v

^N C0- (

wherein R _q and R _{Q have} the meanings given above. The reaction between a compound of the formula (IV) and a mixture of a compound of the formula (VIII) and a compound of the formula (IX) can be carried out, for example, without a solvent or in the presence of an inert solvent such as benzene, ethanol, dioxane, tetrahydrofuran, acetonitrile , be carried out at a temperature ranging between room temperature and 150 ⁰ C dimethylformamide.

The compounds of formula (VII) are obtained by

Cyclizing a compound of formula (X)

-R _- -N

(X)

wherein R ₁ , R ", R_, R_ and R ₁ " have the meanings given above and using the same experimental conditions as those given above for the cyclization of a compound of the formula (II).

The compounds of the formulas (V), (VI), (VIII) and (IX) are known compounds or they can be can be produced in the usual way. In some cases, they are commercially available products. The compounds according to the invention are active on the central nervous system (CNS), in particular as the central nervous system Depressants, i.e. as sedatives, anticonvulsants, as tranquilizers and as sleep inducers. The activity on the CNS of the compounds according to the invention was, for example evaluated experimentally by behavioral studies using the Irwin technique / Irwin, S., Psychopharmacologia (Berl.) J_3, 222, 19687- In this test it turned out that the compounds according to the invention actively dampen the CNS and in particular Sedatives are and harmless tranquilizers and that they cause hypnosis in mice and rats

able to induce. The animals treated with oral doses ranging from 5 to 100 mg / kg body weight showed the loss of the "righting" reflex without causing temporary depression of the Muscle tone, breathing, frequency, rectal temperature, or other reflexes occurred.

The toxicity of the compounds according to the invention is negligible, so that they can be safely used in ο therapy. Mice and rats that had fasted for 9 hours were treated orally with a single administration of increasing doses and then left on a normal diet. The indicative acute toxicity (LD ₅₀ ) was determined on the seventh day after treatment and was generally above 600 mg / kg.

The compounds according to the invention can be used in one Administer a variety of dosage forms, e.g.

orally in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or Suspensions, rectally in the form of suppositories, parenteral, e.g. by intramuscular or intravenous injections or by infusion.

The dose depends on the age, weight and condition of the patient and the route of administration. For example when administered orally to an adult human, the dose is between about 10 and 100 mg / kg per dose that can be administered 1 to 5 times a day. ·. ■

The invention includes pharmaceutical compositions which contain the compounds according to the invention together with a pharmaceutically acceptable carrier or diluent. 5

The pharmaceutical compositions containing the compounds according to the invention can be used in a conventional manner Manner are prepared and are then brought into a pharmaceutically acceptable form and administered.

Solid oral forms together with the active compound contain, for example, diluents such as Lactose, dextrose, sucrose, cellulose, corn starch or potato starch; Lubricants, e.g. silicon dioxide, Talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; Binder, e.g., starches, gum arabic, gelatin, methyl cellulose, carboxymethyl cellulose, or polyvinylpyrrolidone; Disintegrants, e.g., starch, alginic acid, alginates or sodium starch glycolates; bubbly mixes; Dyes; Sweeteners; Humectants, such as lecithin, polysorbates, lauryl sulfates; and especially non-toxic and pharmacologically inactive Substances as they are commonly used in pharmaceutical formulations. Such drug formulations can be prepared in a known manner, for example by mixing, granulating, tabletting, coated with sugar or applied a film coating. The liquid dispersions for oral administration can be in the form of syrups, emulsions or suspensions.

The syrups can contain a carrier such as sucrose or sucrose with glycerin and / or mannitol and / or sorbitol, in particular a syrup, which is administered to diabetics, is the only carrier Products should contain which are not metabolized to glucose or which are only to a very small extent Mass metabolized to glucose, e.g. sorbitol.

The suspensions and emulsions can be used as carriers, for example, natural resins, agar, sodium alginate, pectin, Contain methyl cellulose, carboxymethyl cellulose or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections can be used together with the active compound contain a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, Glycols such as propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions can be used as carriers, for example sterile Contain water, but preferably contain sterile aqueous, isotonic saline solutions.

Suppositories may contain a pharmaceutically acceptable carrier with the active compound, e.g. cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester or lecithin.

