MXPA01001548A - New pharmaceutical uses for nos inhibitors - Google Patents

New pharmaceutical uses for nos inhibitors

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Publication number
MXPA01001548A
MXPA01001548A MXPA/A/2001/001548A MXPA01001548A MXPA01001548A MX PA01001548 A MXPA01001548 A MX PA01001548A MX PA01001548 A MXPA01001548 A MX PA01001548A MX PA01001548 A MXPA01001548 A MX PA01001548A
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Mexico
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formula
compound
pyridin
pharmaceutically acceptable
phenyl
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MXPA/A/2001/001548A
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Spanish (es)
Inventor
John Adams Lowe Iii
Jolanta Nowakowski
Robert Alfred Volkmann
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Pfizer Products Inc
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Publication of MXPA01001548A publication Critical patent/MXPA01001548A/en

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Abstract

The present invention relates to new pharmaceutical uses for compounds that exhibit activity as nitric oxide synthase (NOS) inhibitors. Specifically, it relates to the use of NOS inhibitors, particularly selective neuronal NOS (N-NOS) inhibitors:(a) alone or in combination with another active agent for the treatment of psoriasis;(b) in combination with an antiinflammatory agent for the treatment of inflammatory disorders;(c) in combination with a narcotic analgesic (e.g., opiates such as morphine or demerol) for the treatment of pain;(d) alone or in combination with other active agents for the enhancement of cognition;and (e) alone or in combination with other active agents for the treatment of sleep disorders such as apnea, narcolepsy and insomnia.

