MXPA99012095A - 4-AMINOPYRROLE(3,2-d) PYRIMIDINES AS NEUROPEPTIDE Y RECEPTOR ANTAGONISTS - Google Patents

Abstract

Compounds of formula (I) are effective for treatment of conditions associated with an excess of neuropeptide Y.

Description

4-AMINOPLRROL (3.2-d) PYRlMlDINES AS ANTAGONISTS OF THE NEUROPEPTIDE RECEPTOR AND BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to the use of certain substituted 4-aminopyrrole (3,2-d) pyrimidine derivatives that selectively bind to mammalian Neuropeptide receptors. It also relates to the use of such compounds and compositions in the treatment of disorders related to an excess of neuropeptide Y, such as eating disorders and certain cardiovascular diseases.

RELATED TECHNICAL DESCRIPTION Neuropeptide Y, a peptide isolated for the first time in 1982, is widely distributed in peripheral central neurons and is responsible for a multitude of biological effects in the brain and periphery. Various studies in animals have shown that the activation of neuropeptide Y receptors is related to vasoconstriction, Wahlestedt et al., Regul. Peptides., 13: 307-318 (1986), McCauley and Westfall, J. Pharmacol. Exp. Ther., 261: 863-868 (1992) and Grundemar et al.

Br. J. Pharmacol.105: 45-50 (1992); and with the stimulation of behavior regarding consumption, Flood and Morley, Peptides, 10: 963-966 (1989), Leibowitz and Alexander, peptides, 12: 1251-1260 (1991) and Stanley and others Peptides, 13: 581-587 (1992). Grundemar and Hakanson. TIPS, May 1994 (vol.15), 153-159, conclude that, in animals, neuropeptide Y is a potent stimulus of food ingestion, and an inducer of vasoconstriction that leads to hypertension. They further define that low levels of neuropeptide Y (NPY) are associated with a loss of appetite. These reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals. EP0759441 and U.S. 5,576,337 report that physiological disorders related to neuropeptide Y include: disorders or diseases of the heart, blood vessels or the renal system, such as angiospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction sudden cardiac death, arrhythmia, peripheral vascular disease and abnormal renal disorders such as poor fluid flow, abnormal mass transport or renal failure; disorders related to increased sympathetic nerve activity, for example, during or after coronary artery surgery and operations and surgery in the gastrointestinal tract; brain diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, cerebrovascular accident and disorders related to stroke, cerebral angiospasm and hemorrhage, depression, anxiety, schizophrenia and dementia; disorders related to pain or nociception; diseases related to gastrointestinal motility and abnormal secretion, such as different forms of ileus, urinary incontinence and Crohn's disease; disorders due to abnormal ingestion of beverages and foods, such as anorexia and metabolic disorders; diseases related to sexual diffusion and reproductive disorders; disorders or conditions associated with inflammation; respiratory diseases, such as asthma and disorders related to asthma and bronchoconstriction; and diseases related to an abnormal release of hormones such as luteinizing hormone, growth hormone, insulin and prolactin. WO 96/14307 discloses substituted benzylamine derivatives that selectively bind to human neuropeptide Y receptors. In Pharm. Chem. J. 22, 185 (1988); 8, 14 (1974); and 7, 19 (1973) describes the synthesis of certain 4-aminopyrrole (3,2-d) pyridines. It was described that these compounds possess antibacterial and antitumor activity.