The invention is described in the following examples.

example 1

5.2 g of 3-amino-1,5-diphenyl-parazol was g with 4.4 g of ethyl acetoacetate in polyphosphoric acid (52: 28 g of ^H 3 ^PO 4 ^{and 24} 9 ^P 2 O 5 ^ ^with stirring at 100 ⁰ C for 1 After cooling the reaction mixture, it was diluted with ice water and neutralized with 35% NaOH, the solution was extracted with ethyl acetate and then the organic phase was evaporated to dryness in vacuo to give 2.5 g of 1,2-diphenyl-5-methyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one; F: 147-148 ⁰ C.

NMR (CDCl ₃ ) δ ppm: 2.37 (s) (3H, CH ₃ ),

5.91 (bs) (1H, C-6 proton),

6.55 (s) (1H, C-3 proton),

7.4 0 (m) (10H, phenyl protons).

In an analogous way were produced:

5-methyl-1- (2-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

5-methyl-1- (2-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo- [1,5a} pyrimidin-7-one,

1- (2-chloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,
30th

1- (2,4-dichloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (2,5-dichlorophenyl) -5 ~ methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

5-methyl-2-phenyl-1- (2-trifluoromethyl-phenyl) -1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

5-methyl-1- (3-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

5-methyl-1- (3-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

1- (4-methoxyphenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo- [1/5-a] pyrimidin-7-one,
15th

1- (2,6-dichlorophenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (3-Fluoro-phenyl) -S-methyl-2-phenyl-IH, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

5-methyl-2-phenyl-1- (3-trifluoromethyl-phenyl) -1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one, F: 149-150 ° C,

5-methyl-1- (4-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

5-methyl-i- (4-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,
30th

1- (4-chloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

1- (3-chloro-phenyl) -5-methyl-2-phenyl -1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one, F: 133-134 ° C,

1- (4-Fluoro-phenyl) -S-methyl ^ -phenyl-IH, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

5-methyl-2-phenyl-1- (4-trifluoromethyl-phenyl) -1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1-Benzyl-5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1-t-Butyl-5-methyl-2-phenyl-iH, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,
15th

1,5-dimethyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

5-methyl-2-phenyl-1- (2-pyridyl) -iH, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

5-methyl-2-phenyl-1- (3-pyridyl-1H, 7H-pyrazolo [1,5-a] -pyriraidin-7-one,

2- (4-chloro-phenyl) -1-phenyl-5-methyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

2- (4-methoxyphenyl) -1-phenyk-5-methyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,
30th

5-methyl-1-phenyl-2- (3-pyridyl) -iH, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1,2-bis (3-chloro-phenyl) -5-methyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one and

1- (3-Chloro-phenyl) -2- (4-methoxyphenyl) -5-methyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one.

Example 2
10

According to the method according to Example 1, using appropriately substituted acetoacetates, the the following connections established:

1,2-Diphenyl-5-trifluoromethyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one, F: 142-143 ° C,

1 ^ -Diphenyl-ö-ethyk-S-methyl-IH, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,
20th

1,2-Diphenyl-5-methy1-6-propy1-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1 ^ -Diphenyl-e-isopropyl-S-methyl-IH, 7H-pyrazolo-C1 / 5-a] pyrimidin-7-one,

5,6-Dimethyl-1,2-diphenyl-IH, 7H-pyrazolo [1,5-a] -pyrimidin-7-one, F: 178-180 ⁰ C,

6-chloro-1,2-diphenyl-5-methyl-1 H, 7H-pyrazolo [1,5-a] pyrimidin-7-one, F: 208-210 ⁰ C ,. .

1,2-Diphenyl-6-methoxy-5-methyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1,2-Diphenyl-6-ethoxy-5-methyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1,2-Diphenyl-6-hydroxy-5-methyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-6-one,

6-acetoxy-1,2-diphenyl-5-methyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1 ^ -Diphenyl-ö-isopropoxy-S-methyl-IH ^ H-pyrazolo-

[1,5-a] pyrimidin-7-one, 15th

1 ^ -Diphenyl-S-methyl-ö-propoxy-IH ^ H-pyrazolo [1, 5-a] pyrimidin-7-one,

6-Allyloxy-1 ^ -diphenyl-S-methyl-IH, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1,2-Diphenyl-5-ethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1,2-Diphenyl-5-propyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one, F: 120-122 ⁰ C,

