MXPA99005775A - Isoquinolinamine and phthalazinamine derivatives which interact with crf receptors - Google Patents

Abstract

Disclosed are compounds that are highly selective partial agonists or antagonists at human CRF1 receptors that 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. The compounds have formula (I) or the pharmaceutically acceptable salts thereof wherein Ar, R1, R2, R3, R4 and W are various organic and inorganic substituents.

Description

CERTAIN DERIVATIVES OF ISOQÜINOLINAMINE AND 'FTALAZINAMINE INTERACTING WITH CRF RECEPTORS.

Field of Invention This invention provides novel compounds of Formula I that interact with CRF receptors.

The invention provides pharmaceutical compositions comprising compounds of Formula I. This further relates to the use of such compounds in the treatment of stress-related disorders such as post-traumatic stress disorders (PTSD) such as depression, headache and anxiety. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I: where Ref: 030684 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 or trisubstituted with halogen, hydroxy, C? -C6 alkyl, or C? -C6 alkoxy, with the proviso that at least one of the positions in Ar ortho for the point of attachment to the phthalazinamine or isoquinilinamine ring is substituted; Ri and R2 are the same or different and represent hydrogen, C6-C6alkyl, halogen, hydroxy, Ci-Ce alkoxy, NH2, NH (Ccy6alkyl), N (C6alkyl) 2, N02, cyano, trifluoromethyl; R3 and R4 are the same or different and represent C? -C6 alkyl optionally substituted with halogen, hydroxy, or Ci-Ce alkoxy; or C? -C6 alkylaryl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which it is optionally mono- or disubstituted with halogen, hydroxy, Ci-Cß alkyl, Ci-Cβ alkoxy; or Cj.- C6alkyl-Y-R5, wherein Y is O, S, NH, N (Ci-C alquilo alkyl), and Rs is hydrogen or Ci-Ce alkyl; and is N or C-Rβ, where Re is hydrogen or Ci- C6 alkyl.

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

The invention further encompasses methods for the treatment of mammals, such as, for example, humans and companion animals (ie cats and dogs), which suffer from PTSD, depression, and / or anxiety. Such methods comprise administering to a mammalian patient an effective amount of a compound of Formula I to alleviate depression, anxiety or PTSD.

Detailed description of the invention.

In addition to the compounds of Formula I above, the invention provides compounds encompassed by Formula II: p wherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5- pyridinyl, each of which is mono-, di- - or trisubstituted with halogen, hydroxy, Ci-Cß alkyl, Ci-Cß alkoxy with the proviso that at least one of the positions in Ar ortho for the point of attachment to the phthalazinamine ring is substituted; Ri and R2 are the same or different and represent hydrogen, C? -C6 alkyl, halogen, hydroxy, C1-5 alkoxy, NH2, NH (C6 alkyl), (Ci-Ce alkyl) 2, N02, cyano, trifluoromethyl; and R3 and R are the same or different and represent: C6-C6 alkyl optionally substituted with halogen, hydroxy, or Ci-Cg alkoxy; or alkylarylCi-Cß, where aryl is phenyl, 1- or 2-naphthyl, 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, Ci-Cß alkyl, Ci-Cβ alkoxy, "or Ci-Cßalkyl- -Rs, where Y is O, S, NH, N (alkylC? ~ Cß), and R5 is hydrogen or Ci-Cß alkyl- Preferred compounds of formula II are those wherein R3 and R4 independently represent Ci-Ce alkyl optionally substituted by halogen, hydroxy, C ± -Cβ alkoxy, Ar is phenyl which is mono-, di- or trisubstituted with halogen, hydroxy, Ci alkyl -Ce, or C? -C6 alkoxy, with the proviso that at least one of the positions in the phenyl group ortho for the point of attachment to the phthalazinamine ring is substituted. Most preferred compounds of Formula II are those where Ri and R2 are independently hydrogen; and R3 and R independently represent Ci-Cß alkyl optionally substituted with halogen, hydroxy, Ci-Ce alkoxy, Ar is phenyl which is trisubstituted at positions 2, 4 and 6 (both the para and ortho positions relative to the linking point for the phthalazinamine ring) with C1-C3 alkyl, more preferably methyl. Particularly preferred compounds of Formula II are those in which R3 and R4 are independently hydrogen or Ci-C alkyl, for example methyl, ethyl, propyl, butyl or cyclopropylmethyl.