BRIEF DESCRIPTION OF THE INVENTION This invention provides a compound of formula wherein B, D and E are independently selected from CR1, CR9 or N, with the proviso that at least one of B, D and E must be CR1 or CR9, and at least one of B, D and E it must be N; and F and G are selected from N, NR4 or CR5, with the proviso that at least one of F or G must be N or NR4; and one of the dashed lines represents one link and the other one has no link; and when B and E are both N, then one of F or G must be CR5; and R1, R3, R4, R5 and R9 is independently selected from H, C? -C6 alkyl, Ci-C? thioalkyl C? -C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl Ci-C?, perfluoroalkoxy C? -C6) (CH2) n-cycloalkyl C3-C7, (CH2) n-cycloalkenyl C3-C7 and (CH2) nAr, each alkyl, alkenyl, alkynyl, alicyclic and Ar independently substituted with one to three substituents selected from among the group consisting of Br, Cl, F, NR6R7, or (C 1 -C 7 alkyl), No 2) CN, COOH, OH, SH and; NH (CH2) nPh, NH (CH2) n (C3-C7 cycloalkyl), NH (CH2) n-C3-C7 cycloalkenyl, NH (CH2) nmorpholinyl, NH (CH2) npiperazinyl or NH (CH2) npyrimidinyl, each ring independently substituted with one to three substituents selected from the group consisting of Br, Cl, F, NR6R7, or (Ci-Cß alkyl), C?-C6 alkyl, S (O) m-d dC alquilo alkyl, NO 2, CN, COOH, OH, SH and; < when it is R2 it is if m or n is zero, the other will be at least 2; and H is S, O, NR8 or a bond; and R8 is hydrogen, alkyl, C6C6 or aryl; (C? -C6 alkyl) -C (O) - or aryl-c (O) -; R6 and R7 are independently selected from hydrogen, Ci-Cß alkyl, (C?-C6 alkyl) (C?-C6 alkoxy), (CH 2) N N [(C?-C6 alkyl)] 2 and (CH 2) OH OH; and n is an integer from zero to six; m an integer from zero to two; k is an integer from two to four; Ar is an aromatic hydrocarbon or a heterocyclic ring of three to seven atoms or a bicyclic heterocyclic ring, at least one atom of which is a nitrogen, sulfur or oxygen atom; and with the proviso that if F is NR4, G is CR5, B and E are N; D is CR1; R1 is methyl, R3 is phenyl and R4 and R5 are hydrogen, then R2 will not be Net2, HN (CH2) 2Net2, HN (CH3) 2COOH, NHCH2CH2OH, HNPh, HN (CH2) 2Ph, Piperidiniio, morpholinyl, NHNH2, HNCH (CH3) 2, HN (CH2) 3CH3, HNCH2CH (CH3) 2, HNCH (CH3) CH2 (CH2) 3CH3, HNCH2CH = CH2, and with the additional proviso that if F is NR4, G is CR4, B and E are N; D is CR1; R1 and R3 are both methyl and R4 and R5 are both hydrogen, then R2 will not be HN CH2CH2N (C2H5) 2l HNCH2CHS HNCH2C6H5 HN (CH2) C6 and with the additional proviso that if F is NR4, G is CR5, B and E are N; D is CR1; R3, R4 and R5 are hydrogen, then R1 and R2 should not be equal and will be and with the additional condition that when B, F are N; G is NR4; D is CR1; E is CR9; R1 and R3 and R4 are H, then R2 will not be NH2, Nme2, NHMe, OH, OMe, when B and G are N: F is NR4; E is CR9; D is CR1; R1, R4, and R9 are H; and R2 is OMe, then R3 will not be when B and G are N: F is NR4; E is CR9; D is CR1; R1, R3 and R9 are H; and R2 is NH2, then R4 will not be ; and when B and F are N: G is NR4; E is CR9; D is CR1; R1 and R9 are H; R3 and R4 are CH3, then R2 will not be when B and F are N: G is NR4; E is CR9; D is CR1; R1 and R9 are H, R3 is CH3 and R4 is CH2CH2OH, then R2 will not be NH2 or when B and F are N: G is NR4; E is CR9; D is CR1; R1 is CH3; R3 is CH3; R9 is H and R4 is then R2 will not be NMe2, NHMe or when E and F are N: G is NR4; B is CR9; D is CR1; R1; R3, R4 and R9 are H, then R2 will not be NH2, OH, OCH3, NMe) NHEt, NHMe, when E and F are N: G is NR4; B is CR9; D is CR1; R1 is CH3; and R3, R4 and R9 are H, then R2 will not be NH2 or OH; and when E and F are N; G is NR4; B is CR9; D is CR1: R1 is CH2CH2CH3; and R3, R4 and R9 are H, then R2 is not + to NH2 or OH; and when E and F are N; G is NR4; B is CR9; D is CR1; R1, R4; and R9 are H and R2 is OCH3, then R3 will not be when E and G are N; F is NR4; B is CR9; D is CR1; R2 is NH2; R1, R3; and R9 are H, then R4 will not be CH3 or when E and F are N; G is NR4; B is CR9; D is CR1; R2 is OH; R1, R4; and R9 are H, then R3 will not be CH3, Et, or when E and G are N; F is NR4; B is CR9; D is CR1; R2 is OH, R1 and R9 are H and R4 is then R3 will not be Et, cyclopropyl, propyl or butyl; and when E and G are N; F is NR4; B is CR9; D is CR1; R2 is OH; R1 and R9 are H and R4 is then R3 will not be Et, cyclopropyl, propium or butyl; and when E and G are N; F is NR4; B is CR9; D is CR1; R2 is OH; R1 and R9 are H and R3 is CH2CH2CH2CH3, then R4 will not be when E and F are N; G is NR4; B is CR9; D is CR1; R1, R4 and R9 are H and R3 is 2,4-dimethoxyphenyl, then R2 will not be when E and G are N; F is NR; B is CRa; D is CR 1 '; D R1 'and Rs are H; R ^ is OH and R3 is CH2CH2CH3, then R4 will not be when E and F are N; G is NR4; B is CR9; D is CR1; R1 and R9 are H; R2 is N (CH2C6H5) 2 and R3 is CH3) then R4 will not be CH2CH2C6H5 or CH2CH2CH2CH3; and when E and F are N; G is NR4; B is CR9; D is CR1; R1 and R9 are H; R2 is N (CH2C6H5) and R4 is CH (CH3) CH2CH3, then R3 will not be when E and F are N; G is NR 44; D B is ^ CDR9-, G D > esr. r CtR- > eleven -; D R11 and t R- > 9a r s.o? Rn H; R¿ is NH2 and R3 is CH3, then R4 will not be when E and F are N; G is NR4; B is CR9; D is CR1; R1 and R9 are H; R2 is NH2 and R4 is CH (CH3) CH2CH3j then R1 will not be the following compounds are not included in the invention; -OH ^ -OH This invention further provides a compound of formula: wherein: R1, R3, R4 and R5 are independently selected from H, C? -C6 alkyl, Ci-C? alkoxy, Ci-C? thioalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C? -C6 perfluoroalkyl, perfluoroalkoxy Ci-Cß, (CH2) n-phenyl, (CH2) n-pyridyl, (CH2) n-pyrimidyl, (CH2) n-C3-C7 cycloalkyl, (CH2) n-C3-C7 cycloalkenyl, (CH2) n- furanyl, (CH2) n-thienyl, each alkyl, alkenyl, aikinyl, phenyl, heterocyclic and alicyclic group independently substituted with one to three substituents selected from the group consisting of Br, Cl, F, NR6R7 or (C? C6), C? -C6 alkyl, S (O) m (C? -C6 alkyl), NO2, CN, COOH, OH, SH and; R2 is NR6R7, NH (CH2) nPh, NH (CH2) n (C3-C7 cycloalkyl), NH (CH2) n, C3-C7 cycloalkenyl, NH (CH2) nmorpholinyl, NH (CH) n Piperazinyl or NH (CH2) n Pyrimidinyl, each ring independently substituted with one to three substituents selected from the group consisting of Br, Cl, F, NR6R7, O (C 1 -C 6 alkyl), C 1 -C 6 alkyl, S (O) m -C 6 alkyl, NO 2, CN, COOH, OH, SH and; when R2 is if m or n is zero, the other of m or n will be at least 2; and G is S, O, NR8 or a bond; and R8 is hydrogen, d-Cß alkyl or aryl; and R 6 and R 7 are independently selected from hydrogen, (C 1 -C 6 alkyl) (C 1 -C 6 alkoxy), (CH 2) kN [(C 1 -C 6 alkyl)]: and (CH2) kOH; and n is an integer from zero to six; m is an integer from zero to two; k is an integer from two to four; and their pharmaceutically acceptable salts; and with the proviso that if R1 is methyl, R3 is phenyl and R4 and R5 are hydrogen, then R2 will not be NET2, HN (CH2) 2NET2, HN (CH3) 2COOH, HNCH2CH2OH, HNPh, HN (CH2) 2Ph, piperidinyl, morpholinyl, NHNH2, HNCH (CH3) 2, HN (CH2) 3CH3, HNCH2CH (CH3) 2, HNCH (CH3) CH2 (CH2) 3CH3, HNCH2CH = CH2, and with the additional proviso that if R1 and R3 are both methyl and R4 and R5 are both hydrogen, then R2 will not be HN CH2CH2N (C2H5) 2, HNCH2C6H £ HN (CH2) C6 and with the additional proviso that if R3 R4 and R5 are hydrogen, then R1 and R2 will not both be equal and will be In another aspect, this invention provides a compound selected from the group consisting of: 2-methyl-4-isopropylamino-6-phenyipyrrolo [3,2-d] pyrimidine; 6-methyl-2-phenyl-4-pyrrolidin-1 -ii-1 H-imidazo [4,5-c] pyridine; 5-methyl-7-pyrrolidin-1-yl-2-thiazol-2-yl-3H-imidazo [4,5-b] pyridine; 2- (1 H-imidazol-2-yl) -5-methyl-7-pyrrolidin-1-yl-3 H -imidazo [4,5-b] pyridine; 2-cyclohexyl-5-methyl-7-pyrrolidin-1-yl-3H-imidazo [4,5-b] pyridine; 2- (2,4-dimethoxy-phenyl) -7-methoxy-5-methyl-3H-imidazo [4,5-b] pyridine; 7-methoxy-5-methyl-2-phenyl-3H-imidazo [4,5-b] pyridine; 5-methyl-2-pyridin-4-yl-7-pyrrolidin-1-yl-3H-imidazo [4,5-b] pyridine; 5-methyl-2-pyridin-3-yl-7-pyrrolidin-1-yl-3H-imidazo [4,5-b] pyridine; 5-methyl-2-pyridin-2-yl-7-pyrrolidin-1-yl-3H-imidazo [4,5-b] pyridine; 2- (4-fluoro-phenyl) -5-methyl-7-piperidin-1-yl-3H-imidazo [4,5-b] pyridine; (S) -4- (2-methoxymethyl-pyrrolidin-1-yl) -2-methyl-6-phenyl-5H-pyrrolo [3,2-d] pyrimidine; (f? S) -2-methyl-6-phenyl-4- [2- (2-pyrrolidin-1-yl-ethyl) -piperidin-1-yl] -5H-pyrrolo [3,2-d-pyrimidine]; 5-methyl-2-phenyl-7-pyrrolidin-1-yl-1 H-imidazo [4,5-b] pyridine; 5-methyl-2-phenyl-7-piperidin-1-yl-1 H-imidazo [4,5-b] pyridine; 1- (2-methyl-6-phenyl-5H-pyrrolo [3,2-d] pyrimidin-4-yl) -decahydro-quinoline; l '^ - methyl-e-phenyl-SH-pyrrolotS ^ -dlpyrimidin ^ -i-tl ^ jbiperidinyl; (R) -4- (2-methoxymethyl-pyrrolidin-1-yl) -2-methyl-6-phenyl-5H-pyrrolo [3,2, -d] pyrimidine; (S) -2-methyl-6-phenyl-4- (2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -5H-pyrrolo [3,2-d-pyrimidine; and ®-dimethyl- [1- (2-methyl-6-phenyl-5H-pyrrolo [3,2-d] pyrimidin-4-yl) -pyrrolidin-3-yl] -amine. In another aspect, this invention provides a composite of the structure wherein R1 is Ci-Cß alkyl, R1 is Ar and R2; R2, R3 and Ar have the meanings described above. In another aspect, this invention provides a method for inhibiting or alleviating a pathological disorder or physiological condition is a mammalian subject, characterized by, or associated with an excess of neuropeptide Y, comprising administering to said subject an effective amount of a compound of formula I. The compounds of this invention are basic in nature and can form a wide variety of salts with various inorganic and organic acids. The pharmaceutically acceptable acids of the compounds of formula I are those that form non-toxic acid addition salts, ie, salts that contain pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate , isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, patotenate, bitartrate, ascorbate, succinate, maleate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, stanesulfonate, benzenesulfonate and p-toluenesulfonate.

