GB1573569A

GB1573569A - Pyrimidine derivatives

Info

Publication number: GB1573569A
Application number: GB5748/77A
Authority: GB
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1976-02-19
Filing date: 1977-02-11
Publication date: 1980-08-28
Also published as: JPS52105198A; FR2342970A1; DE2707101A1; FR2342970B1

Description

(54) PYRIMIDINE DERIVATIVES (71) We, E. R. SQUIBB & SONS INC., a corporation organised and existing under the laws of the State of Delaware, United States of America, of Lawrenceville Princeton Road, Princeton, New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:- This invention provides new derivatives of pyrazolo[ 1 ,5-a]pyrazolo[4',3': 5,6]pyrido- [3,4-e]pyrimidine. These compounds may be used as antiinflammatory agents and central nervous system depressants.

More specifically the present invention provides compounds of the formula

wherein Z is

RX is hydrogen, lower alkyl phenyl, phenyllower alkylene, benzoyl or substituted phenyl or benzoyl wherein the phenyl or benzoyl substituent is one or two halogens, lower alkyl or trifluoromethyl groups; R2 and R3 each is hydrogen, lower alkyl or phenyl; R4 is hydrogen, lower alkyl, phenyl, carboxy or lower alkoxycarbonyl; R5 is hydrogen, lower alkyl, phenyl-lower alkylene, benzoyl, substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl or

R7 N-lower R8 alkylene; R5 is lower alkoxy, substituted lower alkoxy wherein the substituent is

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or tri fluoromethyl groups, halo,

or --SS-R9: R6 is hydrogen or lower alkyl; R7 is hydrogen, lower alkyl or substituted lower alkyl wherein the lower alkyl substituent is

phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R8 is hydrogen or lower alkyl, or R7 and R8 together with the nitrogen form one of the unsubstituted or substituted heterocyclics pyrrolidino; morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkyl; R9, R'O and R1' each is hydrogen or lower alkyl; and acid addition salts thereof.

The invention also extends to pharmaceutical compositions comprising such compounds or salts and a pharmaceutical carrier.

The various groups represented by the symbols are of the following types and have the same meanings throughout this specification: The lower alkyl groups are straight or branched chain hydrocarbon groups having up to seven carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tbutyl and pentyl. The lower alkylene groups are divalent radicals of the same kind.

Examples of the phenyl-lower alkylene groups are benzyl, phenethyl and phenylisopropyl. The C1-C4 and especially the C1-C2 lower alkyl and lower alkylene groups are preferred. The lower alkoxy groups likewise have up to seven carbon atoms. The C1-C4 and C1-C2 groups are similarly preferred and especially preferred groups, respectively.

The substituted phenyl, substituted phenyloxy and substituted benzoyl groups are simply substituted groups bearing on the phenyl ring one or two halogen (preferably one), lower alkyl, lower alkoxy or trifluoromethyl groups, for example, p-chlorophenyl, o-chlorophenyl, p-bromophenyl, mchlorophenyl, m-bromophenyl, p-tolyl, o- tolyl, o-ethylphenyl, p-methoxyphenyl, pchlorophenyloxy, o-chlorophenyloxy, pbromophenyloxy, m-chlorophenyloxy, mbromophenyloxy, p-tolyloxy, o-tolyloxy, o- ethylphenyloxy, p-trifluoromethylphenyloxy, 3,4-dichlorophenyloxy, 3,5-dimethylphenyloxy, p-bromobenzoyl, m-bromobenzoyl, 3,5-dichlorobenzoyl, p-methylbenzoyl, o-ethylbenzoyl and p-trifluoromethylbenzoyl. Chlorine, bromine and methyl are the preferred substituents (only one) in both instances.

The halogens in each instance are the four common halogens but chlorine and bromine, especially chlorine, are preferred.

The lower alkanoyl groups are the acyl groups of the lower(C2-C7) fatty acids, e.g., acetyl, propionyl, butyryl and isobutyryl.

Those with up to four carbons in the chain are preferred. especially acetyl.

The lower alkoxy-lower alkylene and lower alkylthio-lower alkylene groups represented by R5 include such groups as methoxy-methylene, ethoxymethylene, methoxyethylene, methylthiomethylene, methylthioethylene, ethylthiomethylene and ethylthioethylene.

The amino-lower alkylene groups are e.g., aminomethyl, aminoethyl, etc. The di-lower alkylaminolower alkylene groups are groups wherein the nitrogen is substituted with two lower alkyl groups. In addition, the two lower alkyl groups may join in forming a heterocycle which may include an additional hetero atom. Preferably the lower alkyl and lower alkylene groups have up to 4 and especially 1 or 2 carbons. Thus, groups such as dimethylaminomethyl, diethylaminomethyl, dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl, piperidinomethyl, piperidinoethyl, morpholinomethyl, morpholinoethyl, thiamorpholinomethyl, thiamorpholinoethyl, piperazinomethyl, piperazinoethyl, piperazinopropyl are included.

The amino groups

wherein R7 and R8 each represents hydrogen or lower alkyl include the amino group, lower alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino and butylamino and dilower alkylamino groups such as dimethylamino, diethylamino, methylethylamino, dipropylamino and dibutylamino (preferably, but not necessarily, both lower alkyl groups are the same in a given compound). R7 and R8 can also join with the nitrogen to form one of the heterocyclic radicals pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl. These heterocyclic radicals may be unsubstituted or substituted with a lower alkyl or hydroxy-lower alkyl group.

The preferred heterocyclics are piperidino, morpholino and 4-methylpiperazino.

The substituted lower alkoxy groups represented by R5' and the substituted lower alkylamino groups represented by R7 may bear an amino group

as described above resulting in R5' substituents which are amino-lower alkoxy groups (--O-lower

R'O alkylene -N ) R11 and amino-lower alkyleneamino groups (-NH-lower

R10 alkylene-N R" respectively, including, for example, aminomethoxy, aminoethoxy, aminopropoxy, methylaminoethoxy, ethylaminoethoxy, ethylaminopropoxy, dimethylaminomethoxy, dimethylaminoethoxy, dimethylaminopropoxy, diethylamino-ethoxy, dimethylaminobutoxy, diethylaminopropoxy, aminoethylamino, aminopropylamino, methylaminopropylamino, ethylaminoethylamino, dimethylaminomethylamino, diethylaminomethylamino, dimethylaminoethylamino, diethylaminoethylamino and dimethylaminopropylamino. Preferred are those groups wherein the lower alkyl and lower alkylene groups have up to 4 carbons, especially 1 to 2 carbons. Especially preferred group of this type are di-lower alkylamino-lower alkoxy especially dimethylaminopropoxy and dilower alkylamino-lower alkylene-amino, especially dimethylaminopropylamino.

In compounds of the formula

the preferred groups are those wherein R1 is lower alkyl, especially ethyl; R2 is hydrogen or lower alkyl, especially hydrogen; R3 is hydrogen or lower alkyl, especially methyl; R4 is hydrogen or lower alkyl, especially hydrogen; R5 is lower alkyl, especially methyl, ethyl and isopentyl, or di-lower alkylamino-lower alkylene, especially dimethylaminopropyl and dimethylaminoethyl; R6 is lower alkyl or hydrogen, especially hydrogen.

In compounds of the formula

the preferred groups are those wherein R' is hydrogen or lower alkyl, especially the latter and most especially ethyl; R2 is hydrogen or lower alkyl, especially hydrogen; R3 is hydrogen or lower alkyl, especially methyl; R4 is hydrogen or lower alkoxycarbonyl, especially ethoxycarbonyl; R5' is amino, mercapto, lower alkylmercapto, especially methylmercapto, lower alkylamino, especially C1-C4-lower alkylamino, lower alkoxy, especially C1- C5-lower alkoxy, di(lower alkyl)amino, especially C1-C4-di(lower alkyl)amino, di(lower alkyl)amino-lower alkylamino, especially wherein the lower alkyl groups are C1-C4 and most especially dimethylaminoethylamino and dimethylaminopropylamino, or di(lower alkyl)amino-lower alkoxy, especially wherein the lower alkyl and lower alkoxy groups are C1-C4 and most especially dimethylamino-propoxy. R6 is hydrogen or lower alkyl, especially hydrogen.

The products of the examples are representative of the various compounds of this invention and constitute especially preferred embodiments.

The new compounds of formula I may be formed by the following series of reactions.

The symbols in the structural formulas have the same meaning as previously described.

A pyrazolo[3,4-b]pyridine of the formula

(produced according to the procedure given in U.S. Patent No. 3,761,487) is made to react with an iminonitrile of the formula

or a ketonitrile of formula

in an organic solvent such as alcohol.

By this reaction a hydrazone of the formula

is formed.

Treatment of the compound of formula V with a base, e.g., an alkali metal alkoxide such as sodium ethoxide or potassium ethoxide in alcoholic solution or with an organic acid and a Lewis acid such as zinc chloride or boron trifluoride (the organic acid may be a solvent such as acetic acid) yields a compound of the formula

Compounds of formula Ia wherein R5 is other than hydrogen, are obtained by treatment of a cyclized compound of formula VI wherein R5 is hydrogen, obtained as just described, with the halide R5-hal, wherein hal is a halogen, preferably chlorine or bromine, and R5 has the meaning defined above, in the presence of a base, preferably a base of an alkali metal, such as sodium hydride, sodium or potassium alcoholate, sodium metal or sodium or potassium hydroxide, in a solvent, such as dimethylformamide or diethyleneglycol dimethyl ether.

Reaction of the compound of formula VI with a chlorinating agent such as phosphorus oxychloride or phosphorus pentachloride results in the formation of a compound of the formula.

Compounds of formula Ib wherein R5' is lower alkoxy, amino-lower alkoxy or phenyloxy are now produced by reaction of the compound of formula VII with an alcoholate of the formula R12-O-Me (VIII) wherein Me is an alkali metal such as sodium or potassium and R12 is lower alkyl, aminolower alkyl

lower alkyl, phenyl, or substituted phenyl.

Compounds of formula I wherein R5' is lower alkylthio are obtained by reaction of a compound of formula VII with an alkali metalmercaptide of the formula R12-S-Me (IX) wherein Me is again an alkali metal such as sodium or potassium and R12 is lower alkyl.

Compounds of Formula I wherein R5 is mercapto are obtained by reaction of a compound of formula VI with an alkali metal sulfide such as sodium sulfide.

Compounds of formula I wherein R5 is an amino group or amino-lower alkylene group are produced by reaction of a compound of formula VII with an amine of the formula

H2N-lower

R7 alkylene-N R8 (X) at elevated temperatures.

When R4 is lower alkoxycarbonyl, the free carboxylic acid is obtained by hydrolysis, e.g., with a base such as sodium hydroxide.

The compounds of formula I form salts which are also part of this invention. The salts include acid addition salts, particularly the physiologically acceptable members.

These salts are formed by reaction with one or more equivalents of a variety of inorganic and organic acids providing acid addition salts including, for example, hydrohalides (especially hydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate, succinate, aryland alkanesulfonates like benzenesulfonate, methane-sulfonate, cyclohexanesulfamate and toluenesulfonate, etc. The acid addition salts frequently provide a convenient means for isolating the product, e.g., by forming and precipitating a salt (which is not necessarily non-toxic) in an appropriate medium in which the salt is insoluble, then after separation of the salt, neutralizing with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of formula I. Other salts can then be formed from the free base by reaction with an equivalent or more of acid containing the desired anion.

Additional experimental details are found in the examples.

The compounds of this invention have central nervous system depressant activity and can be used as psychotropic agents, e.g., as ataratic agents for the relief of anxiety and tension states, for example, in mice, cats, rats, dogs and other mammalian species. For this purpose a compound or mixture of compounds of formula I, or physiologically acceptable acid addition salt thereof, is preferably administered orally, but parenteral routes such as subcutaneously, intramuscularly, intranenously or intraperitoneally in the described dosages, can also be employed. A single dose, or preferably 2 to 4 divided daily doses, provided on a basis of about 5 to 50 mg per kilogram per day, preferably about 10 to 25 mg per kilogram per day, is appropriate.