The invention also provides compounds of Formula III: m 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 or trisubstituted with halogen, hydroxy, C? -C6 alkyl, Ci-C? alkoxy with the proviso that at least one of the positions in Ar ortho for the linking point for the phthalazinamine ring is substituted; and R3 and R are the same or different and represent Ci-Ce alkyl optionally substituted with halogen, hydroxy, or Ci-Cβ alkoxy; or alkylaryl Ci-Ce, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each which is optionally mono- or disubstituted with halogen, hydroxy, Ci-Ce alkyl, Ci-Cß alkoxy, "or Ci-Cßalkyl-Y-Rs, wherein Y is O, S, NH, N (Ci-Cß alkyl), and Rs is hydrogen or Ci-Cß alkyl- Preferred compounds of Formula III are those wherein R 3 and R 4 independently represent C 1 -C 6 alkyl optionally substituted with halogen, hydroxy, C 1 -C 6 alkoxy, Ar is phenyl which is mono-, di- or trisubstituted with halogen, hydroxy, Ci-Cβ alkyl, or Ci-Ce alkoxy, with the proviso that at least one of the positions in the phenyl group ortho for the point of attachment to the phthalazinamine ring is substituted.

More preferred compounds of Formula III are those wherein R3 and R independently represent Ci-Ce alkyl optionally substituted by halogen, hydroxy, or Ci-Cβ alkoxy, Ar is phenyl which is tri-substituted at positions 2, 4, and 6 (both the positions for and ortho relative to the point of attachment for the phthalazinamine ring) with C1-C3 alkyl, more preferably methyl. Particularly preferred compounds of Formula III are those wherein R 3 and R 4 are independently hydrogen or C 1 -C 4 alkyl, for example methyl, ethyl, propyl, butyl or cyclopropylmethyl.

The invention provides compounds of formula IV: 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, C? -C6 alkyl, Ci-C? alkoxy with the proviso that at least one of the positions in Ar ortho to the point of attachment for the isoquinolinamine ring is substituted; Ri and R2 are the same or different and represent hydrogen, C6-C6 alkyl, halogen, hydroxy, Ci-Ce alkoxy, NH2, NH (Ci-Ce alkyl), N (CiC6 alkyl) 2, N02, cyano, trifluoromethyl; R3 and R4 are the same or different and represent: Ci-Ce alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy; or C? -C6 alkylaryl, where aryl. is phenyl, 1- or 2-naphthyl, 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, C? -C6 alkyl, C? -C6 alkoxy; or Ci-Cealkyl-Y-Rs, wherein Y is O, S, NH, N (C 1 -C 6 alkyl), and Rs is hydrogen or Ci-Cß aikyl; and R6 is hydrogen or C? -C6 alkyl.

Preferred compounds of Formula IV are those wherein R3 and R4 independently represent Ci-Cß alkyl optionally substituted with halogen, hydroxy, Ci-Ce alkoxy, Ar is phenyl which is mono-, di- or trisubstituted with halogen, hydroxy, Ci-alkyl. Cß, or i-Cβ alkoxy, with the proviso that at least one of the positions in the phenyl group ortho for the point of attachment to the isoquinolinamine ring is substituted. More preferred compounds of Formula IV are those wherein R3 and R4 independently represent Ci-Ce alkyl optionally substituted with halogen, hydroxy, or Ci-Cß alkoxy, Ar is phenyl which is tri-substituted at positions 2, 4, and 6 ( both the positions for and ortho relative to the point of attachment for the isoquinolinamine ring) with C 1 -C 3 alkyl, more preferably methyl. Particularly preferred compounds of Formula IV are those in which R 3 and R 4 are independently hydrogen or C 1 -C 4 alkyl, for example methyl, ethyl, propyl, butyl or cyclopropylmethyl.

The invention also provides compounds of formula V: where 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, Ci-Cß alkyl, C?-C6 alkoxy with the proviso that at least one of the positions in Ar ortho to the point of attachment for the isoquinolinamine ring is substituted; R3 and R are the same or different and represent: C?-Cß alkyl optionally substituted with halogen, hydroxy, or d-C6 alkoxy; or alkylaryl Ci-Ce, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each which is optionally mono- or disubstituted with halogen, hydroxy, Ci-Cß alkyl, Ci-Cß alkoxy; or C? -C6alkyl-Y-R5, wherein Y is 0, S, NH, (C 1 -C 6 alkyl), and Rs is hydrogen or C 1 -C 6 alkyl; and Rβ is hydrogen or Ci-Cß alkyl- Preferred compounds of Formula V are those wherein R 3 and R 4 independently represent Ci-Cß alkyl optionally substituted with halogen, hydroxy, Ci-Cβ alkoxy, Ar is phenyl which is mono-, di- or trisubstituted with halogen, hydroxy, alkyl C? -C6, or Ci-Ce alkoxy, with the proviso that at least one of the positions in the phenyl group ortho to the point of attachment to the isoquinolinamine ring is substituted. More preferred compounds of Formula V are those where R3 and R4 independently represent Ci-Ce alkyl optionally substituted with halogen, hydroxy, or Ci-Cß alkoxy, Ar is phenyl which is tri-subs tu tuted at positions 2, 4, and 6 (both the positions for and ortho relative to the point of attachment for the isoquinolinamine ring) with C1-C3 alkyl, more preferably methyl. Particularly preferred compounds of Formula V are those in which R3 and R are independently hydrogen or Cj-C alkyl, for example methyl, ethyl, propyl, butyl or cyclopropylmethyl.

