AU612356B2 - New pharmacologically active pyrazolopyridines - Google Patents

Description

vj

AUSTRALIA

PatentIs Act 6'&2 35: 6 t rv LETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specificavion Lodged: Accepted: Published: Priority Related Art: APPLICANT'S REF.: (Div. of 2227C,;83 Name(s) of Applicant(s): 3RUPPC LEPETIT S. P. A.

Address(es) of Applicant(s): Via R. Lepetit, 34 21040 Gerenzano (Varese) 1TALY Actual Inventor(s): Giorgio Winters Address for Service is: PHILLIPS, ORMIONDE AND FITZPATRICK Patent and Trade Mvark Attorneys 367 Collins Street Melbourne, Australia, 3000 Complete Specification for the invention entitled: NEW PHARMACOLOGICALLY ACTIVE PYRAZOLOPYRIDINES The following statement is a full description of this invention, including the best method of performing it known to -pplicant(s): P 19,3, 84 la The present.application is a divisional application from Australian Patent application number 22270/83. The entire disclosure of which is incorporated herein by reference.

The present invention is directed to a new class of pharmacologically active 4,7-dihydropyrazolo [3,4-bl-pyridines.

More particularly, the present invention resides in a 4,7-dihydropyrazolo [3,4-b]pyridin-5-carboxylic acid derivative of formula o0 3

O

1

COOR

°o CH3 o 003 1 w 1 2 3 wherein R, R R and R have the following meanings: R represents hydrogen, R represents phenyl, R represents 2-nitrophenyl and R 3 represents ethyl; R represents hydrogen, R represents phenyl, R 2 represents 3-nitrophenyl and R represents methyl; R represents phenyl, R represents phenyl, R represents 3-nitrophenyl and R 3 represents methyl; 1 2 R represents methyl, R represents phenyl,

R

represents 2-nitrophenyl and R 3 represents ethyl or 2-methylethyl; R repre s m R 1 represents methyl, R represents yl, represents phenyl and R 3 represents ethyl; R represents methyl, R 1 represents methyl, R 2 represents 2-nitrophenyl and R 3 represents methyl or ethyl; 2 R represents methyl, R represents methyl, R 2 represents 3-nitrophenyl and R 3 represents methyl; 1 2 R represents methyl, R represents methyl, R represents 2-chlorophenyl and R 3 represents ethyl; 1 2 R represents methyl, R represents ethyl, R represents 2-nitrophenyl and R 3 represents ethyl; 1 2 R represents methyl, R represents propyl, R represents 2-nitrophenyl and R 3 represents ethyl; 1 2 R represents methyl, R represents propyl, R represents 3-nitrophenyl and R represents methyl;

I

R represents methyl, R represents 1-methylethyl,

R

2 represents 2-nitrophenyl and R 3 represents methyl, ethyl or 1-methylethyl; R represents methyl, R represents 1-methylethyl,

R

2 represents 3-nitrophenyl and R 3 represents ethyl; R represents methyl, R 1 represents 1-methylethyl,

R

2 represents 2-trifluoromethylphenyl and R 3 represents ethyl; R represents methyl, R 1 represents 1-methylethyl, 2 3 R represents 2-fluorophenyl and R 3 represents ethyl; R represents methyl, R represents butyl, R represents 2-nitrophenyl and R 3 represents methyl; v

'A

3 R represents methyl, R i represents 2-methylpropyl, R represents 2-nitrophenyl and R 3 represents methyl or ethyl; R represents methyl, R represents 2,2-dimethylethyl, R 2 represents 2-nitrophenyl and R 3 represents methyl or ethyl; R represents methyl, R 1 represents cyclchexyl, R 2 1 0 represents 2-nitrophenyl and R 3 represents methyl or ethyl; a2 R represents ethyl, R represents methyl, R 2 represents 2-nitrophenyl-and R 3 represents methyl; R represents methyl, R represents methyl, R 2 represents 2-nitrophenyl, R represents 1,1-dimethylethyl; "20 R represents methyl, R 1 represents methyl, R 2 represents 3-fluorophenyl, R 3 represents ethyl; R represents methyl, R represents methyl, R 4 represents 2,3-dichlorophenyl, R 3 represents propyl; R represents methyl, R 1 represents methyl, R represents 2,3-chlorofluorophenyl,

R

3 represents n-butyl; R represents methyl, R represents methyl, R 2 represents 2,6-dichlorophenyl,

R

3 represents i-propyl; R represents hydrogen, R represents phenyl, R 2 represents 2-nitrophenyl, R 3 represents l,1-dimethylethyl; 4 R represents hydrogen, R 1 represents phenyl, R 2 represents 3-fluorophenyl, R 3 represents ethyl; R represents hydrogen, R represents phenyl, R 2 represents 2,3-dichlorophenyl, R represents propyl; R represents hydrogen, R 1 represents phenyl, R 2 represents 2 ,3-chlorofluorophenyl,

R

3 represents n-butyl; R represents methyl, R represents ethyl, R 2 represents 2-nitrophenyl, R 3 represents 1,1-dimethylethyl; R represents methyl, R represents ethyl, R 2 represents 3-fluorophenyl, R 3 represents ethyl; R represents methyl, R represents ethyl, R 2 represents 2,3-diclorophenyl, R 3 represents propyl; 2 R represents methyl, R represents propyl, R 2 represents 1,3-chlorofluorophenyl, R 3 represents n-butyl; 1 R represents methyl, R represents propyl, R 2 represents 2-nitrophenyl, R 3 represents 1,1-dimethylethyl; R represents methyl, R 1 represents propyl, R 2 represents 3-fluorophenyl, R represents ethyl; R represents methyl, R represents propyl, R 2 represents 2,3-dichlorophenyl, R 3 represents propyl; R represents methyl, R Irepresents propyl,R2 represents 2,3-chlorofluorophenyl, R3 represents n-butyl; R represents methyl, R 1 represents (1,1dimthy~etylR 2represents 3-nitrophenyl,R3 represents 1,1-dimethylethyl; R represents methyl, P represents (l,l-dirnethyl)ethyl, R 2 ,reoresents 3-fluorophenyl,R3 represents ethyl; R represents methyl, R 1represents (1 1 l-dimethyl)ethyl, RP represents 2,3-dichlorophenyl, R 3represents propyl; represents methyl, P represents (l,l-dimethyl)ethyl, P represents 2,3-chilorofluorophenyl, P3 represents n-butyl; and the physiologically acceptable salts thereof.

