MXPA99006171A - 3-ARYL SUBSTITUTED PYRAZOLO[4,3-d]PYRIMIDINE DERIVATIVES;CORTICOTROPIN-RELEASING FACTOR RECEPTOR (CRF1 - Google Patents

Abstract

This invention encompasses compounds of formula (I), wherein Ar represents a mono-, di- or trisubstituted aryl group where at least one position on Ar ortho to the point of attachment to the pyrazole ring is substituted;and R1 represents lower alkyl;R2 is hydrogen or lower alkyl;and R3 and R4 independently represent organic and inorganic substituents, which compounds are highly selective partial agonists or antagonists at human CRF1 receptors and are useful in the diagnosis and treatment of treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.

Description

DERIVATIVES OF PIRAZOLO (4.3-Dl PIRAMIDINA 3-ARILO SUBSTITUIDOS; LINGADOS SPECTFTCOS OF THE RECEIVER OF THE FACTOR OF RELEASE OF CORTICATROPINA FIELD OF THE INVENTION This invention relates to certain pyrazolo [4, 3-d] pyrimidine derivatives which selectively bind to receptors of corticotropin releasing factor (CRF). More specifically, the invention relates to pyrazolo [4, 3-d] pyrimidine derivatives substituted with 3-aryl. The invention also relates to pharmaceutical compositions comprising such compounds. It also refers to the use of such compounds in the treatment of stress-related disorders, such as post-traumatic stress disorder (PTSD) as well as depression, headache and anxiety.

BACKGROUND OF THE INVENTION International Application PCT / US93 / 11333 describes pyrazolo [3, 4-d] pyrimidines which are CRF antagonists. Bull. Chem. Soc. Japan. 52 (1), 208-11, Ref .: 30744 (1979) describes the synthesis of 3-phenyl-pyrazolo [4, 3-d] pyrimidines.

DESCRIPTION OF THE INVENTION This invention provides novel compounds of Formula I that interact with CRF receptors. The invention provides pharmaceutical compositions comprising compounds of Formula I. It also relates to the use of such compounds in the treatment of stress-related disorders such as stress or post-traumatic stress disorders (PTSD) as well as depression, headache and anxiety. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I: wherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions of Ar at the point of attachment or linking to the pyrazole ring is substituted; Ri is lower alkyl; R 2 is "hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy having 1-6 carbon atoms: R 3 and R 4 are the same or different and represent hydrogen, lower alkyl, lower alkoxy lower alkyl, lower hydroxy alkyl, or alkenyl phenyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4- or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, phenyl-, 2-, 3-, or 4-pyridinyl-, 2- or 3-thienyl-, or 2-, 4- or 5-pyrimidinyl-lower alkyl, each of these is optionally mono- or disubstituted with lower alkyl; cycloalkyl or cycloalkyl lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl; or 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally monosubstituted with lower alkyl; as long as both R3 and R are not hydrogen; or R3 and R4 taken together represent - (CH2) n ~ A- (CH2) - wherein n is 2, "or 3; A is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein R is alkyl lower, phenyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4- or 5-pyrimidinyl, or phenyl-, 2-, 3- or 4-pyridinyl-, 2- or 3- thienyl-, or 2-, 4- or 5-pyrimidinylalkyl, and m is 1, 2 or 3.

These compounds are highly selective partial agonists or antagonists in CRF receptors and are useful in the diagnosis and treatment of disorders or disorders related to stress or tension such as post-traumatic stress disorder (PTSD) as well as depression and anxiety.