The compounds of this invention also have antiinflammatory properties and are useful as antiinflammatory agents, for example, to reduce local inflammatory conditions such as those of an edematous nature or resulting from proliferation of connective tissue in various mammalian species such as rats and dogs when given orally in dosages of about 1 to 50 mg/kg/day, preferably 2 to 15 mgikWday, in single or 2 to 4 divided doses, as indicated by the carrageenan edema or delayed hypersensitivity skin reaction tests in rats.

They can also be used topically.

The compounds of the invention can be utilized by formulation in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspension for parenteral administration.

about 10 to 300 mg. of a compound or mixture of compounds of formula I or physiologically acceptable acid addition salt is compounded with a physiologically acceptable vehicle, carrier, excipients, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

Illustrative of the adiuvants which may be incorporated in tablets, capsules and the like are the foilowing: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry.

When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Of course, any material used in preparing the dosage unit should be pharmaceutically pure and substantially non-toxic in the amounts employed.

For topical administration as an antiinflammatory agent, a conventional lotion, ointment or cream containing about 0.1 to 3 percent by weight of a compound of formula I or its salt is formulated.

The following examples are illustrative of the invention. All temperatures are in degrees celcius.

Example 1 2,4 - Dimethyl - 8 - ethyl - 4H - pyrazolo 1 I ,Saipyrazolo[4',3':5,6l - pyrido[3,4- e]pyrimidin - 5(8H) - one a) 4 - [2 - (2 - cyano - 1 - methyl-ethyl- idene)hydrazino] - 1 - ethyl - 1H pyrazolo[3,4-e]pyridine - 5 - carb oxylic acid, ethyl ester 660 g of 1 - ethyl - 4 - hydrazino - 1M pyrazolo[3,4-b] - pyridine - 5 - carboxylic acid, ethyl ester (3 mol.) and 246 g. of 3iminobutyronitrile (3 mol.) are refluxed with stirring in 3 liters of butanol for 12 hours.

The solvent is distilled off and the residual 4 - [2 - (2 - cyano - 1 - methylethylidene)hydrazino] - 1 - ethyl - lH - pyrazolo[3,4-b] - pyridine - 5 - carboxylic acid, ethyl ester is recrystallized from alcohol, yield 756 g. (80%); m.p. 190--1910.

b) 8 - ethyl - 2 - methyl - 4H - pyrazolo [1 ,5-a]pyrazolo[4',3':5,6] - pyrido[3,4 e]pyrimidin - 5(8H) - one 750 g. of 4 - [2 - (2 - cyano - 1 - methyl- ethylidene)hydrazino] - I - ethyl - 1H - pyrazolo[3,4-e]pyridine- 5- carboxylic acid, ethyl ester (2.8 mol.) are refluxed with stirring in 3 liters of acetic acid containing 50 g. of zinc chloride for 24 hours. The solution is cooled to room temperature and after the addition of about 3 liters of cold water, 8 - ethyl - 2 - methyl - 4M pyrazolo[l,5 a]pyrazolo[4',3':5,6]pyrido[3,4- e]pyrimidin - 5(8H)- one crystallizes and is filtered off. The purification of the compound is accomplished by dissolving in the theoretical amount of aqueous sodium hydroxide and acidifying the mixture with acetic acid. Yield 562 g. (75%); m.p.

285-2860C.

c) 2,4 - dimethyl - 8 - ethyl - 4H pyrazolo[ 1,5 - a]pyrazolo[4',3':5,6]pyrido [3,4-e]pyrimidin - 5(8H)- one 2.7 g. of 8 - ethyl - 2 - methyl - 4H pyrazolo[ 1 ,5-a]pyrazolo - [4',3':5,6]pyrido [3,4-e]pyrimidin - 5(8H) - one (0.01 mol.) are added to a suspension of 0,03 g. of sodium hydride in 50 ml. of diethylene glycol dimethyl ether at reflux temperature.

The temperature is maintained for one hour and then lowered to 1200. 2.8 g. of methyl iodide are added and heating is continued for 10 hours. the precipitated sodium iodide is filtered off, the solution evaporated to dryness and the residue recrystallized from ethyl-acetate, yield 1.9 g. (68%); m.p.

2062070.

Example 2 4,8 - Diethyl - 2 - methyl - 4H - pyrazolo [1 ,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5(8H) - one By substituting ethyl iodide for the methyl iodide in the procedure of Example 1(c), 4,8 - dimethyl- 2- methyl- 4H pyrazolo[l,5 - a]pyrazolo[4',3':5,6]pyrido - [3,4-e]pyrimidin - 5(8H) - one is obtained in 71% yield, m.p. 178--180" (ethyl acetate).

Example 3 8 - Ethyl - 2 - methyl - 4 - (3 - methyl butyl) - 4H - pyrazolo[1,5-a]- pyrazolo - [4',3':5,6]pyrido[3,4-e]- pyrimidin - 5(8H) - one By substituting I - bromo - 3 - methylbutane for the methyl iodide in the procedure of Example l(c), 8 - ethyl - 2 methyl- 4 - (3 - methylbutyl) - 4H pyrazolo[l,5 - alpyrazolo[4',3':5,6]pyrido - [4,3-e]pyrimidin - 5(8H)- one is obtained, yield 59%, m.p. 126--1280 (ethyl acetate).

Example 4 4- [3 - (Dimethylamino)propyl] - 8 ethyl - 2 - methyl - 411 - pyrazolo - [1 ,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e] pyrimidin - 5(8 H) - one 5.4 g. of 8 - ethyl - 2 - methyl - 4H pyrazolo[l,5 - a]pyrazolo [4',3': 5,6]pyrido [3,4e]pyrimidin - 5(8H)- one (0.02 mol.) are added to a solution of 1.5 g. of a sodium methoxide in 50 ml. of diethylene glycoldimethyl-ether. The solution is refluxed with stirring for 30 minutes and then the temperature lowered to 100 . After the addition of 3 g. of dimethylaminopropyl chloride, the mixture is stirred for 24 hours.

The inorganic precipitate is filtered off, the filtrate evaporated to dryness and the residue dissolved in 30 ml. of water. The aqueous solution is brought to pH 10 with sodium hydroxide and extracted three times with 50 ml. portions of diethylether. The ether layers are combined, dried with sodium sulfate and the solvent is distilled off. The residue is crystallized with ether to obtain 2.8 g. (40%) of 4 - [3 - (dimethylamino) - propyl] - 8 - ethyl - 2 - methyl 4H - pyrazo1o[ I ,5-a]pyrazolo[4',3':5,6] pyrido[3,4-e]pyrimidin - 5(8H)- one, m.p. 65680 (propanol). Treatment of the product with acetic acid yields the acetate salt.

Example 5 8 - Ethyl - 2 - methyl - 4 - (2 morpholino)ethyl - 4H - pyrazolo[l,5 a] - pyrazolo[4',3':5,6]pyndo[3,4-ei- pyrimidin - 5(8H) - one 2.7 g. of 8 - ethyl - 2 - methyl - 4H pyrazolo[l,5 - a]pyrazolo[4',3':5,6]pyrido - [3,4-e]pyrimidin - 5(8H) - one (0.01 mol.) and 0.3 g. of sodium are refluxed for one hour in 30 ml. of diethylene glycoldimethylether with stirring. The temperature is lowered to 900 and 2 g. of 1-- chloro - 2 morpholinoethane are added and stirring is continued for 24 hours. The inorganic precipitate is filtered off, the solvent removed in vacuo and the crystalline product, 8 - ethyl - 2 - methyl - 4 - (2 morpholino)ethyl - 4H - pyrazolo[l,5-a] pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin - 5(8H)- one is recrystallized from ethyl acetate, yield 3.1 g. (81%); m.p. 140--1410.

Example 6 8 - Ethyl -2 - methyl -4 - (2 - piperidino) ethyl - 4H - pyrazololl,5-a] pyrazolo[4',3':5,6]pyrido [3,4-e]- pyrimidin - 5(8H) - one By substituting for the dimethylaminopropyl chloride in Example 4 the equivalent amount of 1 - chloro - 2- piperidino ethane, 8 - ethyl - 2 - methyl - 4- (2- piperidino) - ethyl - 4H - pyrazolo[l,5-a] pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin - 5(8H)- one is obtained, yield 62%; m.p.

134--137" (ethyl acetate).

Example 7 4 - [2 - (Diethylamino)ethyl] - 8 - ethyl 2- methyl- 4H - pyrazolol,5-a] [1 ,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e] pyrimidin - 5(8H) - one By substituting for the 1 - chloro - 2 morpholinoethane in Example 5 the equivalent amount of 1 - chloro - 2dimethylaminoethane, 4 - [2 (diethylamino)ethyl - 8 - ethyl - 2 methyl - 4H - pyrazolo[l,5-a] pyrazolo[4',3':5,6]pyrido[3,4 - e] pyrimidin - 5(8H) - one is obtained, yield 63 ,4; m.p. 9O920 (ethyl acetate).

Example 8 2,4 - Dimethyl - 4H - pyrazolo[l,5-a] pyrazolo[4',3':5,6]pyrido[3,4-e] pyrimidin - 5(8H) - one By substituting an equivalent amount of 4 - hydrazino - 1H - pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester for the I - ethyl - 4 - hydrazino - 111 - pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example l(a) and continuing as in parts (b) and (c), 2 - methyl - 411 - pyrazolo - [1,5 a]pyrazolo[4',3': 5,6]pyrido] 3,4 - elpyrimidin5(8H)- one and 2,4 - dimethyl- 4H pyrazolo[ 1 ,5-aipyrazolo[4',3': 5,6] - pyrido [3,4-e]pyrimidin - 5(8H) - one are obtained.

Example 9 4 - Butyl - 8 - ethyl - 2 - methyl - 4H pyrazolo[ 1,5 - alpyrazolo[4',3' ;5,6] pyrido[3,4-e]pyrimidin - 5(8H) - one By substituting butyl iodide for the methyl iodide in the procedure of Example l(c), 4 - butyl - 8 - ethyl - 2 - methyl - 4H - pyrazolo[ 1 5-a]pyrazolo[4',3':5,6]- pyrido[3,4 - elpyrimidin - 5(8H)- one is obtained.

Example 10 2 - Methyl - 4 - Phenylmethyl - 4H pyrazolo[ 1,5-a] [4',3':5,6]pyrido[3,4-e]- pyrimidin - 5(8H) - one By substituting the 2- methyl- 411 pyrazolo[1 5 - a]pyrazolo[4',3':5,6]pyrido [3,4-e]pyrimidin - 5(8H) - one of Example 8 for the 8 - ethyl - 2 - methyl - 4H - pyrazolo[l,5-a] pyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidin 5(8H)- one and benzyl iodide for the methyl iodide in the procedure of Example 1(c), 2 - methyl - 4 - phenylmethyl - 4H pyrazolo[l,5 - a]pyrazolo[4',3':5,6]pyrido [3,4-e]pyrimidin - 5(8H) - one is obtained.

Example 11 8 - Ethyl - 2 - methyl - 4 - phenylethyl 4H - pyrazolo [1,5-a] [4',3': 5,6]pyrido- [3,4elpyrimidin - 5(8H) - one By substituting phenylethyl bromide for the methyl iodide in the procedure of Example l(c), 8 - ethyl - 2 - methyl - 4 phenylethyl - 4H - pyrazolo[l,5-a]pyrazolo - [4',3':5,6]pyrido[3,4 - e]pyrimidin5(8H) - one is obtained.

Example 12 2,4,8 10 - Tetramethyl - 4H - pyrazolo [1 ,5-a]pyrazoloE4',3':5,6]pyrido[3,4e]- pyrimidin - 5(8H) - one By substituting 1,3- dimethyl- 4hydrazino - 1H - pyrazolo - [3,4-b]pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 111 pyrazolo[3,4-b]pyridine - 5- carboxylic acid, ethyl ester in the procedure of Example l(a) and proceeding as in parts (b) and (c), 2,8,10 - trimethyl - 4H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4 - e] pyrimidin - 5(8H)- one and 2,4,8,10 tetramethyl - 4H - pyrazolo[l,5-a] pyrazolo[4',3' : 5,6]pyrido [3,4-e]pyrimidin - 5(8H) - one are obtained.