The invention also encompasses intermediates for preparing compounds of Formula I. Among these intermediates are the compounds of Formula VI: wherein X is NH2 or N02; Ri, R2, and Re are as previously defined by Formula I; Ra is hydrogen or Rb0 C- where Rb represents Ci-Cß alkyl; 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, Ci-Cß alkyl, C?-C6 alkoxy with the proviso that at least one of the positions in Ar ortho for the point of attachment for the isoquinolinamine ring is substituted.

Preferred groups Ar are the 2,4,6-tri (Ci-Ce) alkylphenyl groups, more preferably 2,4,6-trimethylphenyl groups.

The invention also encompasses intermediates of Formula VII: wherein X is NH2 or N02; Ri, R2, and β are as previously defined by Formula I; Ra is hydrogen or Rb? 2C- where Rb represents Ci-Cß alkyl; 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, Ci-Cß alkyl, Ci-C alco alkoxy with the proviso that at least one of the positions in Ar ortho to the point of attachment for the isoquinolinamine ring is substituted.

Preferred groups Ar are the 2,4,6-tri (C? ~ C6) alkylphenyl groups, more preferably 2,4,6-trimethylphenyl groups.

The invention also encompasses intermediates of Formula VIII: wherein Ri, R2, and Re are as previously defined by 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-, di- or trisubstituted. with halogen, hydroxy, Ci-Ce alkyl, Ci-Ce alkoxy with the proviso that at least one of the Ar ortho positions for the linking point for the isoquinolinamine ring is substituted.

Preferred groups Ar are the 2,4,6-tri (Ci-Cβ) alkylphenyl groups, more preferably 2,4,6-trimethylphenyl groups.

Intermediates useful for preparing phthalazinamines of the invention are also encompassed by the invention. In this way, the compounds of Formula IX are within the invention: IX wherein Ri and R2 are as previously defined by the 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-, di- or trisubstituted. with halogen, hydroxy, Ci-Cg alkyl, C? -C? alkoxy with the proviso that at least one of the positions in Ar ortho for the linking point for the benzene ring is substituted.

Preferred groups Ar are the 2,4,6-tri (C? -C6) alkylphenyl groups, more preferably 2,4,6-trimethylphenyl groups.

The invention also encompasses the compounds of Formula X: where Ri and R2 are as defined above by the 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-, di- or or trisubst: uido with halogen, hydroxy, Ci-Cβ alkyloxy C? -Cs alkyls with the proviso that at least one of the positions in Ar ortho to the binding point for the phthalazinone ring is substituted.

Preferred groups Ar are the 2,4,6-tri (C? -C6) alkylphenyl groups, more preferably 2,4,6-trimethylphenyl groups.

The invention also encompasses compounds of Formula XI: i where Ri and R2 are as defined above by the Formula I; And it is a halogen, preferably chlorine or bromine; and Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5- pyridinyl, each of which is mono-, di- or trisubstituted with halogen, hydroxy, C? -C6 alkyl, Ci-C? alkoxy with the proviso that at least one of the positions in Ar ortho for the linking point for the phthalazinamine ring is substituted.

Preferred groups Ar are the 2,4,6-tri (Ci-Cd) alkylphenyl groups, more preferably 2,4,6-trimethylphenyl groups.

Representative compounds of the invention, which are encompassed by Formula I, include, but are not limited to, the compounds in Table I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, metasulphonic, nitric, benzoic, citric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH2) n- COOH where n is 0-4, and the like. Those skilled in the art will be able to recognize a wide variety of pharmaceutically acceptable non-toxic addition salts.

The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will be able to recognize various synthetic methodologies that can 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 can be separated by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example using chiral CLAP column.

In the compounds of the invention, the group Ar is preferably a phenyl group which is mono-, di- or trisubstituted with halogen, hydroxy, Ci-Ce alkyl, or Ci-Cß alkoxy, with the proviso that at least one of the Positions in the phenyl ortho group for the point of attachment to the isoquinolinamine ring or phthalazinamine is substituted.