Further the present Lnvention resides in. a 4 ,7-dihydrocyrazolo[3,4-b]pyridin-5-carboxylic acid derivative off the formula 2

COOP

CH3 1 2 3 wherein R, R, Rand R have the following meanings: 6 a) R represents hydrogen, R 1 represents phenyl, R represents 2-nitrophenyl and R 3 represents ethyl; 1 2 b) R represents hydrogen, R represents phenyl, R represents 3-nitrophenyl and R 3 represents methyl; c) R represents phenyl, R represents phenyl, R 2 represents 3-nitrophenyl and R 3 represents methyl; 1 2 d) R represents pthyl, R represents phenyl, R represents 2-nitrophenyl and R 3 represents ethyl or 2-methylethyl; e) R represents methyl, R represents methyl,

R

represents phenyl and R 3 represents ethyl; E) R represents methyl, R 1 represents methyl, R 2 represents 2-nitrophenyl and R represents methyl or ethyl; g) R represents methyl, R 1 represents methyl, R represents 3-nitrophenyl and R 3 represents methyl; 1 2 h) R represents methyl, R represents methyl, R 2 represents 2-chlorophenyl and R 3 represents ethyl; i) R represents methyl, R 1 represents ethyl, R 2 represents 2-nitrophenyl and R 3 represents ethyl; 1) R represents methyl, R 1 represents propyl, R 2 represents 2-nitrophenyl and R 3 represents ethyl; m) R represents methyl, R represents propyl, R 2 represents 3-nitrophenyl and R 3 represents methyl; r 7 o) R represents methyl, R 1 represents 1-methylethyl,

R

2 represents 2-nitrophenyl and R 3 represents methyl, ethyl or 1-methylethyl; q) R represents methyl, R represents 1-methylethyl,

R

2 represents 3-nitrophenyl and R 3 represents ethyl; r) R represents methyl, R represents 1-methylethyl,

R

2 represents 2-trifluoromethylphenyl and R 3 represents ethyl; s) R represents methyl, R 1 represents 1-methylethyl, 3 R~ represents 2-fluorophenyl and R represents ethyl; t) R represents methyl, R 1 represents butyl, R represents 2-nitrophenyl and R 3 represents methyl; u) R represents methyl, R 1 represents 2-methylpropyl,

R

2 represents 2-nitrophenyl and R 3 represents methyl or ethyl; v) R represents methyl, R represents 2,2-dimethylethyl, R 2 represents 2-nitrophenyl and R 3 represents methyl or ethyl; z) R represents methyl, R represents cyclohexyl,

R

2 represents 2-nitrophenyl and R 3 represents methyl or ethyl; w) R represents ethyl, R 1 represents methyl, R represents 2-nitrophenyl and R 3 represents methyl; and the physiologically acceptable salts thereof.

ic II- 8 Still further, the present invention resides in a process for preparing a compound or described above which comprises: aprocess for preparing a compound of claim 1 to 4 which comprises: a) reacting a 5-aminopyrazole derivative of formula N N

\N

wherein R, and R are as above, a) with an equimolar amount or a slight molar defect of an alpha,beta-unsaturated ketoester of formula wherein the substituents are as above, in an inert organic solvent; b) alternatively, reacting a 5-aminopyrazole of the above formula with an aldehyde of formula R 2 CHO and 3 an acetoacetic acid ester of formula CH 3 COCH2COOR3 wherein the substituents are as above, in about equimolar proportions.

I

./2 -9-

(C

1 -C )Alkyl groups, as defined in the present application,'include: mEthyl, ethyl, propyl, isopropyl, n-butyi, isobutyl, pentyl, hexyl, and the like, (C 3

C

7 )Cycloalkyl groups, a cyclopropyl, 1:yclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups.

(C 1

C

6 )Aikoxy groups include: methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy groups.

grup of 1 to )Aky caronp andsC In c4live whichs are groups ofl1tol4gcarbs andms ic-Clsive grhups are included in the above definition of (C C )alkyl groups and (C 1 C 6 )al'Koxy groups, respectively.

The term "halo" represents halogen atoms selected from chloro, bromo 'and fluoro, while nalo(C 1

C

4 )alkyl groups are halogena-lkyl' groups of I to 4 carbon atoms inclusive, wherein some or all the hydrogen atoms are replaced with halogen atoms. Representative examples of halo(C 1

C

4 )al .l groups are: trif luorcmethyl, chlorodifluoromethyl, bromochlorofluoromethyl, trichlcromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1-chloro-2,2,2-trifluioroethyl, and the like.

'Physiologically acceptable salts" are pharmaceutically acceptable salts wherein the whole toxicity of the compound is not increased compared with the non-salt.

These acid addition salts are obtained by treating compounds of the above formula I with pharmaceutically acceptable acids.

1/3 S- 10 Representative examples of acids suitable for the i formation of physiologically acceptable salts are: hydrohalide, sulfuric, phosphoric and nitric acids; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, alpha-ketoglutaric, glutamic, aspartic, maleic, hydroxymraleic, pyruvic acid; phenylacetic, benzoic, para-aminobenzoic, anthranilic, 1C para-hydroxybenzoic, salicylic, para-aminosalicylic or embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid.

These or other salts of the new compounds may also be used for purifying the resulting compounds by converting them into salts, isolating the latter and liberating the free compound from them. When according to the above outlined procedures, compounds of formula I are obtained as the corresponding salts of pharmaceutically acceptable acids, they may be converted into the corresponding free base by treatment with an alkali agent.

The free base may in turn be transformed into the corresponding salts by reaction with predetermined pharmaceutically acceptable acids. In view of the close relationship between the new compounds in the free form and in the form of their salts what has been said above and hereinafter with reference to the free compounds concerns also the corresponding salts.

I

11 An outline of the process for the production of the compounds of the invention is the following:

R

1 R2 3 4 N

H-R

0 H 3

R

2 III

II

CH

3

I

0 0 A 5-aminopyrazole derivative of formula II, wherein R,

R

1 and R 4 are defined as above, is reacted with a substituted a)8-unsaturated ketoester of formula III, also named 2-vynilidenacetoacetate, wherein the substi- I, tuents are as above.

This reaction can be carried out employing different molar proportions of the two reactants, however an equimolar proportion or a slight excess of the aminopyrazole reactant is preferred.

The reaction solvent is an organic solvent which does not unfavourably interfere with the reaction course.

Representative examples of such solvents are:

(C

1

-C

4 )alkanols such as methanol, ethanol, propanol, isopropanol, and t-butanol and the like, glycols and represt!11- I i L-U-LLUVT_12Y~t!'Cyy1 12 their ethers. One of the preferred ether-glycols is the mono-methyl ether of the ethylene glycol (methylcellosolve The reaction temperature is generally between 40 0 C and the reflux temperature.

The. reaction time obviously varies considerably depending on the reaction conditions, however, the reaction is generally complete in 15 minutes to 20-60 hours. In any case, the reaction course can be monitored by means of the usual techniques such as TLC using a suitable eluting mixture such as methanol/chloroform 1:9 or n-hexane/ethanol 8:2.

Based on these data the skilled man is able to optimize the reaction conditions, and in particular the reaction time.

Alternatively, at least in some instances, the dihydropyrazolopyridines of the invention can be prepared by reacting a 5-aminopyrazole derivative with about an equimolar proportion of an aldehyde of formula R2-CHO and an acetoacetic acid ester of formula 3 2 3

CH

3

COCH

2 COOR wherein R and R are as above, in an organic solvent, preferably a lower alkyl alcohol.

In any case the reaction is preferably carried out under nitrogen stream and in the dark. The work up procedures include: extraction with solvents, precipitation by non-solvents, purification by chromatography, especially flash-chromatography, and crystallization.

13 4 The compounds of formula I wherein R is as above but different from hydrogen, can also be obtained by recting the corresponding compound of formula I wherein R is hydrogen with a suitable alkylating agent.

Representative examples of suitable alkylating agents include lower alkyl or optionally substituted benzyl chlorides, bromides or iodides.

The starting materials of formula II 9 ff v 8, e a a a 2' are prepared essentially by following the techniques known for the preparation of 5-pyrazolamines and Sdescribed in reference books such as "The Chemistry of S heterocyclic compounds", Vol. XX, pages 41-43, Wiley and Wiley publisher, New York, 1964.