DETAILED DESCRIPTION OF THE INVENTION In addition to the compounds of Formula I above, the invention encompasses the compounds of Formula II: p wherein Ra represents halogen, hydroxy, lower alkyl, or lower alkoxy; Rb and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 are the same or different and represent hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl; as long as both R3 and R are not hydrogen. Preferred compounds of Formula II are those wherein R3 and R independently represent alkyl of 1 to 6 carbon atoms (ie, lower alkyl) optionally substituted with halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, Ar is phenyl which is mono-, di-, or trisubstituted with halogen, hydroxy, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms, provided that at least one of the positions in the ortho of the phenyl group at The point of attachment to the pyrazole ring is substituted The most preferred compounds of Formula II are those wherein Ar is phenyl which is trisubstituted with alkyl of 1 to 6 carbon atoms, with the proviso that at least one of the Positions in the ortho of the phenyl group to the point of binding or linking to the pyrazole ring is substituted The most preferred compounds of Formula II are those wherein Ar is phenyl which is trisubstituted at positions 2, 4, and 6 ( for and both position ortho relative to the point of linking to the pyrazole ring) with alkyl of 1 to 3 carbon atoms, more preferably methyl. Particularly preferred compounds of Formula II are those wherein R 3 and R 4 are independently hydrogen or alkyl of 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, butyl, or cyclopropylmethyl, provided that both R 3 and R Do not be hydrogen The invention aincludes the compounds of Formula III: m wherein Ra represents halogen, hydroxy, lower alkyl, or lower alkoxy; Rb and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, or alkenyl, phenyl, 2-, 3-, or 4-pyridinyl, or 2-, 4- or 5-pyrimidinyl, each one of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy; or phenyl-, 2-, 3-, or 4-pyridinyl-, or 2-, 4- or 5-pyrimidinyl-lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl; as long as both R3 and R are not hydrogen. In addition, the invention includes the compounds of Formula IV: IV wherein Ra represents halogen, hydroxy, lower alkyl, or lower alkoxy; Rb, and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 taken together represent with the nitrogen atom to which they are attached, represent - (CH2) n- - (CH2) m- where n is 2, or 3; A is methylene, 1,2-phenylene, oxygen, sulfur or NR 6, wherein R 6 is lower alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2-, or 3-thienyl or 2-, 4- or 5-pyrimidinyl, or phenyl-, 2-, 3- or 4-pyridinyl-, 2- or 3-thienyl-, or 2-, 4- or 5-pyrimidinylalkyl; and m is 1, 2 6 3. Preferred compounds of the invention have Formula V: wherein af Rbf- and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, with the proviso that both Ra and Rc are not hydrogen; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, alkenyl, 2-hydroxyethyl or 3-hydroxypropyl, so long as both R3 and R are not hydrogen. ~ Other preferred compounds of Formula V are those wherein R3 and R4 independently represent alkyl of 1 to 6 carbon atoms (ie, lower alkyl) optionally substituted with halogen, hydroxy, or alkoxy of 1 to 6 carbon atoms. More preferably, the compounds of the Formula V are those in which Ra, Rb, and Rc are methyl. Particularly preferred compounds of Formula V are those wherein Ra, Rb, and Rc are methyl, Ri and R2 independently represent lower alkyl, and R3 and R4 are independently hydrogen or alkyl of 1 to 4 carbon atoms, for example, methyl , ethyl, propyl, butyl, or cyclopropylmethyl, provided that both R3 and R are not hydrogen. Other preferred compounds of the invention have Formula VI: wherein Rar R and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, with the proviso that both Ra and Rc are not hydrogen; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, alkenyl, 2-hydroxyethyl or 3-hydroxypropyl, as long as both R3 and R4 are not hydrogen. Other preferred compounds of Formula VI are those wherein R3 and R4 independently represent alkyl of 1 to 6 carbon atoms (ie, lower alkyl) optionally substituted with halogen, hydroxy, or alkoxy "of the β carbon atoms.