Where Ar is phenyl, the carbon atom by which the phenyl group is linked to the isoquinolinamine or phthalazinamine ring is defined at position 1. In this manner, the ortho positions for the point of attachment are in positions 2 and 6, and the position for is in the 4-position of the phenyl group.

By the terms alkyl (Ci-Ce) and lower alkyl, it means straight or branched chain alkyl groups having from 1 to 6 carbon atoms or 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 Ci-Cß alkyl groups are methyl, ethyl, butyl or cyclopropylmethyl.

By the terms "alkoxy" (Ci-Ce) and "lower alkoxy", they mean straight or branched chain alkoxy groups having from 1 to 6 carbon atoms.

By Ci-Cβ alkyl hydroxy means a Ci-Cg alkyl group bearing a terminal hydroxy moiety.

By C 1 -C 6 alkoxy Ci-Cß alkyl means a group of the formula - (CH 2) O O (CH 2) and CH 3, where x and y independently represent integers from 1 to 6.

By the term alkenyl Ci-Ce, it means straight or branched chain hydrocarbon groups having from 1 to 6 carbon atoms and at least one double bond.

By halogen, halo, or halide, it means fluoro, chloro, bromo and iodo substituents.

By aryl (Ci-Cβ) alkyl, it means aryl groups linked to the family group by a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Aryl groups include phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2-or 3-thienyl or 2-, 4-, or 5-pi imidinyl and are optionally substituted with more than two selected groups of halogen, hydroxy, alkyl (C? -C6) and alkoxy (Ci-C?) - Representative examples of the compounds according to the invention are shown in Table 1 below.

Table 1 Compound No.

The pharmaceutical utility of the compounds of this invention is indicated by the following assays for CRF receptor activity. nsayo for the CRF receptor binding activity The binding of the CRF receptor is carried out using a modified version of the assay described by Grigoriadis and De Souza (Biochemical, Pharmacological and Autoradiographic Methods for the Study of Receptors of the Corticotropin-Releasing Factor, Methods in Neurosciences, Vol. 5, 1991). The membrane pellets containing the CRF receptors were resuspended in a Tris d50 mM buffer solution with a pH of 7.7, containing 10 mM MgCl2 and 2 mM EDTA and centrifuged for 10 minutes at 48000 g. The membranes were again washed and brought to a final concentration of 1500 mg / ml in a buffering buffer solution (Tris buffer above with 0.1% BSA, 15 mM bacitracin and 0.01 mg / ml aprotinin). For the binding assay, 100 ml of the membrane preparation was added to 96 microtube well plates containing 100 ml of 125 I-CRF (SA 2200 Ci / mmol, final concentration of 100 pM) and 50 ml of the drug. The binding was carried out at room temperature for 2 hours. The plates were then harvested on a Brandel 96-well cell harvester, and the filters were counted for gamma emissions on a Wallac 1205 beta-plate liquid scintillation counter. The non-specific binding was defined by cold CRF lmM. The IC5o values were calculated with the RS / 1 non-linear curve fitting program (BBN Software Products Corp., Cambridge MA).

The compounds of the invention typically have binding affinities, expressed as IC 50 values from about 0.5 nanomolar (nM) to about 10 micromolar (μM).

The compounds of general formula I can be administered orally, locally, parenterally, by inhlation or spraying, or ractally in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. 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 general formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of the general formula I can be present in conjunction with one or more pharmaceutically acceptable carriers and / or diluents and / or non-toxic adjuvants and if desired other active ingredients. The pharmaceutical compositions containing the compounds of the general formula I can be in a form suitable for oral use for example, as tablets, dragees, lozenges, aqueous or oily suspensions, powders or dispersible granules, emulsions, hard or soft capsules or syrups. or elixirs.

The compositions intended for oral use can be prepared according to some method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents., flavoring agents, coloring agents and preservatives, in order to provide acceptable and pharmaceutically suitable preparations. The tablets contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of the tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, sodium phosphate or calcium phosphate, granulating and disintegrating agents, for example, corn starch or alginic acid.; binding agents 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 delay disintegration and absorption in the intestinal tract and thus provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, wherein the active ingredient is mixed water cone or an oily medium, for example peanut oil, liquid paraffin or olive oil.

