MXPA98008541A - N-aminoalquil-2-antraquinoncarboxamidas; new specific ligands of the dopam receiver subtype - Google Patents

Abstract

The present invention relates to compounds of the formula (I) or pharmaceutically acceptable addition salts thereof wherein: R1, R2, R3, R4, R5, R6 and R7 are the same or different and represent hydrogen, halogen, alkyl, alkoxy, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, -O2CRi, -NHCORï, -CORï, -SOmR, where R is C1-C6 alkyl and wherein m is 0.1, 2, R1, R2, R3, R4, R5 R6 and R7 independently represent -CONRIR ", -NRIR" where R and R "independently represent hydrogen or C1-C6 alkyl, R8 is hydrogen or lower alkyl, X represents an optionally substituted alkylene group, Y represents a cyclic mono-, di- or tri-substituted, these compounds are useful in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease, movement disorders such as Parkinsonism and dystonia, and other disorders that respond to dopaminergic block such as substance abuse. Obsessive Compulsive Disorders and Disorders. In addition, the compounds of this invention could be useful in the treatment of extrapyramidal side effects associated with the use of conventional neuroleptic agents.

Description

N-Aminoalkyl-2-anthraquinonecarboxamides; New Spectral Ligands of the Dopamine Receptor Subtype BACKGROUND OF THE INVENTION Field of the Invention This invention relates to anthraquinonecarboxamide derivatives which selectively bind to the subtypes of the brain dopamine receptor. More specifically, it relates to carboxamides N-Aminoalkylantraquinonecarboxamide and to pharmaceutical compositions comprising such compounds. It also relates to the use of such compounds in the treatment or prevention of various neurophysiological disorders such as schizophrenia and other diseases of the central nervous system.

Description of Related Art The therapeutic effect of conventional antipsychotics, known as neuroleptics, is thought to be generally exerted through the blockade of dopamine receptors. However, neuroleptics are often REF .: 028679 responsible for the undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to the blockade of D2 receptors in the striatal region of the brain. The D3 receptor subtype has been recently identified (Sokoloff et al., Nature, 347, 146 (1990)). Its unique location in limbic brain areas and its differential recognition of several antipsychotics indicates that the D3 receptor plays a significant role in the etiology of schizophrenia. The selective D3 antagonists are. thinks that antipsychotics are effective free of the neurological side effects shown by conventional neuroleptics.

The U.S. Patent No. 5,395,835 discloses N-aminoalkyl-2-naphthalamides which are said to have affinity to dopamine D3 receptors.

Murray et al., Bisorg. Med. Chem. Let. £ 219 (1995), describes 4-carboxamidobiphenyls which are said to have affinity to dopamine D3 receptors.

BRIEF DESCRIPTION OF THE INVENTION This invention provides novel compounds of Formula I which interact with the subtypes of the receptor, dopamine. Thus, the invention provides compounds of the general Formula I useful in the treatment and / or prevention of various neurophysiological disorders. The invention also provides pharmaceutical compositions comprising the compounds of Formula I.

Because dopamine D3 receptors are concentrated in the lxmbic system (Taubes, Science, 265: 1034 (1994)) which control perception and emotion, compounds that interact with these receptors are also useful in the treatment of cognitive disorders. Such disorders include cognitive deficits that are a significant component of the negative symptoms (social abstinence and irresponsibility) of schizophrenia. Other disorders that involve memory deficiency or attention deficit disorders can also be treated with the compounds of this invention which interact specifically with the D3 dopamine receptor subtype.

In addition, the compounds of this invention could be useful in the treatment of depression, memory deficiency or Alzheimer's disease by regulating the D3 receptors which selectively exist in the limbic area known to control emotion and cognitive functions. The compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blocking such as substance abuse and obsessive compulsive disorder (Goodman et al., Clin. Psychopharmacol., 7:35 (1992). of the invention interact with the types of the dopamine receptor resulting in the pharmacological activity of these compounds.