Example 13 4 - Propionyl - 2,3,8 - triethyl- 4H pyrazolo[l,5 - a]pyrazolo[4',3':5,6] - pyrido[3,4-e]pyrimidin - 5(8H) - one By substituting 1 - isopropyl - 4hydrazino - 1H - pyrazolo - [3,4-b]pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 111 pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester and 2 - ethyl - 3 - iminopentanonitrile for the 3-iminobutyronitrile in the procedure of Example 1(a), proceeding as in part (b) and then substituting propionyl bromide for the methyl iodide in part (c), 2,3,8 - triethyl 4H - pyrazolo - [1,5-a]pyrazolo[4',3': 5,6] pyrido[3,4)e]pyrimidin - 5(8H)- one and 4 - propionyl - 2,3,8 - triethyl - 4H pyrazolo[1,5-a]pyrazolo- [4',3':5,6]pyrido [3,4-e]pyrimidin - 5(8H)- one, respectively, are obtained.

Example 14 4 - (4 - Chlorobenzoyl) - 10 - ethyl - 2 methyl - 4H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4-e] pyrimidin - 5(8H) - one By substituting 4- hydrazino - 3ethyl - 1H - pyrazolo - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid propyl ester for the 1 - ethyl - 4 - hydrazino - 1H pyrazolo[3,4-b]pyridine - 5- carboxylic acid, ethyl ester in the procedure of Example 1(a), proceeding as in part (b) and then substituting proceeding as in part (b) and substituting benzoyl iodide for the methyl iodide in part (c), 2- methyl - 8 - phenyl - 411 pyrazolo[1,5 - a]pyrazolo [4',3': 5,6]pyrido [3,4-e]pyrimidin - 5(8H)- one and 4benzoyl - 2 - methyl - 8 - phenyl - 4H pyrazolo[l,5 - a]pyrazolo[4',3':5,6]pyrido - [3,4-e]pyrimidin - 5(8H) - one, respectively, are obtained.

Example 16 8 - Ethyl - 2,4,6 - trimethyl- 4H pyrazolo[l,5 - a]pyrazolo[4',3':5,6] pyrido[3,4e]pyrimidin - 5(8H) - one By substituting 1 - ethyl - 4 - hydrazino 6 - methyl - 1H - pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester for the I - ethyl - 4 - hydrazino - 1H pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 1, 2,6 - dimethyl- 8 - ethyl - 4H - pyrazolo[l,5-a]pyrazolo[4',3':5,6]- pyrido[3,4-elpyrimidin - 5(8H)- one and 8- ethyl - 2,4,6 - trimethyl- 411 pyrazolo[ 1 ,5-alpyrazolo[4',3':5,6lpyrido[3,4- e]pyrimidine - 5(8H)- one, respectively, are obtained.

Example 17 8 - Benzyl - 2 - methyl - 4 - (3 - methyl butyl)- 4H - pyrazolo[l,5-al - pyrazolo[4',3':5,61pyrido[3,4-e]- pyrimidin - 5(8H) - one By substituting 1 - benzyl - 4hydrazino - 1H - pyrazolo[3,4-b]pyridine 5 - carboxylic acid, ethyl ester for the 1 ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- blpyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example l(a), proceeding as in part (b) and substituting I bromo - 3 - methylbutane for the methyl iodide in part (c) (as in Example 3), 8 benzyl - 2 - methyl - 411 pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidin 5(8H)- one and 8 - benzyl - 2 - methyl 4 - (3-methylbutyl) - 4H - pyrazolo[l,5-a] pyrazolo [4',3': 5,6] pyrido[3,4-e]pyrimidin 5(8H) - one, respectively, are obtained.

Example 18 4 - Methyl - 8 - phenylethyl - 3 - propyl 411 - pyrazolo[1,5-a]pyrazolo- [4',3':5.6]pyrido[3,4-e]pyrimidin 5(8H) - one By substituting 1 - phenylethyl - 4hydrazino - 1H - pyrazolo[3,4-b]pyridine 5 - carboxylic acid. methyl ester for the 1 ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid, ethyl ester and 2-iminomethylpentano-nitrile for the 3iminobutyronitrile in the procedure of Example I (a) and proceeding as in parts (b) and (c), 3 - propyl - 8 phenethyl- 411 - pyrazolo[l,5-a]pyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidin - 5(8H) one and 4 - methyl - 8 - phenylethyl - 3 propyl - 4H - pyrazolo - [1,5-a]pyrazolo [4',3':5,6lpyrido[3,4elpyrimidin - 5(8H)one, respectively, are obtained.

Example 19 8 - Ethyl - 4 - methyl - 2 - phenyl - 4H pyrazolo[ 1 ,5-a]pyrazolo[4',3': 5,6lpyrido [3,4-e]pyrimidin - 5(8H) - one By substituting 3 - imino - 3 - phenylpropionitrile for the 3-iminobutyronitrile in the procedure of Example l(a) and proceeding as in parts (b) and (c), 8 - ethyl 2 - phenyl - 4H - pyrazolo[1,5-alpyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidin - 5(8H)one and 8 - ethyl - 4 - methyl - 2 phenyl - 4H - pyrazolo[1,5-alpyrazolo- [4',3':5,6lpyrido[3 4-elpyrimidin - 5(8H) one, respectively, are obtained.

Example 20 4 - Methyl - 4H - pyrazoio[l,5-alpyrazolo- [4' ,3': 5,6]pyrido[3,4-e] - pyrimidin 5(8H)- one By substituting 4- hydrazino - 111 - pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 hydrazino - 111 - pyrazolo[3,4-b]pyridine 5 - carboxylic acid, ethyl ester and the 3iminopropionitrile for the 3-iminobutyronitrile in the procedure of Example l(a) and proceeding as in parts (b) and (c), 4H pyrazolo[ 1,5 - alpyrazolo[4',3':5,6]pyrido [3,4-e]pyrimidin - 5(8H) - one and 4 methyl - 4H - pyrazolo[1,5-alpyrazolo- [4',3':5,61pyrido[3,4-e]pyrimidin - 5(8H) one, respectively, are obtained.

Example 21 8 - Benzoyl - 2 - methyl - 4 - phenyl - 4H - pyrazolo[l,5-a]pyrazolo [4',3': 5,6]pyrido[3,4-e]pyrimidin - 5 (8H)- one a) 1 - Furfuryl - 2 - methyl - 4 - phenyl 4H - pyrazolo[1,5-alpyrazolo- [4',3':5,6lpyrido[3,4-elpyrimidin 5(8H)- one By substituting 4- hydrazino - I furfurylpyrazolo - [3,4-b]pyridine - 5 carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid, ethyl ester in Example l(a) and proceeding as in parts (a) and (b), 8 - furfuryl - 2 - methyl - 4H pyrazolot 1,5 - a]pyrazolo[4',3': 5,6]pyrido [3,4-e]pyrimidin - 5(8H) - one is obtained.

This compound is now processed as in Example 1, part (c), substituting bromo benzene for the methyl iodide. A small amount of copper catalyst is added to obtain 1 - furfuryl - 2 - methyl - 4 - phenyl - 4H - pyrazolo[l,5-alpyrazolo[4',3':5,61- pyrido[3,4-e]pyrimidin - 5(8H) - one.

b) 2 - Methyl - 4 - phenyl - 411 - pyrazolo [1,5-alpyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5(8H) - one 0.01 mol. of 1 - furfuryl - 2 - methyl 4 - phenyl - 4H - pyrazolo[l,5-a]pyrazolo- [4' .3':5,61pyrido[3,4-e]pyrimidin - 5(8H) is heated in 50 ml. of diethyleneglycol dimethyl ether containing 0.01 mol. of selenium dioxide at reflux temperature with stirring for two hours. The mixture is filtered hot and evaporated to dryness.

Crystalline 2 - methyl - 4 - phenyl - 4H pyrazolo[l,5 - a]pyrazolo[4',3':5,6]pyrido [3,4-e]pyrimidin - 5(8H) - one remains.

c) 8 - Benzoyl - 2 - methyl - 4 - phenyl 4H - pyrazolo[l,5-a]pyrazolo [4',3':5,61pyrido[3,4-e]pyrimidin - 5(8H)- one 0.01 mol. of 2 - methyl - 4 - phenyl 4H - pyrazolo[1,5-a]pyrazolo[4',3':5,6]- pyrido[3,4-elpyrimidin - 5(8H)- one and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature. On addition of 50 ml. of water, 8 - benzoyl - 2 - methyl - 4 - phenyl - 4H - pyrazolo[l,5-alpyrazolo[4',3':5,6]- pyrido[3,4-e]pyrimidin - 5(8H)- one is filtered off.

Example 22 2,4 - Dimethyl - 8 - (4 - methylbenzoyl) 4H - pyrazolo[l,5-a]pyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidin - 5(8H)- one By substituting 1 - (4 - methylbenzoyl) 4- hydrazino - 1H - pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 1H pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example l(a) and proceeding as in parts (b) and (c), 2 - methyl - 8 - (4 - methyl benzoyl) - 411 - pyrazolo[l,5-alpyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidin - 5(8H)one and 2,4 - dimethyl - 8 - (4 - methylbenzoyl) 4H - pyrazolo[l,5-alpyrazolo- [4',3':5,6]pyrido[3.4-e]pyrimidin - 5(8H) one, respectively, are obtained.

Example 23 4 - (2 - Aminoethyl) - 2,6 - dimethyl - 8 ethyl - 4H - pyrazolo[l,5-alpyrazolo [4',3':5,6]pyrido[3,4-elpyrimidine 5(8H)- one By substituting the 2,6 - dimethyl - 8 ethyl - 4H - pyrazolo[l,5-alpyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidin- 5(8H)- one obtained in Example 16 in the procedure of Example 4 and substituting 2chloroethylamine for the dimethylaminopropyl chloride, 4 - (2 - aminoethyl) - 2,6 dimethyl - 8 - ethyl - 411 - pyrazolo[l,5-a]- pyrazolo[4',3': 5,6]pyrido [3,4-e]pyrimidin 5(8H) - one is obtained.

The hydrochloride salt is obtained by treating the above product with ethanolic HCI.

Example 24 4 - (3 - Ethoxypropyl) - 8 - ethyl - 2 methyl - 4H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5(8H) - one By substituting 3-ethoxypropyl chloride for the dimethylaminopropyl chloride in the procedure of Example 4, 4- (3 ethoxypropyl)- 8 - ethyl - 2 - methyl - 4H - pyrazolo[l,5 - a]pyrazolo[4',3':5,6] pyrido[3,4-e]pyrimidin - 5(8H)- one is obtained.

Example 25 2 - Methyl - 4 - methylthiomethyl - 4H pyrazolo[1,5 - a]pyrazolo[4',3':5,6] pyrido[3,4- e]pyrimidin - 5(8H) - one By substituting methylthiomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 4 and substituting the 2 - methyl - 4H - pyrazolo [1,5 - alpyrazolo[4',3':5,6lpyrido[3,4 - e] pyrimidin - 5(8H)- one obtained in Example 8 for the 8 - ethyl - 2 - methyl 411 - pyrazolo[l,5-alpyrazolo[4',3':5,61- pyrido[3,4-e]pyrimidin - 5(8H)- one, 2methyl- 4- methylthiomethyl- 4H pyrazolo[l,5 - alpyrazolo[4',3':5,6]pyrido [3,4-e]-pyrimidin - 5(8H) - one is obtained.

Example 26 8 - Benzoyl - 2 - methyl - 4 - (p - methyl phenyl) - 4H - pyrazolo[l,5 - a] pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5(8H) - one By substituting p-methylphenyl bromide for the bromobenzene in the procedure of Example 21 a, and proceeding as in parts b and c, 8 - benzoyl - 2 - methyl - 4 - (p methylphenyl)- 411 - pyrazolo[1,5-a]- pyrazolo - [4',3':5,6lpyrido[3,4-el- pyrimidin - 5(8H) - one is obtained.