The aqueous suspensions contain the active materials in admixture with the excipients suitable for the manufacture of the aqueous suspensions. Such excipients are suspending agents for example, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, dispersing or wetting agents can be a naturally occurring phosphatide, for example, lecithin, or products of the condensation of an alkylene oxide with fatty acids for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols for example, heptadecaethylene oxyketanol, or products of the condensation of ethylene oxide with derived partial esters of fatty acids and hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides for example polyethylenesorbitan monooleate. The aqueous suspensions may also contain one or more preservatives for example, ethyl or n-propyl p-hydrobenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending active ingredients in a vegetable oil for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents such as those set forth above may be added to provide acceptable oral preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules 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 and one or more preservatives. Suitable wetting or dispersing agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example, sweetening, flavoring or coloring agents.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil for example olive oil or arachis oil, or a mineral oil for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums such as acacia gum or tragacanth gum, naturally occurring phosphatides, for example, soy, lecithin, and partial esters or esters derived from fatty acids and hexitol, anhydrides, for example monooleate. of sorbitan and products of the condensation of the aforementioned partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and 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 mucilage, a preservative and coloring and flavoring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those appropriate wetting or dispersing agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent for example, as a solution of 1,3-butanediol. Among the acceptable vehicles and solvents that can be used is water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, sterile oils may conventionally be employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable solutions.

The compounds of the general formula I can also be administered in the form of suppositories for rectal administration of the medicament. These compositions can be prepared by mixing the medicament 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 medicament. Such materials are cocoa butter and polyethylene glycols.

The compounds of the general formula I can be administered parenterally in a sterile medium. The medication, depending on the vehicle and the concentration used, can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

The dose levels of the order from about 0.1 mg to about 140 mg per kilogram of body weight per day, are useful for the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the host 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 will be understood, however, that the specific dose level for a 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 rapidity of excretion, combination of medications and the severity of the particular disorder that is. submit to therapy.

A representative illustration of the methods suitable for the preparation of the compounds of the present invention is shown in Schemes I and II. Those skilled in the art will recognize that the starting materials may vary, and additional steps employed to produce the compounds encompassed by the present invention. For example, in certain situations, the production of reactive portions such as amino groups will be required.

Scheme I where Ar 'Ri, R2, R3, R4 and R6 are as defined above by Formula I Scheme II In the above scheme, R? ~ R, Rß, W and Ar carry the definitions previously established by 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 construed as limiting the invention in scope or spirit of the specific processes and the compounds described therein.

Example 1.

A. Ethyl 1- (2,4,6-trimethylphenyl) -1,2-dihydro-2-isoquinolinecarboxylate A solution of 2-mesitylmagnesium bromide in THF (1.0 M, llmL, llmmol) was added to an ice-cold solution of isoquinoline (1.3 g, 10 mmol) in THF (10 mL). After 5 minutes, ethyl chloroformate was added slowly dropwise and the mixture was further stirred at 0 ° C for 10 minutes before it was quenched with a saturated solution of NH 4 Cl. The mixture was poured into 0.5N hydrochloric acid and extracted twice with ethyl ether. The combined organics were washed with brine, dried over Na 2 SO, filtered and concentrated in vacuo to give 3.58 g of the title compound (quantitative) as an oil which was used in the next reaction without further purification.

B. Ethyl 4-nitro-l (2,4,6-triethylphenyl) -1,2-dihydro-2-isoquinolinecarboxylate To a solution of the product from step A (1.6 g, 5.0 mmol) in acetic acid (8 ml) was carefully added nitric acid (90%, 0.35 ml, 7. 5 mmol) with external cooling. After the addition, the mixture was allowed to cool to room temperature and was further stirred for 2.5 h.

The resulting yellow suspension was filtered and the collected crystalline solid was washed with methane and dried by air to give 0.83 g of the dihydronitroisoquinoline, m.p., 171 ° C (dec.) C. 4-Nitro-1- (2,4,6-trimethylphenyl) -isoquinoline.

Hydrobromic acid (3.0 M in HOAc, 1 L) was added to a suspension of dihydronitroisoquinoline (0.83 g) in glacial HOAc (2 L). The mixture was heated to 100 ° C for 1 day with occasional addition of more brohydric acid solution (3 mL total). After the reaction, the mixture was allowed to cool to room temperature, concentrated in vacuo, diluted with water, and extracted twice with ethyl ether. The organic mixtures were washed by saturated aHC 3 solution, dried over NaSO, filtered, concentrated in vacuo, and chromatographed on silica gel (5% to 10% ethyl acetate in hexane) to give 234 mg of nitroisoquinoline (35%) as solids together with 95 mg of 4-bromo-l (2,4,6-trimethylphenyl) isoquinoline (13%).

D. 4-amino-1- (2,4,6-trimethylphenyl) -isoquinoline.

A solution of nitroisoquinoline (210 mg, 0.72 mmol) in MeOH (10 mL) was placed in a Parr hydrogenation bottle, to which was added concentrated HCl (ca. 0.1 mL) and 10% palladium on carbon (ca. 10 mg). The mixture was stirred under 50 psi hydrogen pressure for 4 hours and filtered on celite. The filtrate was diluted with IN NaOH and extracted 3 times with CH2C12, and the combined extracts were dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed on silica gel (33% to 67% ethyl acetate hexane) to give 135 mg of the inoisoquiniline as an oil.