1,2-Diphenyl-5-isopropyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,
30th

5-chloromethyl-1, 2-diphenyl-1H, -7H-pyrazolo [1, 5-a] pyrimidin-7-one, F: 138-14 0 ⁰ C,

5-dichloromethyl-i, 2-diphenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1,2-Diphenyl-5-methoxymethyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1,2-Diphenyl-5-ethoxymethyl-iH, 7H-pyrazolo [1/5-a] -pyrimidin-7-one,

5-diethoxymethyl-1,2-diphenyl-1H, 7H-pyrazolo [1,5-aJ-pyrimidin-7-one,

1,2-Diphenyl-5-hydroxymethyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,
15th

5-acetoxymethyl-i, 2-diphenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1- (4-methyl-phenyl) -2-phenyl-5-trifluoromethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (4-Nitro-pheny1) -2-pheny1-5-trifluoromethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (4-chloro-phenyl) -2-phenyl-5-trifluoromethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (3-chloro-phenyl) -2-phenyl-5-trifluoromethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,
30th

1- (4-Fluoro-phenyl) -2-phenyl-5-trifluoromethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

2-phenyl-5-trifluoromethyl-1- (3-trifluoromethyl-phenyl) iH, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1,2-bis (3-chloro-phenyl) -5-trifluoromethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (3-chloro-phenyl) -2- (4-methoxyphenyl) -5-trifluoromethy1-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-chloro-5-methyl-1- (4-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-chloro-5-methyl-1- (4-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one, 15th

6-chloro-1- (4-chloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-chloro-1- (3-chloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-chloro-1- (4-fluoro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-chloro-5-methyl-2-phenyl-1- (3-trifluoromethyl-phenyl) -iH, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-chloro-1,2-bis (3-chloro-phenyl) -5-methyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one, 30th

6-chloro-1- (3-chloro-phenyl) -2- (4-methoxyphenyl) -5-methy1-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

5,6-dimethyl-1 - (4-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

5,6-Dimethyl-1- (4-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-aJpyrimidin-7-one,

1- (4-chlorophenyl) -5,6-dimethyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (3-chloro-phenyl) -S ^ -dimethyl ^ -phenyl-IH, 7H-pyrazolo- [1 ₇ 5-] pyrimidin-7-one,

1- (4-fluoro-phenyl) -5,6-dimethy1-2-pheny1-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one, 15th

5,6-dimethyl-2-phenyl-1- (3-trifluoromethyl-phenyl) -1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1,2-bis- (3-chloro-pheny1) -5,6-dimethy1-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

1- (3-chloro-phenyl) -2- (4-methoxyphenyl) -5,6-dimethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-methoxy-5-methyl-1- (4-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-methoxy-5-methyl-1- (4-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one, 30th

1- (4-chloro-phenyl) -6-methoxy-5-methy1-2-pheny1-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (3-Chloro-pheny1) -6-methoxy-5-methy1-2-phenyliH, 7H-pyrazolo [1/5-a] pyrimidin-7-one,

1- (4-Fluoro-phenyl) -o-methoxy-S-methyl ^ -phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

6-methoxy-5-methyl-2-phenyl-1- (3-trifluoromethylphenyl) -1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1,2-bis (3-chloro-phenyl) -6-methoxy-5-methyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one and

1- (3-chloro-phenyl) -6-methoxy-2- (4-methoxy-phenyl) ■ 5-methyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one. 15th

Example 3

-20 3 g isopropylidene-N- (1,2-diphenyl-pyrazol-3-yl) -amino-methylenemalonate, F: 235-237 ° C, dissolved in 30 ml of diphenyl ether, was refluxed for 8 minutes. After cooling, the solvent became evaporated in vacuo and the residue eluted using ethyl acetate purified in a flash column. The purified product was recrystallized from CH ^ Cl ^ isopropyl ether, 0.9 g of 1,2-diphenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one received, F: 146-148 ° C.