More particularly, when R 4 is different from hydrogen, they can be prepared according to Micaelis, Annales der Chemie, 339, 117 (1905), and Micaelis et al., Berichte der Org. Chem. 40, 4488, which describes techniques which are well known in the art.

The above starting materials wherein the substituent at position is benzylamine, i.e. R is benzyl, or substituted benzyl, can be prepared reacting the corresponding derivative wherein R is hydrogen with benzyl chloride, bromide, or iodide. Suitable reaction PuUL+.Wi Lk

I

P193/84 1 "I III .I I i- i i; i 14 solvents are organic solvents such as benzene, toluene, chloroform, dimethylformamide, and methylene chloride.

The reactants are usually contacted in equimolar proportions in the presence of an excess of a tertiary amine such as trimethylamine and triethylamine or an inorganic base.

The preparation of the 2-vynilidenacetoacetate derivatives of formula III is known.from the chemical literature.

The compounds of the invention possess pharmacological activity and therefore they can be used as medicines.

With the term "use" all industrial applicable aspect and acts of said use, including their embodying into pharmaceutical compositions are intended.

In particular, the compounds of the invention show in vitro calcium-antagonist activity and in vivo ariihypertensive action. The possible therapeutic indications include therefore the anti-angina and vasodilating indications.

The in vitro activity can be ascertained by means of a test for antagonism of the calcium-induced contractions in K -depolarized taenia of the Guinea-pig caecum.

According to the above technique, strips of taenia (1-2 mm diameter, 2-2.5 cm relaxed length), were dissected ~I~UI 15 i from the caecum of male guinea-pigs (250-350 g) and set i up in 20 ml isolated-organ baths containing K'-depolarizing Tyrode solution maintained at 35*C and gassed with 02 and 5% CO2. The composition of the K -Tyrode solution was (mmol/1): NaC1 97; KC1 40; NaHCO 3 11.9; NaH 2 P0 4 0.4; glucose 5.5; pH 7.1. Contractile responses were measured under isotonic conditions (ig load) using a Harvard isotonic transducer connected to a Rikadenki potentiometric recorder.

Cumulative concentration-response curves were obtained to CaC1 2 (30-3,000 pnnol/l) by increasing the Ca 2 concentration at 3 min intervals in logarithmic increments /Van Rossum, Arch. Int. Pharmacodyn., 143 299-330, 1963)/. A 20 min wash-out period (6 changes of bathing fluid) was allowed between curves. The 100% response was taken as the maximum contractile response of the tissue during the second concentration-response curve, and all subsequent contractions were calculate as a percentage of this value. Dose ratios were calculated as the ratio of the concentration of Ca 2 which produced a 50% maximal response (EC 50 in the presence and *j absence of the antagonist. Apparent pA 2 values were calculated by the method of Arunlakshana and Schild, Br.

J. Pharmac. Chemother., 14, 48-58, (1959), by plotting log (dose ratio-1) against negative log (molar concentration antagonist). Student's test was used for comparison of mean values. Values in the text refer to mean fr L 16 SEM. All concentrations are the final concentration of drug in the bathing solution, The compounds are initially tested at a fixed concentration (10 ug/ml). In these conditions the compounds of the invention shows antagonism of Ca 2 induced contractions in K -depolarized taenia. More particularly, the compounds of Examples 1, 2, 8, 16, 18, 21, show a PA 2 value in the range 8.2-9, cause concentration-dependent displacement to the right of cumulative concentration- 2+ Gresponse curves to Ca 2 have a rapid onset of action and Scause a rapid relaxation of Ca 2 (300 uM)- induced contraction at low concentrations (0.G1-0.1 uM).

SC I- The in vivo activity can be ascertained by means of the so-called "pithed rat preparation" The rats are infused with angiotensin II in order to 0 evaluate the blood pressure.

o o The procedure allows evaluation of hypotensive effects in the absence of autonomic reflexes.

The compounds of the invention produce dose-dependent o 20 depression of blood pressure, without affecting heart 0o rate. The compounds in this test are administered either intraveneously or intraduodenally.

According to the above technique, male Sprague-Dawley rats (250-330 g) were anaesthetized with sodium pentobarbitone (40-50 mg/kg, pithed and respired with oxygen.

Body temperature was maintained between 35.0 and 36.51C.

Blood pressure was measured from the left carotic artery -T i I C I -r r I ii I 17 and the antagonists were administered cumulatively via the left jugular vein or via a cannula placed in the duodenum. Blood pressure was maintained between 75-120 mmHg by an intraveneous infusion of angiotensin II (0.2-1.0 pg/kg/min). Heart rate was calculated from the

ECG.

In the above test, the compound of Example 1 shows a very significant dose-dependent depression of blood pressure, at a dose of 0.1-3 uimol/kg, and did not cause second degree atrioventricular block at any dose-level tested.

The cardiovascular activity of the compounds of the invention was demonstrated also in the spontaneously hypertensive rats described by K. Aoki in the Japan Cir.

Journal, Vol. 27, p. 289, (1963). The arterial pressure was evaluated according to H. Friebel, E. Vredom, as described in Arch. Exp. Phat. Pharmak., Vol. 232, p. 416 (1958).

Some of the compounds of the invention shows a lowering of the arterial pressure of at least 15% when administered at a dose inferior to 1/10 of the LD 50 This 15% threshold is generally considered predictive of significant cardiovascular activity.

Table I summarizes the results obtained in this test for some representative compounds of formula I: I c 18 TABLE I Compound of dose drop of the example No. mg/Kg blood pressure These results were confirmed in renal hypertensive dogs where significant drops of the systolic blood pressure are observed upon oral administration of the compounds of the invention.

The results obtained in the above test by representative compounds of the invention are summarized in Table II, below: 19 TABLE 1I Compounds of Dose (os) drop of the blood example No. mg/Kg pressure 16 3 40 (lasting for 5-7 h) ]0 18 1 38 (lasting for about 7 h) 21 0.1 33 3 Generally the compounds of the invention possess prolonged duration of action.

In fact representative examples possess a duration of antihypertensive action on animals of 8 to 12 h or more at a doses equal to the ED50 value.

The compounds may be administered in various manners to a 0 o achieve the desired effect. The compounds may be admini- S stered alone or in the form of pharmaceutical preparations to the patient being treated either orally or parenterally, such as, intraveneously or intramuscularly.

The formulation of suitable pharmaceutical compositions can be carried out by the skilled man according to the general common knowledge in the art, and referring to reference books, such as the "Remington's Pharmaceutical Sciences" Handbook, Mack Publishing Company, U.S.A.

-I 20 The amount of compound administered will vary with the severity of the hypertension, and the mode of administration. For oral administration the antihypertensively effective amount of compound is from about 0.01 mg/kg (milligrams per kilograms) of patient body weight per day to about 10 mg/kg of patient body weight per day and preferably from about 0.05 mg/kg of patient body weight per day to about 5 mg/kg of patient body weight per day.

For parenteral administration the antihypertensively effective amount of compound-is from about 0.001 mg/kg of S patient body weight per day up to about 5 mg/kg of patient body weight per day and preferably from about 0 S° 0.01 mg/kg of patient body weight per day up to about 2 mg/kg of patient body weight per day.

For oral administration a unit dosage may contain, for example, from 0.50 to 100 mg of the active ingredient.

For parenteral administration a unit dosage may contain, for example, from 0.05 to 70 mg of the active ingredient.