E. N-propyl-1- (2,4,6-trimethylphenyl) -4-isoquinolinamine.

The aminoisoquinoline (50 rag, 0.19 mmol) was dissolved in propionic acid (0.5 mL) and NaBH4 (30 mg) was added in portions as a solid. After 5 minutes, the mixture was heated to 100 ° C for 45 minutes before re-cooling to room temperature. The mixture was diluted with HCl 1 N and stirred vigorously for 4 minutes, basified with cold NaOH, and extracted 3 times with CH2C12. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give 55 mg of the title compound as an oil which was used in the next reaction without further purification.

F. N-cyclopropylmethyl-N-propyl-1- (2, 4, 6-trimethylphenyl) -4-isoquinolinamine (Compound 1) • To a solution of the product from step E (72 mg, 9.24 mol) in DMSO (0.7 mL) was added potassium t-butoxide (40 mg, 0.36 mmol), followed by slow dropwise addition of bromomethylcyclopropane (0.028 mL, 0.3 mmol). The mixture was stirred at room temperature for 1 hour, diluted with aqueous NH 4 Cl, and extracted twice with 50% ethyl ether in hexane. The combined organics were dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel (6% to 10% ethyl acetate in hexane) to give 62 mg of the title compound as an XH NMR oil (CDC13 ): d 0.10 (m, 2H), 0.78 (t, 3H), 1.00 (m, ÍH), 1.50 (q, 2H), 186 (s, 6H), 2.38 (s, 3H), 2.45 (d, 2H) ), 2.56 (t, 2H), 4.07 (s, 2H), 6.98 (s, 2H), 7.42 (5, ÍH), 7.52 (d, ÍH), 7.66 (t, ÍH), 8.48 (d, ÍH) , 8.53 (s, ÍH) ppm.

The following compounds were prepared essentially in accordance with the procedures set forth in Example 1.

Example 2 N-cyclopropylmethyl-N-ethyl-1- (2,4,6-trimethylphenyl) -isoquinolinamine.

Example 3 N-benzyl-N-propyl-1- (2,4,6-trimethylphenyl) -4-isoquinolinamine.

Example 4 N-cyclopropylmethyl-N- (2-methoxyethyl) -1- (2,4,6-trimethylphenyl) -4-isoquinolinamine.

Example 5 N, N-dipropyl-1- (2,4,6-trimethylphenyl) -4-isoquinolinamine.

Example 6 N-cyclopropylmethyl-N-propyl-3-methyl-1- (2,4,6-trimethylphenyl) -4-isoquinoline.

Example 7 A 2- (2,4,6-Trimethylbenzyl) -benzoic acid Aluminum chloride (60 g, 0.45 mol) was added in portions to a solution of phthalic anhydride (30 g, 0.20 mol) and mesitylene (40 mL) in 150 mL of 1,2-dichloroethane at 0 ° C, the mixture of The reaction was stirred at room temperature for 2 hours, and then it was emptied into ice water. The mixture was acidified with 37% hydrochloric acid and extracted with ether. The ether extract was washed with IN hydrochloric acid, water, and concentrated to give 59 g of the title compound as white solids which were used in the next reaction are further purification.

B. 4- (2,4-, 6-trimethylphenyl) -1 (2H) phthalazinone.

A mixture of 2- (2,4,6-trimethylbenzoyl) benzoic acid (5.0 g, 18.7 mmol) and hydrazine hydrate (2 mL) in 15 mL of EtOH was stirred under reflux for 8 hours. The solvent was then stirred for the mixture. The residue was heated to dissolve for about 10 minutes and then solidified by cooling. The resulting yellow solids were triturated with ether and filtered. The solid was washed with IN NaOH and water, and dried to give 1.8 g of the title compound as yellow solids, m.p. 259-62 ° C.

C. 4 - (2,, 6-trimethylphenyl) -4-chloro-phthalazine.

A solution of 4- (2,, 6-trimethylphenyl) -1 (2H) phthalazinone (1.0 g) in 5 mL of POCI3 was heated at 80 ° C for 2 hours. Excess POCI3 was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with NaHCO 3 solution and water. The ethyl acetate solution was then dried over Na 2 SO 4 and concentrated to a yellow solid which was used in the next reaction without further purification.