Compounds that interact with NPY receptors and inhibit the activity of neuropeptide Y in said receptors are useful in the treatment of numerous disorders associated with the neuropeptideT. Therefore, this invention provides a method for using compounds of formula I that selectively bind to neuropeptide Y receptors and are useful in the treatment of disorders or diseases of the heart, blood vessels or the renal system, such as angiospasm, heart failure. , shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrhythmia, peripheral vascular disease and abnormal renal disorders such as poor fluid flow, abnormal mass transport or renal failure; disorders related to increased sympathetic nerve activity, for example, during or after coronary artery surgery and operations and surgery in the gastrointestinal tract; brain diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, cerebrovascular accident and disorders related to stroke, cerebral angiospasm and hemorrhage, depression, anxiety, schizophrenia and dementia; disorders related to pain or nociception; diseases related to gastrointestinal motility and abnormal secretion, such as different forms of ileus, urinary incontinence and Crohn's disease; disorders due to abnormal ingestion of beverages and foods, such as anorexia and metabolic disorders; diseases related to dysfunction or conditions associated with inflammation; respiratory diseases, such as asthma and disorders related to asthma and bronchoconstriction; and diseases related to an abnormal release of hormones such as hormone liteinizante, growth hormone, insulin and prolactin. This invention further relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. This invention further relates to compositions useful for treating obesity and related disorders, comprising effective amounts of a compound of this invention and a β3-adrenergic agent or a thyromimetic agent. A preferred β3-adrenergic agent is (4- (2- (2- (6-aminopyridin-3-yl) -2-hydroxyethylamino) ethoxy) phenyl) -acetic acid and its salts and prodrugs.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I are prepared by methods that are known in the chemical literature. The compounds can be prepared by the general procedures of Sokolova, and others, Pharm.

Chem. J., 8, 14 (1974) and ibid, 7, 19 (1973) or Modnikova, and others, Pharm.

Chem. J., 22, 185 (1988). The above references are incorporated herein by reference. The compounds of the invention can be prepared by the following reaction sequence. ' (a) (b) The compounds (a) and (b) can also be prepared by the methods described in Chem. Pharm. Bull. (Tokyo) 12, 1024 (1964) and J Am. Chem. Soc, 74, 4897 (1952) or other conventional synthesis methods. The average chemist skilled in the art will recognize that changes in reaction conditions may be necessary when different R groups are present. For example, protecting groups may be necessary when one of the R groups contains an additional functional group. The compound se is conveniently prepared from the compound (b) with a chlorinating agent such as phosphorus oxychloride. The compounds of the invention can be prepared by the following reaction sequence.

The pharmacological utility of the compounds of this invention is indicated by the following assay of the activity of the human NPY1 receptor.

Assay of human NYP1 receptor binding activity The procedure used is similar to that described by Gordon et al (J. Neurochem 55: 506-513, 1990). SK-N-MC cells were purchased from the ATCC (Rockville, MD). Cells were maintained at 37 ° C and 5% CO2 in modified Dulbecco's essence medium (DMEM) with L-glutamine and 100 mg / 1 sodium pyruvate, which was supplemented with 10% fetal bovine serum and 25 mM HEPES ( pH 7.3). The binding assay was performed in 24-well plates (Falcon) when the cells were confluent. Being careful not to disturb the cells on the bottom of the wells, the media was aspirated and 0.5 ml of Dulbecco's phosphate buffered saline (DPBS) with calcium and magnesium were added to each well. The DPBS was aspirated and an additional aliquot of DPBS was added and aspirated. To start the assay, binding buffer composed of serum-free DMEM containing 0.5% bovine serum albumin, 0.1% bicitracin, and 0.1 nM phenylmethylsulfonyl fluoride was added to each well. A pre-incubation of the cells and the binding buffer was performed for 30 minutes at room temperature, at which time the drug dilution and [125IPYY (NEN-DuPont: 50,000-75,000 cpm, approximately 50 pM) were added providing a volume end of 250 μ1. The non-specific binding is defined with 1 mM NPY (porcine or human, Bachem California). After an incubation of 3 hours at room temperature, the plates were placed on ice and the wells were aspirated. The cells were washed 4 to 6 times with 0.5 ml of DPBS cooled on ice. A diluted solution of Triton X-100 (1%) was then added to each well. After approximately 1 hour at room temperature, an aliquot of each well was transferred to a 12x75 mm test tube, and the amount of [125l] was quantified in a gamma counter with an efficiency of 80 to 85% (Genesys 5000, Laboratory Technologies ). The IC 50 values were calculated with a RS / 1 non-linear curve fitting program (BBN Software Products Corp. Cambridge, MA).