S'"?O0 Since the compounds of the invention generally possess a S long lasting duration of'action they might be conveniently administered once or twice a day, however, repetitive daily administrations may be, at least in some instances, desirable and will vary with the conditions of the patient and the mode of administration.As used herein, the term "patient" is taken to mean a warm blooded animal, humans included.

I ~B 1 21 For oral administration the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions. The solid unit dosage forms can be a capsule which can be of the ordinary gelatin type, either hard or soft, containing for example lubricants and inert fillers, such as lactose, sucrose and cornstarch.

In another embodiment the compounds of the invention can be tabletted with conventional tablet bases such as 0 lactose, sucrose and cornstarch in combination with binders, such as acacia, cornstarch or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stea- S rate.

For parenteral administration the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils which can be employed in these preparations are those of mineral petroleum, animal, vegetable or synthetic origin. For example, peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol can be used as liquid carriers for injectable solutions.

I I 22 For rectal administration the compounds are administered in the form of suppositories, admixed with conventional vehicles such as, for example, cocoa butter, wax, spermaceti, polyvinylpyrrolidone, or polyoxyethylenglycols and their derivatives.

The compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compres- J 1,0 sed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, a silicone rubber manufactured by the Dow-Corning Corporation. The oral route is generally the preferred route of administration of the compounds of the S invention, while the capsule is generally the preferred S pharmaceutical formulation.

The following are illustrative pharmaceutical formulations which may be employed in practicing the present invention: A capsule is prepared with: 4,7-Dihydro-1,3,6-trimethyl-4-(2-nitrophenyl)-lH-pyrazolo/3,4-b/pyridin-5-carboxylic acid methyl ester 50 mg 23 Saccharose Polyvinylpyrrolidone Sodium dioctylsulfosuccinate Magnesium stearate Corn starch q.

A tablet is prepared with: 4, 7-Dihydro-1, 3, 6-trimethyl-4-(2-nitrophenyl) -lH-pyrazolo/3, boxylic acid methyl ester Saccharose Polyvinylpyrrolidone Sodium dioctylsulIfosuccinate Magnesium stearate Corn starch q.

A sugar coated tablet is prepared with: phenyl) -LIH-pyrazolo/j,4- boxylic acid methyl ester ?olyvinylpyrrolidone 0 Sodium carboxymethylcellulose Avicel 0IR mg Titanium dioxide Magnesium stearate Corn starch Gum arabic Talc Kaolin Saccharose q.

10 mg 2 mg 0.5 mg 2.5 mg sto 150 Mg 100 30 5 1.4 8 to 250 50 2 1.5 2 2.5 8 5 10 2 s. to 150 mg Mg Mg mg Mg mg mg mg mg mg mg mg mg mg Mg mg -24- The following examples are intended to further illustrate the present invention, but, as such, cannot be construed as limitating the scope of the invention.

Example 1: 4, 7-dihydro-1, 3, 6-trimethyl-4-(2-nitrophenyl) -1H-pyrazoloL3,4-b7pyridin-5-carboxylic acid methyl ester.

S Methyl-2-(2-nitrobenzyliden)acetoacetat-e (10 g; 0.040 Mol) is added to 1,3-Dimethyl-5-pyrazolamine (4.89 g; 0.044 mol) in ethanol (40 ml) The mixture is refluxed for about 5 hours, then the solvrent is evaporated uinder reduced pressure and the residue is taken up in ethyl ether and recovered by filtration. M.p. 216-220*C.

~0 Example 2: 4 ,7-dihydro-1,3,6-trimethyl-4- (2-nitrophenyl)-lH-pyrazoloL3,4-b7pyridin-5--carboxylic acid ethyl ester.

The reaction is carried out essentially as above, using ethyl-2--( 2 -nitrobenzyliden)acetoacetate and refluxing for about 3 hours. M.p. 194-198 0

C.

Examople 3: 4, 7-dihydro-I 3, 6-trimethyl-4- (3-l,.trophenyl) -1H-pyrazolo/3, 4-b7py-ridi4n-5--carboxylic zacid methyl ester.

1,3-Dimethyl--5-pyrazolamine (3.33 g; 0.030 mol) is dissolved in ethanol (35 ml) and methyl-2-(3-nitrobenzyliden)acetoacetate (6.75 g; 0.27 mol) is added ~~thereto. The mixture is ref luxed for about 5 hours, then Sthe solvent is evaporated under reduced pressure and the residue is taken up in rethylene chloride, washed with 2% hydrochloric acid and then with s~aturated aqueous sodiumn bicarbonate, the organic phase is dried over sodium 0 sulphate and then the solvent is evaporated. The solid a compound of the title is recovered by filtration, after taking up in ethyl ether. M.p. 163-166*C.

Example 4: 0:4,7/-dihydro-1,3,6-trimethyl-4-phenyl-1H-pyrazolo/3,4acid ethyl ester, hydrochloride.

Ethyl-2-benzJ.idenacetoacetate (50 mmol) is added to (0.050 ml) in ethanol (40 ml) 'i'

II

:1

I

ii ii i i i I t 1 i i i j 26 The mixture is refluxed for about 3 hours. The solvent is evaporated and the residue is taken up in ethyl ether, collected by filtration, and dried. The obtained solid is then dissolved in methanol and added with a mixture of hydrochloric acid/methanol (45 mmol of HC1); the product of the title precipitates by addition of ethyl ether.

M.p. 232 0 C (dec.).

REFERENCE EXAMPLE 1 13 4,7-dihydro-1,3,6-trimethyl-4-(2-methylphenyl)-lH-pyrazolo- [3,4-b]pyridin-5-carboxylic acid ethyl ester, hydrochloride.

1,3-Dimethyl-5-pyrazolamine (0.050 mol) in ethanol (50 ml) is added with ethyl-2-(2-methylbenzyliden)acetoacetate (0.050 mol). The mixture is refluxed for about 90 minutes, then, after cooling to room temperature, further ethyl-2- S(2-methylbenzyliden)acetoacetate (0.050 mol) has added thereto and the temperature is risen again to the reflux temperature and heating is continued for further 90 minutes. The reaction o mixture is then cooled, the solvent is evaporated, and residue is taken up in ethyl ether, collected by filtration and dried.

The solid is then worked up as in the above example to give the product of the title. M.p. 235 0 C (dec).

By operating essentially as above the following compounds are obtained, starting from the suitable reactants.

27 Example 4, 7-dibhydro-1, 3, 6-trirnethyl-4-(2-chiorophenyl) -lH-pyrazolo/3,4-b/pyridin-5-carboxylic acid ethyl ester, hydrochloride.

Starting from 1,3-dimethyl-5--pyrazolamine and ethyl-2- (2-chlorobenzyliden)acetoacetate. M.p. 240-242'C.

2-O Example 6,.

4,7-dihydro-1,3,G-trimethyl-4-(3-nitrophenyl)-lH-pyrazolo/3,4-b/pyridin-5--carboxylic acid ethyl ester, hydrochloride.

o 00D '000 Starting from 1,3-dimethyl-5-pyrazolamine and ethyl- 2-(3-nitrobenzyliden)acetoacetate. M.p. 237*C (dec.).

Example 7- 1-Ethyl-4 ,7-dihydro-3, 6-dimethyl-4- (2-nitrophenyl) -lH-pyrazolo/ 4-b7pyridin-5--carboxylic acid methyl ester, hydrochloride.