Therefore, a broad embodiment of the invention relates to a compound of Formula I: or the pharmaceutically acceptable acid addition salts wherein: Rlf R 2, R 3, R 4, R 5, R b and R 7 are the same or different and represent hydrogen, halogen, alkyl, alkoxy, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy; -02CR ', NHCOR', -COR ', -SOmR', where R 'is C-C6 alkyl and where m is 0, 1 or 2; or R1 # R2, R3, R4, Rs, R6 and R7 independently represent -CONR'R ", -NR'R" where R * and R "independently represent hydrogen or C ^ -C3 alkyl, - R8 is hydrogen or lower alkyl; X represents an alkylene group having 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; And represents a cycloalkylamino group.

Thus, the invention relates to the use of compounds of the Formula I in the treatment and / or prevention of neuropsychological disorders including, but not limited to, schizophrenia, Alzheimer's disease, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory deficiency, cognitive deficits, motor disorders similar to Parkinson's disease such as dystonia and movement disorders and extrapyramidal side effects related to the use of neuroleptic agents.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention demonstrate high affinity and selectivity in the binding of the D3 receptor subtype. Therefore, these are of use in the treatment of schizophrenia, psychotic depression and mania. Other diseases regulated by dopamine such as Parkinsonism and tardive dyskinesias can be treated directly or indirectly by regulating the D3 receptors.

The invention in this manner provides such compounds and compositions useful in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia. The compounds of this invention are also useful in the treatment of extrapyramidal side effects associated with the use of conventional neuroleptic agents. In addition, the compounds of the present invention are useful for the treatment of other disorders that respond to indolent dopa blocking such as substance abuse and obsessive compulsive disorder.

In addition to the compounds of the general Formula I described above, the invention encompasses the compounds of the Formula IA: or the pharmaceutically acceptable acid addition salts thereof wherein; X, Rj., R2, R3, R4, R5, R6, R7 and Ra are defined as above for Formula I; Y Y represents a cycloalkyl group of the formula: wherein R9 and R10 independently represent alkyl; Z is nitrogen or carbon; Y is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl, indenyl or dihydroindenyl, preferably 4- (1,2-dihydro) indenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, benzofuranyl, benzothienyl; each of which is optionally substituted with up to three groups independently selected from halogen, C 1 -C 3 alkyl, C 4 -C 4 alkoxy, alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of Formula IA include those wherein Rj.-R7 are hydrogen; R i is hydrogen, methyl or ethyl; and X is alkylene of 3-5 carbon atoms. « In addition, the invention encompasses the compounds of the Formula IB: ffi wherein Rx-Rg, X, Z and R9 and R10 are as defined above for Formula I.

Preferred compounds of Formula IB include those wherein Ra is hydrogen, methyl, or ethyl and X is alkylene of 3-5 carbon atoms. Particularly preferred compounds of Formula IB are those wherein R i, is hydrogen and X is butylene, e.g. ex. , C4 alkylene.

The invention also encompasses the compounds of the Formula II: II wherein Rβ, X, Z and are as defined above for Formula JE.

Preferred compounds of Formula XI include those wherein R8 is hydrogen and X is alkylene of 3-5 carbon atoms.

In other preferred compounds of Formula II, R8 is hydrogen and X is alkylene of 3-5 carbon atoms, and is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three independently selected groups of halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy and hydroxy.

The invention also encompasses compounds of the Formula HA: HE HAS wherein R8, X and are as defined above for Formula I.

Preferred compounds of the Formula HA include those where Ra is hydrogen, methyl, or ethyl, and X is alkylene of 3-5 carbon atoms.

In other preferred compounds of Formula IIA, R8 is hydrogen and X is alkylene of 3-5 carbon atoms, and W is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C ^ Cs alkyl, Cx-C4 alkoxy, and hydroxy. The most preferred compounds of the Formula HA are those wherein R8 is hydrogen; A is C3.5 alkylene; and is quinolinyl, isoquinolinyl, phenyl or naphthyl optionally substituted with up to 2 groups at positions 2 and / or 3 (related to the point of attachment of the group to the piperazine ring), the groups are independently selected from chlorine, methyl and methoxy Particularly preferred compounds of the Formula HA are those wherein R8 is hydrogen; A is C4 alkylene; and W is naphthyl, 8-quinolinyl, or phenyl optionally substituted with up to two groups at positions 2 and / or 3 (related to the point of attachment of the group to the piperazine ring) the groups are independently selected from chlorine, methyl and methoxy.