Binding of [1251PYY in the Human NPY Receptors Expressed in sf9 Cells. Sf9 cells infected with NPY receptors are collected at 48 hours. At the time of collection, the cell pellets are resuspended in lysis buffer (20 mM Tris-HCl, pH 7.4, 5 mM EDTA, 0.5 μg / ml leupeptin, 2 μg / ml aprotonin and 200 μM PMSF) and homogenized using a Polytron (posisicón 3, 25 to 30 seconds). The homogenates are centrifuged at 4 ° C for 5 minutes at 200 x g (approximately 1500 rpm) to pellet the nuclei. The supernatant is collected in a new tube and centrifuged at 48,000 x g for 10 minutes. The pellets are washed once in lysis buffer and centrifuged. The final pellet resuspended are washed using PBS and resuspended in PBS and stored in aliquots at -80 ° C. The purified membranes are washed using PBS and resuspended in binding buffer (50 mM Tris-HCl, pH 7.4, 5 mM KCI, 120 mM NaCl, 2 mM CaCl 2, 1 mM MgCl 2, 0.1% bovine serum albumin (BSA) ). The membranes (20 μg / reaction tube) are added to polypropylene tubes containing [125I] PYY (porcine), shifters ranging from 10"12 M to 10" 5 M, and buffer to provide a final volume of 0.250 ml. . The unspecified binding is determined in the presence of NPY (human) 1 μ; and it constitutes 10% of the total union. After about 2 hours of incubation at room temperature, the reaction is stopped by rapid filtration in vacuo. Samples are filtered on previously soaked Whatman GF / C filters (1.0% polyethyleneamine) and rinsed twice with 5 ml of cold binding buffer without BSA. A gamma counter is used to count the filters with an efficiency of 85%. The IC50 values were calculated with a RS / 1 non-linear curve fitting program (BBN Software Products Corp. Cambridge, MA).

Functional Assay of NPY Receptors Expressed in Oocytes The experiments were performed on Xenopus oocytes. The oocytes were prepared and maintained using conventional protocols (Dascal and Lotan, in Methods in Molecular Biology; Protocols in Molecular Neurobiology, eds. Longstaff & Revest, Humana, Clifton, N.J., 13: 1992). For present experiments, oocytes were obtained from 6 frogs. Oocytes were evaluated 2 to 7 days after a joint injection of GIRKI mRNA and subtype H17 of NPY-1 or NPY-5 (25 mg of each, 50 or total volume). Two measurements of voltage correction with electrodes were carried out using a Warner Instrumments Oocyte OC 725B corrector. The data was collected on a Macintosh microcomputer and analyzed using Superscope software. The voltage and current electrodes were removed from the glass tube (D.O. 1.5 mM) in a Brown / Flaming micropipette (Sutter Instruments, model P-87). The electrodes contained 3M KCI and had a resistance of 0.5-2 Mohms. The oocytes were washed in normal external solution containing; 90 mM NaCl, 1 mM KCI, 1 mM MgCl 2, 1 mM CaCl 2, 5 mM HEPES, pH 7.4. Before introducing the NPY agonists or antagonists, a high solution was applied with the amount of K + it contained; 1 mM NaCl, 90 mM KCI, 1 mM MgCl 2, 1 mM CaCl 2, 5 mM HEPES to allow the recording of the rectified K + inlet current. Drugs were applied diluted in high K7 medium. 100 μM stocks of NPY, PP or NPY peptide fragments or PYY peptide fragments in water were prepared and frozen until needed. The oocyte tension was corrected at -80 mV with two electrodes. The oocytes were initially superfused with normal external medium (approximately 4 ml / min flow rate). Before applying the drugs, the cells were superfused with a high amount of K + solution to allow activation of the rectified K + inlet stream. In oocytes co-injected with NPY receptor and GIRK1 mRNA, NPY agonists induced an additional input current over the resting K + current. Due to desensitized responses. at slow but variable speeds, accumulated dose applications were administered to generate response curves to the concentration. Two to four doses of agonists were applied to each cell. The responses to the dose of agonists in each cell were normalized against the response to a maximum concentration of human NPY. The dose response curves were fitted with a logistic equation using Kaleidagrafh software (Abelbeck software, Reading, PA). The compounds of this invention and the pharmaceutically acceptable salts thereof (the active compounds) can be administered orally, topically, parenterally, by inhalation or aerosol, or rectally, conventional pharmaceutically acceptable non-toxic vehicles, adjuvants and excipients. . The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, intrasternal or infusion techniques. In addition, a pharmaceutical formulation containing a compound of general formula I and a pharmaceutically acceptable carrier is provided. One or more active compounds may be present associated with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and, if desired, other active ingredients. Pharmaceutical compositions containing active compounds may be in a form suitable for oral use, for example, as tablets, troches, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard and soft gelatin capsules or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art of manufacturing 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 pharmaceutically elegant and appetizing preparations. The tablets contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulation and disintegration agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or gum arabic 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 gastrointestinal tract and thus provide a sustained action over a longer period. For example, a delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules, in the that the active ingredient is mixed with water or an oily medium, for example, peanut oil or liquid paraffin or olive oil. The aqueous suspensions contain the active materials mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents can be a phosphatide of natural origin, for example, lacitin, or condensation products of an alkylene oxide with fatty acids, for example, poly (ethylene oxide) stearate, or ethylene oxide condensation products with long-chain aliphatic alcohols, for example, heptadecaethyloxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxides with partial esters derived from 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-hydroxyinzoate, 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 the active ingredients in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those described above, and 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 powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suitable suspending agents are exemplified by those already mentioned above. Additional excipients may be present, for example, adulterants, flavorings and colorants. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may 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 natural gums, for example, gum arabic, or gum tragacanth, natural phosphatides, for example, soy, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate or products of condensation of said partial esters with ethylene oxide, for example, sweeteners, flavorings and colorants may also be present. The elixir syrups can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain an emollient, a preservative and flavoring and coloring 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 technique using the wetting and dispersing agents and the suitable suspending agents that have been 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, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as solvents or suspension medium. For these purposes, any mild nonvolatile oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as acid can be used in injectable preparations. The active compounds can also be administered in the form of a suppository for oral rectal administration of the drug. These compositions can be prepared by mixing the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures, but liquid at rectal temperature and which therefore melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The active compounds 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 can be dissolved in the vehicle. Dosage levels in the order of about 0.1 mg to about 15 mg of active compound per kilogram of body weight per day are useful in the treatment of the above-mentioned disorders (approximately 0.5 mg to approximately 7 g per patient per day). The amount of active compound that can be combined with carrier materials to produce an individual dosage 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 50 mg of active compound. However, it will be understood that the specific dose level for a particular patient will depend on a number of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration and speed of the particular disease that is being treated. This invention further relates to compositions useful for treating obesity and related disorders, comprising effective amounts of a compound of this invention and a β3-adrenergic agent or a thyromimetic agent. (4- (2- (2- (6-Aminopyridin-3-yl) -2-hydroxyethylamino) ethoxy) phenyl) acetic acid is described in the international patent application, publication number WO 96/35671, of assignment common, which description is incorporated herein by reference, as a β3-adrenergic agent. Accordingly, (4- (2- (2- (6-aminopyridin-3-yl) -2-hydroxyethylamino) ethoxy) phenyl) acetic acid has utility in the treatment of obesity. The ß3-adrenergic agents have been classified into the subtypes ß-i, ß2 and ß3- The agonists of the ßi receptors promote the activity of adenyl cyclase. The activation of p2 receptors induces the relaxation of smooth muscle tissue, which produces a decrease in blood pressure and the onset of tremors in skeletal muscle. Activation of ß3 receptors is known to stimulate adipose tissue in glycerol and fatty acids. The activation of ß3 receptors also stimulates the metabolic rate, thus increasing energy expenditure. Therefore, the activation of ß3 receptors promotes the loss of fat mass. Compounds that stimulate β3 receptors are therefore useful as antiobesity agents.