M.p. 230-232*C.

Starting from 3-ethyl-l-methyl-5-pyrazolamine and methyl-2- (2-nitrobenzyliden),acetoaceta-te.

-28- The reflux is preferably carried out under nitrogen stream.

Essentially following the procedure outlined in the above exam~ples, the following compounds or the corresponding acid addition salts can be prepared: 4, 7-dihydro-l, 3, 6-trirnethyl-4- (2-nitrophenyl) -lH-pyrazolo/3,4-blpyridin-5-carboxylic acid (1,1-dimethyl)ethyl o -b 0 ester 00 4, 7-d ihydro- 1,3, 6- trixnethy1- 4- fluorophenyl1) 1H-pyo0oo 0 razolo/3,4-b/pyridin-5--carboxylic acid ethyl ester o 4, 7 -dihydro-1,3,6-trimethyl-4-(2,3-dichlorophenyl)-lH-pyoo razolo /3 ,4-b/pyridin--5-carboxylic acid propyl 000 4,7-dihvdro-1,3,6-trimethyl-4-(2,3-chlorofluorophenyl)- -lH-p:yrazoloL3, 4-b/pyridin-5-carboxylic acid n-butyl ester 29 4, 7-dihydro- 1, 3,6-trimfethyl 4 6-dichloropheflyl) H-pyrazolo/3,4-b/pyridin'-5carboxylic acid i-propyl ester REFERENCE EXA MPLE 2: 4, 7-dihydro- 1, 6 -dimethylI-3-phenyl- 4- (2 -me thy lphenyl) -l1Hpyrazolo/3,4-b/pyridin-5-carboxylic acid ethyl ester, hydrochloride.

Ethyl- 2- (2-methylbenzyliden) acetoacetate (0.050 mol) is added to l-Methyl-3-phenyl-5-pyrazolamine (0.050 mol) in ethanol (50 ml) and refluxed for 90 minutes. The mixture is then cooled to room temperature, further ethyl-2- (2-methylbenzyliden) ace toacetate (0.050 mol) has added thereto, and the mixture refluxed for further 90 minutes.

The reaction mixture is then cooled, the solvent is evaporated, and the residue is taken up in ethyl ether, collected by filtration, and dried. The product is dissolved in methanol and added with a mixture of hydrochloric acid arnd methanol (45 mmol of HCl) The product of the title precipitates by adding ethyl ether.

M.P. 187 0 C (dec.).

E-ssentially following the procedure of the above example the following compounds are obtained, starting from the suitable reactants: 30 4, 7-dihydro-., 6-dixnethyl-3-phenyl-4- 2 -nitrophenyl) -pyrazolo/3, 4-b/pyridin-5-carboxylic acid ethyl ester, hydrochloride.

Starting from l-methyl- 3 -phenyl.-5-pyrazolamine and ethyl- 2 2 -nitrobenzyliden) acetoacetate. M.P. 175'C (dec.).

Example 9: 4,7-dihydro-1,6-dimethyl-3-phenyl-4-(2-nitrohenyl)- -lH-pyrazolo/3,4-b7pyridin-5-carboxylic acid isopropyl. ester, hydrochloride.

CC Starting from l-methyl-3-phenyl-5-pyrazolamine and 0 o isopropyl- 2 2 -nitrobenzyliden) acetoacetate.

M.P. 162-167*C (dec.).

Example 4, 7-Dihydro-6-methyl-4- (2-riit-rophenyl) -3-phenyl-1Hpyrazolo/3, 4-b7pyridin-5-carboxylic acid ethyl ester-.

M.P. 185-187 0 C (methanol) Starting from 3-phenyl-5-(lH)pyrazolamine and ethyl-2-(2-nitrobenzyliden) acetoacetate. The reflux is carried out under nitrogen stream and in the dark.

-31 Example 11: 4,7-dihydro--6-methyl-1,3-diphenyl-4-(3-nitrophenyl)- 1-H-pyrazoloL3, 4-b7pyridin-5-carboxylic acid methyl ester.

Me-thyl-2- (3--ntrobenzyliden) acetoacetate is added to 1,3-diphenyl-5-pyrazolamine (0.010 mol) in ethanol (16 ml) and refluxed for 90 minutes under nitrogen. After cooling to room temperature, the solvent is evaporated under reduced pressure, the residue is taken up in ethyl ether, discarding the insolubles, and then the solvent is evaporated. Upon crystallization from methanol, the product of the title is obtained.

M.P. 186-189 0

C.

Example 12: 4,7-dihydro--6-methyl-3-phenyl-4- (3-nitrophenyl)-1H--pyra- ?0 zolo/ ,4-b7pyridin-5-carboxylic acid methyl ester.

3 3-Phenyl-5-pyrazolanine (5 m mol) is dissolved in ethanol (12 ml) methyl-2-(3',nitrobenzyliden)acetoacetate is added thereto,and ref~uxed for 3 hours, under nitrogen stream. The reaction mixture is then cooled to room temperature, the solvent is evaporated under reduced K t 32 pressure, and the residue is taken up in methylene chloride. The product is purified by silica gel column chromatography, eluting with methylene chloride/methanol, 99:1. The solvent is then evaporated from the collected fractions, and the residue is crystallized from ethyl acetate/ni-hexane to give the product of the title. M.p.

240-241 0

C.

Essentially following the above procedures, the followi.ng 11b compounds or the corresponding acid addition salts can be prepared: 7-dihydro-6-methyl-3-phenyl-4- (2-nitrophenyl) -lH-py-.

razolo/3, 4-b7pyridin-5-carboxylic acid (l-dimethyl)ethyl ester 4,7-dihydro-6-methyl-3-phenyl-4- (3-f luorophenyl) -IH-pyrazolo/3, 4-b7pyridin--5-carboxylic acid ethyl ester 29 4 7-dihydro-6-methy'k -3-phenyl-4- 3-dichlorophenyt) -lH-pyrazolo/3, 4-blpyridin-5-carboxylic acid propyl ester 4, 7-dihydro-6-methyl-3-phenyl-4- (2 3-chlorof luorophenyl) -lH-pyrazolo/3,4--bipyridin-5-carboxylic acid n-butyl ester 33 Exapl e 13: 3-Ethyl-4, 7-dihydro-l, 6-dimethyl-4- (2-nitrophenyl) -18-pyrazolo/3, 4-b/pyridin-5-carboxylic acid ethyl ester, hydrochloride.

m.p. 243-247 0 C (Dec.) (ethanol) Starting from 3 -ethyl -I -methyl- 5-pyrazolanine and ethyl- 2- (2-nitrobenzyliden) acetoacetate.

Essentially following the procedures outlined in the above examples, the following compounds or the corresponding acid addition salts can be prepared: 4, 7-dihydro-1, 6-dimethy 1- 3-ethyl- 4- (2-nitrophenyl) )H-pyrazolo/3, 4-b7pyridin-5-carboxylic acid (1,1-dimethyl)ethyl ester 4,7-dihydro-1, 6-dihiethyl-3-ethyl-4- (3-fluorophenyl) -lH- V III -pyrazolo/3, 4-b/pyridin-5-carboxylic acid ethyl ester 4 7-dihydro-l, 6-dimethyl-3-ethyl-4- 3-dichlorophenyl) -lH-pyrazolo/3, 4-b/pyridin-5-carboxylic acid propyl ester 4, 7-dihydro-1, 6-dimethyl-3-ethyl-4- 3-chlorof luorophenyl) -lH-pyrazolo/3, acid n-butyl ester blooded animal, humans included.