Example 27 4 - [2 - (Diethylamino)ethyl] - 2,8,10 trimethyl- 411 - pyrazolo[l,5 - ai- pyrazolo[4',3':5,6]pyrido[3,4 - e] pyrimidin - 5(8H) - one By substituting diethylamin oethyl chloride for the dimethyl - amino - propyl chloride and utilizing the 2,8,10-trimethyl - 4H - pyrazolo[l,5 - a]pyrazolo [4',3':5,6]pyrido[3 ,4-e]pyrimidin - 5(8H) one product of Example 12 instead of 8 ethyl - 2 - methyl - 4H - pyrazolo[l,5-a]pyrazolo [4',3': 5,6]pyrido[3,4 - e]pyrimidin - 5(81H) - one in the procedure of Example 4, 4 - [2 - (diethylamino)ethyl] - 2,8,10 trimethyl - 4H - pyrazolo[1,5-alpyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidin - 5(8H)one is obtained.

Example 28 4 - Dimethylaminomethyl - 2 - methyl 8 - phenyl - 4H - pyrazolo[l,5-a] pyrazolo[4',3':5,6]pyrido[3,4-e[- pyrimidin - 5(8H) - one By substituting dimethylaminomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 4 and utilizing 2- methyl- 8 - phenyl- 411 - pyrazolo[l,5 - a]pyrazolo[4',3':5,6]pyrido- [3,4-e]pyrimidin - 5(8H)- one product of Example 15 instead of 8 - ethyl - 2 methyl - 4H - pyrazolo[ 1 ,5-a]pyrazolo- [4',3':5,61pyrido[3,4-e]pyrimidin - 5(8H)one, 4 - dimethylamino - methyl- 2methyl - 8 - phenyl - 411 - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidin - 5(8H) - one is obtained.

Example 29 8 - Ethyl - 2 - methyl - 4-(2-thia- morpholino)ethyl - 4H - pyrazolo[l,5 a]pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5(8H) - one By substituting 1 - chloro - 2- thiamorpholinoethane for the 1 - chloro - 2 morpholinoethane in the procedure of Example 5, 8 - ethyl - 2 - methyl - 4 - (2 thiamorpholino)ethyl- 4H- pyrazolo[l,5- alpyrazolo[4',3':5,6lpyridol3,4 el pyrimidin - 5(8H)- one is obtained.

Example 30 2 - Methyl - 4 - (3 - piperazino)propyl 4H - pyrazolo[l,5-alpyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidin - 5(8H)- one By substituting 3-piperazinopropyl chloride for the 1 - chloro - 2morpholinoethane in the procedure of Example 5 and utilizing the 2 - methyl 4H - pyrazolo[l ,5-a]pyrazolo[4',3':5,6]- pyrido[3,4-e]pyrimidin - 5(8H)- one product of Example 8, 2 - methyl - 4 - (3 piperazino)propyl- 411 - pyrazolo[1,5-a]- pyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidin - 5(8H) - one is obtained.

Example 31 The following ingredients are used to make 1,000 200 mg. tablets each containing 100 mg. of active ingredient: 2,4-dimethyl-3-ethyl-4H pyrazolo[ I 5-alpyrazolo- [4',3':5,6]pyrido] [3,4-e] pyrimidine-5(8H)-one 100 gm.

Polyvinyl pyrrolidone 7.5 gm.

Lactose 20 gm.

Magnesium stearate 3.5 gm.

Corn starch 17.5 gm.

Avicel-Trade Mark (micro crystalline cellulose 51.5 gm.

The medicament and lactose are thoroughly admixed. The polyvinyl pyrrolidone is dissolved in ethanol USP to make a 30% solution. This solution is used to granulate the mixture of medicament and lactose. The granulation is passed through a No. 16 screen and air dried. The dried granulation is then passed through a No. 20 screen. To the screened granulate are added the magnesium stearate, Avicel and the corn starch and the mixture is blended. The blend is then compressed into 200 mg.

tablets on a standard concave punch. The tablets are then veneer coated with methyl cellulose in a spray pan.

Example 32 N - Butyl - 8 - ethyl - 2 - methyl - 8H pyrazolo[l,5 - a] pyrazolo[4',3':5,6] pyrido[3,4-e]pyrimidin - 5 - amine a) 4 - [2 - (2 - Cyano - 1 - methylethyl- idene)hydrazinol - 1 - ethyl - 111 - pyrazolo[3,4-b]pyridine - 5 carboxylic acid, ethyl ester 249 g of 1 - ethyl - 4 - hydrazino - 1H pyrazolo[3,4-b]- pyridine - 5 - carboxylic acid, ethyl ester (1 mol) and 82 g of 3-aminocrotono-nitrile (1 mol) are heated together in 1.5 liters of butyl alcohol with stirring for 24 hours. The solvent is removed in vacuo and the residual 4 - [2 - (2 - cyano - 1 - methyl ethylidene)hydrazino] - 1 - ethyl - 111 - pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester is recrystallized from alcohol, yield 309 g (80%); m.p. 190--1910.

b) 8 - Ethyl - 2 - methyl - 4H - pyrazolo [1 ,5-alpyrazolo[4',3': 5,6]pyrido[3,4-el- pyrimidin - 5(8H) - one 309 g of 4 - [2 - (2 - cyano - I - methylethylidene)hydrazino] - 1 - ethyl - 111 pyrazolo[3,4-e]pyridine - 5- carboxylic acid, ethyl ester (0.8 mol) are refluxed with stirring in 1 liter of acetic acid, containing 50 g of zinc chloride, for 24 hours. The solution is cooled to room temperature and after addition of about 1 liter of cold water, 8 ethyl - 2 - methyl - 4H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4- el - pyrimidin - 5(8H) - one crystallizes and is filtered off. Purification of the compound is accomplished by dissolving in the theoretical amount of aqueous sodium hydroxide and acidifying the solution with acetic acid, yield 161 g (75%), m.p. 2852860.

c) 5 - Chloro - 8 - ethyl - 2 - methyl - 8H - pyrazolo[l,5-a]pyrazolo [4',3':5,61pyrido[3,4-e]pyrimidine 161 g of 8 - ethyl - 2 - methyl - 4H pyrazolo [1,5 - alpyrazolo[4',3':5,6lpyrido [3,4-e]pyrimidin - 5(8H)- one (0.06 mol) are heated with stirring in 1 liter of phosphorus oxychloride at 800 for 48 hours. The mixture is decomposed by pouring onto crushed ice.

The 5 - chloro - 8 - ethyl - 2 - methyl 8H - pyrazolo[ 1 ,5-alpyrazolo[4',3':5,6] pyrido[3,4-e]pyrimidine is filtered off and recrystallized from butyl alcohol, yield 148 g (86 '); m.p. 179--1800.

d)N -Butyl -8 methyl -2-methyl - 8H pyrazolo[1,5 - a]pyrazolo[4',3':5,6] - pyrido[3,4-e]pyrimidin - 5 - amine 5.7 g of 5 - chloro - 8 - ethyl - 2 methyl- 811 - pyrazolo[l,5-a]pyrazolo- [4',3': 5,6]pyrido[3,4-e]pyrimidine (0.02 mol) are dissolved in 50 ml of dry alcohol. After addition of 1.5 g of n-butylamine, the mixture is heated at reflux temperature with stirring for 12 hours. The solvent is removed and the crystalline residue is treated with water. The N- butyl- 8- ethyl - 2 methyl- 811 - pyrazolo[l,5-a]pyrazolo- [4',3':5,6lpyrido[4,3-elpyrimidin - 5 - amine is filtered off and recrystallized from ethyl acetate, yield 5 g (77%); m.p. 160--162 .

Example 33 8 - Ethyl - 2 - methyl - N - (1 - methyl- propyl) - 8H - pyrazolo[l,5-a] pyrazolo - [4',3':5,6]pyrido[3,4 - e] pyrimidin - 5 - amine, hydrate (1:1) By substituting 1 - methylpropylamine for the n-butylamine in the procedure of Example 32 (d), 8 - ethyl - 2 - methyl - N (1 - methyl - propyl) - 8H - pyrazolo [1,5 - alpyrazolo[4',3':5,6lpyridol[3,4 - el - pyrimidin - 5 - amine, hydrate (1:1) is obtained in 81% yield, m.p. 94--970 (alcohol).

Example 34 8 - Ethyl - 2 - methyl - N - (1 - methyl- ethyl) - 8H - pyrazolo[l,5-a]pyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidin - 5 amine By substituting 1 - methylethylamine, for the n-butylamine in the procedure of Example 32 (d), 8 - ethyl - 2 - methyl - N (1 - methylethyl) - 8H - pyrazolo[l,5-a]- pyrazolo[4',3': 5,6]pyrido[3,4 - e]pyrimidin - 5 - amine is obtained, yield 78%; m.p. 981000 (alcohol).

Example 35 N- [3 - (Dimethylamino)propyl] - 8 ethyl - 2 - methyl - 811 - pyrazolo [ 1,5-a]pyrazolo[4',3':5,61pyrido[3,4-e]- pyrimidin - 5 - amine 2.9 g of 5- chloro - 8- ethyl - 2methyl - 811 - pyrazole[l,5-a]pyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidine (0.01 mol) are dissolved in 30 ml of alcohol. 2.5 g of 3 (dimethylamino) - propyl - 1 - amine are added and the mixture is refluxed for 5 hours. The solvent is distilled off in vacuo and the crystalline residue extracted twice with 50 ml portions of ethyl acetate.

The solvent is removed until the volume is about 20 ml and then cooled. N - [3 (dimethylamino)propyl] - 8 - ethyl - 2methyl - 8H - pyrazolo[1,5-a]pyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidin - 5 - amine crystallizes and is filtered off, yield 2.8 g (80 < ); m.p. 178--179 (ethyl acetate).

Example 36 N- [2 - (Dimethylamino)ethyl] - 8 ethyl - 2 - methyl - 8H - pyrazolo [1,5-a]pyrazolo[4' ,3': 5,6]pyrido[3,4-e]- pyrimidin - 5 - amine By substituting 2 - (dimethylamino)- ethyl - 1 - amine for the 3 - (dimethylamino)propyl - 1 - amine in the procedure of Example 35, N - [2 - (dimethylamino)ethyl] - 8 - ethyl - 2 - methyl - 8H pyrazolo[1,5 - a]pyrazolo[4',3': 5,6]pyrido [3,4-e]pyrimidin - 5 - amine is formed, yield 75%; m.p. 124--126 (ethyl acetate).

Example 37 8 - Ethyl - 2 - methyl - 5 - (4 - methyl 1 - piperazinyl) 8H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidine By substituting 4-methylpiperazine for the 3 - (dimethylamino)propyl - 1 - amine in the procedure of Example 35, 8 - ethyl 2 - methyl - 5 - (4 - methyl - 1 - piper- azinyl) - 811 - pyrazolo[1,5-alpyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidine is formed in 69% yield; M.P. 167-169 (ethyl acetate).

Example 38 8 - Ethyl - 2 - methyl - 5 - (1 - piperidinyl)- 811 - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4-el- pyrimidine By substituting piperidine for the 3 (dimethylamino)propyl - 1 - amine in the procedure of Example 35, 8 - ethyl - 2 methyl - 5 - (1 - piperidinyl) - 8H pyrazolo[1,5 - a]pyrazolo[4',3':5,6]pyrido - [3,4-e]pyrimidine is obtained, yield 71%; m.p. 176--177 (alcohol).

Example 39 8 - Ethyl - 2 - methyl - 5 - (4 - morpho linyl)- 811 - pyrazolo[l,5-a]pyrazolo [4',3':5,6]pyrido[3 ,4-e] pyrimidine By substituting morpholine for 3 - (dimethylamino)propyl- 1 - amine in the procedure of Example 35, 8 - ethyl - 2 methyl - 5 - (4 - morpholinyl) - 8H - pyrazolo[1,5 - alpyrazolo[4',3':5,6]pyrido [3,4-e]pyrimidine is obtained, yield 76%; m.p. 179--180 (alcohol).