The most preferred compounds of Formula VI are those wherein Ra, Rb »- and Rc are methyl. Particularly more preferred compounds of Formula VI are those wherein Ra, Rb and c are methyl, Ri and R2 independently represent lower alkyl, and R3 and R4 are independently hydrogen or alkyl of 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, butyl, or cyclopropylmethyl, provided that both R3 and R4 are not hydrogen. The invention also encompasses intermediates for preparing compounds of Formula I. Among these intermediates are the compounds of Formula VII: vn wherein Rs is hydrogen or lower alkyl; Ri and R2 are as defined for Formula I: Ra is hydrogen, or Rb02C- wherein R represents alkyl of 1 to 3 carbon atoms; and Ar is phehyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-di- or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions of Ar at the point of binding to the pyrazole ring is substituted. Preferred Ar groups are 2, 4, 6-tri (Ci- C6) alkylphenyl groups, most preferably the 2,4,6-trimethylphenyl groups. Preferred Rs groups are hydrogen and methyl. "The invention further includes intermediates of Formula VIII: vm where Ri and R2 are as defined above for the Formula I; Ra is hydrogen or Rb02C- wherein Rb represents alkyl 1 to 6 carbon atoms; and Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-di- or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions of Ar in the The point of attachment to the pyrazole ring is substituted. Preferred Ar groups are 2, 4, 6-tri (dC) alkylphenyl groups, most preferably 2,4,6-trimethylphenyl groups. The invention further includes intermediates of Formula IX: wherein R 0 is hydrogen or lower alkyl; Ri and R2 are as defined above for Formula i; and Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono- or di-substituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions of Ar at the point of attachment to the pyrazole ring is substituted. Preferred Ar groups are 2, 4, 6-tri (C? ~ C6) alkylphenyl groups, most preferably 2,4,6-trimethylphenyl groups. The RD groups are methyl and ethyl. Also, the intermediates of the Formula X are within the invention: wherein R 0 is hydrogen or lower alkyl; Ri and R2 are as defined above for Formula i; and Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono- or di-substituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions of Ar at the point of attachment to the 2,4,4-dioxo-3-oximinobutanoate portion of alkyl is substituted. Preferred Ar groups are 2,4,6-tri (O.-Cß) alkylphenyl groups, most preferably 2,4,6-trimethylphenyl groups. Preferred R0 groups are methyl and ethyl. The invention also includes the compounds of Formula XI: XI wherein R 0 is hydrogen or lower alkyl; Ri and R2 are as defined above for Formula i; and Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono- or di-substituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions of Ar at the point of attachment to the alkyl-2,4-dioxobutanoate moiety is substituted. Preferred Ar groups are 2, 4, 6-tri (C? ~ C) alkylphenyl groups, most preferably 2,4,6-trimethylphenyl groups. Preferred Rs groups are methyl and ethyl. Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to, the compounds in Table 1 and their pharmaceutically acceptable salts. The pharmaceutically acceptable salts, non-toxic, include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, iohydric, alkanoic such as acetic H00C- (CH2 ) n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable, non-toxic addition salts. The present invention also encompasses acylated prodrugs of the compounds of Formula I.

Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare pharmaceutically acceptable, non-toxic addition salts and acylated prodrugs of the compounds encompassed by Formula I.

When a compound of formula I is obtained as a mixture of enantiomers, these may be separated by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral HPLC column. In the compounds of the invention, the group Ar is preferably a phenyl group which is mono-, di-, or trisubstituted with halogen, hydroxy, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms, with the condition that at least some of the positions in the ortho position of the phenyl group at the point of attachment with the isoquinolinamine or phthalazinamine ring be replaced. Where Ar is phenyl, the carbon atom by which the phenyl group joins the pyrazole ring is defined as position 1. Thus, the ortho positions at the point of attachment are positions 2 and 6, and the position for at position 4 of the phenyl group. By the terms alkyl (1 to 6 carbon atoms) and lower alkyl are meant straight or branched chain alkyl groups having from 1 to 6 carbon atoms as well as cyclic alkyl groups such as, for example, cyclopropyl, cyclobutyl, or cyclohexyl. Specific examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl. Preferred alkyl groups of 1 to 6 carbon atoms are methyl, ethyl, propyl, butyl or cyclopropylmethyl. By the terms "alkoxy (1 to 6 carbon atoms)" and "lower alkoxy" are meant straight or branched chain alkoxy groups having from 1 to 6 carbon atoms. By hydroxy alkyl of 1 to 6 carbon atoms or hydroxyalkyl is meant an alkyl group of 1 to 6 carbon atoms carrying or carrying a terminal hydroxy portion. By alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms (lower alkyl alkoxy) is understood to mean a group of the formula - (CH 2) xO (CH 2) and CH 3, wherein x and y independently represent integers from 1 to β. By the term alkenyl of 1 to 6 carbon atoms or lower alkenyl is meant straight or branched chain hydrocarbon groups having from 1 to 6 carbon atoms and at least one double bond. By halogen, halo or halide is meant substituents of fluorine, chlorine, bromine and iodine. By aryl (Ci-Cd) alkyl, for example, phenylalkyl, pyridinylalkyl, pyrimidinylalkyl, and thienylalkyl, is meant aryl groups attached to the parent or parent group by a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Thus, aryl groups include phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, A-, or 5-pyrimidinyl. These aryl groups are optionally substituted with up to two groups selected from halogen, hydroxy, alkyl (from 1 to átomos carbon atoms), and alkoxy (from 1 to átomos carbon atoms). Representative examples of the compounds according to the invention are shown in Table 1 below.