34 Example 14: 4,7-Dihydro-1,6-dimethyl-4- (3-nitrophenyl)-3--propyl-lH- -pyrazolo/3,4--b/pyridin--S-carboxylic acid methyl ester, hydrochloride..

M.P. 240*C (methanol) Starting from 3 -propyl-l-methyl-5-pyrazolamine and met hyl-2- (3-nitrobenzyliden)acetoacetate.

Examele 4,7-Dihydro-1,6-dimethy-4-I2-fitrophefl)-3-PrOPYl- -1H-pyrazolo/3,4-b7pyridin-5-carboxylic acid methyl ester.

M.P. 175-186*C.

Starting from 3-propyl-1-'methyl-5-pyrazolamine and methyl-2- (2-nitroben~yliden) acetoacetate.

~2,d Essentially following the pr )cedures outlined in the above examples, the following compounds or the corresponding acid addition salts can be prepared: 4,7-dihydro-1,6-dimethyl-3-propanyl-4-(2-nitrophenyl)-1H- -pyrazolo/3, 4-blpyridin-S-carboxylic acid 1-dimethyl) ethyl ester 4,7-dihydro-1,6-dimethyl-3-propanyl-4-(3-fluorophenyl) -lH--pyrazoloL 4-b7pyridin-5--carboxylic acid ethyl ester 4, 7-dihydro-l 6-dimethyl-3-propanyl-4- 3-dichjlorophenyl) -lH,-pyrazolo/3, 4-b7pyridin-5-carboxylic acid propyl ester 4, 7-dihydzo-1, 6-dinethyl-3-propanyl-4- 3-chlorof luorophenyl) -lH-pyrazolo/3, 4-b 7 acid n-butyl ester Essentially following the procedure described in Example 4, the following compounds are obtained: Example 16: phenyl) -IH-pyrazolo/3, 4-b7pyridin-5-carboxylic acid ethyl ester, hydrochloride.

Starting from 1-me thyl- 3- (1-me thy lethyl) and ethyl- 2- (2-nitrobenzyliden) acetoacetate.

M.P. 218*C (Dec.).

-36 Example 17: 4,7-dihydro-1,6-dimethyl-3-(l-methylethyl)-4-(2-nitzophenyl) -lH-pyrazolol3, 4-b7pyridin-5-carboxylic acid (1-methylethyl) ester, hydrochloride.

Starting from i-rnethyl--3- (1-methylethyl) and (I -me thy le thyl) 2- (2-ni trobenzyliden) acetoacetate.

M.p. 229-231 0 C (Dec.).

Example 18: 4,7-Dihydro-1,6-dimethyl-3-(l-methylethyl)-4-2-itrophenyl) -lH-pyrazolo/3,4-b7pyridin-5-carboxylic acid methyl ester, hydrochloride.

M.p. 222-228'C.

Starting from 1-methyl-3-(l-methylethyl) (2,79 g; 0.02 mol) 2-nitrobe-nzaldehyde (3,02 g; 210 0.02 mol) and methyl acetoacetate (2,32 g; 0.02 mol), in propanol (30 ml) The mixture is ref luxed for about 8 hours under nitrogen stream and in the dark and then worked up as usual.

37 Example 19: 4 (2-Fluorophenyl) 7-dihydro-1, 6-dimethyl-3- (1-methylethyl) -lE-pyrazoloL3, 4-b7pyridin-5-carboxylic acid ethyl ester, hydrochloride.

210-2170C (Dec.) Starting from 1-methyl-3- (1-methylethyl) (2,78 g; 0.02 mci), 2-fluorobeanzaldehyde (2,48 g; 0.02 mol) and ethyl acetoacetate (2,6 g; 0.02 mol) izz isopropanol (30 ml) The mixture is refluxed for about 8 hours. The apparatus is protected from air and light as usual and the work up procedure is not dissimilar from those above described.

Example 4, 7-Dihydro-l, 6-dimethyl-3- (1-methylethyl) (3-nitrophenyl) -lH-pyrazolo/3, 4-b7pyridin-5-carboxylic acid ethyl -ester, hydrochloride.

M.P. 249-253*C (methanol) Starting from 1-methyl-3- (1-methy'Lethyl) (0.02 mol), 3-nitrobenzaldehyde (0.02 mci) and ethyl acetoacetate (0.02 mol).

mm -38 Examole 21: 4,7-Dihydro-l,6-dimethyl-3-(2-methvlpropyl)-4-(2-nitro phenyl)-1H-pyrazolo/3,4-b7pyridin-5-carboxylic methyl ester, hydrochloride.

M.p. 160-1670C (isopropanol/ethyl ether) l-methyl-3-(2-methylpropyl)-5-pyrazolamine (0.015 mol) methyl-2-(2-nitrobenzyliden)acetoacetate (0.015 mol) in absolute ethanol are refluxed- for about 24 hours.

Then the solvent is evaporated under vacuum and the residue is dissolved in ethyl acetate and reacted with a molar equivalent of 15% HCl/ethvl ether.

After washing with wetter and drying, the ethereal phase is evaporated under vacuum leaving the crude product which is purified by flash chromatography and salified as usual.- Examole 22: 4,7-Dihydro-1,6-diethyl-3-(2-methylpropyl)-4-(2-nitro phenyl)-lH-pyrazolo/3,4-b7pyridin-5-carboxylic acid ethyl ester, hydrochloride.

M.p. 158-161 0 C (isopropanol/ethyl ether) Starting from 1-methyl-3-(2-methylpropyl)-5-pyrazolamine and ethyl 2-(2-nitrobenzyliden)acetoacetate.

39 Example- 23: 3-Butyl-4, 7-dihydro-1, 6-diinethyl-4- (2-nitrophenyl) -1I--pyrazoloL3, 4-blpyridin-5--carboxylic acid methyl ester.

M.P. 191-2011C (ethyl ether) Starting from 3-butyl-l-mrethyl-5-pyrazolamine and methyl-2- (2-nitrobenzyliden) acetoacetate in equimolar .1o, proportions.

Essentially following the Procedures outlined in the above examples, the following compounds or the corresponding acid addition salts can be prepared: 4, 7-dihydro-1, 6-dimethyl-3-(1, 1-dimethyl) ethyl-4- (3-nitrophenyl) -1H-pyrazoloL3, 4-b7pyridin-5carboxylic acid (1,1-dimethyl)ethyl ester 4, 7-dihydro-1, 6-e.-Imethyl-3- 1-dixnethyl) ethyl-4- (3f luorophenyl-' fl-pyrazolo3 4 acid ethyl ester (2,3-dichlorophenyl) -lH-pyrazolo/ 4-'o7pyridin-5carboxylic acid propyl ester 4, 7-dihydro-1, 6-dirnethyl-3- 1-dilnethyl) ethyl-4- 3-chiorofluorophenyl) -1H-pyrazolo/3, 4-b7p yridin-5-carboxylic acid ri-butyl ester Example 24: 4,7-Dihydro-N,6-dimethyl-3- (l,1-dimethylethyl)-4-(2-nitro pheny.) -lH-oyrazolo/3, acid methyl ester, hydrochloride.

163-172 0 C (Dec.) (ethanol/ethyl ether) Reflux under nitrogen stream and possibly purify the oily free base by flash chromatography using 350 ml of silica gel and CHCl /CH OH, 95:5 as the eluent, before a 3 salifying as usual.