In addition, the present invention provides compounds of Formula III: III wherein Rj.-R10, X and are as defined above for Formula I.

Preferred compounds of Formula III include those where Ra is hydrogen and X is alkylene of 3-5 carbon atoms. Particularly preferred compounds of Formula III are those wherein R8 is hydrogen, and X is butylene, e.g. ex. , C4 alkylene.

In other preferred compounds of Formula III, R8 is hydrogen, X is alkylene of 3-5 carbon atoms, and is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three independently selected groups of halogen, alkyl C-, -Ce, C -.- C4 alkoxy, and hydroxy.

The invention also encompasses compounds of the Formula HIA: ÍÍI? wherein R8, X and are as defined above for Formula JE.

Preferred compounds of Formula IIIA include those wherein R8 is hydrogen, methyl, or ethyl, and X is alkylene of 3-5 carbon atoms.

In other preferred compounds of Formula IIIA, R8 is hydrogen and X is alkylene of 3-5 carbon atoms, and W is dihydroindenyl, quinolinyl,. isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C-C6 alkyl, C ^ d alkoxy, and hydroxy.

The most preferred compounds of the Formula HIA are those where R8 is hydrogen; A is C3-s alkylene; and is quinolinyl, isoquinolinyl, phenyl or naphthyl optionally substituted with up to 2 groups at positions 2 and / or 3 (related to the point of attachment of the group to the tetrahydropyridine ring), the groups are independently selected from chlorine, methyl and methoxy Particularly preferred compounds of the Formula HIA are cyclohexae where R "is hydrogen; A is C4 alkylene; and is naphyl, 8-quinolinyl, or phenyl optionally substituted with up to two groups at positions 2 and / or 3 (relative to the point of attachment of the phenyl group to the tetrahydropyridine ring), the groups are independently selected from chlorine , methyl and methoxy.

In addition, the invention provides the compounds of Formula IV: wherein R? -Rj.0, X and W are as defined above for Formula I.

Preferred compounds of Formula IV include cyanols wherein Rβ is hydrogen and X is alkylene of 3-5 carbon atoms. Particularly preferred compounds of the Formula IV are those where R8 is hydrogen, and X is butylene, p. ex. , C4 alkylene.

In other preferred compounds of Formula IV, R8 is hydrogen, X is alkylene of 3-5 carbon atoms, and is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three independently selected groups of halogen, C ^ -C3 alkyl, CJ.-C4 alkoxy, and hydroxy.

The invention also encompasses compounds of the Formula VAT: VAT wherein R3, X and are as defined above for Formula I.

Preferred compounds of the Formula IVA include those where Rβ is hydrogen, methyl, or ethyl, and X is alkylene of 3-5 carbon atoms.

In other preferred compounds of the Formula IVA, R8 is hydrogen and X is alkylene of 3-5 carbon atoms, and W is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, Cj.-C6 alkyl, C- alkoxy, and hydroxy.

The most preferred compounds of the Formula IVA are those where R8 is hydrogen; A is C3-s alkylene; and is quinolinyl, isoquinolinyl, phenyl or naphthyl optionally substituted with up to 2 groups at positions 2 and / or 3 (relative to the point of attachment of the group to the piperidine ring), the groups are independently selected from chlorine, methyl and methoxy Particularly preferred compounds of the Formula IVA are those where R "is hydrogen; A is C4 alkylene; and is naphthyl, 8-quinolinyl, or phenyl optionally substituted with up to two groups at positions 2 and / or 3 (relative to the point of attachment of the phenyl group to the piperidine ring), the groups are independently selected from chlorine, methyl and methoxy.

Preferred compounds of the invention include W groups selected from the following In the previous groups, the following definitions apply: Ra is halogen; R "represents alkoxy; Rc represents alkyl; Ra represents hydrogen, Ra or Rc.

In those formulas where more than one of the same substituents appear, those substituents are the same or different.

Particularly preferred groups of the invention include 2-methoxyphenyl; 2,3-dimethylphenyl; 1-naphthyl; 1-isoquinolyl; 1,2-dihydroindenyl; 8-quinolinyl; 2-chlorophenyl; 2, 3-dichlorophenyl; 2,6-dimethylphenyl; 2,6-dichlorophenyl; 2-methyl-3-chlorophenyl; and 2-methylphenyl.