Example 40 8 - Ethyl - 2 - methyl - N - [3 - (trifluoro- methyl)phenyll - 8H - pyrazolo[l,5-a]- pyrazolo [4',3':5,6]pyrido[3 4-el- pyrimidin - 5 - amine 5.8 g of 5 - chloro - 8 - ethyl - 2 methyl- 811 - pyrazolo[l,5-alpyrazolo- [4',3':5,61 pyrido[3,4 - e]pyrimidine (0.02 mol), 3 g of triethylamine and 3.3 g of 3-trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml of water and filtered off.

Recrystallization from alcohol yields 6 g of 8 - ethyl - 2 - methyl - N - [3-trifluoro methyl) - phenyll - 8H - pyrazolo[1,5-al- pyrazolo[4',3':5.6]pyrido[3.4 - e]pyrimidin 5 - amine; yield (73 X") m.p. 205--206 .

Example 41 N,N,8 - Triethyl- 2 - methyl - 811 - pyrazolo[l,5 alpyrazolo[4',3':5,6] - pyrido[3,4-e]pyrimidin - 5 - amine 8.6 g of 5 - chloro - 8 - ethyl - 2 methyl- 811 - pyrazolo[l,5-alpyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidine (0.03 mol) and 7.2 g of diethylamine are suspended in 50 ml of butyl alcohol and heated with stirring in an autoclave for 10 hours at 150 After this time, the solvent is removed, the residue is treated with water and filtered off.

Recrystallization from alcohol yields 8 g (83%,) of N,N,8 - triethyl - 2 - methyl 8H - pyrazolo[l,5-alpyrazolo[4',3':5,6l pyrido[3,4-elpyrimidin - 5 - amine; m.p.

106--108 .

Example 42 8 - Ethyl - 2 - methyl - 8H - pyrazolo[l,5 a]pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5 - amine By substituting aqueous ammonia (70%) for the diethylamine in the procedure of Example 41, 8 - ethyl - 2 - methyl - 8H pyrazolo[l,5 - alpyrazolo[4',3':5,6]pyrido - [3,4 - e]pyrimidin - 5 - amine is obtained, yield 69 z; m.p. 248--250 (DMF).

Example 43 8 - Ethyl - N,2 - dimethyl - 8H - pyrazolo [1,5-alpyrazolo[4',3':5,61pyrido[3,4 - e]- pyrimidin - 5 - amine By substituting methylamine for the diethylamine in the procedure of Example 41, 8 - ethyl - N,2 - dimethyl - 8H pyrazolo[l,5 - alpyrazolo[4',3':5,6]-pyrido [3,4 - e]pyrimidin - 5 - amine is obtained, yield 76 /"; m.p. 254--255 (butyl alcohol) Example 44 5 - (Butylamino)- 8 - ethyl - 8H pyrazolo[l,5 - a]pyrazolo[4',3':5,6] pyrido[3,4-e]pyrimidine - 3- carb oxylic acid, ethyl ester a) 4 - [2 - (Cyano - 3 - ethoxy - 3 - oxo 1- propenyl)hydrazino] - 1 - ethyl - 1H - pyrazolo[3,4-b]pyridine - 5 carboxylic acid, ethyl ester 249 g of 1 - ethyl - 4 - hydrazino - 1H pyrazolo[3,4-bl - pyridine - 5 - carboxylic acid, ethyl ester (1 mol) are suspended in 1.5 liters of n-butyl alcohol. The mixture is heated with stirring at reflux temperature.

At this point, 169 g of ethoxymethylenecyanoacetic acid, ethyl ester ( I mol), dissolved in 500 ml of warm butyl alcohol, are dropped in. After the addition is completed, heating is continued for 2 hours.

The solution is cooled in an ice-bath and the precipitated 4 - [2 - (2 - cyano - 3ethoxy - 3 - oxo - 1 - propenyl) - hydr azinol - I - ethyl - 1H - pyrazolo[3,4-b1- pyridine - 5 - carboxylic acid, ethyl ester is filtered off, yield 351 g (94 SO): m.p. 170- 172 (butyl alcohol).

b) 8 - Ethyl - 5,8 - dihydro - 5 - oxo - 4H - pyrazolo[l,5-alpyrazolo- [4',3': 5,6]pyrido[3,4-e]pyrimidine - 3 carboxylic acid, ethyl ester 351 g of 4 - [2 - (2 - cyano - 3 - ethoxy 3 - oxo - 1 - propenyl) - hydrazino] - 1 - ethyl - 1H - pyrazolo[3,4-blpyridine - 5 carboxylic acid, ethyl ester are heated in 2 liters of acetic acid containing 50 g of zinc chloride for 24 hours. After this time, the solution is cooled and 2 liters of cold water are added. The precipitated 8 - ethyl - 5,8 dihydro - 5 - oxo - 4H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4- el - pyrimidine - 3 - carboxylic acid, ethyl ester is filtered off and purified by dissolving in the theoretical amount of sodium hydroxide in water and precipitating the compound with acetic acid, yield 256 g (83%); m.p.

263--265 .

c) 5 - Chloro - 8 - ethyl - 8H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4 e] pyrimidine - 3 - carboxylic acid, ethyl ester 256 g of 8 - ethyl - 5,8 - dihydro - 5 oxo - 4H - pyrazolo[l,5-alpyrazolo- [4',3':5,6lpyrido[3,4-elpyrimidine - 3 carboxylic acid, ethyl ester are refluxed in 1 liter of phosphorus oxychloride for 24 hours. The excess phosphorus oxychloride is decomposed by pouring the solution on ice and the crystallized 5 - chloro - 8 ethyl - 811 - pyrazolo[l,5-a]pyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidine</

Example 45 5 - [(I - Metl0yipropyl)aminol - 8 - ethyl 8H - pyrazolo[l,5-a]pyrazolo [4',3':5,6lpyrido[3,4-elpyrimidine - 3 carboxylic acid, ethyl ester By substituting l-methylpropylamine for the n - butyl - amine in the procedure of Example 44(d), 5 - [(1 - methylpropyl)amino] - 8 - ethyl - 8H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4 -e] - pyrimidine - 3 - carboxylic acid, ethyl ester is obtained, yield 71; m.p. 94--97 .

Hydrolysis with aqueous sodium hydroxide solution yields the free carboxylic acid.

Example 46 8 - Ethyl - 5 - (methylamino) - 811 pyrazolo[l,5 - a]pyrazolo[4',3':5,6] - pyrido[3,4-e]pyrimidine - 3 carboxylic acid, ethyl ester 3.5 g of 5 - chloro - 8 - ethyl - 8H pyrazolo[l,5 - alpyrazolo[4',3':5,6]pyrido [3,4-e]pyrimidine - 3- carboxylic acid, ethyl ester (0.01 mol) and 3.5 g of methylamine are heated in 50 ml of alcohol in an autoclave for 10 hours at 100 . The solvent is removed in vacuo and the residue treated with water, filtered off and recrystallized from butyl alcohol, yield 2.9 g (86 M,); m.p. 321--322 .

Example 47 5 - (Diethylamino) - 8 - ethyl - 811 pyrazolo[l,5 - a]pyrazolo[4',3':5,6] pyrido[3,4-e]pyrimidine - 3 - carboxylic acid, ethyl ester By substituting diethylamine for the methylamine in the procedure of Example 46, 5 - (diethylamino) - 8 - ethyl - 8H pyrazolo[l,5 - a]pyrazolo[4',3':5,6]pyrido [3,4 - e]pyrimidine - 3 - carboxylic acid, ethyl ester is formed, yield 73; m.p.

17W172 (alcohol).

Example 48 5 - Amino - 8 - ethyl - 8H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4 - e] pyrimidine - 3 - carboxylic acid, ethyl ester By substituting an equivalent amount of 30% aqueous ammonia for the methylamine in the procedure of Example 46, 5 - amino 8 - ethyl - 811 - pyrazolo[l,5-a]pyrazolo- [4',3':5,6]pyrido[3,4 - e]pyrimidine - 3 carboxylic acid, ethyl ester is formed, yield 68%; m.p. 331--332 (DMF).

Example 49 8- Ethyl - 5 - (4 - methyl- 1 - piperazinyl)- 8H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4 - e] pyrimidine - 3 - carboxylic acid, ethyl ester 3.5 g of 5 - chloro - 8 - ethyl - 811 pyrazolo [1,5 - a]pyrazolo [4',3':5,6]pyrido [3,4-e]pyrimidine - 3- carboxylic acid, ethyl ester (0.01 mol) are dissolved in 20 ml of butanol. 2 g of N-methylpiperazine are added and the solution is refluxed with stirring for 12 hours. After evaporation of the solvent, the residue is extracted three times with 50 ml portions of ethyl acetate.

The ethyl acetate is distilled off until the volume is about 30 ml. The 8 - ethyl - 5 (4 - methyl- I - piperazinyl)- 811 pyrazolo[l,5 - a]pyrazolo[4',3':5,6]pyrido [3,4-e]pyrimidine - 3 - carboxylic acid, ethyl ester crystallizes, yield 3.1 g (76%); m.p. 111--113 (ethyl acetate).

Example 50 8 - Ethyl - 5 - (I - piperidinyl)- 8H pyrazolo[l ,5 - a]pyrazolo[4',3':5,6] - pyrido[3,4-e]pyrimidine - 3 carboxylic acid, ethyl ester By substituting piperidine for the Nmethylpiperazine in the procedure of Example 49, 8 - ethyl - 5 - (1 - pip eridinyl) - 8H - pyrazolo[1,5-a]- pyrazolo[4',3': 5,6]pyrido[3,4 - e]pyrim idine - 3 - carboxylic acid, ethyl ester is obtained, yield 2.6 g (67%) m.p. 183--184 (ethyl acetate).

Example 51 5 - [[3 - (Dimethylamino)propyl]amino]8 ethyl - 811 - pyrazolo[l,5-a]pyrazolo [4',3': 5,6]pyrido[3,4-e]pyrimidine - 3 carboxylic acid, ethyl ester By substituting 3 - (dimethylamino)- propylamine for the N-methylpiperazine in the procedure of Example 49, 5 - [[3 (dimethylamino)propyl]-amino] - 8 ethyl - 8H - - pyrazolo[l,5-a] - pyrazolo [4' ,3 ' 5,6]pyrido[3,4-e]pyrimidine - 3 carboxylic acid, ethyl ester is obtained, yield 62%; m.p. 212--215 (ethyl acetate).

Example 52 5 - [3 - (Dimethylamino)propoxyl - 8 ethyl - 2 - methyl - 811 - pyrazolo [1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidine To a suspension of 3.6 g of sodium hydride in 100 ml of dry benzene 15.3 g of 3- (dimethylamino)propanol are added and the mixture is refluxed for 6 hours. After this time, 28.6 g of 5 - chloro 8 - ethyl - 2 methyl - 8H - pyrazolo[l,5-alpyrazolo- [4',3':5,6]pyrido13,4-e]pyrimidine are added in small portions with stirring. The solution is refluxed for 10 hours, and then the solvent is distilled off. The residue is treated with water, filtered off and recrystallized from ethyl acetate, yield 25 g (71%); m.p. 62 640.

Example 53 5 - Butoxy - 8 - ethyl - 2 - methyl - 8H pyrazolo[l,5-a]pyrazolo[4',3':5,61- pyrido[3,4-e]pyrimidine By substituting n-butyl alcohol for the 3 (dimethylamino)propanol in the procedure of Example 52, 5 - butoxy - 8 - ethyl - 2 methyl- 811 - pyrazolo[l,5-a]pyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidine is obtained, yield 71%; m.p. 103-1040 (methanol).