Composite Table No.

The pharmaceutical utility of the compounds of this invention is indicated by the following assay for CRF receptor activity Assay for the binding activity of the CRF receptor The binding of CRF receptors is performed using a modified version of the assay described by Grigoriadis and De Souza (Biochemical, Pharmacological, and Autoradiographic Methods to Study Corticotropin-Releasing Factor Receptors, Methods in Neurosciences, Vol. 5, 1991). The membrane pellets containing CRF receptors are resuspended in 50 mM Tris buffer, pH 7.7 containing 10 mg of MgCl 2 and 2 mM of EGTA and centrifuged for 10 minutes at 48,000 g. The membranes are again washed and brought to a final concentration of 1500 μg / ml in binding buffer (Tris buffer described above with 0.1% BSA)., 0.15 mM bacitracin and 0.01 mg / ml aprotinin.). For the binding or binding assay, lOOμl of the membrane prepaon is added to 96-well icrotube plates containing 100μl of 125 I-CRF (SA 2200 Ci / mmol, final concenton of 100 pM) and 50μl of drug. The binding or bonding is carried out at room tempere for 2 hours. The plates are then harvested or recovered in a Brandel 96-cell cell harvester and the filters are counted by gamma emissions in a Wallac 1205 Betaplate liquid scintillation counter. The non-specific binding is defined by 1 μM of cold CRF. IC5o values are calculated with the RS / 1 non-linear curve setting programs (BBN Sofware Products Corp., Cambridge, MA). The compounds of the invention typically have binding or binding attributes, expressed as IC 50 values, from about 0.5 nanomolar (nM) to about 10 micromolar (μM). The binding or binding characteristics for representative examples of the invention are shown in Table 1. TABLE 1 Compound Number ICso i nM) 1 1.4 2 1.8 The numbers of compounds are related to the compounds described in the following examples: The compounds of the general formula I can be administered orally, topically, parenterally, by inhalation or aspersion or rectally in formulations of unit dose containing conventional non-toxic pharmaceutically acceptable adjuvants, vehicles and carriers. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular injections, intrasternal injection or infusion techniques. In addition, a pharmaceutical formulation comprising a compound of the general formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of the general formula I can be presented in association with one or more pharmaceutically acceptable, non-toxic carriers, and / or diluents and / or adjuvants and if other active ingredients are desired. The pharmaceutical compositions containing compounds of the general formula I may be in a form suitable for oral use, for example, as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible granules or powders, emulsion, hard or soft capsules, or syrups. or elixirs. Compositions proposed for oral use can be prepared according to any method known in the art for the manufacture or production of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, agents dyes and preserving agents to provide palatable and pharmaceutically elegant preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable, non-toxic excipients, which are suitable for the manufacture or production of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carboan, lactose, calcium phosphate or sodium phosphate; granulation and disintegration agents, for example, corn starch, or alginic acid; binding agents or binders, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged or sustained action over a longer period. For example, a time delay material such as glycerol monostearate or glycerol distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the ingredient active is mixed with water or an oily medium, for example peanut oil, olive oil or liquid paraffin.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspension-forming agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; the dispersing agents or humectants may be a naturally occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols. long chain, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from the acids fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those described above, flavoring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible granules and powders suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be gums which are naturally present, for example acacia gum or tragacanth gum, phosphatides which are naturally present, for example soybeans, lecithin and esters or partial esters derived from fatty acids and hexitol , anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening or flavoring agents. The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulsifier, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of an injectable, sterile, aqueous or oleaginous suspension. This suspension can be formulated in accordance with known technique using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be sterile injectable solutions or suspensions in an originally acceptable, non-toxic solvent or diluent, for example as a solution in 1,3-butanediol. Among the acceptable solvents and vehicles that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, sterile oils are conventionally used as a solvent or suspension-forming medium. For this purpose, any fixed or tasteless oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the general formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The compounds of the general formula I can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents They can be dissolved in the vehicle. Dosage levels of the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated above (approximately 0.5 mg aabout 7 g per patient per day) . The amount of active ingredient that can be combined with the carrier materials produces a unique dosage form that will vary depending on the patient treated and the particular mode of administration. The unit dosage forms will generally contain from about 1 mg to about 500 mg of an active ingredient. It is understood, however, that the specific dosage levels for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, administration, and rate of excretion, combination of drugs and the severity of the particular disease that undergoes the therapy. A representative illustration of suitable methods for the preparation of the compound of the present invention is shown in Scheme 1. Those skilled in the art will recognize that the starting materials can be varied and the additional steps employed to produce compounds encompassed by the present invention. For example, in certain situations, the protection of reactive portions such as amino groups will be required.