It has been reported that certain thyromimetic compounds possess the ability to induce weight loss by mechanisms other than suppression of appetite, for example, by stimulating the peripheral metabolic rate of adipose tissue. For example, the peripheral patents of adipose tissue. For example, U.S. Nos. 4,451,465, 4,772,631, 4,999,377 and 5,284,971 describe compounds that possess thermogenic properties in doses that cause few or no side effects, such as cardiac stimulation. The descriptions of the U.S. Nos. 4,451, 465, 4,772,631, 4,999,377 and 5,284,971 are incorporated herein by reference in their entirety. It is well known to those skilled in the art that the selectivity of the thermogenic effect is an important requirement for a therapeutic agent useful in the treatment, for example, of obesity and related disorders. When obesity is treated, satisfactory results are generally obtained when the combination of the present invention, ie, a compound of this invention combination with (4- (2- (2- (6-aminopyridin-3-yl) -2) ®-hydroxyethylamino) ethoxy) phenyl) acetic, prodrugs or pharmaceutically acceptable salts thereof (hereinafter referred to as "active ingredients or compounds") are administered to animals, including humans, orally or parenterally. Oral administration is preferred, being more convenient and avoiding the possible pain and irritation of the injection. However, in circumstances in which the subject can not swallow the medication, or absorption after oral administration is limited, either by disease or other abnormality, it is essential that the drug be administered parenterally. By any of the routes the dosage of the compound of Formula I varies in the range from about 0.01 to about 50 mg / kg of body weight of the subject / day, preferably from about 3.0 to about 30 mg / kg of body weight per day, and , most preferably, from about 1 to about 10 mg / kg of body weight per day, administered in one or in divided doses. The dosage of the compound that modifies the feeding behavior varies in the range of about 0.01 to about 15 mg / kg. of body weight per day at approximately 10 mg / kg. of body weight per day, administered in one or divided doses. As a consequence of their action in the treatment of pathological disorders, the compounds of the present invention possess utility for treating ungulate animals such as swine, cattle, sheep and goats. The active compounds of the invention can be further used for the treatment of domestic pets, for example, companion animals such as dogs and cats. The administration of an active compound of formula I can be carried out orally or parenterally. An amount of an active compound of formula I is administered so that an effective dose is received, generally a daily dose which, when orally administered to an animal, normally ranges from 0.01 to 20 mg / kg of body weight, preferably 0.05 to 10 mg / kg of body weight. For convenience, the medication can be carried out in the drinking water so that the therapeutic dose of the agent is ingested with the daily water supply. The agent can be dosed directly into the drinking water, preferably in the form of a water-soluble liquid concentrate (such as an aqueous solution of a water-soluble salt). For convenience, the active compound can also be added directly to the food, such as, or in the form of a food supplement of the animal, also called a concentrated preparation or pre-mix. A concentrated preparation or pre-mix of the therapeutic agent in a vehicle is more commonly used for the inclusion of the agent in the food. Suitable vehicles are liquids or solids, as desired, such as water, different flours such as alfalfa meal, soy flour, cotton oil meal, linseed oil meal, corn cob meal and cornmeal, molasses, urea , bone meal and mineral mixture as commonly used in poultry feed. A particularly effective vehicle is the respective animal's own food; that is, a small portion of said food. The vehicle facilitates a uniform distribution of the active materials in the final food with which the concentrate is mixed. It is important that the compound is mixed homogeneously in the concentrate and, subsequently, in the food. In this regard, the agent can be dispersed or dissolved in a suitable oil vehicle such as soybean oil, corn oil, cottonseed oil and the like, or in a volatile organic solvent and then mixed with the vehicle.

It will be appreciated that the proportions of active material in the concentrate can vary widely since the amount of agent in final food can be adjusted by mixing the appropriate proportion of concentrate with the food to obtain a desired level of therapeutic agent. High potency concentrates can be mixed by the food manufacturer with a protein carrier such as soybean meal or other flours, as described above, producing concentrated supplements that are suitable for direct feeding of animals. In such cases, animals are allowed to consume the usual diet. Alternatively, such concentrated supplements can be added directly to the food and produce a nutritionally balanced finished food containing a therapeutically effective level of a compound according to the invention. The mixtures are thoroughly homogenized by conventional procedures, such as in a body mixer, in order to ensure homogeneity. > If the supplement is used as a surface dressing for the food, it will also help to ensure the uniformity of the distribution of the active material throughout the upper surface of the seasoned food. In general, drinking water and food effective for the treatment of pets are prepared by mixing a compound of the invention with a sufficient amount of animal feed, providing about 10"3 to 500 ppm of the compound in the feed or water.

The preferred medicated feedstuffs for swine, cattle, sheep and goats contain from 1 to 400 grams of active compound per ton of feed, with the optimal amount for these animals usually being 50 to 300 grams per tonne of feed. Preferred poultry and pet foods typically contain from about 1 to about 400 grams, and preferably from 10 to 400 grams of active compound per ton of feed. For parenteral administration to animals, the compounds of the present invention can be prepared in the form of a paste or a granule and administered in the form of an implant, usually under the skin of the head or ear of the animal in which it is intended to increase the deposition of lean meat. the proportion of lean meat to fat. In general, parenteral administration involves the injection of a sufficient amount of the compounds of the present invention to provide the animal with 0.01 to 20 mg / kg body weight / day of active ingredient. The preferred dose for poultry, cattle, sheep, goats and domestic pets varies in the range of 0.05 to 10 mg / kg of body weight per day of active ingredient. The following example preparations illustrate the preparation of the compounds of the invention.

PREPARATION 1 2-Methyl-4-chloro-β-phenylprirrolor3,2-d1pyrimidine A mixture of 9 g of Compound (b) and 170 ml of boiling phosphorus oxychloride is heated for 21 hours. After evaporation of the excess phosphorus oxychloride, the reaction mass is diluted with ice water. The precipitate, that is, the hydrochloride of (c), is mixed with 50 ml of water, 100 ml of ethyl acetate are added and the mixture is neutralized with vigorous stirring and cooling, with ammonia water to obtain an alkaline reaction ( with phenophthalein). After separating the layers, the lower water layer is extracted twice with ethyl acetate (50 ml of each time). The ethyl acetate extracts are combined and evaporated in vacuo. The sediment (c) is separated by filtration. Yield 7.43 g (76.2%), m.p. 184-185 ° C (in ethyl acetate).

PREPARATION 2 The compounds of the invention can be prepared by the following reaction sequence. (a) (b) Compound (a) can be prepared by the method described in J. Med. Chem. 37, 1252 (1994) or other conventional procedures. The average chemist will recognize that changes in reaction conditions may be necessary when other R groups are present. For example, protecting groups may be necessary when one of the R groups contains an additional functional group. The preparation of compound II, R1 = CH3, R2 = H, R3 = N (CH2), R4 = cyclohexyl, is illustrated in Example 5.