Example 4, 7-Dihydro-1 ,6-dimethyl-3- 1-dimethylethyl) -4-(2-nitrophenyl) -1H'-pyrazoloL3, 4-b7pyridin-5-carboxylic ethyl ester, hydrochloride.

M.p. 140-160 0 C (Dec.) Work up as in Exampl 24.

Example 26: 3-Cyclohexyl-4 ,7-dihydro-l, 6-dixnethyl-4- (2-nitrophenyl) lH-pyrazolo/3, 4-b7pyridin--5-carboxylic acid methyl ester, hydrochloride.

IL M.P. 2J9-228*C (isopropanol/ethyl ether) 41 Starting from 3-cyclohexyl-l-methyl-5-pyrazolamine and methyl-2-(2-nitrobenzyliden)acetoacatate in equimolar proportions, in absolute ethanol.

The mixture is refluxed for about 24 hours using the usual precautions (in the dark, under nitrogen stream), the solvent is stripped off and the residue is dissolved in ethyl. acetate. The solvent is washed with 1% HC1 and water, dried, and evaporated to dryness. The crude residue is purified by flash chromatography. After SQ dissolving the obtained product in ethyl ether/isopro- S panol, dihydrogen chloride in ethyl ether is added thereto and the obtained solid is collected and S crystallized from isopropanol/ether.

f SExample 27: 3-Cyclohexyl-4,7-dihydro-l,6-dimethyl-4-(2-nitrophenyl)- 1H-pyrazolo/3,4-b7pyridin-5-carboxylic acid ethyl ester, hydrochloride.

S 20 M,p. 160-165 0 C (Dec.) Starting from 3-cyclohexyl-l-methyl-5-pyrazolamine and 2-methyl-2-(2-nitrobenzyliden) acetoacetate in about equimolar proportions.

Work up as usual.

-42 xanle 2 8: "One pot" preparation of 4,7-dihydro-1,6-dimethyl-3-phenyl- 4 (3-nitrophenyl) -1H-py'razoloL3, 4-b7-pyridinacid ethyl ester, hydrochloride.

3-Nitrobenzaldehyde (3.02 g; 0.02 moi), ethyl acetoacetate (2.6 g; 0.02 mol), 1-meathyl-3-pheriyl-5-pyrazolarnine (3.46 g; 0.02 mol) in absolute ethanol (30 ml) are refluxed under nitrogen and in the darkness.

After about 5 hours, the mixture is cooled to 0 0 C and the insolubles are collected by filtration and discarded. The filtrate is concentrated under reduced pressure, the residue is dissolved in ethyl ether and the product of the title is precipitated by addition of hydrogen chloride/ethyl ether. The collected solid can be further purified by making a suspension of it in water, alkalinizing the pH with NaHCO 3 extracting with ethyl ether and precipitating with hydrogen chloride ether.

M.p. 212-215*C.

Preparation 1: Preparation of 1-methyl-3-(l-methylethyl)-5(lH)-pyrazolamine 4-Methyl-3-oxo-pentanenitrile (39.58 g; 0,356 mol) dissolved in glacial acetic acid (400 ml) and methylhydrazine (18.05 g; 0.382 mol) is-added thereto, at 15-200C.

43 The reaction mixture is heated to 70-75 0 C under nitrogen stream for about 5 hours. Then the mixture is cooled, and the solvent is evaporated under reduced pressure. The residue is taken up with water (200 ml) and the pH adjusted to about 9. After extraction with methylene chloride, the solvent of the dried organic layer is stripped off. The residue is taken up in ethyl ether and recovered by filtration. M.p. 115-1180C.

S Preparation 2: i I* Preparation of N-benzyl-1,3-dimethyl-5(1H)-pyrazolamine.

A mixture of 1,3-dimethyl-5(1H)-pyrazclamine (2 mmol) and Sbenzylchloride (2 mmol) in methylene chloride (10 ml) in the presence of triethylamine (1 ml) is heated to the o reflux temperature, for about 6 hours. The reaction mixture is then cooled, washed with water and the organic solvent is evaporated to dryness. The compounds of the title crystallizes out from a mixture ethyl ether/petroleum ether. M.P. 95-97 0

C.

Claims (8)

1. A 4,7-dihydropyrazolo/3,4-b7pyridin-5-carboxylic acid derivative of formula 2 R i COOR N 3 1 2 3 wherein R, R R and R have the following meanings: 1 2 R represents hydrogen, R represents phenyl, R 3 o represents 2-nitrophenyl and R represents ethyl; 0 0 1 2 R represents hydrogen, R represents phenyl, R j 20 represents 3-nitrophenyl and R represents methyl; 1 2 R represents phenyl, R represents phenyl, R represents 3-nitrophenyl and R 3 represents methyl; R represents methyl, R represents phenyl, represents 2-nitrophenyl and R represents ethyl or .,oz1 2-methylethyl; 1 2 R represents methyl, R represents methyl, R represents phenyl and R 3 represents ethyl; R represents methyl, R 1 represents methyl, R represents 2-nitrophenyl and R 3 represents methyl or ethyl; R represents methyl, R~ represents methyl, R 2 represents 3-nitrophenyl and R 3represents mothyl; represents methyl, R 1represet ehl R 2 3 t ehl represents 2-chlorophenyl. and R 3represents ethyl; R represents methyl, R1represents ethyl, R 2 represents 2-nitrophenyl and R 3represents ethyl; R represents methyl, R 1represents propyl,R2 represents 2-nitrophenyl and R 3represents ethyl; R represents methyl, 2 ersnlkrpl 3 represents 3-nitrophenyl- and R represents methyl; o2 R represents methyl, R 1represents 1-methylethyl, R 2represents 2-nitrophenyl and R 3represents methyl, ethyl or 1-methylethyl; R represents methyl, R represents 1-methylethyl, .0 R 2represents 3-nitrophenyl and R 3 represents ethyl; R represents methyl, R represents 1-methylethyl, 2 3 R represents 2-trifluoromethylphenyl and R represents ethyl; R represents methyl, R 1 represents 1-methylethyl, 2 3 R represents 2-fluorophenyl and R represents ethyl; R represents methyl, RIrepresents butyl,R2 represents 2-nitrophenyl and R 3 represents methyl; -46- R represents methyl, R1represents 2-methyipropyl, R zrepresents 2-nitrophenyl and R 3 represents methyl or ethyl; R represents methyl, R Irepresents 2,2-dimethyl- ethyl, R2represents 2-nitrophenyl and R 3 represents mnethyl or ethyl; R represents methyl, R ersns ylhxl R 2 represents 2-nitrophenyl1 and R3represents methyl or ethyl; 12 0R represents ethyl, R represents methyl,R 011 3 0 represents 2-nitrophenyl- and R represents methyl; 0R represents methyl, Rrepresents methyl,R 0 represents 2-ni"trophenyl, R 3 represents 1, 1-dirnethylethyl; mehl rpeet methyl, R 2 represents 3-fluorophenyl,,R 3 represents ethyl; R represents methyl, RIrepresents methyl,R2 represents 2,3-dichlorophenyl, R3represents propyl; o 0 4 oR represents m-ethyl, RIrepresents methyl, P. 2 represents 2,3-chlorofluorophenyl, R 3 represents n-butyl; R represents methyl, RIrepresents methyl,R2 represents 2,6-dichlorophenyl, R3represents i-propyl; R represents hydrogen, R 1represents phenyl, R 2 represents 2-nitrophenyl, R3represents 1,1-dimethylethyl; 47 R represents hydrogen, R 1 represents phenyl, R 2 represents 3-fluorophenyl, R represents ethyl; R represents hydrogen, R ersnsphenyl, represents 2,3-dichiorophenyl, R3represents propyl; Rrepresents hydrogen, R represents phenyl.,R represents 2,3-chlorofluorophenyl, R 3represents n-butyl; R represents methyl, RIrepresents ethyl,R2 represents 2-nitrophenyl, R 3 represents 1, 1-dimethylethyl; R represents mnethyl, R 1represents ethyl, R2 represents 3-fluorophenyl, R 3 represents ethyl; R represents methyl, R1represents ethyl,R2 o 0 represents 2,3-diclorophenyl, R 3represents propyl; 9 oR represents methyl, R I represents propyl, R2 represents 2,3-chlorofluorophenyl, R 3 represents n-butyl; 1 R represents methyl, R represents propyl, R F represents 2-nitrophenyl, R 3 represents I, 1-dimethylethyl; 1 2 R represents methyl, R represents propyl, R represents 23-diorophenyl, 3 represents propyl -1 -48 R represents methyl, R Irepresents propyl,R2 represents 2,3-chiorofluorophenyl, R3 represents n -buty I; R represents methyl, R1represents (l,1-dixnethyl)ethyl, R 2represents 3-nitrophenyl, R 3 represents 1 ,1-dimethyletbyl; R represents methyl, RIrepresents (l,l-dimethyl)ethyl, R2represents 3-fluorophenyl, R 3 represents ethyl; R represents methyl, R 1represents (1,1-dimethyl)ethyl, R-represents 2,3-dichlorophenyl, R r ,epresents propyl; R represents methyl, R Irepresents (1,1-dimethyl)ethyl, R2represents 02,3-chiorofluorophenyl, R 3 _epresents n-butyl; o~ 0 and the physiologically acceptable salts thereof. 0 2. A 4,7-dihydropyrazolo/3i,4.-b7pyridin-5-carboxylic acid derivative of formula 2 3 1. COOR J I I wherein R, R, R 2and R 3have the following meanings: 49 a) R represents hydrogen, R1 represents phenyl, R 2 represents 2-nitrophenyl and R 3 represents ethyl; b) R represents hydrogen, R 1 represents phenyl, R 2 represents 3-nitrophenyl and R 3 represents methyl; c) R represents phenyl, R represents phenyl, R 2 represents 3-nitrophenyl and R 3 represents methyl; d) R represents methyl, R represents phenyl, R 2 represents 2-nitrophenyl and R 3 represents ethyl or