NMR (CDCl ₃ ) δ ppm: 5.91 (d) (1H, C-6 proton),

6.52 (s) (1H, C-3 proton),

7.22 (m) (10H, phenyl protons),

7.88 (d) (1H, C-5 proton). 5

In an analogous manner, the following compounds were made

manufactured:

1- (4-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1- (4-Nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1- (4-chlorophenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

1- (3-chloro - phenyl) -2-phenyl-1H, 7H-pyrazolo [1, 5-a] -pyrimidin-7-one,
20th

1- (4-Fluoro-phenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,

2-phenyl-1- (3-trifluoromethyl-phenyl) -1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

1-Benzyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1-phenyl-2- (3-pyridyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one, . -

2-phenyl-1- (2-pyridyl) -1H, 7H-pyrazolo [1, 5-a] pyrimidin-7-one,

1,2-bis (3-chloro-phenyl) -1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one, and

1-Methy1-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one.

Example 4

1.4 g of 1,2-diphenyl-5-methyl-1H, 7H-pyra _z olo [1,5-a] -pyrimidin-7-one in 50 ml of benzene were stirred at room temperature for 2 hours with 0.95 g N-bromo-succinimide implemented. The precipitate was dissolved by adding chloroform and the solution was washed with water. It was then evaporated to dryness in vacuo and the residue was recrystallized from chloroform-isopropyl alcohol, 1.6 g of 6-bromo-1,2-diphenyl-5-methyl-1H, 7H-pyrazolo [1,5-a] -pyrimidine being obtained received.

The following compounds were prepared in an analogous manner:

6-bromo-1,2-diphenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,
30th

6-bromo-1,2-diphenyl-5-trifluoromethyl-IH, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

6-Bromo-5-methyl-1- (4-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

6-Bromo-5-methyl-1- (4-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

6-Bromo-1- (4-chloro-phenyl) -5-methyl-2-phenyl-iH, 7H-pyrazolo- [1,5-a] pyriniain-7-one,

6-Bromo-1- (3-chloro-ohenyl) -Β-pyrazolo [1,5-a] pyrimidin-7-one,

6-Bromo-1- (4-fluoro-phenyl) -5-methyl-2-phenyl-iH, 7H-pyrazolo [1,5-a] pyrimidin-7-one,
15th

6-Bromo-5-methyl-2-phenyl-1- (3-trifluoromethyl-phenyl) ■ iH, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

6-chloro-1,2-diphenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one and

6-chloro-1,2-diphenyl-5-trifluoromethyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one.

Example 5

4 g of 5-methyl-1- (4-nitrophenyl) ^ -phenyl-IH ^ H -pyrazolo- [1,5-a] pyrimidin-7-one were mixed with 25 g of SnCl ₂ -2H ₂ O in

15 ml of 37% HCl and 45 ml. Acetic acid with stirring

implemented at 60 ⁰ C for 2 hours. After cooling, the precipitate was filtered off and washed with water and then suspended in 2N NaOH with stirring. The product was filtered, washed with water until neutral and then recrystallized from chloroform-ethanol, 2.8 g of 1- (4-aminophenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo- [1 , 5-a] pyrimidin-7-one.

The following compounds were prepared in an analogous manner:

1- (4-Aminophenyl) -2-phenyl-1H, 7H-pyrazolo [1,5-a] -pyrimidin-7-one,
15th

1- (4-Aminophenyl) -2-phenyl-5-trifluoromethyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (4-Aminophenyl) -5,6-dimethyl-2-phenyl-iH, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1- (4-Aminophenyl) -6-chloro-5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one and

1- (4-Aminophenyl) -6-methoxy-5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one.

Example 6

2.2 g of 5-chloromethyl-1,2-diphenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one, melting point: 138-14O ° C., were mixed with 1 g of pyrrolidine in 150 ml of 2 -Butanone treated under reflux for 16 hours. After cooling, the solution was evaporated to dryness in vacuo and the residue was purified over a Si0 ₂ column using chloroform-methanol 97: 3 as the eluent. When recrystallizing the product obtained from CH _? C1 “isopropyl ether gave 1.6 g of 1,2-diphenyl-5- (pyrrolidin-1-yl-methyl) -1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one.