Scheme 1 In the above scheme, Rx-R4, and Ar have the definitions described above for Formula I. The descriptions in this application of all articles and references, including patents, are incorporated herein by reference. The invention is further illustrated by the following examples which are not constructed as P¡- limiting the invention in scope or spirit for the specific procedures and compounds described therein.

Example 1 A. Ethyl 2, 4-dioxo-4- (2,4,6-trimethylphenyl) butanoate 7.4 g of NaH (60% dispersion in mineral oil) was cautiously added to a solution of 2 ', 4', 6'-trimethylacetophenone (15 g, 92.6 mmol) and diethyl oxalate (20 g, 139 mmol) in 500 mL of anhydrous toluene. The reaction mixture was slowly heated to reflux under N2. It was refluxed for approximately 20 minutes, then cooled, poured into an aqueous HCl solution cooled with ice and extracted with ether. The extracts were washed with brine, dried over Na 2 SO 4, filtered through a small pad of silica gel and concentrated to give 16.2 g of a red oil which was used in the next reaction without further purification.

B. ethyl 2, 4-dioxo-3-oximino-4- (2,4,6-trimethylphenyl) butanoate The N203 gas was passed slowly into a stirred solution of the product of step A (16.2 g) in 300 mL of ethanol until the disappearance of the initial material was confirmed by TLC. The N203 gas was generated by the addition of drops of 12N aqueous HCl solution in a slurry of NaN02. The solvent was removed from the mixture and 200 mL of water was added to the residue. The product was extracted into ether. The ether extract was dried over Na2SO4, and r was evaporated to give 16.1 g of a semi-solid.

C. ethyl 4-amino-l-methyl-5- (2,4,6-trimethylphenyl) pyrazole-3-carboxylate 20 0.63 g of methyl hydrazine at 0 ° C were added dropwise to a solution of the product from step B (4.0 g, 13.8 mmol) and 1.6 mL of hydrochloric acid in 100 mL of methanol.

The reaction mixture was stirred at room temperature for 4 hours, and then concentrated. The resulting residue was partitioned between water and ethyl acetate. The organic phase was separated and washed once with brine. Then the ethyl acetate solution was mixed with 100 L of water. Solid excess Na2S204 was added in a small portion until TLC showed the completion of the reduction. The organic phase was separated, washed with water and brine, and dried over Na2SO4. Evaporation gave 3.1 g of the title compound as a foam.