2-methylethyl; °o O e) R represents methyL, R represents methyl, R 03 R 3 15 represents phenyl and R represents ethyl; 1 2 f) R represents methyl, R represents methyl, R represents 2-nitrophenyl and R 3 represents methyl or ethyl; g) R represents methyl, R represents methyl, R represents 3-nitrophenyl and R represents methyl; 1 2 h) R represents methyl, R represents methyl, R 3 represents 2-chlorophenyl and R represents ethyl; 1 2 i) R represents methyl, R represents ethyl, R represents 2-nitrophenyl and R represents ethyl; 1 2 R represents methyl, R represents propyl, R represents 2-nitrophenyl and R 3 represents ethyl; m) R represents methyl, R represents propyl, R represents 3-nitrophenyl and R3 represents methyl; 50 o) R represents m-ethyl, Rrepresents I-methylethyl, 2 3 Rrepresents 2-nitrophenyl and R represents methyl, ethyl or 1-methylethyl; I q) R represents methyl, R represents 1-methylethyl, Rrepresents 3-nitrophenyl and R represents ethyl; r) R represents methyl, R' represents I-methylethyl, Repeet 2-tri-fluoromethyJlphenyl an~d R 3 represents ethyl: S) R represents methyl, R' represents l-methylathyl, R' represents 2-fl'jorcphenyl and Rrepresents ethyl; t) R represents methyl, R represents butyl, R 3 -represents 2-nitrophenyvi and R rpent;methyl; U) R represents methyl, R, represents 2-methylprcpyl, R 2 represents 2-nitroohenyl and R represenits methyl or ethyl; 17) R reDrese±nts methyl, R1represents 2,2-dimet1-hyl- ethyl, R 2repres-,nts 2-nitrophenyl andR3 represents methyl or ethyl; Z) R represents methyl, R 1 represents cyclohexyl, R 2 represents 2-nitzophenyl and R 3 represents methyl or ethyl; 51 W) R represents ethyl, R represents methyl, R 2 3 represents 2-nitrophenyl and R represents methyl; and the physiologically acceptable salts thereof.

3. A compound of claim I which is 4,7-dihydro- -1 S-dimethyl-3- (1-niethylethyl) (2-nitrophenyl) li-pyrazolo/,4-b7pyridin-5-carboxylic acid ethyl or In methyl ester, or a physiologically acceptable salt tereo. t h

4. A compound of claim 1 which is 4,7-dihydro- -l,6-diethyl-3-t2-methylpropyl)-4-(2-nitrophenyl)- H-orazo o/3,4-7D/yrdn-5-carboxylic acid methyl c:ter, or a, physiologically,. acceptable salt thereof. S, A process for preparing a compound of claim I to 4 which comorss: a) reacting a 5-ianinopyrazola derivative of formula 2 2il NN 2 wherein R, and R Iare as above, 0' I- -52- a) with an equimclar amount or a slight molar defect of an alpha,beta-unsaturated ketoester of formula 2 3 00R CBH 3 wherein the substituents are as above, in an inert organic solvent; aoo b) alternatively, reacting a 5-aminopyrazole of the 00 2 .oo 15 above formula with an aldehyde of formula R CHO and. 0 o an acetoacetic acid ester of formula CH COCH COOR wherein the substituents are as above, in abot equimolar proportions. °0 20 6. A process as in claim 5 wherein the inert o 'o organic solvent is selected from: lower alkyl alcohols lCh a pthanol me thano_ _propanol, isopopanol) o.,ao Is and their ethers.

7. A process as in claim 5 wherein the reaction 00 -0 temperature is bet,4een 40°C and the reflux temperature.

8. A compound of claim 1, 2, 3 or 4 when used as a medicine. Il 9. Use of a compound of claim 1, 2, 3 or 4 for preparing a medicament for the treatment of hypertension. j ay t;/ C I %-44.Y L 4 0 z-) I^ I i i 3 -53- A pharmaceutical composition comprising a compound of claim 1, 2, 3 or 4 in admixture with a pharmaceutically acceptable carrier.

11. A compound as claimed in claim 1 or 2 substantially as hereinbefore described with reference to any one of the examples.

12. A process as claimed in claim 5, substantially as hereinbefore described with reference to any one of the examples. 0000 o o 13. A process, as claimed in claim 6, wherein the lower o o alkyl alcohols are selected from ethanol, methanol, propanol o or isopropanol. o oo 0000 .oo0 DATED: 2 August, 1990 0 ooo0 PHILLIPS ORMONDE FITZPATRICK Attorneys for: GRUPPO LEPETIT S.P.A. QA 0000 0 0 0000 00 0 ooo Oo o a 0 0 G 0 S I WDP 4798N c