The following compounds were prepared in an analogous manner:

5- (N, N-diethylamino-methyl) -1,2-diphenyl-iH, 7H-pyrazolo [1,5-a] pyrimidin-7-one, 20th

1,2-Diphenyl-5- (morpholino-methyl) -1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

5- (N, N-dimethylamino-methyl) -1,2-dipheny1-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one,

1,2-Diphenyl-5- (thiomorpholino-methyl) -1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

5- (N-Isopropylamino-methyl) -1,2-diphenyl-1H, 7H-pyrazolo [1 , 5-a] pyrimidin-7-one., -

1,2-Diphenyl-5- (imidazol-1-yl-methyl) -IH ^ H-pyrazolo- [1,5-a] pyrimidin-7-one,

5- (N-t-Butylamino-methyl) -1,2-diphenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one,

1,2-Diphenyl-5- (piperidino-methyl) -IH ^ H-pyrazolo- [1,5-a] pyrimidin-7-one,

5- (Hexahydro-1H, azepin-1-yl-methyl) -1,2-diphenyl-1H, 7H-pyrazolo [1,5-a] pyrimidine and

1,2-Diphenyl-S - [(4-methyl-piperazin-1-yl) -methyl] -1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one.
15th

Example 7

2 g of 1- (4-aminophenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo- [1,5-a] pyrimidin-7-one were stirred into 30 ml of acetic acid containing 5 ml of 37 -% - HCl, ^{heated at 60 0} C for 1 hour. After cooling, the precipitate was filtered and washed with acetic acid and then with water, 1.9 g of 1- (4-aminophenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one hydrochloride, F:> 350 ° C.

The following compounds were prepared in an analogous manner:

1- (4-Aminophenyl) -2-phenyl-iH, 7H-pyrazolo [1,5-a] -pyrimidin-7-one hydrochloride and

1- (4-Aminophenyl) -2-phenyl-5-triflupromethyl-pyrazolo- [1 1 5-a] pyrimidin-7-one hydrochloride.

Example 8
10

Tablets, each weighing 75 mg and containing 25 mg of the active substance, were like is made as follows:

Composition (for 10,000 tablets)

1,2-diphenyl-5-methyl-1H, 7H-pyrazolo-

[1,5-a] pyrimidin-7-one 250 g

Lactose .. 355 g

Corn starch 120 g

Talc powder 17.5 g

Magnesium stearate 7.5 g

1,2-Diphenyl-5-methyl-1H, 7H-pyrazolo [1,5-a] pyrimidin-7-one, Lactose and half the corn starch were mixed together and the mixture was then cooked through put a sieve with 0.5 mm openings. 10g corn starch were suspended in 100 ml of warm water. The paste obtained was used to granulate the powder used. The granules were dried on a

Sieve with a mesh size of 1.4 mm crushed and then the remaining amount of starch, talc and magnesium stearate were added and then mixed thoroughly and in tablet presses with 5 compressed into tablets with a diameter of 6 mm.

Claims (7)