Example 54 8 - Ethyl - 2 - methyl - 5 - (1 - methyl- ethoxy) - 8H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidine By substituting 2-propanol for the 3 - (dimethylamino)propanol in the procedure of Example 52, 8 - ethyl - 2 - methyl - 5 - (I methylethoxy) - 8H - pyrazolo-[1,5-a] pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine is obtained, yield 68 /"; m.p. 129--1300 (ethyl acetate).

Example 55 8 - Ethyl - 2 methyl - 5 - (3 - methyl butoxy) sH - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidine By substituting 3 - methylbutyl alcohol for the 3 - (dimethylamino)propanol in the procedure of Example 52, 8 - ethyl - 2 methyl- 5 - (3 - methylbutoxy) - 8H pyrazolo [1,5-a] - pyrazolo[4',3':5,6]pyrido- [3,4 - elpyrimidine is obtained, yield 67%; m.p. 60--620 (ethyl acetate).

Example 56 5 - Ethoxy - 8 - ethyl - 2 - methyl - 8H pyrazolo[ 1 ,5-a]pyrazolo[4',3':5,6]- pyrido[3,4-e]pyrimidine 2.3 g of sodium are dissolved in 100 ml of dry alcohol with stirring. The solution is heated at reflux temperature and, at this point, 28.6 g of 5 - chloro - 8 - ethyl - 2 methyl - 8H - pyrazolo[l,5-a]pyrazolo [4',3':5,61pyrido[3,4-e]pyrimidine are added in small portions. Heating and stirring is continued for 6 hours. The precipitated sodium chloride is filtered off, the solvent is removed and the residual 5 - ethoxy - 8 ethyl - 2 - methyl - 8H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine is recrystallized from methanol, yield 82%; m.p. 142--1440.

Example 57 5 - [3 - (Dimethylamino)propoxy] - 8 ethyl - 8H - pyrazolo[l,5-a] pyrazolo[4',3':5,6lpyrido[3,4 - e]pyrim - idine - 3 - carboxylic acid, ethyl ester To a suspension of 3.6 g of sodium hydride in 100 ml of dry benzene 15.3 g of 3- (dimethylamino)propanol are added dropwise at reflux temperature with stirring.

Heating is continued for 10 hours. After this time, 34.4 g of 5 - chloro - 8 - ethyl - 8H pyrazolo[ 1 ,Slpyrazolo[4',3':5,6lpyrido[3,4- el pyrimidine - 3 - carboxylic acid, ethyl ester are added and the solution is refluxed for 5 additional hours. The solution is evaporated to dryness and the residue is treated with water, filtered off and recrystallized from ethyl acetate. 12 g of 5 [3 - (dimethylamino)propoxy] - 8 - ethyl 8H - pyrazolo[l ,5-a]pyrazolo[4',3': 5,6]- pyrido[3,4 - e]pyrimidine - 3 - carboxylic acid, ethyl ester are obtained (29.3%); m.p.

106107 .

Example 58 8 - Ethyl - 5 - (3 - methylbutoxy) - 8H pyrazolo[l,5 - a]pyrazolo[4',3':5,6] - pyrido[3,4-e]pyrimidine - 3 carboxylic acid, ethyl ester By substituting 3-methyl-butyl alcohol for the 3- (dimethylamino)propanol in the procedure of Example 57, 8 - ethyl - 5 (3 - methylbutoxy) - 8H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4 - e] pyrimidine - 3 - carboxylic acid, ethyl ester is obtained, yield 61%; m.p. 117--1180 (ethyl acetate). Hydrolysis with aqueous sodium hydroxide yields the free carboxylic acid.

Example 59 5 - Ethoxy - 8 - ethyl - 811 - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4 - el pyrimidine - 3 - carboxylic acid, ethyl ester By substituting for the 5 - chloro - 8 ethyl - 2 - methyl - 8H - pyrazolo[l,5-al pyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidine in the procedure of Example 56, 5 - chloro 8 - ethyl-8H-pyrazolo-[l,5 - a]-pyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidine - 3 carboxylic acid, ethyl ester, 5 - ethoxy - 8 ethyl - 811 - pyrazolo[l,5-alpyrazolo [4',3': 5,6] pyrido[3 ,4-e]pyrimidine - 3 carboxylic acid, ethyl ester is formed, yield 75%; m.p. 167--1680 (alcohol).

Example 60 8 - Ethyl - 2 - methyl - 8H - pyrazolo[l,5 alpyrazolo[4',3':5,6] - pyrido[3,4e]- pyrimidine - 5 - thiol 5.6 g of 5 - chloro - 8 - ethyl - 2 - methyl 4H - pyrazolo[l,5-a]pyrazolo[4',3':5,6]- pyrido[3,4-e]pyrimidine (0.02 mol) are dissolved in 100 ml of dimethylformamide. 2 g of powdered sodium sulfide are added and the mixture is stirred for 1 hour. After this time, the solution is carefully acidified with acetic acid. 8 - Ethyl - 2 - methyl - 8H pyrazolo[l,5 - a]pyrazolo[4', 3':5,6]pyrido [3,4-e]pyrimidine - 5 - thiol precipitates and is filtered off, yield 5.1 g (91 ,; m.p. 320- 3220 (DMF).

Example 61 8 - Ethyl - 5 - mercapto - 8H - pyrazolo- [1,5 - a]pyrazolo [4' ,3':5,6]pyrido[3,4-e] pyrimidine - 3 - carboxylic acid, ethyl ester By substituting for the 8 - ethyl - 2 methyl- 411 - pyrazolo[l,5-a]pyrazolo- [4',3':5,61pyrido[3,4-e]pyrimidin - 5(8H) one in the procedure of Example 50, 5 chloro - 8 - ethyl - 8H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4 - e] - pyrimidine - 3- carboxylic acid, ethyl ester, 8 - ethyl - 5 - mercapto - 8H pyrazolo[2,5 - a]pyrazolo[4',3': 5,6]pyrido [3,4-e]pyrimidine - 3- carboxylic acid, ethyl ester is formed, yield 86%; m.p. 238 240 (DMF).

Example 62 8 - Ethyl - 2 - methyl - 5 - (methylthio) 8H - pyrazolo[l,5-a]pyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidine 5.6 g of 5 - chloro - 8 - ethyl - 2 methyl- 811 - pyrazolo[l,5-a]pyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidine (0.02 mol) and 3 g of sodium methylmercaptide are refluxed together in 50 ml of dimethylformamide with stirring for 2 hours. The mixture is cooled to room temperature and diluted with 50 ml of water. 8 - Ethyl - 2 methyl - 5 - (methylthio) - 8H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6pyrido[3,4 - e] pyrimidine is filtered offhand recrystallized from butyl alcohol, yield 3.5 g (59%); m.p.

168--169".

Example 63 N - Butyl - 2 - methyl - 811 - pyrazolo [l,5-a]pyrazolo[4',3':5,6]pyrido - [3,4-e]pyrimidine - 5 - amine By substituting an equivalent amount of 4- hydrazino - 111 - pyrazolo[3,4-b]- pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 111 - pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 32 (a), and continuing as in parts (b), (c) and (d), 5 - chloro - 2 - methyl 811 - pyrazolo[l,5 - a]pyrazolo[4',3':5,6] pyrido[3,4 - e]pyrimidine and N butyl - 2 - methyl - 8H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6lpyrido [3,4 - e]pyrimidine - 5 - amine respectively, are obtained.

Example 64 N,2,8,10 - Tetramethyl - 8H - pyrazolo [1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5 - amine By substituting 1,3- dimethyl - 4hydrazino - 111 - pyrazolo[3,4-b]pyridine 5 - carboxylic acid, ethyl ester for the 1 ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 32 (a) and proceeding as in parts (b) and (c), and substituting methylamine for the butylamine in part (d), 5 - chloro - 2,8,10 - trimethyl 8H - pyrazolo[l ,5-a]pyrazolo[4',3':5,6] J.

pyrido[3,4-e]pyrimidine and N,2,8,10 - tetramethyl - 8H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6lpyridol [3,4 - e]pyrimidin 5 - amine are obtained.

Example 65 2,3 - Diethyl- 8 - isopropyl - 5 phenoxy - 8H - pyrazolo[l,5-a] pyrazolo[4',3': 5,6]pyrido[3,4-e]- pyrimidine By substituting 1 - isopropyl - 4hydrazino - 111 - pyrazolo[3,4-b]pyridine 5 - carboxylic acid, ethyl ester for the 1 ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid, ethyl ester and 3 - amino - 2 - ethyl - 2 pentenonitrile for the 3-aminocrotononitrile in the procedure of Example 32 (a), proceeding as in parts (b) and (c), then following the procedire of Example 52, but substituting phenol for the 3 - (dimethylamino)propanol, 5 - chloro - 2,3 - diethyl8- isopropyl - 8H - pyrazolo[l,5-a] pyrazolo[4',3': 5,6]pyrido[3,4 - elpyrimidine and 2,3 - diethyl - 8 - isopropyl - 5 phenoxy - 8H - pyrazolo[l,5 - a] pyrazolo[4',3': 5,6]pyrido[3,4 - e]pyrimidine, respectively, are obtained.

Example 66 5 - (4 - Chlorophenyloxy) - 10 - ethyl - 2 methyl - 8H - pyrazolo[l,5-a] pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidine By substituting 4- hydrazino - 3ethyl - 1H - pyrazolo - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid propyl ester for the 1 - ethyl - 4 - hydrazino - 1H pyrazolo[3,4-b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 32(a), proceeding as in parts (b) and (c), then following the procedure of Example 52 but substituting 4-chlorophenol for the 3 - (dimethylamino)propanol, 5 - chloro - 10 - ethyl - 2methyl - 8H - pyrazolo[l,5-alpyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidine and 5 (4 - chorophenyloxy) - 10 - ethyl - 2 - methyl - 8H - pyrazolo[l,5 - ] .

pyrazolo[4',3': 5,6]pyrido[3,4 - e]pyrimidine, respectively, are obtained.

Example 67 5 - Benzyloxy - 2 - methyl - 8 - phenyl - 8H - pyrazolo[l,5-a]pyrazolo [4',3': 5,6]pyrido [3,4-e]pyrimidine By substituting 4- hydrazino - 1 - phenyl - 111 - pyrazolo[3,4-b]pyridine - 5 carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 32(a), proceeding as in parts (b) and (c), then proceeding as in Example 52 but substituting phenylmethanol for the 3 (dimethylamino)propanol, 5 - chloro - 2 methyl - 8 - phenyl - 8H - pyrazolo[l,5-a] pyrazolo[4',3':5,6]pyrido [3,4 - e]pyrimidine and 5- benzyloxy- 2- methyl- 8phenyl - 8H - pyrazolo[l,5 - a] pyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidine, respectively, are obtained.

Example 68 N - Butyl - 8 - ethyl - 2,6- dimethyl 8H - pyrazolof l,5 - a]pyrazolo [4',3':5,6]pyrido[3,4 - e]pyrimidine - 5 - amine By substituting 1 - ethyl - 4 hydrazino - 6 - methyl - 111 - pyrazolo- [3,4-blpyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino 1H - pyrazolo[3,4-b]pyridine - 5 carboxylic acid, ethyl ester in the procedure of Example 32, 5 - chloro - 2,6 - dimethyl 8 - ethyl - 8H - pyrazolo[l,5-a]pyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidine and N butyl- 8 - ethyl - 2,6 - dimethyl- 811 - pyrazolo[l,5 - a]pyrazolo[4',3': 5,6]pyrido - [3,4 - e]pyrimidine - 5 amine, respectively, are obtained.

Example 69 8 - Benzyl - 2 - methyl - 8H - pyrazolo [1 ,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5 - thiol By substituting 1 - benzyl - 4hydrazino - 111 - pyrazolo[3,4-b]pyridine 5 - carboxylic acid, ethyl ester for the 1 ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 32(a), proceeding as in part (b), then proceeding as in Example 50, 8 - benzyl - 2 - methyl 8H - pyrazolo[l,5 - a]pyrazolo[4',3':5,6] pyrido[3,4 - e]pyrimidine - 5 - thiol is obtained.