D. 2, 5-dimethyl-3- (2,4,6-trimethylphenyl) -2,6-dihydro-2H-pyrazolo [4, 3-d] pyrimidin-7-one A solution of the product from step C (3.1 g) in 100 mL of anhydrous CH3CN was saturated with HCl gas, stirred at room temperature overnight, and then concentrated. The residue was partitioned between a solution of aqueous NaHCO3 and ethyl acetate. The organic layer was separated, washed one with brine, dried over Na 2 SO 4 and concentrated. The residue was triturated with ether. The solid was collected by filtration to give 1.0 g of the title compound as a white solid, m.p. 264-66 ° C. 2, 5-dimethyl-3- (2,4,6-trimethylphenyl) -2,4-dihydro-2H-pyrazolo [4, 3-d] pyrimidine-7-thione A mixture of the product of step D (0.6 g, 2.2 mmol) and P2Ss (1.0 g, 2.2 mmol) in 50 mL of dioxane was heated to reflux for 2 hours. The solvent was evaporated.

The residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over Na 2 SO 4 and concentrated to give 0.60 g of the title compound as a yellow foam.

F. N-propyl-2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d]? Irimidin-7-amine A solution of the product from step E (0.6 g) and 1 mL of propylamine in 10 mL of ethanol was heated to reflux for 3 hours. Evaporation of the volatile product gave 550 mg of the title compound as a foam.

G. N, N-dipropyl-2, 5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7-amyr? A (Compound 1) A mixture of the product of step F (400 mg, 1.2 mmol), KOH powder (1.0 g) and 1-brmopropane (1 mL) in 2 mL of DMSO was heated at 60 C for 8 hours. Then the excess bromopropane was evaporated. The mixture was divided between water and ether. The aqueous layer was separated and extracted with ether. The combined ether extracts were washed with water and brine, dried over Na 2 SO 4 and concentrated to an oil. The oil was purified by column chromatography on silica gel to give 260 mg of the title compound as an oil. 1H NMR (CDCI3): d 0.97 (t, 6H), 1.76 (m, 4H), 1.96 (s, 6H), 2.32 (s, 3H), 2.45 (s, 3H), 3.77 (s, 3H), 3.40-4.30 (br, 4H), 6.95 (s, 2H) ppm. The hydrochloride salt was prepared in ether / molten HCl at 210-13 ° C.

Example 2 and Example 3 N-ethyl-5-methyl-3- (2, 4, 6-trimethylphenyl) -1H-pyrazolo [4,3-d] pyrimidin-7-amine A solution of 5-methyl-3- (2,4,6-trimethylphenyl) -lH-pyrazolo [4, 3-d] pyrimidine-7-thione (250 mg, was prepared in a manner similar to the compound of step E in Example 1) and 25 mL of ethylamine (in 2M methanol) was heated to reflux for 3 hours. Evaporation of the volatile product gave 255 mg of the title compound as a foam. ÍL 1 - N, N-diethyl-l-ethyl-5-methyl-3- (2,4,6-trimethylphenyl) -1H-pyrazolo [4, 3-d] pyrimidin-7-amine (Example 2) (Compound 2 ) 2. N, N-diethyl-2-ethyl-5-methyl-3- (2, 4, 6-trimethylphenii; 2H-pyrazolo [4, 3-d] pyrimidin-7-amine (Example 3) A mixture of the product from step A (250 mg, 0. 85 mmol), KOH powder (0.5 mg) and 1-bromopropane (0.5 L) in 2 mL of DMSO was heated at 60 ° C for 2 hours. Then the excess bromopropane was evaporated. The mixture was divided between water and ether. The aqueous layer was separated and extracted with ether. The combined ether extracts were washed with water and brine, dried over Na 2 SO 4 and concentrated to an oil. The oil was purified by column chromatography on silica gel using Hexane / EtOAc (100/30, v / v). The fraction of the fastest movement, comprising the title compound (example 2) was collected. Evaporation of the solvents gave 26 mg of the title compound (example 2) as an oil. XH NMR (CDC13): d 1.24 (t, 6H), 1.37 (t, 3H), 2.08 (s, 6H), 2.31 (s, 3H), 2.60 (s, 3H), 3.58 (q, 4H), 4.44 (q, 2H), 6.94 (s, 2H) ppm. The slowest motion fraction, comprising the compound of the 5 title (example 3) was collected. Evaporation of the solvents gave 80 mg of the title compound (example 3) as an oil. XH NMR (CDC13): d 1.32 (t, 6H), 1.36 (t, 3H), 1.98 (s, 6H), 2.33 (s, 3H), 2.47 (s, 3H), 4.03 (q, 2H), 3.60-4.40 (br, 4H), 6.97 (s, 2H) ppm.