HOFFMANN · EITLE & PARTNER PATENT- AND LAWYERS PATENTANWÄLTE DIPL.-INQ. W. EITLE DR. RER. NAT. K. HOFFMANN DIPL.-ΙΝβ. W. LEHN DlPL1-INd. K. FOCHSLE DR. RER. NAT. B. HANSEN · DR. RER. NAT. HA. BROWN. DIPL.-ING. K. QDRa DIPL-ΙΝΘ. K. KOHLMANN RECHTSANWALT A. NETTE 41 629 o / wa - 1 - FARMITALIA CARLO ERBA SpA, MILAN / ITALY iH / 7H-Pyrazolo / T, 5-a7pyriinidin-7-one-derivatives, processes for their production and pharmaceuticals, which these contain PATENT CLAIMS 1. 1H, 7H-pyrazolo / 1, S-a / pyrimidin - ^ - one derivatives of the general formula (I) RN N- 'LI r / V% 2 3 • ^R 4 10 where mean: ARABELLASTRASSE 4 D-8OOO MUNICH 81 TELEPHONE C0893 O11O87. TELEX Ö-29619 TELECOPLER 918356 ^R 1 (a) C .._ g-alkyl or benzyl; (b) pyridyl which is unsubstituted or substituted by C-6 alkyl; (c) Phenyl that is unsubstituted or by one or more substituents selected from halogen, trihalomethyl, C _1-6 -alkyl, C 1 -C 4 -alkoxy, hydroxy, formyloxy, C "_ _ß -alkanoyloxy, nitro, amino, formylamino and C 1-4 alkanoylamino, is substituted; (a) pyridyl or (b) phenyl which is unsubstituted or substituted by one or more substituents selected from halogen, trihalomethyl, nitro, Cg-alkoxy and C, _g -alkyl; R ^ hydrogen or C-_g-alkyl which is unsubstituted or substituted by one or more substituents selected from _{halogen, hydroxy, C 1} , -alkoxy, formyloxy, C ₀ , -alkanoyloxy and the -NC ^ p group wherein each R ₅ and Rg independently of one another are hydrogen, C _1- , -alkyl, phenyl or benzyl or R _c and R, together with the nitrogen atom, are which they are bound, a heterocyclic ring selected from N-imidazolyl, hexahydro-N-azepinyl, N-pyrrolidinyl, N-piperazinyl, piperidino, thiomorpholino and morpholino, form, each of the heterocyclic rings being unsubstituted or substituted by C.
C. _1-6 -alkYl; . Hydrogen, halogen, C ₁ _ _g alkyl, hydroxy, .g alkoxy, C ₃ _ ₄ ~ alkenoyloxy, formyloxy or ₀ - alkanoyloxy; as well as pharmaceutically acceptable salts thereof. 2. A compound of the general formula (I) according to Claim 1, in which: ^R 1
(a ¹ ) C _1-4 alkYl or benzyl; (b ¹ ) pyridyl which is unsubstituted or substituted by methyl, (c ¹ ) phenyl which is unsubstituted or substituted by one or two substituents selected from halogen, trifluoromethyl, C _1-4 alkYl, C _1-4 alkOXy, nitro, amino, formylamino and C 1-4 alkanoylamino; R _{2 is} phenyl which is unsubstituted or substituted by one or two substituents selected from chlorine, fluorine, trifluoromethyl, nitro, C _1-4 -Al] CyI and C 1-4 alkoxy; 5 R-, hydrogen or C, ₄ -alkyl, unsubstituted or substituted by one to three substituents, selected from chlorine, fluorine, hydroxy, C _1-4 -alkoxy, formyloxy, C ₀ ^ - alkanoyloxy and the -N ^ Cn - A group in which R ₁ - and R, each independently of one another, _{denote hydrogen, C 1-4} -alkyl or phenyl or R ₅ and R _fi together with the nitrogen atom to which they are bonded form a heterocyclic ring selected from N-imidazolyl , hexahydro-N-azepinyl, N-pyrrolidinyl, N-piperazinyl, piperidino, morpholino and thiomorpholino, each of the heterocyclic rings is unsubstituted or substituted by C ₁ _ ₃ alkyl; R ₄ is hydrogen, halogen, C ^ ₄ alkyl, hydroxy, C _1-4 -alkoxy, C ₄ alkenyloxy or alkanoyloxy C_ _fi; as well as the pharmaceutically acceptable salts thereof. 3. Compound of the general formula (I) according to Claim 1, in which:
30th ^R 1 (a ") C _1-4 -Al] CyI, benzyl or pyridyl, (b ") phenyl which is unsubstituted or substituted by one or two substituents, selected from chlorine, fluorine, trifluoromethyl, Methyl, C "-alkoxy, nitro, amino, formylamino and C" -alkanoylamino; R "is phenyl which is unsubstituted or substituted by one or two substituents selected from halogen, trifluoromethyl, nitro, C _1-4 alkyl and C 1-4 alkoxy; Hydrogen or C ₁₄ -alkyl, unsubstituted or substituted by one to three substituents selected from halo, hydroxy, C "-alkoxy, formyloxy, C ₂ _ ₄ alkanoyloxy and -NC ^ J ^ group, wherein R ^ and R _fi are each independently hydrogen or C ~ ₄ Mean alkyl or Rr- and R, together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from unsubstituted N-imidazolyl, unsubstituted hexahydro-N-azepinyl, unsubstituted N-pyrrolidinyl, N-piperazinyl which is unsubstituted or is substituted by C ₁ -C alkyl, piperidino and morpholino, each of which is unsubstituted or substituted by methyl, and unsubstituted thiomorpholines; R. hydrogen, halogen, C., alkyl, hydroxy, C _1-3 alkoxy, allyloxy or C 1-4 alkanoyloxy; as well as pharmaceutically acceptable salts thereof. 5 4. Compound according to claim 1, namely 1,2-Diphenyl-5-methyl-1H, 7H-pyrazolo / T, 5-a7 ~ pyrimidin-7-one,