When a compound of the invention is obtained as a mixture of enantiomers, these enantiomers could be separated, when desired, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.

Representative compounds of the present invention, which are encompassed by Formula JE, include, but are not limited to, the compounds in Figure JE and their pharmaceutically acceptable salts. The present invention also encompasses prodrugs, such as acylated prodrugs, of the compounds of Formula JE. Those skilled in the art will recognize various synthetic methodologies which could be employed to prepare pharmaceutically acceptable non-toxic addition salts and prodrugs of the compounds encompassed by Formula JE.

Representative compounds of the present invention, which are encompassed by Formula JE, include, but are not limited to, the compounds in Table 1 and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic, such as acetic, HOOC- (CH2 ) n-C00H where n is 0-4 and similar. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable non-toxic addition salts.

By "alkyl" and "lower alkyl" is meant straight and branched chain alkyl groups having from 1-6 carbon atoms, e.g. ex. , alkyl C ^ Cg.

By "lower alkoxy" and "alkoxy" is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms, e.g. ex. , alkoxy C.-C,; By halogen is meant fluorine, chlorine, bromine and iodine.

The amino group represented by Y above includes the groups represented by the formulas where it is defined above.

Particularly preferred W groups of the invention are dihydroindenyl, quinolinyl, isoquinolinyl, or phenyl, wherein the phenyl is optionally substituted with up to two substituents independently selected from halogen, Cj.-C4 alkyl, and Ci-C * alkoxy. These optional phenyl substituents are preferably at the 2 and / or 3 positions of the phenyl group relative to the point of attachment of the phenyl group to the 6-membered ring containing nitrogen.

Representative examples of the compounds according to the invention are shown in Table 1 below. The bottom number of each compound is its compound number. Each of these compounds could be prepared according to the general reaction of Scheme I discussed below.

The compounds 1-5 in Table 1 have the following general formula A: where R and R8 are defined in the table.

Table 1 Number of R¡¡R Compound H3C CH3 H '- & Number of R «R Compound Particular compounds according to the invention include: N- (l- { 4- [4- (2,3-dichlorofenyl) piperazin-1-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride N- (l- { 4- [4- (l-naphthyl) pi? erazin-l-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride N- (L-. {4- [4- (2, 3-dimethylphenyl) piperazin-1-yl].] butyl) -2-anthraquinonecarboxamide hydrochloride N- (1 - { 4 - [4 - (2-me t i 1 -3-chlorophenyl) piperazin-1-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride N- (1 -. {4 - [4-f-enyl-1, 2, 3, 6-tetrahydropyridin-1-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride N- (l- { 4- [4- (S-quinolinyl) piperazin-l-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride N- (L-. {4- [4- (2-methylphenyl) piperazin-1-yl].] butyl) -2-anthraquinonecarboxamide hydrochloride N- (1- (4- 4- (2-methoxyphenyl) piperazin-1-yl].} Butyl) -2-anthraquinonecarboxamide The invention also relates to the use of compounds of the general Formula JE in the treatment of neoropsychological disorders. The pharmaceutical utility of the compounds of this invention is indicated by the following assays for the affinity of the dopamine receptor subtype.

ASSAY FOR ACTIVITY OF THE LINK OF THE RECEIVER D. AND D ^ Tablets of COS cells containing recombinantly produced D2 or D3 receptors of the African Green monkey were used for the assays. The sample was homogenized in 100 volumes (p / vol) of buffer HCl Tris 0.05 M at 4 ° C and pH 7.4. The sample was then centrifuged at 30,000 x g and resuspended and rehomogenized. The sample was then centrifuged as described and the final tissue sample was frozen until use. The tissue was resuspended 1:20 (w / vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations were performed at 48 ° C and contain 0.4 ml of tissue sample, 0.5 nM 3H-YM09151-2 and the compound of interest in a total incubation of 1.0 ml. The non-specific link is defined as the linkage found in the presence of 1 mM spiperone; without other additions, the non-specific link is less than 20% of the total link. The binding characteristics of the representative compounds of the invention for the D2 and D3 receptor subtypes are shown in Table 2 for rat striatal homogenates.