The following compounds were prepared essentially according to procedures set forth above in Examples 1,2 and 3.

Example 4 N-Cyclopropylmethyl-N-propyl-2, 5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7-amine (Compound 3).

Example 5 N-Ethyl-N-propyl-2, 5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7-amine.

Example 6 N-Butyl-N-ethyl-2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [A, 3-d] pyrimidin-7-amine.

Example 7 N, N-D-butyl-2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7-amine.

Example 8 N, N-Diallyl-2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7-amine.

Example 9 N-Ethyl-2, 5-dimethyl-3- (2,4-, 6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7-amine.

Example 10 7- (1-morpholino) -2,5-dimethyl-3- (2,4-, 6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidine.

Example 11 N-Benzyl-N-ethyl-2,5-dimethyl-3- (2,4-, 6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidir.-7-amine.

Example 12 N, N-Di [l- (2-methoxy) ethyl] -2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7-amine.

The invention and the way and process to make and use these, are now described in complete, clear, concise and exact terms as enabling an expert person - in the technique to which it belongs, to make and use them. It is well understood that the method describes preferred embodiments of the present invention and that the modifications can be made without departing from the spirit or scope of the present invention as set out in the claims. To particularly note and distinctly claim the subject matter with respect to the invention, the following claims conclude this specification.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which refers to the manufacture of the objects to which it refers.

Having described the invention as above, the content of the following is claimed as property

Claims (22)

1. A compound of the formula: or pharmaceutically acceptable salts thereof characterized in that Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di, or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions Ar to the point of attachment or linkage with the pyrazole ring is substituted; Ri is lower alkyl; R 2 is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy having from 1-6 carbon atoms; R3 and R4 are the same or different and represent hydrogen, lower alkyl, lower alkyl, lower alkyl, hydroxy, or alkenyl; phenyl, 2-, 3-, or 4-pyridinyl, 2-, or 3-thienyl or 2-, 4- or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy; phenyl-, 2-, 3-, or 4-pyridinyl-, 2- or 3-thienyl-, 2-, 4-, or 5-pyrimidinyl-lower alkyl, each of which is optionally mono- or disubstituted with alkyl lower; cycloalkyl or cycloalkyl lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl; or 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally substituted with lower alkyl; as long as both R3 and R4 are not hydrogen; or R3 and R4 taken together represent - (CH) n-A- (CH2) - wherein n is 2, or 3; A is methylene, 1,2-phenylene, oxygen, sulfur or NR6, - wherein R6 is lower alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4- or 5-pyrimidinyl, or phenyl-, 2-, 3- or 4- pyridinyl-, 2- or 3-thienyl-, or 2-, 4- or 5-pyrimidinylalkyl; and m is 1, 2 6 3.

2. A compound of the formula: or pharmaceutically acceptable salts thereof characterized in that: Ra represents halogen, hydroxy, lower alkyl, or lower alkoxy; Rb and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 are the same or different and represent hydrogen, lower alkyl, lower alkenyl cycloalkyl, cycloalkyl lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl; as long as both R3 and R4 are not hydrogen.