COMPOUND (b) 2-Chloro-6-methyl-3-nitro-4-pyrrolidin-1-yl-pyridine Pyrrolidine (16.7 ml, 13.1 g) was added to a solution of 20.0 g of compounds (a) in DMSO (290 ml). The reaction mixture was kept at room temperature for 2 hours and then added to 400 ml of ethyl acetate / hexanes 1: 1. The resulting solution was washed with three 100 ml portions of saturated aqueous sodium chloride and the combined organic extracts were re-extracted with 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by crystallization from ethyl acetate / hexanes 1: 1. Yield, 10.94 (45%), m.p. 151-156 ° C.

COMPOUND (c) Benzyl- (6-methyl-3-nitro-4-pyrrolidin-1-yl-pyridin-2-yl) amine Benzylamine (1.6 ml, 1.5 g) was added to a solution of 0.5 g of compound (a) in 4 ml of toluene. The solution was refluxed for 42 hours, cooled to room temperature and poured into 25 ml of water. The mixture was extracted with ethyl acetate (3 x 25 mL) and the combined extracts were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (25% ethyl acetate in hexanes). Yield, 556 mg (86%).

COMPOUND (d) 6-Methyl-4-pyrroiidin-1-yl-pyridine-2,3-diamine Palladium on charcoal (10%, 250 mg) was added to a solution of compound (c) (0.77 g) in ethanol (100 ml) in a 250 ml Parr shaker flask. The bottle was charged with hydrogen at a pressure of 3.1 x 105 Pa and the reaction mixture was stirred for 14.5 hours at room temperature. The catalyst was removed by filtration through Celite® and the filtrate was concentrated in vacuo to provide Compound (d). Yield, 630 mg (95%).

PREPARATION 3 The compounds of Formula III can be prepared by the following sequence: (and) The compound (e) can be prepared by the procedure described in Chem. Pharm. Bull., 31, 2288 (1983) or other conventional procedures. The average chemist will recognize that changes in reaction conditions may be necessary when other R groups are present. For example, protecting groups may be necessary when one of the R groups contains an additional functional group. The preparation of Compound III, R1 = CH3, R2 = H, R4 = phenyl, is illustrated by the following examples.

EXAMPLE I 2-Methyl-4-isopropylamine-6-phenylpyrrolor3,2-d1dipiri idine A mixture of 1.22 g of the compound of preparation 1, 0.6 of isopropylamine, 1 g of potash and 35 ml of water was heated in an autoclave at 150 ° C (bath temperature) for 5 hours. The precipitate was separated by filtration, washed with water and ethyl acetate and recrystallized from a 75-85% ethanol solution.

EXAMPLE 2 6-Methyl-2-phenyl-4-pyrrolidin-1-yl-1 H-imidazoin 4,5-c-pyridine The title compound was prepared by the procedure of Example 5. The structure was confirmed by MS.

EXAMPLE 3 -Methyl-7-pyrrolidin-1-yl-2-thiazol-2-yl-3H-imidazo [4,5-blpyridine] The title compound was prepared by the procedure of Example 5. The structure was confirmed by MS.

EXAMPLE 4 2-f1H-lmidazol-2-yl-5-methyl-7-pyrroiidin-1-in-3IH-in? Idazor4,5-b1pyridine The title compound was prepared by the procedure of Example 5. The structure was confirmed by MS.

EXAMPLE 5 2-CyclohexyI-5-methyI-7-pyrrolidin-1-i8-3H "imidazor4,5-blpyridine A mixture of 6-methyl-4-pyrrolidin-1-yl-pyridine-2,3-diamine (70 mg), cyclohexanecarboxaldehyde (0.088 ml, 0.082 g) in 1.8 ml of nitrobenzene was refluxed for 1 hour. The reaction mixture was cooled to room temperature and loaded directly onto a column of silica gel. The product eluted with a gradient of dichloromethane spends 10% methanol dichloromethane. The fractions containing the product were concentrated in vacuo, suspended in methanol, filtered and re-concentrated to provide Compound II. Yield 36 mg (35%). Ms 285 (M + 1).

EXAMPLE 6 2-2f2,4-Dimethoxy-phenyl) -7-methoxy-5-methyl-3H-imidazor4.5-blpyridine The title compound was prepared by the procedure of the example. The structure was confirmed by MS.

EXAMPLE 7 7-Methoxy-5-methyl-2-phenyl-3H-imidazo8.5-b1pyridine The title compound was prepared by the procedure of Example 5. The structure was confirmed by MS.

EXAMPLE 8 -Methyl-7-pyridin-4-yl-7-pyrrolidin-1-yl-3H-imidazof4,5-b1pyridone The title compound was prepared by the procedure of example. The structure was confirmed by MS.

EXAMPLE 9 -Methyl-2-pyridin-3-yl-7-pyrrolidin-1-yl-3H-imidazoi; 4,5-b1pyridine The title compound was prepared by the procedure of example 5. The structure was confirmed by Ms.

EXAMPLE 10 -Methyl-2-pyridin-2-yl-7-pyrroidin-1-yl-3H-imidazof4,5-blpyridine The title compound was prepared by the procedure of Example 5. The structure was confirmed by Ms.

EXAMPLE 11 - (4-Fluoro-phenyl) -5-methyI-7-piperidin-1-yl-3H-i? Nridazor4,5-blpyrid »na The title compound was prepared by the procedure of Example 5. The structure was confirmed by Ms.

EXAMPLE 12 ÍS) -4- (2-Methoxymethyl-pyrrolidin-1-ip-2-methyl-β-phenyl-5H-pyrrolor3,2-dlpyrimidine The title compound was prepared by the procedure of Example 1. The structure was confirmed by mass spectrometry (MS).

EXAMPLE 13 (RS) -2-MetiI-6-phenyI-4-r2-y2-pyrrolidin-1-yl-ethyl > -piperidin-1-in-5H-pyrrolor3.2-dlpyrimidine The title compound was prepared by the procedure of Example 1. The structure was confirmed by mass spectrometry (Ms).

EXAMPLE 14 -Methyl-2-phenyI-7-pyrrolidin-1-yl-1 H-imidazor4,5-blpiridane The title compound was prepared by the procedure of Example 5. The structure was confirmed by Ms.

EXAMPLE 15 -Methyl-2-phenyl-7-piperidin-1-yl-1 H-imidazor4.5-blpyridine The title compound was prepared by the procedure of Example 5. The structure was confirmed by Ms.

EXAMPLE 16 1-f2-Methyl-6-phenyl-5-HI-pyrrolor-3, 2-d1-pyrimidin-4-yl-decah-dro-quinoin The title compound was prepared by the procedure of Example 1. The structure was confirmed by mass spectrometry (Ms).

EXAMPLE 17 1'-i2Metia-β-phenyI-5H-pyrrolor3,2-d1-pyrimidin-4-ylH1.4'1-bipiperidinyl The title compound was prepared by the procedure of Example 1. The structure was confirmed by spectrometry (Ms).

EXAMPLE 18 ÍR) -4- (2-Methoxymethyl-pyrrolidin-1-ip-2-methyl-β-phenyl-5H-pyrrolor3,2-dlpyrimidine The title compound was prepared by the procedure of Example 1. The structure was confirmed by spectrometry (Ms).

EXAMPLE 19 ÍS) -2-Methyl-6-phene-4-y2-pyrrolidin-1-ylmethi-pyrroiidin-1-ip-5H-pyrroor3.2-dlpyrimidine The title compound was prepared by the procedure of Example 1. The structure was confirmed by spectrometry (Ms).