Example 70 N - Butyl - 8 - phenylethyl - 3 - propyl 8H - pyrazolo[l,5-a]pyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidin - 5 amine By substituting I - phenylethyl- 4hydrazino - 111 - pyrazolo[3,4-b]pyridine 5 - carboxylic acid, methyl ester for the 1 ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- b]pyridine - 5 - carboxylic acid, ethyl ester and 2-aminomethylenepentanonitrile for the 3-aminocrotononitrile in the procedure of Example 32(a) and proceeding as in parts (b), (c) and (d), 5 - chloro - 8 - phenylethyl - 3 - propyl - 8H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6lpyrido[3,4 - e]pyrimidine and N- butyl- 8- phenylethyl- 3 propyl - 811 - pyrazolo[l,5-a]pyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidin - 5 amine, respectively, are obtained.

Example 71 N - butyl - 8 - ethyl - 2 - phenyl - 811 pyrazolo[l,5 - a]pyrazolo[4',3':5,6l pyrido[3,4-elpyrimidin - 5 - amine By substituting 3 - amino - 3 - phenylcrotononitrile for the 3 - aminocrotononitrile in the procedure of Example 32 (a)and proceeding as in parts (b), (c) and (d), 5 - chloro - 8 - ethyl - 2 - phenyl - 8H pyrazolo[ I ,5-a]pyrazolo [4',3': 5,6]pyrido[3,4elpyrimidine and N - butyl - 8 - ethyl - 2 phenyl - 811 - pyrazolo[l,5-alpyrazolo- [4',3':5,6]pyrido[3,4-e]pyrimidin - 5 amine, respectively, are obtained.

Example 72 8 -Benzoyl -N -butyl -2 -methyl-8H pyrazolo[1,5 - a]pyrazolo[4',3':5,6] pyrido[3,4-elpyrimidin - 5 - amine a) N - Butyl - 8 - furfuryl - 2 - methyl 8H - pyrazolo[l,5-a]pyrazolo [4',3':5,6]pyrido[3,4-e]pyrimidin - 5 amine By substituting 4 - hydrazino - I - furfurylpyrazolo[3,4-b]pyridine - 5 carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 111 - pyrazolo[3,4- blpyridine - 5 - carboxylic acid, ethyl ester in Example 32 a and proceeding as in parts a and b, 8 - furfuryl- 2- methyl- 4H pyrazolo[1,5 - a]pyrazolo[4',3':5,6lpyrido [3,4-e]pyrimidin - 5(8H) - one is obtained.

This compound is now processed as in Example 32, parts c and d to obtain N butyl- 8 - furfuryl - 2 - methyl - 811 - pyrazolo[1,5 - a]pyrazolo[4',3': 5,61 pyrido [3,4-elpyrimidin - 5 - amine.

b) N - Butyl - 2 - methyl - 8H - pyrazolo [1,5-alpyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5 - amine 0.01 mol of N - butyl - 8 - furfuryl - 2 methyl- 811 - pyrazolo[l,5-a]pyrazolo- [4',3':5,6]pyrido[3,4 - e]pyrimidin - 5 amine is heated in 50 ml of diethyleneglycol dimethyl ether containing 0.01 mol of selenium dioxide at reflux temperature with stirring for two hours. The mixture is filtered hot and evporated to dryness. N butyl - 2 - methyl - 8H - pyrazolo[1,5-a]- pyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidin 5 - amine remains.

c) 8 - Benzoyl - N - butyl - 2 - methyl 8H - pyrazolo[l,5-a]pyrazolo [4',3':5,61pyrido[3,4 - elpyrimidin - 5 amine 0.01 mol of N - butyl - 2 - methyl - 8H pyrazolo[1,5 - a]pyrazolo[4',3' :5,6lpyrido [3,4-elpyrimidin - 5 - amine and 0.02 mol of benzoyl chloride are stirred overnight in 50 ml of dry pyridine at room temperature. On addition of 50 ml of water, 8 - benzoyl - N butyl - 2 - methyl - 8H - pyrazolo[l,5-a]- pyrazolo[4',3': 5,6]pyrido [3,4 - e]pyrimidin 5 - amine is filtered off.

Example 73 N - Butyl - 2 - methyl - 8 - (4 - methyl benzoyl) - 8H - pyrazolo[ll5-al- pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidin - 5 - amine By substituting 1 - (4 - methylbenzoyl) 4- hydrazino - 1H - pyrazolo[3,4-blpyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 1H pyrazolo[3,4-blpyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 32(a) and proceeding as in parts (b), (c) and (d), 5 - chloro - 2 - methyl - 8 (4 - methylbenzoyl) - 8H - pyrazolo[1,5-a]- pyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidine and N- butyl - 2- methyl- 8- (4- methylbenzoyl)- 8H - pyrazolo[l,5-a]pyrazolol [4',3':5,6]pyrido[3,4 - elpyrimidin - 5 - amine, respectively, are obtained.

Example 74 5 - (2 - Aminoethoxy - 2,6 - dimethyl 8 - ethyl - 811 - pyrazolo[1,5-al- pyrazolo[4',3':5,6]pyrido[3,4 - e] pyrimidine By substituting the 5- chloro - 2,6 dimethyl - 8 - ethyl - 811 - pyrazolo[l,5-alpyrazolo[4',3':5,6]pyrido[3,4 - e]pyrimidine obtained in Example 68 in the procedure of Example 52 and substituting ethanolamine for the 3-(dimethylamino)propanol, 5 - (2 aminoethoxy) - 2,6 - dimethyl - 8 - ethyl 8H - pyrazolo[1 ,5-alpyrazolo[4',3':5,6]- pyrido[3,4-e]pyrimidine is obtained.

Example 75 8 - Ethyl - 2 - methyl - 5 - [(3 - propyl amino)propoxy]8H - - pyrazolo[l ,5-a]- pyrazolo[4',3': 5,6]pyrido [3,4-e]- pyrimidine By substituting 3(propylamino)propanol for the 3(dimethylamino)propanol in the procedure of Example 52, 8 - ethyl - 2 methyl- 5 - [(3 - propylamino)propoxyl 811 - pyrazolo[1,5-alpyrazolo[4',3':5,6]- pyrido[3,4-elpyrimidine is obtained.

Example 76 8 - Ethyl - 2 - methyl - 5 - (1 - piper- azinyl) - 8H - pyrazolo[l,5-a]- pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidine By substituting piperazine for the 3-(dimethylamino) - propyl - I - amine in the procedure of Example 35, 8 - ethyl - 2 methyl - 5 - (1 - piperazinyl) - 8H pyrazolo [1 ,5-alpyrazolo - [4',3': 5,6]pyrido- [3,4-elpyrimioine is obtained.

Example 77 N - Butyl - - ethyl - 2,3 - diphenyl 8H - pyrazolo[l5 - a]pyrazolo [4',3':5,6]pyrido[3,4 - elpyrimidin - 5 amine By substituting 3- amino - 2,3 - diphenylcrotononitrile for the 3-aminocrotononitrile in the procedure of Example 32, 5 - chloro - 8 - ethyl - 2,3 - diphenyl 8H - pyrazolo[l,5 - a]pyrazolo[4',3':5,61- pyrazolo[3,4-elpyrimidine and N - butyl 8 - ethyl - 2,3 - diphenyl - 8H - pyrazolo [1,5 - a]pyrazolo[4',3':5,6lpyrido[3,4 - el pyrimidin - 5 - amine, respectively, are obtained.

Example 78 8 - Ethyl - 2 - methyl - 5 thiamorpholino - 811 - pyrazolo[l,5-a]- pyrazolo[4',3':5,6lpyrido[3,4-e]- pyrimidine By substituting thiamorpholine for the 3 (dimethylamino)propyl - 1 - amine in the procedure of Example 35, 8 - ethyl - 2 methyl - 5 - thiamorpholino - 811 - pyrazolo[ 1 ,5-alpyrazolo[4',3': 5,61pyrido- [3,4-e]pyrimidine is obtained.

Example 79 8 - Ethyl -2 - methyl - 5 - (1 - pyrazolyl) 811 - pyrazolo[1,5-alpyrazolo - [4',3': 5,6]pyrido[3,4-e]pyrimidine By substituting pyrazole for the 3 - (dimethylamino) - propyl - 1 - amine in the procedure of Example 35, 8 - ethyl - 2 methyl - 5 - (1 - pyrazolyl) - 8H pyrazolo[ 1,5 - alpyrazolo[4',3': 5,61pyrido [3,4-elpyrimidine is obtained.

Example 80 8 - Ethyl - 2 - methyl - 5 - pyrrolidino 8H - pyrazolo[l,5-alpyrazolo [4',3': 5,6]pyrido[3,4-e]pyrimidine By substituting pyrrolidine for the 3 - (dimethylamino) - propyl - 1 - amine in the procedure of Example 35, 8 - ethyl - 2 methyl - 5 - pyrrolidino - 8H - pyrazolo- [1,5 - a]pyrazolo[4',3':5,6]pyrido[3,4 - el - pyrimidine is obtained.

Example 81 8 - Ethyl - 2 - methyl - 5 - (dihydro pyridazin - 1 - yl) - 8H - pyrazolo [1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]- pyrimidine By substituting dihydropyridazine for the 3 - (dimethylamino)propyl- l - amine in the procedure of Example 35, 8 - ethyl - 2 methyl - 5 - (dihydropyridazin - 1 - yl) 8H- pyrazolo - [l,5-a]pyrazolo[4',3':5,6]- pyrido[3,4-e]pyrimidine is obtained.

Example 82 The following ingredients are used to make 1,000 200 mg tablets each containing 100 mg of active ingredient: N-butyl-8-ethyl-2-methyl-8H- pyrazolo-[1,5-a]pyrazolo- [4',3':5,6]pyrido-[3,4-el pyrimidine-5-amine 100 gm.

Polyvinyl pyrrolidone 7.5 gm.

Lactose 20 gm.

Magnesium stearate 3.5 gm.

Corn starch 17.5 gm.

Avicel-Trade Mark (microcrystalline cellulose) 51.5 gm.

WHAT WE CLAIM IS: 1. A compound of the formula

wherein Z is

R1 is hydrogen, lower alkyl, phenyl, phenyllower alkylene, benzoyl or substituted phenyl or benzoyl wherein the phenyl or benzoyl substituent is one or two halogens, lower alkyl or trifluoromethyl groups; R2 and R3 each is hydrogen, lower alkyl or phenyl; R4 is hydrogen, lower alkyl, phenyl, carboxy or lower alkoxycarbonyl; R5 is hydrogen, lower alkyl, phenyl-lower alkylene, benzoyl, substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl or

R7 N-lower R8 alkylene R5' is lower alkoxy, substituted lower alkoxy wherein the substituent is

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or trifluoromethyl groups, halo,

or -S-R9; R6 is hydrogen or lower alkyl; R7 is hydrogen, lower alkyl or substituted lower alkyl wherein the lower alkyl substituent is

phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R8 is hydrogen or lower alkyl, or R7 and RB together with the nitrogen form one of the unsubstituted or substituted hetero-cyclics pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkyl; R9, R10 and R11 each is hydrogen or lower alkyl; or such a compound in acid addition salt form.

2. A compound as in Claim 1 having the formula

wherein R1 is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted phenyl or benzoyl; R2, R4 and RB each is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl or phenyl; R5 is hydrogen, lower alkyl, phenyl-lower alkylene, benzoyl, substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, amino-lower alkylene or

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

Example 82 The following ingredients are used to make 1,000 200 mg tablets each containing

100 mg of active ingredient: N-butyl-8-ethyl-2-methyl-8H- pyrazolo-[1,5-a]pyrazolo- [4',3':5,6]pyrido-[3,4-el pyrimidine-5-amine 100 gm.

Polyvinyl pyrrolidone 7.5 gm.

Lactose 20 gm.

Magnesium stearate 3.5 gm.

Corn starch 17.5 gm.

Avicel-Trade Mark (microcrystalline cellulose) 51.5 gm.