3. A compound of the formula: or pharmaceutically acceptable salts thereof characterized in that: Ra represents halogen, hydroxy, lower alkyl, lower alkoxy; Rb and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl or alkenyl; phenyl, 2-, 3-, or 4-pyridinyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally substituted with halogen, hydroxy, lower alkyl, or lower alkoxy; or phenyl, 2-, 3-, or 4-pyridinyl, or 2-, 4- or 5-pyrimidinyl-lower alkyl, each of which is optionally mono- or disubstituted with halogen, lower alkyl; as long as both R3 and R4 are not hydrogen.

4. A compound of the formula: or pharmaceutically acceptable salts thereof characterized in that R a represents halogen, hydroxy, lower alkyl, or lower alkoxy; R and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; Ri is lower alkyl; R2 is hydrogen, or lower alkyl; and R3 and R4 taken together represent with the nitrogen atom to which they are attached represent - (CH2) n-A- (CH2) m- where n is 2, or 3; A is methylene, 1,2-phenylene, oxygen, sulfur or NR 6, wherein R 6 is lower alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4- or 5-phenyl. pyrimidinyl, or phenyl-, 2-, 3- or 4-pyridinyl-, 2- or 3-thienyl-, or 2-, 4- or 5-pyrimidinylalkyl; and m is 1, 2 or 3.

5. A compound of the formula: or pharmaceutically acceptable salts thereof, characterized in that: Ra / R and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, provided that both R3 and R are not hydrogen; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, alkenyl, 2-hydroxyethyl or 3-hydroxy-ropyl, provided that both R3 and R4 are not hydrogen;

6. A compound according to claim 5, characterized in that Ra, R and Rc are methyl.

7. A compound according to claim 6, characterized in that Rx and R2 independently represent lower alkyl.

8. A compound of the formula: or pharmaceutically acceptable salts thereof, characterized in that: Ra / Rb and Rc independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, provided that both R3 and R4 are not hydrogen; Ri is lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, alkenyl, 2-hydroxyethyl or 3-hydroxypropyl, provided that both R3 and R4 are not hydrogenated

9. A compound according to claim 8, characterized in that Ra, R and Rc are methyl.

10. A compound according to claim 9, characterized in that Rx and R2 independently represent lower alkyl.

11. A compound according to claim 1, characterized in that it is N, N-Dipropyl-2, 5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7- amine

12. A compound according to claim 1, characterized in that it is N, N-Diethyl-1-ethyl-5-methyl-3- (2,4,6-trimethylphenyl) -lH-pyrazolo [4, 3-d] pyrimidine- 7-amine.

13. A compound according to claim 1, characterized in that it is N, N-Diethyl-2-ethyl-5-methyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidine- 7-amine.

14. A compound according to claim 1, characterized in that it is N-Cyclopropylmethyl-N-propyl-2,5-dimethyl-3- (2,4,6-tri-ethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidine. -7-amine.

15. A compound according to claim 1, characterized in that it is N-Ethyl-N-propyl-2, 5-dimethyl-3- (2,, 6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidine-7 -amine.

16. A compound according to claim 1, characterized in that it is N-Butyl-N-ethyl-2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidine- 7-amine.

17. A compound according to claim 1, characterized in that it is N, N-Diethyl-2, 5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7- amine.

18. A compound according to claim 1, characterized in that it is N, N-Diallyl-2, 5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidin-7- amine

19. A compound according to claim 1, characterized in that it is N-Ethyl-2,5-dimethyl-3- (2,4-, 6-trimethylphenyl) -2H-? Irazolo [4, 3-d] pyrimidin-7-amine .

20. A compound according to claim 1, characterized in that it is 7 (1-Morpholino) -2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidine.

21. A compound according to claim 1, characterized in that it is N-Benzyl-N-ethyl-2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4, 3-d] pyrimidine- 7-amine.

22. A compound according to claim 1, characterized in that it is N, N-Di [(1- (methoxy) ethyl] -2,5-dimethyl-3- (2,4,6-trimethylphenyl) -2H-pyrazolo [4 , 3-d] pyrimidin-7-amine.