EXAMPLE 20 (R) -Dimethyl- | '1- (2-methyI-6-phenyl-5H-pyrrolor-3,2-dlpyrimidin-4-ip-pyrrole »din-ip-amine The title compound was prepared by the procedure of Example 1. The structure was confirmed by spectrometry (Ms).

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula wherein: B, D and E are independently selected from CR1, CR9 or N, with the proviso that at least one of B, D and E must be CR1, and at least one of B, D and E must be be N; and F, G are selected from N, NR4 or CR5, with the proviso that at least one of F or G must be N NR14; and one of the broken lines represents one link and the other represents absence of link; and when B and E are both N, then one of F or G must be CR5; and R1, R3, R4, R5 and R9 are independently selected from H, Ci-Cß alkyl, Ci-Cß alkoxy, Ci-Cß thioalkyl, C2-C6 alkylen, C2-C6 alkynyl, Ci-Cß perfluoroalkyl, Ci-Cß perfluoroalkoxy , (CH2) n-cycloalkyl C3-C7, (CH2) n-cycloalkenyl C3-C7 and (CH2) nAr, each alkyl, alkenyl, aquilino, alicyclic and Ar group being independently substituted with one to three substituents selected from the group formed by Br, Cl, F, NR6R7, or (Ci-Cß alkyl), N02) CN, COOH, OH, SH and; R2 is NR6R7V NH (CH2) nPh, NH (CH2) n (C3-C7 cycloalkyl), NH (CH2) n-C3-C7 cycloalkenyl, NH (C2) nmorpholinyl, NH (CH2) npiperazinyl or NH (CH2) npyrimidinyl, each ring being independently substituted with one or three substituents selected from the group consisting of Br, Cl, F, NR6R7, or (Ci-Cß alkyl). alkyl d-Ce, S (O) m-C 1 -C 6 alkyl, NO 2, CN, COOH, OH, SH and; or < when R2 is if m or n is zero, the other of m or n will be at least 2; and G is S, O, O, NR8 or a bond; and R8 is hydrogen, Ci-Cd alkyl or aryl; (C 1 -C 2 alkyl) -C (O) - or aryl-C (O) -; R6 and R7 are independently selected from hydrogen, Ci-Cß alkyl, (C?-C6 alkyl) (C?-C6 alkoxy), (CH 2) kN [(d-Cß alkyl)] 2 and (CH ?JkOH; and n is an integer from zero to six, m is an integer from zero to two, k is an integer from two to four, Ar is an aromatic hydrocarbon or a heterocyclic ring of three to seven atoms or a bicyclic heterocyclic ring, at least one atom of the which is a nitrogen, sulfur or oxygen atom, and with the proviso that if F is NR4, G is CR5, B and E are N, D is CR1, R1 is methyl, R1 is phenyl and R4 and R5 are hydrogen, then R2 will not be NEt2, HN (CH2) 2NEt2, HN (CH3) 2COOH, HNCH2CH2OH, HNPh, HN (CH2) 2Ph, HN (CH2) 2 piperidinyl, morpholinyl, NHNH2, HNCH (CH3) 2, HN (CH2) 3CH3, HNCH2CH (CH3) 2) HNCH (CH3) CH2 (CH2) 3CH3, HNCH2CH = CH2) and with the additional proviso that if F is NR4, G is CR5, B and E are N; D is CR1 and R3 are both methyl and R4 and R5 are both hydrogen, then R2 will not be HN CH2CH2N (C2H5) 2, HNCH2CH; HNCH2C6H5 HN (CH2) C6 and with the additional proviso that if F is NR4, G is CR5, B and E are N; D is CR1; R4 and R5 are hydrogen, so R1 and R2 should not be equal and will be and with the additional condition that when B, F are N; G is NR4; D is CR1; E is CR9; R1, R3 and R4 are H, then R2 will not be NH2, NME2, NHMe, OH, OMe, when B and G are N; F is NR4; E is CR9; D is CR1; R1, R4 and R9 are H; and R2 is OMe, then R3 will not be when B and G are N; F is NR4; E is CR9; D is CR1; R1, R3 and R9 are H; and R2 is NH2, then R4 will not be when B and F are N; G is NR4; E is CR9; D is CR1; R1 and R9 are H; R3 and R4 are CH3, then R2 will not be ; Y when B and F are N; G is NR4; E is CR9; D is CR1; R1 and R9 are H; R3 is CH3, and R4 is CH2CH2OH, then R2 will not be NH2 or when B and F are N; G is NR4; E is CR9; D is CR1; R1 is CH3; R3 is CH3; R9 is H and R4 is then R will not be NMe2, NHMe or when E and F are N; G is NR4; B is CR9; D is CR1; R1; R3; R4 and R9 are H, then R2 will not be NH2 > OH, OCH3, NMe2, NHEt, NHMe, when E and F are N, G is NR4; B is CR9; D is CR1; R1 is CH3; and R3, R4 and R9 are H, then R2 will not be NH2 or OH; and when E and F are N; and G is NR4; B is CR9; D is CR1; R1 is CH2CH2CH3; and R3, R4 and R9 are H, then R2 will not be NH2 or OH; and when E and F are N; G is NR4; B is CR9; D is CR1; R1, R4; and R9 are H and R2 is OCH3, then R3 will not be when E and G are N; F is NR4; B is CR9; D is CR1; R2 is NH2; R1, R3; and R9 are H, then R4 will not be CH3 or when E and F are N; G is NR4; B is CR9; D is CR1; R2 is OH; R1, R4; and R9 are H, then R3 will not be CH3) Et, or when E and G are N; F is NR4; B is CR9; D is CR1; R2 is OH; R1 and R9 are H, and R4 is then R3 will not be Et, cyclopropyl, propyl or butyl; and when E and G are N; F is NR4; B is CR9; D is CR1; R2 is OH; R1 and R9 are H and R4 is then R3 will not be Et, cyclopropyl, propyl or butyl; and when E and G are N; F is NR4; B is CR9; D is CR1; R2 is OH; R1 and R9 are H and R3 will not be twenty Yy when E and F are N; G is NR4; B is CR9; D is CR1; and R1, R4; and R9 are H and R3 is 2,4-dimethoxyphenyl, then R2 will not be when E and G are N; F is NR4; B is CR6; D is CR1; R1 and R9 are H; R2 is OH and R3 is CH2CH2CH3, then R4 will not be when E and F are N; G is NR4; B is CR9; D is CR1; R1 and R9 are H; R2 is N (CH2C6H5) 2 and R3 is CH3) then R4 will not be CH2CH2C6H5 or CH2CH2CH2CH3; and when E and F are N; G is NR4; B is CR9; D is CR1; R1 and R9 are H, R2 is N (CH2C6H5) and R4 is CH (CH3) CH2CH3, then R3 will not be when E and F are N; G is NR4; B is CR, D is CR1 and D R9a are H, R is NH2 and R3 is CH3, then R4 will not be when E and F are N; G is NR4; B is CR9; D is CR1; R1 and R9 are H, R2es is NH2 and R4 is CH (CH3) CH2CH3, then R3 will not be the following compounds are not included in the invention; -OH OH 2. - A compound according to claim 1, of formula: wherein: R1, R3 and R4 are independently selected from H, d-Cß alkyl, C Cß thioaicyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cß perfluoroalkyl, Ci-Cß perfluoroalkoxy, (CH2) n-phenyl , (CH2) n-pyridyl, (CH2) n-pyrimidyl, (CH2) n-C3-C7 cycloalkyl, (CH2) n-C3-C7 cycloalkenyl, (CH2) n-furanyl, (CH2) n-thienyl, each alkyl, alkenyl, alkynyl, phenyl, heterocyclic and acyclic group independently substituted with one to three substituents selected from the group consisting of Br, Cl, F, NR6R7, or (Ci-Cß alkyl), C?