TABLE 2 Compound Number1 D2 Ki (nM) D3 K ± (nM) 1 154 4 4 61 2 6 45 2 7 106 1 t The compound numbers relate to compounds shown above in Table 1.

The compounds of the general formula JE could be administered orally, topically, parenterally, by inhalation or atomized or rectally in dosage unit 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 the general Formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of the general formula JE could be present in association with one or more pharmaceutically stable non-toxic carriers and / or diluents and / or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing the compounds of the general Formula J could be in a form suitable for oral use, for example, as tablets, pills, aqueous or oily suspensions, powders or dispersible granules, emulsion, hard or soft capsules, or syrups or elixirs.

The compositions intended for oral use could be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions could contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents for provide preparations pleasant to taste and pleasant. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients could be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulation and disintegration agents, for example, corn starch, or alginic acid; binding agents, for example, gelatin or acacia starch and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets could be uncoated or they could be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a prolonged action for a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate could be employed.

Formulations for oral use could 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 active ingredient it is mixed with water 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 preparation of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; the dispersing or humidifying agents could 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 chain alcohols. long, 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 fatty acids and hexitol anhydrides , for example polyethylene monooleate sorbitan. The aqueous suspensions may have one or more preservatives, for example ethyl p-hydroxybenzoate, or n-propyl, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions could be formulated by suspending the active ingredients in a vegetable oil, for example, peanut oil, olive oil, lime 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 such as those set forth above, and the flavoring agents could be added to provide pleasing preparations to taste. These compositions could be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders or granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in the mixture with a dispersing or moisturizing agent, suspending agent and one or more preservatives. The dispersing or humidifying agents and the suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the invention could also be in the form of oil-in-water emulsions. The oily phase could be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents could be naturally occurring gums, for example 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 sorbital monoleate, and condensation products of partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

The syrups and elixirs could be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a softener, a preservative and flavoring and coloring agents. The pharmaceutical compositions could be in the form of a sterile or oleaginous injectable aqueous suspension. This suspension could be formulated according to the known art using the appropriate dispersing or humidifying agents and suspending agents mentioned above. The sterilized injectable preparation could also be sterilized injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that could be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed oils, sterilized as a solvent or suspension medium, are conveniently employed. For this purpose any non-irritating fixed oil could 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 could 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 is 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 general Formula I could be administered parenterally in a sterilized medium. The drug, depending on the vehicle and the concentration used, can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. 9 Dosage levels in 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 (about 0.5 mg to about 7 g per patient per day). The amount of the active ingredient that could be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular form of administration. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.

It will be understood, however, that the specific dosage level 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, route of administration, and rate of excretion, combination of the drug and the severity of the therapy subjected to the particular disease.

Preparation of N-Amxnoalk ^ xlantraqxiinoncarboxamxdas The compounds of Formula JE, and the pharmaceutically acceptable acid addition salts thereof, could be prepared according to the reactions shown below in Scheme 1.

Scheme 1 V S0C12? H 'X "Y I wherein Rt, R2, R3, R4, R5, R6, R7, R8 and X and Y are as defined above for Formula JE.

As shown, a compound of Formula V could be cLCtivated by treating the acid V with an activating agent such as, for example, thionyl chloride at reflux (S0C12) or the like. The resulting activated species, p. ex. , an acyl chloride, could subsequently be reacted with the required compound of Formula VI at room temperature, optionally in an appropriate solvent such as chloroform, to provide a compound of Formula JE as the desired product.

Where they are not commercially available, the compounds of Formula V could be known procedures or procedures analogous to those described in the literature. The compounds of Formula VI are known or capable of being prepared by various methods known in the art. Example 1 below provides a representative preparation of a compound of Formula VI.

For those skilled in the art they will recognize that the initiator materials could be varied and / or the additional steps employed as needed to produce the compounds encompassed by the present invention, as demonstrated by the following examples. In some cases of protection of certain reactive functionalities it may be necessary to achieve some of the above transformations. In general, the need for such protective groups will be apparent to those skilled in the art of organic synthesis in addition to the conditions necessary to bind and remove such groups.