The medicament and lactose are thoroughly admixed. The polyvinyl pyrrolidone is dissolved in ethanol USP to make a 30% solution. This solution is used to granulate the mixture of medicament and lactose. The granulation is passed through a No. 16 screen and air dried. The dried granulation is then passed through a No. 20 screen. To the screened granulate are added the magnesium stearate, Avicel and the corn starch and the mixture is blended. The blend is then compressed into 200 mg.

tablets on a standard concave punch. The tablets are then veneer coated with methyl cellulose in a spray pan.

WHAT WE CLAIM IS: 1. A compound of the formula

wherein Z is

R1 is hydrogen, lower alkyl, phenyl, phenyllower alkylene, benzoyl or substituted phenyl or benzoyl wherein the phenyl or benzoyl substituent is one or two halogens, lower alkyl or trifluoromethyl groups; R2 and R3 each is hydrogen, lower alkyl or phenyl; R4 is hydrogen, lower alkyl, phenyl, carboxy or lower alkoxycarbonyl; R5 is hydrogen, lower alkyl, phenyl-lower alkylene, benzoyl, substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl or

R7 N-lower R8 alkylene R5' is lower alkoxy, substituted lower alkoxy wherein the substituent is

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or trifluoromethyl groups, halo,

or -S-R9; R6 is hydrogen or lower alkyl; R7 is hydrogen, lower alkyl or substituted lower alkyl wherein the lower alkyl substituent is

phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R8 is hydrogen or lower alkyl, or R7 and RB together with the nitrogen form one of the unsubstituted or substituted hetero-cyclics pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkyl; R9, R10 and R11 each is hydrogen or lower alkyl; or such a compound in acid addition salt form.
2. A compound as in Claim 1 having the formula

wherein R1 is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted phenyl or benzoyl; R2, R4 and RB each is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl or phenyl; R5 is hydrogen, lower alkyl, phenyl-lower alkylene, benzoyl, substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, amino-lower alkylene or

R7 N-lower R8

alkylene wherein R7 and R8 each is lower alkyl or together join to complete the heterocycle piperidine, morpholine, thiamorpholine or piperazine; or such a compound in acid addition salt form.
3. A compound as in Claim 2 wherein R1 is lower alkyl; R2, R3, R4 and R6 each is hydrogen or lower alkyl; and R5 is lower alkyl or di-lower alkylamino-lower alkylene.
4. A compound as in Claim 2 wherein R1, R2, R3, R4 and R6 each is hydrogen or lower alkyl; and R5 is hydrogen, lower alkyl, phenyl-lower alkylene, phenyl, amino-lower alkylene, di-lower alkylamino-lower alkylene, piperidino-lower alkylene, morpholino-lower alkylene or piperazinolower alkylene.
5. A compound as in Claim 2 wherein the lower alkyl and lower alkylene groups have up to 4 carbon atoms.
6. A compound as in Claim 2 wherein R5 is lower alkyl.
7. A compound as in Claim 2 wherein R5 is di-lower alkylamino-lower alkylene.
8. A compound as in Claim 2 wherein R5 is piperidino-lower alkylene.
9. A compound as in Claim 2 wherein R5 is morpholino-lower alkylene.
10. A compound as in Claim 2 wherein R1 is ethyl, R3 is methyl and R2, R4 and R6 each is hydrogen.
11. A compound as in Claim 10 wherein R5 is methyl.
12. A compound as in Claim 10 wherein R5 is ethyl.
13. A compound as in Claim 10 wherein R5 is isopentyl.
14. A compound as in Claim 10 wherein R5 is 3-dimethylaminopropyl.
15. A compound as in Claim 10 wherein R5 is 2-piperidinoethyl.
16. A compound as in Claim 10 wherein R5 is 2-morpholinoethyl.
17. A compound as in Claim 10 wherein R5 is 2-diethylaminoethyl.
18. A compound as in Claim 1 having the formula

wherein R1 is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted phenyl or benzoyl wherein the phenyl or benzoyl substituent is one or two halogens, lower alkyl or trifluoromethyl groups; R2 and R3 each is hydrogen, lower alkyl or phenyl; R4 is hydrogen, lower alkyl, phenyl, carboxy or lower alkoxycarbonyl; R5' is lower alkoxy, substituted lower alkoxy wherein the substituent is

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or trifluoromethyl groups, halo,

or -S-R9; R6 is hydrogen or lower alkyl; R7 is hydrogen, lower alkyl or substituted lower alkvl wherein the lower alkyl substituent is

phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R8 is hydrogen or lower alkyl, or R7 and R8 together with the nitrogen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkyl; R9, R10 and R11 each is hydrogen or lower alkyl; or such a compound in acid addition salt form.
19. A compound as in Claim 18 wherein R1, R2, R3 and R6 each is hydrogen or lower alkyl; R4 is hydrogen or lower alkoxycarbonyl; R5' is amino, mercapto, lower alkylamino, di(lower alkyl)amino, di(lower alkyl)amino-lower alkylamino or di(lower alkyl)amino-lower alkoxy.
20. A compound as in Claim 18 wherein R2 and R6 each is hydrogen.
21. A compound as in Claim 18 wherein R5' is lower alkylamino.
22. A compound as in Claim 18 wherein R5' is lower alkoxy.
23. A compound as in Claim 18 wherein Rs' is di(lower alkyl)amino-lower alkylamino.
24. A compound as in Claim 18 wherein R5, is di(lower alkyl)amino-lower alkoxy.
25. A compound as in Claim 18 wherein R5' is halogen.
26. A compound as in Claim 18 wherein R5' is lower alkylmercapto.
27. A compound as in Claim 20 wherein R1 and R3 each is lower alkyl, R4 is hydrogen and R5' is lower alkylamino.
28. A compound as in Claim 20 wherein R1 and R3 each is lower alkyl, R4 is hydrogen and R5' is lower alkoxy.
29. A compound as in Claim 18 wherein R1 is lower alkyl, R2 and R6 are hydrogen, R3 is hydrogen or lower alkyl, R4 is hydrogen or alkoxycarbonyl and R5' is halogen.
30. A compound as in Claim 18 wherein R1 is ethyl, R2, R4 and R0 is hydrogen, R3 is methyl and R5' is chloro.
31. A compound as in Claim 18 wherein R1 is ethyl, R2, R3 and R6 each is hydrogen, R4 is ethoxycarbonyl and R5' is chloro.
32. A compound as in Claim 20 wherein R1 is ethyl, R3 is methyl, R4 is hydrogen and R5' is butylamino.
33. A compound as in Claim 20 wherein R1 is ethyl, R3 is methyl, R4 is hydrogen and R5' is ethoxy.
34. A compound as in Claim 20 wherein R1 is ethyl, R3 is methyl, R4 is hydrogen and R5' is 3-(dimethylamino) propylamino.
35. A compound as in Claim 20 wherein R1 is ethyl, R3 is hydrogen, R4 is ethoxycarbonyl and R5' is 3-(dimethylamino)propylamino.
36. A compound as in Claim 20 wherein R1 is ethyl, R3 is methyl, R4 is hydrogen and R5' is 3-methylbutoxy.
37. A compound as in Claim 20 wherein R1 is ethyl, R3 is methyl, R4 is hydrogen and R5' is l-methylethoxy.
38. A compound as in Claim 20 wherein R1 is ethyl, R3 is methyl, R4 is hydrogen and R5' is l-methylethylamino.
39. Process for preparing a compound of the formula

wherein Z is

R1 is hydrogen, lower alkyl, phenyl, phenyllower alkylene, benzoyl or substituted phenyl or benzoyl wherein the phenyl or benzoyl substituent is one or two halogens, lower alkyl or trifluoromethyl groups: R2 and R3 each is hydrogen, lower alkyl or phenyl; R4 is hydrogen, lower alkyl, phenyl, carboxy or lower alkoxycarbonyl: R5 is hydrogen, lower alkyl, phenyl-lower alkylene, beuzoyl, substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl or

R7 N-lower R8 alkylene R5' is lower alkoxy, substituted lower alkoxy wherein the substituent is

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or trifluoromethyl groups, halo,

or -S-R9; R6 is hydrogen or lower alkyl; R7 is hydrogen, lower alkyl or substituted lower alkyl wherein the lower alkyl substituent is

phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R8 is hydrogen or lower alkyl, or R7 and R8 together with the nitrogen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkyl; R9, R10 and R11 each is hydrogen or lower alkyl; and acid addition salts thereof which comprises reacting a compound of the formula

wherein R1, R2 and R6 are defined as above with a compound of the formula

wherein R3 and R4 are defined as above to form a compound of the formula

wherein R1, R2, R3, R4 and R6 are defined as above, treating this compound with a base in alcoholic solution or with an organic acid and a Lewis acid catalyst to form a compound of the formula

wherein R1, R2, R3, R4 and R6 are defined as above and, if desired, reacting a compound of Formula VI with a halide of the formula R5-hal wherein hal is halogen and R5 is defined as above or, if desired, reacting a compound of Formula VI with a chlorinating agent to form a compound of the formula

wherein R1 R2, R3, R4 and R6 are defined as above and reacting the compound of Formula VII with a compound of the formula R12-O-Me wherein Me is an alkali metal and R12 is lower alkyl, amino-lower alkyl

lower alkyl), phenyl or substituted phenyl or with a compound of the formula R12-S-Me wherein Me is an alkali metal and R12 is lower alkyl or with an alkali metal sulfide or with an amine of the formula

or 112N-lower

R7 alkylene-N R8 wherein R7 and R8 are defined as above.
40. The process of Claim 39 for preparing a compound of the formula

wherein R1, R2, R3, R4, R5 and Re are defined as in Claim 39 which comprises treating a compound of the formula

wherein R1, R2, R3, R4 and R6 are defined as in Claim 39 with abase in alcoholic solution or with an organic acid and a Lewis acid catalyst to form a compound of the formula

wherein R1, R2, R3, R4 and R6 are defined as in Claim 39 and, if desired, reacting a compound of Formula VI with a halide of the formula R5-hal wherein hal is halogen and R5 is defined as in Claim 39.
41. The process of Claim 39 for preparing a compound of the formula

wherein R1, R2, R3, R4, R5, and R6 are defined as in Claim 39 which comprises reacting a compound of the formula

wherein R1, R2, R3, R4 and R6 are defined as in Claim 39 with a chlorinating agent to form a compound of the formula

wherein R1, R2, R3, R4 and R6 are defined as in Claim 39 and reacting the compound of Formula VII with a compound of the formula R12-O-Me wherein Me is an alkali metal and R12 is lower alkyl, amino-lower alkyl

lower alkyl), phenyl or substituted phenyl or with a compound of the formula R12-S-Me wherein Me is a alkali metal and R12 is lower alkyl or with an alkali metal sulfide or with an amine of the formula

or H2N-lower

R7 alkylene-N R8 wherein R7 and R8 are defined as in Claim 39.
42. A compound as in Claim 2 wherein prepared by a process as in Claim 40.
43. A compound as in Claim 18 when prepared by a process as in Claim 41.

-
44. A compound according to Claim 2 as named in any of Examples 1 to 30.
45. A compound according to Claim 18 as named in any of Examples 32 to 81.
46. A pharmaceutical composition comprising a compound according to any one of Claims 2 to 17, 42 or 44 and a pharmaceutical carrier.
47. A pharmaceutical composition comprising a compound according to any one of Claims 18 to 38, 43 or 45 and a pharmaceutical carrier.
48. A pharmaceutical composition according to Claim 46 in the form of a tablet, capsule, syrup, elixir, lotion, ointment or cream.
49. A pharmaceutical composition according to Claim 47 in the form of a tablet, capsule, syrup, elixir, lotion, ointment or cream.
50. A composition according to Claim 46 or 48 which includes a binder, an excipient, a disintegrating agent, a lubricant, a sweetening agent, a flavouring agent, a dye or a preservative.
51. A composition according to Claim 47 or 49 which includes a binder, an excipient, a disintegrating agent, a lubricant, a sweetening agent, a flavouring agent, a dye or a preservative.