10 1,2-Diphenyl-5-trifluoromethyl-1H, 7H-pyrazolo- / 1 , 5-a / pyrimidin-7-one; 1, 2-diphenyl-1H, 7H-pyrazolo / T, 5-a7pyrimidin-r7 one; 5-methyl-1- (4-methyl-phenyl) -2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 5-methyl-1 (4-nitro-phenyl) -2-phenyl-1H, 7H-pyrazolo / 1,5-a / pyrimidin-7-one; 1- (4-chloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 25th 1- (3-chloro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 1- (4-fluoro-phenyl) -5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; rUGD? PL 1H 5-methyl-2-phenyl-1- (3-trifluoromethyl-phenyl) -1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 1-benzyl-5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 1-t ~ butyl-5-methyl-2-phenyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 1,5-dimethyl-2-phenyl-iH, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 5-methyl-2-phenyl-1 (2-pyridyl) -iH 1 H -pyrazolo- / T, 5-a7-pyrimidin-7-one; 15th 5-methyl-2-phenyl-1- (3-pyridyl) -1H, 7H-pyrazolo- / T, 5-a7pyrimidin-7-one; 1,2-bis (3-chloro-phenyl) -S-methyl-iH 1 H -pyrazolo- / T, 5-a7-pyrimidin-7-one; 1- (3-chlorophenyl) -2- (4-methoxyphenyl) -5-methyl-1H, 7H-pyrazolo / 1, 5-a7pyriinidin-7-one; 1,2-diphenyl-5,6-dimethyl-1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 6-chloro-1,2-diphenyl-5-methyl-iH, 7H-pyrazolo- / T, 5-a7pyriinidin-7-one; 30th 1 ^ -Diphenyl-G-methoxy-S-methyl-IH ^ H-pyrazolo- / 1,5-a7-pyrimidin-7-one; 1 ^ -Diphenyl-e-ethoxy-S-methyl-IH ^ H-pyrazolo- / T, 5-a7pyrimidin-7-one; 5- (N, N-diethylamino-methyl) -1,2-diphenyl-1H, 7H-pyrazolo / T, 5-a7pyrirnidin-7-one; 1,2-Diphenyl-5- (pyrrolidin-1-yl-methyl) -1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 1,2-diphenyl-5- (imidazol-1-yl-methyl) -1H, 7H-pyrazolo / T, 5-a7-pyrimidin-7-one; 1,2-diphenyl-5-methoxymethyl-1H, 7H-pyrazolo- / T, 5-a7pyrimidin-7-one;
15th as well as pharmaceutically acceptable salts thereof. 5. Process for the preparation of a compound of general formula (I) and pharmaceutically acceptable Salzen.davon according to claim 1, characterized in that one (a) a compound of the general formula (II)
25th (ID 30 wherein R ₁ , R ", R-. and R. have the meanings given in claim 1 and R _{7 is} a nucleophilic group which can be cleaved from the carbon atom to which it is bonded during the cyclization of the compound of the formula (II), or a salt thereof is cyclized, (b) a compound of the general formula (III) COOH (III) in which R ₁ and R ~ have the meanings given in claim 1 and R _{g is} hydrogen or unsubstituted C, .- alkyl, to give compounds of the formula (I) in which R _{3 is} hydrogen or unsubstituted (!!., - alkyl and R ₄ denotes hydrogen, decarboxylated, or (c) a compound of the general formula (IV) CO CO (IV) thermally cyclized, in which R ₁ and R _{3 have} the meanings given in claim, R "has the meaning given above and each of the radicals R _n and R _1n independently of one another C _{1 c} -alkyl y ι υ 1 ~ o means, to obtain compounds of the formula (I) in which R _{3 is} hydrogen or unsubstituted C _{1 fi} -alkyl and R is hydrogen and, if desired, a compound of the formula (I) is converted into another compound of the formula (I) and / or, if desired, a compound of the formula (I) into a pharmaceutically acceptable salt thereof and / or, if desired, a free compound of the formula (I) from a salt thereof and / or, if desired, separating an isomer mixture into the individual isomers. 6. Medicaments containing as active ingredient a compound of the formula (I) or a pharmaceutically acceptable salt thereof along with a suitable carrier and / or diluent. 7. Medicament according to claim 6 for use as a central nervous system depressant.