The exposures 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 elaborated as limiting the invention in scope or spirit to the specific procedures described therein. These examples illustrate the methods currently preferred for the preparation of the compounds of the invention.

Axis-pplo 1 1- (2-p-ethoxyphenyl) -4- (4-ammonibutyl) iperazine Powdered potassium carbonate (22 g) was added to a solution of 1- (2-methoxyphenyl) -4- (4-ammonibutyl) piperazine (14 g, 0.073 mmol) and N- (4-bromobutyl) phthalimide (20 g). , 0.070 mmol) in 200 mL of dimethylformamide and the resulting mixture was stirred and heated at 80 ° C for 28 h. After cooling to room temperature the mixture was partitioned between water (500 ml) and diethyl ether (500 ml). The organic layer was further washed with two 200 mL portions of water, dried (Na2SO4) and concentrated. The resulting white solid was recrystallized from isopropanol to give 12 g of white crystals. The solid material was placed in hydrazine hydrate (150 mL) and heated to reflux under a nitrogen atmosphere. After 3 h the reaction was cooled and poured and partitioned between water (400 mL) and diethyl ether (200 mL). The potassium carbonate (60 g) was added to the aqueous layer and the resulting solution was extracted with methylene chloride (200 mL). The combined organic extracts were dried (Na2SO4) and concentrated to give 1- (2-methoxyphenyl) -4- (4-aminobutyl) piperazine as a pale yellow oil (8.7 g).

Example 2 1. N - (1 - { 4 - [4 - (2, 3-dichlorophenyl) piperazin-1-yl].} Butyl) -2-anthraquinonecarboxamide hydrochloride The 2-anthraquinonecarboxylic acid (100 mg, 0.45 msl) was refluxed in 5 mL of thionyl chloride for 20 hours. After complete evaporation of the residual thionyl chloride under reduced pressure, a solution of 4- [4- (2, 3-dichlorophenyl) piperazin-1-yl] -1-aminobutane (150 mg, 0.5 mmol) was added in 5 minutes. mL of chloroform followed by 1 g of triethylamine. The resulting mixture was stirred for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and 10% aqueous NaOH. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the titled compound, Compound 1 (183 mg, 80%). The hydrochloride salt (mp 202-205 ° C) was prepared by treating the free base with a mixture of diethyl ether-HCl.

Example 3 The following compounds are prepared essentially according to the procedures set forth above. (a) N- (L-. {4- [4- (l-naphthyl) piperazin-1-yl].] butyl) -2-anthraquinonecarboxamide hydrochloride (mp 240-242 ° C). (b) N- (L-. {4- [4- (2, 3-dimethylphenyl) piperazin-1-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride (mp 244-245 ° C). (c) N- (1- {4- [4- (2-methyl-3-chlorophenyl) piperazin-1-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride (mp 234-236 ° C) . (d) N- (1- {4- [4-phenyl-1,2,3,6-tetrahydropyridin-1-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride (mp 224-226 ° C ). (e) N- (L-. {4- [4- (8-quinolinyl) piperazin-1-yl].] butyl) -2-anthraquinonecarboxamide hydrochloride (mp 230-232 ° C). (f) N- (L-. {4- [4- (2-methylphenyl) piperazin-1-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride (mp 243-244 ° C) (g) N- (L-. {4- [4- (2-methoxyphenyl) piperazin-1-yl].} butyl) -2-anthraquinonecarboxamide hydrochloride (mp 222-223 ° C).

The invention and the way and process to make and use this, is now described in full, clear, concise and exact terms to allow any person with experience in the art to which it belongs, to make and use it. It will be understood that the preferred embodiments described above of the present invention and that the modifications could be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly note and distinctly claim the subject matter related to the invention, the following claims conclude 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.

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

Claims (19)

1. A compound of the formula: or the pharmaceutically acceptable acid addition salts, characterized in that: Rlf R2, R3, R4, R5, R6 and R7 are the same or different and represent hydrogen, halogen, alkyl, alkoxy, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy; -02CR ', NHCOR', -COR ', -SO "R', where R 'is Cx-C6 alkyl and wherein m is 0, 1 or 2; or R-, R2, R3, R4, R5, Re and R7 independently represent -CONR'R ", -NR'R" where R * and R "independently represent hydrogen or Ci-Cg alkyl, - R8 is hydrogen or lower alkyl; X represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; And represents a cycloalkylamino group.