-C6 alkyl, S (0) m (C? -C6 alkyl), N02) CN, COOH, OH, SH and; R2 is NR6R7, NH (CH2) nPh, NH (CH2) n (C3-C7 cycloalkyl), NH (CH2) n, C3-C7 cycloalkenyl, NH (CH2) nmorpholinyl, NH (CH2) nPiperazinyl or NH (CH2) npyrimidinyl, each ring can be independently substituted with one to three substituents selected from the group consisting of Br, Cl, F, NR6R7, O (Ci-Cß alkyl) , alkyl C? -C6, S (O) m-C? -C6 alkyl, No2, CN, COOH, OH, SH and; when R2 is if m or n is zero, the other of m or n will be at least 2; and G is S, O, NR8 or a bond; and R8 is hydrogen, Ci-Cß alkyl or aryl; and R6 and R7 are independently selected from hydrogen, (Ci-Cß alkyl) (C?-C6 alkoxy), (CH 2) k -COOH, (CH 2) kN [(C?-C6 alkyl)] 2 and (CH 2) kOH; and n is integer from zero to six; m is an integer from zero to two; k is an integer from two to four; and with the proviso that if R is methyl, R3 is phenyl and R4 and R5 are hydrogen, then R2 will not be NET2, NH (CH2) 2NET2, HN (CH3) 2COOH, HNCH2CH2OH, HNPh, HN (CH2) 2Ph, piperidinium, morpholinyl, NHNH2, HNCH (CH3) 2, HN (CH2) 3CH3, HNCH2CH (CH3) 2, HNCH (CH3CH2 (CH2) 3CH3, HNCH2CH = CH2j and with the additional proviso that if R1 and R3 are both methyl and R4 and R5 are both hydrogen, then R2 will not be HN CH2CH2N (C2H5) 2, HNCH2CgHc HN (CH2) C6 and with the additional proviso that if R3, R4 and R5 are hydrogen, then R1 and R2 would not be both equal and will be 3. - A compound according to claim 1, selected from the group consisting of: 2-methyl-4-isopropylamino-6-phenylpyrrolo [3,2-d] pyrimidine; 6-methyl-2-phenyl-4-pyrroiidin-1-yl-1 H-imidazo [4,5-cjpyridine; 5-methyl-7-pyrrolidin-1-yl-2-thiazol-2-yl-3H-imidazo [4,5-b] pyridine; 2- (1 H-imidazoI-2-yl) -5-methyl-7-pyrroidin-1-yl-3H-imidazo [4,5-b] pyridine; 2-cyclohexyl-5-methyl-7-pyrrolidin-1-yl-3H-imidazo [4,5-b] pyridine; 2- (2,4-dimethoxy-phenyl) -7-methoxy-5-methyl-3H-imidazo [4,5-b] pyridine; 7-methoxy-5-methyl-2-phenyl-3H-imidazo [4,5-bjpyridine; 5-methyl-2-pyridin-4-yl-7-pyrrolidin-1-yl-3H.imidazo [4,5-b] pyridine; 5-methyl-2-pyridin-3-yl-7-pyrrolidin-1-yl-3H-imidazo [4,5-b] pyridine; 5-methyl-2-pyridin-2-yl-7-pyrrolidin-1-yl-3H-imidazo [4,5-b] pyridine; 2- (4-fluoro-phenyl) -5-methyl-7-piperidin-1-yl-3H-imidazo [4,5-b] pyridine; (S) -4- (2-methoxymethyl-pyrrolidin) -1-yl) -2-methyl-6-phenyl-5H-pyrrolo [3,2-d] pyrimidine; (RS) -2-methyl-6-phenyl-4- [2- (2-pyrrolidin-1-yl-ethyl) -piperidin-1-yl] -5H-pyrrolo [3,2-d] pyrimidine; 5-methyl-2-phenyl-7-pyrrolidin-1-yl-1 H-imidazo [4,5-b] pyridine; 5-methyl-2-phenyl-7-piperidin-1-yl-1 H-imidazo [4,5-bjpyridine; 1- (2-methyl-6'-phenyl-5H-pyrrolo [3,2, d] pyrimidin-4-yl) -decahydro-quinoline; 1, (2-methyl-6-phenyl-5H-pyrrolo [3,2-d] pyrimidin-4-ylH1, 4 '] bipiperidinyl; (R) -4- (2-methoxymethyl-pyrrolidin-li-methyl); β-phenyl-SH-pyrrolotS ^ -dlpyrimidine; (S) -2-methyl-6-phenyl-4- (2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -5H-pyrrolo [3,2-s ] pyrimidine, and (R) -dimethyl- [1 - (2-methyl-6-phenyl-5H-pyrrolo [3,2-d] pyrimidin-4-yl) -pyrrolidin-3-yl] -amine. use of an inhibitory amount of neuropeptide Y of a compound of claim 1 for the manufacture of a medicament for inhibiting or alleviating a pathological condition or physiological disorder in a mammal characterized by, or associated with, an excess of neuropeptide Y. 5.- The use according to claim 4, wherein said pathological condition or physiological disorder is a eating disorder such as obesity or bulimia 6. The use according to claim 5, wherein said pathological condition or physiological disorder is selected. among the group consisting of: disorders or diseases of the heart n, blood vessels or the renal system, such as angiospasm, cardiac insufficiency, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrhythmia, peripheral vascular disease and abnormal renal disorders such as poor fluid flow , transport of anomalous mass or renal insufficiency; disorders related to increased sympathetic nerve activity, for example, during or after surgery of the coronary arteries, and operations and surgery in the gastrointestinal tract; brain diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, cerebrovascular accident and disorders related to stroke, cerebral agiospasm and hemorrhage, depression, anxiety, schizophrenia and dementia; disorders related to pain or nociception; diseases related to gastrointestinal motility and abnormal secretion, such as different forms of ileus, urinary incontinence and Crohn's disease; disorders due to abnormal ingestion of beverages and foods, such as anorexia and metabolic disorders; diseases related to sexual diffusion and reproductive disorders; disorders or conditions associated with inflammation; respiratory diseases, such as asthma and disorders related to asthma and bronchoconstriction; and diseases related to an abnormal release of hormones such as luteinizing hormone, growth hormone, insulin and prolactin. A pharmaceutical composition for treating obesity, comprising effective amounts of a compound according to claim 1 and a β3-adrenergic agent or a thyromimetic agent. 8. - A pharmaceutical composition according to claim 8, wherein said β3-adrenoteric agent is (4- (2- (2- (6-aminopyrid-3-yl) -2- (R) -hydroxyethylamino) ethoxy) ) phenyl) acetic, a prodrug thereof or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.