D. N-Cyclopropylmethyl-N-propyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine (Compound 2).

A mixture of the product of Step C (100 mg), N-propyl-N-cyclopropylmethylamine (0.5 mL) and in 1 mL of toluene was heated at 100 ° C overnight. The mixture was cooled and concentrated. The residue was purified through silica gel column chromatography to give 40 mg of the title compound as an oil. 1R NMR (CDC13): d 0.08 (q, 2H), 0.50 (q, 2H), 0.95 (t, 3H), 1.20 (m, HH), 1.76 (m, 2H), 1.92 (s, 6H), 2.36 (s, 3H), 3.45 (d, 2H), 6.90 (s, 2H), 7.36 (d, ÍH), 7.64 (t, 1H), 7.74 (t, ÍH), 8.19 (d, lH) ppm.

The following compounds were prepared essentially in accordance with the procedures set forth in Example 7.

Example 8 N-Cyclopropylmethyl-N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.

Example 9 N-cyclopropylmethyl-N-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.

Example 10 N-Cyclopropylmethyl-N- (2-methoxyethyl) -4 - (2,4,6-trimethylphenyl) -1-phthalazinamine.

Example 11 N-benzyl-N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.

Example 12 N- (2'-Chlorophenylmethyl-N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.

Example 13 N- (4'-Chlorophenylmethyl-N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.

Example 14 N- (2'-tolymethyl) -N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.

Example 15 N- (2'-methoxy phenylmethyl) -N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.

Example 16 N- (2'-pyridylmethyl) -N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.

The invention and the manner and processes for making and using it are now described in complete, clear, concise and accurate terms to enable any person skilled in the art to do so, make and use it. It will be understood that the above described preferred embodiments of the present invention and that the modifications can be made thereof without departing from the spirit or scope of the present invention as shown in the claims.

For a point appreciated outside or different from the claim of the subject matter of the invention, the following claims lead to this specification.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (31)