2. A compound of the formula: characterized because: R8 is hydrogen or lower alkyl; X is an alkylene group of 2-6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; and W is phenyl, naphthyl, 1- (5, 6, 7, 8-tetrahydro) naphthyl, dihydroindenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, banzofuranyl or benzothienyl, each of which is optionally substituted with up to three independently selected groups of halogen, Cj.-C3 alkyl, Cj.-C4 alkoxy, thioalkyl, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl, or trifluoromethoxy.

3. A compound according to Claim 2, characterized by R8 is hydrogen and X is alkylene of 3-5 carbon atoms.

4. A compound according to Claim 2, characterized in that R8 is hydrogen and X is alkylene of 3-5 carbon atoms, and is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C-Cc alkyl, CL-C4 alkoxy, and hydroxy.

5. A compound of the formula: characterized because: R8 is hydrogen or lower alkyl; X is an alkylene group having 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having 1 to 4 carbon atoms; Y is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl, dihydroindenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, banzofuranyl or benzothienyl, each of which is optionally substituted with up to three groups independently selected from halogen , alkyl-Cs, Cj-C4 alkoxy, thioalguyl, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl, or trifluoromethoxy.

6. A compound according to Claim 5, characterized in that R8 is hydrogen and X is alkylene of 3-5 carbon atoms.

7. A compound according to Claim 5, characterized in that R8 is hydrogen and X is alkylene of 3-5 carbon atoms, and is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C-C3 alkyl, Cj.-C4 alkoxy, and hydroxy.

8. A compound of the formula: characterized because: Ra is hydrogen or lower alkyl; X is an alkylene group having 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having 1 to 4 carbon atoms; Y is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl, dihydroindenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, banzofuranyl or benzothienyl, each of which is optionally substituted with up to three groups independently selected from halogen , alkyl Cj.-CG, Cj.-C4 alkoxy, thioalkyl, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl, or trifluoromethoxy.

9. A compound according to Claim 8, characterized in that R8 is hydrogen and X is alkylene of 3-5 carbon atoms.

10. A compound according to Claim 8, characterized in that Rβ is hydrogen and X is butylene.

11. A compound according to Claim 8, characterized in that R8 is hydrogen and X is alkylene of 3-5 carbon atoms, and is quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three independently selected groups of halogen, alkyl C.-CG, Cx-C4 alkoxy, and hydroxy.

12. A compound according to Claim 11, characterized in that X is butylene.

13. A compound according to Claim 1, characterized in that it is N- (L-. {4- [4- (2, 3-dichlorophenyl) piperazin-1-yl].} Butyl) -2-anthraquinonecarboxamide hydrochloride.

14. A compound according to Claim i, characterized in that it is N- (L-. {4- [4- (1-naphthyl) piperazin-1-yl].} Butyl) -2-anthraquinonecarboxamide hydrochloride.

15. A compound according to claim 1, characterized in that it is N- (1 - {4- [4- (2, 3-dimethylphenyl) piperazin-1-yl].} Butyl) -2-anthraquinonecarboxamide hydrochloride.

16. A compound according to claim 1, characterized in that it is N- (l-. {4- [4- (2-methyl-3-chlorophenyl) piperazin-1-yl] butyl) -2- hydrochloride. anthraquinonecarboxamide.

17. A compound according to claim 1, characterized in that it is N- (L-. {4- [4- (8-quinolinyl) piperazin-1-yl].} Butyl) -2-anthraquinonecarboxamide hydrochloride.

18. A compound according to claim 1, characterized in that it is N- (L-. {4- [4- (2-methylphenyl) piperazin-1-yl].} Butyl) -2-anthraquinonecarboxamide hydrochloride.

19. A compound according to Claim 1, characterized in that it is N- (L-. {4- [4- (2-methoxyphenyl) piperazin-1-yl].} Butyl) -2-anthraquinonecarboxamide hydrochloride.