1. Claims 1. A compound of formula: or the 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, Ci-Ce alkyl, C6-C6 alkoxy with the proviso that at least one of the Ar ortho positions for the point of attachment to the aromatic ring of nitrogen containing members be replaced; Ri and R2 are the same or different and represent hydrogen, Ci-Cß alkyl, halogen, hydroxy, C?-C6 alkoxy, NH 2, NH (CC-C alquilo alkyl), N (CC-Cß-alkyl) 2, N02, cyano, trifluoromethyl; and R3 and R4 are the same or different and represent: Ci-Cß alkyl optionally substituted with halogen, hydroxy, or Ci-Ce alkoxy, or Ci-Cß alkylaryl, wherein aryl is phenyl, 1- or 2-naphthyl, 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, Ci-Ce alkyl, Ci-alkoxy -Cβ; or C? ~ Ce alkyl-Y-R5, where Y is O, S, NH, (C 1 -C 6 alkyl), Rs is hydrogen or C 1 -C 6 alkyl, and W is N or C-R 6, where R is hydrogen or Ccy6 alkyl. A compound of formula or the 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, Ci-Ce alkyl, Ci-Cß alkoxy with the proviso that at least one of the positions in Ar ortho for the point of attachment to the phthalazinamine ring is substituted; they are the same or different and represent hydrogen, Ci-Cß alkyl, halogen, hydroxy, Ci-Cß alkoxy, NH 2, NH (C 1 -C 6 alkyl), N (C 1 -C 2 alkyl), NO 2, cyano, trifluoromethyl; and are the same or different and represent: Ci-Cß alkyl optionally substituted by halogen, hydroxy, or C?-C6 alkoxy; or Ci-Cβ alkylaryl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or -pyridinyl, 2-or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy , Ci-Cß alkyl, Ci-Cβ alkoxy; or C -Calkyl-Y-Rs, wherein Y is O, S, NH, N (Ci-C alquilo alkyl), and R 5 is hydrogen or C 1 -C 6 alkyl. 3. The compound according to claim 2, characterized in that Ar is phenyl mono-, di-, or trisubstituted with halogen, hydroxy, Ci-Cß alkyl, or C? -C6 alkoxy, with the proviso that at least one of the positions ortho in the phenyl group for the binding point to the phthalazinamine ring is substituted. 4. The compound according to claim 3, characterized in that Ri and R2 are hydrogen. 5. The compound according to the rei indication 4, characterized in that R3 and R4 are independently hydrogen or C? -C alkyl. 6. A compound of formula: or the 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, Ci-Cß alkyl, C?-C6 alkoxy with the proviso that at least one of the positions in Ar ortho for the linking point for the phthalazinamine ring is substituted; and R3 and R4 are the same or different and represent Ci-Cß alkyl optionally substituted with halogen, hydroxy, or Ci-Ce alkoxy; or C? -C6 alkylaryl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or -pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each which is optionally mono- or disubstituted with halogen, hydroxy, Ci-Cß alkyl, Ci-Cβ alkoxy; or C 6 -C 6 alkyl-Y-R 5, wherein Y is O, S, NH, N (C 1 -C 6 alkyl), and 5 is hydrogen or Ci-Cß alkyl; 7. The compound according to claim 6, characterized in that Ar is phenyl trisubstituted at positions 2, 4, and 6 relative to the linking point for the phthalazinamine ring with C 1 -C 3 alkyl. 8. The compound according to claim 7, characterized in that Ar is 2,4,6-trimethylphenyl. 9. A compound of formula or the 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, Ci-Cß alkyl, or CI-CÉ alkoxy, with the proviso that at least one of the positions in Ar ortho for the point of attachment to the isoquinoline polymer ring is substituted; Ri and R2 are the same or different and represent hydrogen, Ci-Cß alkyl, halogen, hydroxy, Ci-Cg alkoxy, NH 2, NH (Ci- cyalkyl), N (Ci-Ce alkyl) 2, NO 2, cyano, trifluoromethyl; R3 and R4 are the same or different and represent Ci-Cß alkyl optionally substituted by halogen, hydroxy, or C?-Ce alkoxy; or Ci-Cg alkylaryl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each which is optionally mono- or disubstituted with halogen, hydroxy, C? -C6 alkyl, C? -C6 alkoxy; or C6-C6alkyl-Y-R5, wherein Y is O, S, NH, N (Ci-C alquilo alkyl), and R 5 is hydrogen or Ci-Cβ alkyl; and R 6 is hydrogen or C 1 -C 10 alkyl. The compound according to claim 9, characterized in that Ar is phenyl mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 alkoxy. C6, with the proviso that at least one of the ortho positions in the phenyl group for the point of attachment to the isoquinolinamine ring is substituted. 11. The compound according to claim 10, characterized in that Ri and R2 are hydrogen. 12. The compound according to claim 11, characterized in that R3 and R are independently hydrogen or C? -C4 alkyl. 13. A compound of formula: or the 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, C-C-alkyl, or Ci-Ce alkoxy, with the proviso that at least one of the positions in Ar ortho for the point of attachment to the isoquinolinamine ring is substituted; R3 and R are the same or different and represent Ci-Cß alkyl optionally substituted with halogen, hydroxy, or Ci-Cg alkoxy; or Ci-Cβ alkylaryl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each which is optionally mono- or disubstituted with halogen, hydroxy, Ci-Cß alkyl, C?-C6 alkoxy; or C6-C6alkyl-Y-R5, wherein Y is O, S, NH, N (Ci-C alquilo alkyl), and 5 is hydrogen or C?-C6 alkyl; and R6 is hydrogen or Ci-Cß alkyl. 14. The compound according to claim 13, characterized in that Ar is phenyl trisubstituted at positions 2, 4, and 6 relative to the point of attachment of the isoquinoline ring with C 1 -C 3 alkyl. 15. The compound according to claim 14, characterized in that Ar is 2,4,6-trimethylphenyl. 16. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-N-propyl-1- (2,4,6-trimethylphenyl) -4-isoquinolinamine. 17. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-N-ethyl-1- (2,4,6-trimethylphenyl-4-y soquinolinamine. 18. The compound according to the rei indication 1, characterized in that it is N-benzyl-N-propyl-1- (2,4,6-trimethylphenyl) -4-isoquinolinamine. 19. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-N- (2-methoxy ethyl) -1- (2,4,6-trimethylphenyl) -4-isoquinolinamine. 20. The compound according to claim 1, characterized in that it is N, N-dipropyl-1- (2,4,6-trimethylphenyl) -4-isoquinolinamine. 21. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-N-propyl-3-methyl-1- (2,4,6-trimethylphenyl) -4-isoquinolinamine. 22. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-N-propyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine. 23. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine. 24. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-methyl-4- (2,, 6-trimethylphenyl) -1-phthalazinamine. 25. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-N- (2-methoxyethyl) -4- (2,4,6-trimethylphenyl) -1-phthalazinamine. 26. The compound according to claim 1, characterized in that it is N-benzyl-N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine. 27. The compound according to claim 1, characterized in that it is N (2'-chlorophenylmethyl-N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine. 28. The compound according to claim 1, characterized in that it is N (4'-chlorophenylmethyl-N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine. 29. The compound according to claim 1, characterized in that it is N- (2'-tolylmethyl) -N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine. 30. The compound according to claim 1, characterized in that it is N- (2'-methoxyphenylmethyl) -N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine. 31. The compound according to claim 1, characterized in that it is N (2'-pyridylmethyl) -N-ethyl-4- (2,4,6-trimethylphenyl) -1-phthalazinamine.