Description

NEW PHARMACEUTICAL USES FOR INHIBITORS OF NITRIC OXID SYNTHETASE The present invention relates to new pharmaceutical uses for compounds that exhibit activity as inhibitors of nitric oxide synthetase (NOS). More specifically, it refers to the use of NOS inhibitors and, in particular, to selective NOS (N- NOS) neuronal inhibitors: (a) alone or in combination with another active agent for the treatment of psoriasis; (b) in combination with an anti-inflammatory agent for the treatment of inflammatory disorders; (c) in combination with a narcotic analgesic (opiates such as morphine or demerol, for example) for the treatment of pain; (d) in combination with a serotonin-1 D (5H-TID) agonist (eletriptan or sumatriptan, for example) for the treatment of migraines, recurrent headache or other headaches vascular; (3) alone or in combination with other active agents for the development of cognitive ability; and (f) alone or in combination with other active agents for the treatment of sleep disorders, such as apnea, narcolepsy or insomnia. There are three known NOS isoforms (an inducible form (I-20 NOS) and two constitutive forms called neuronal NOS (N-NOS) and endothelial NOS (E-NOS), respectively). Each of these enzymes carries out the conversion of arginine to citrulline while producing a molecule of nitric oxide (NO) in response to various stimuli. It is believed that Excess production of nitric oxide (NO) by NOS plays a role in the pathology of a number of disorders and conditions of mammals. NO produced by I-NOS, for example, is believed to intervene in diseases related to systemic hypotension, such as toxic shock, and in therapy with certain cytokines. It has been shown that cancer patients treated with cytokines such as interleukin-1 (IL-1), interleukin-2 (IL-2) or tumor necrosis factor (TNF), suffer from cytokine-induced shock, as well as hypotension. due to NO produced by macrophages, ie inducible NOS (I-NOS). See Chemical and Enqineerinq News, Dec. 20, p. 33, (1993). The l-NOS inhibitors can reverse this. Likewise, it is also believed that l-NOS play a role in the pathology of diseases of the central nervous system such as ischemia. Inhibition of l-NOS, for example, has been shown to improve cerebral ischemic damage in rats. See Am. J. Phvsiol., 268, p. R286 (1995): Likewise, the suppression of arthritis by adjuvants has been described by selective inhibition of l-NOS in Eur. J. Pharmacol., 273, p. 15-24 (1995). The NO produced by the N-NOS is believed to intervene in diseases such as cerebral ischemia, pain and tolerance to opiates. The inhibition of N-NOS, for example, reduces the volume of infarction after occlusion of a proximal middle cerebral artery in the rat. See ¡Cerer. Blodd. Flow Metab .. 14, p. 924-929 (1994). Likewise, it has been demonstrated that the inhibition of N-NOS is effective in antinociception, as evidenced by the activity in the last phase of the alginic stimulation in the hind legs induced by formalin and the abdominal constriction tests induced by acetic acid. See Br. J. Pharmacol., 110, p. 219-224 (1994). In addition, the subcutaneous injection of Freund's adjuvant into the rat induces an increase in NOS-positive neurons in the spinal cord that manifests itself in the increased sensitivity to pain, which can be treated with NOS inhibitors. See Japanese Journal of Pharmacoloqy. 75, p. 327-335 (1997). Finally, the reduction of the opioid withdrawal syndrome in rodents has been described by N-NOS inhibition. See Neuropsvchopharmacol., 13, p. 269-293 (1995).
BRIEF DESCRIPTION OF THE INVENTION This invention also relates to a method for the treatment of inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis or asthma, in mammals, including humans, and comprising the administration to said mammals of: (a) a NOS inhibitor compound , or a pharmaceutically acceptable salt thereof; and (b) a compound that shows anti-inflammatory activity (such as sitnyl, morphine or meperedine, or a stereo-anti-inflammatory compound such as cyclooxygenase inhibitors) or a pharmaceutically acceptable salt thereof; wherein the above active agents "a" and "b" are present in such amounts as to make effective the combination of both agents in the treatment of said disorders. This invention also relates to a method for the treatment of pain, acute or chronic, in mammals, including man, and which comprises the administration to said mammals of: (a) a NOS inhibitor compound, or a pharmaceutically salt acceptable thereof; and (b) a narcotic analgesic compound (an opioid such as morphine or demerol) or a pharmaceutically acceptable salt thereof; wherein the above active agents "a" and "b" are present in such amounts as to make effective the combination of both agents in the treatment of acute or chronic pain. This invention also relates to a pharmaceutical composition for the treatment of inflammatory disorders (such as rheumatoid arthritis, osteoarthritis, psoriasis or asthma) in mammals, including man, and comprising: (a) a compound exhibiting anti-inflammatory activity ( such as sentanil, morphine or meperedine, or a steroidal anti-inflammatory compound as the cyclooxygenase inhibitors) or a pharmaceutically acceptable salt thereof; (b) a NOS inhibitor compound, or a pharmaceutically acceptable salt thereof; Y (c) a pharmaceutically acceptable vehicle; wherein the above active agents "a" and "b" are present in such amounts as to make effective the combination of both agents in the treatment of said disorders. This invention also relates to a pharmaceutical composition for the treatment of pain, acute or chronic, in mammals, including man, and comprising. (a) a narcotic analgesic compound (an opiate such as morphine or demerol) or a pharmaceutically acceptable salt thereof; and 10 (b) a narcotic analgesic compound (an opioid such as morphine or demerol) or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the above active agents "a" and "b" are present in such amounts as to make effective the combination of both agents in the treatment of acute or chronic pain. This invention also relates to a pharmaceutical composition for the treatment of a condition selected for the treatment of a condition selected from migraine, recurrent headache and other vascular headaches in mammals, including man, and which comprises: (a) a NOS inhibitor compound, or a pharmaceutically acceptable salt thereof; • ^^ f ^^^^^^ (b) a serotonin-1D (5H-T | D) receptor agonist (eletriptan or sumatriptan) or a pharmaceutically acceptable salt thereof; Y (c) a pharmaceutically acceptable vehicle; wherein the above active agents "a" and "b" are present in such amounts as to make effective the combination of both agents in the treatment of acute or chronic pain. This invention also relates to a method for the treatment of a condition selected from migraine, recurrent headache and other vascular headaches in mammals, including man, and which comprises the administration to said mammals of: (a) a NOS inhibitor compound, or a pharmaceutically acceptable salt thereof; (b) a serotonin-1 D (5H-TID) receptor agonist (eletriptan or sumatriptan) or a pharmaceutically acceptable salt thereof; and wherein the above active agents "a" and "b" are present in such amounts as to make effective the combination of both agents in the treatment of acute or chronic pain. This invention also refers to any of the above processes in which the NOS inhibitor compound is a compound of formula I, II, III, IV, V, VI, as defined below. The term "treating", as used herein, refers to either preventing the disorder or condition to which the term applies, or one or more symptoms of said disorder or condition, or to reversing, alleviating or inhibiting the progress of the same. The term "" treatment "" as used herein, refers to treating, as the term "treating" has been defined above. This invention also relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of sleep disorders, psoriasis, and deficits or cognitive disorders in mammals, including man, comprising an amount of an inhibitory compound NOS of formula I, II, III, IV, V, VI, as defined below, which is effective to treat said condition, as well as a pharmaceutically acceptable carrier. This invention also relates to a method for the treatment of a condition selected from the group consisting of sleep disorders, psoriasis, and deficits or cognitive disorders in mammals, including man, comprising the administration to said mammals of a amount of a NOS inhibitor compound of formula I, II, III, IV, V, VI, as defined below, which is effective to treat or prevent such a condition. This invention also relates to a pharmaceutical composition for the treatment or prevention of a condition selected from the group consisting of sleep disorders, psoriasis, and deficits or cognitive disorders in mammals, including man, comprising an effective amount of a NOS inhibitor compound of formula I, II, III, IV, V, VI, as defined below, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier. This invention also relates to a method for the treatment of a condition selected from the group consisting of sleep disorders, psoriasis, and deficits or cognitive disorders in mammals, including man, which comprises the administration of an effective amount of a NOS inhibitory compound of formula I, II, III, IV, V, VI, as defined below, or a pharmaceutically acceptable salt thereof. Examples of NOS inhibitor compounds that can be used in the methods and pharmaceutical compositions of the present invention are compounds of the formula: in which Ring A is a fused, saturated or unsaturated ring, of 5 to 7 links in which from zero to two of the ring members are heteroatoms independently selected from nitrogen, oxygen and sulfur, provided that two of the adjacent members of the ring are not heteroatoms; X is oxygen or a bond; *" __ TO'?" 'i n is an integer from two to six; and R1 and R2 are independently selected from alkyl (Ci-Cd), aryl, tetrahydronaphthalene and aralkyl, wherein said aryl and the aryl radical of said aralkyl is phenyl or naphthyl and the alkyl radical is a chain linear or branched, from 1 to 6 carbon atoms; and wherein said (C C6) alkyl, aryl, tetrahydronaphthalene and the aryl radical of said araalkyl can be optionally substituted with one to three substituents, preferably with zero to two substituents, which are independently selected from halo groups (chloro, fluoro, bromo or iodo, for example), nitro, hydroxy, cyano, amino, alkoxy (CrC4), and alkylamino (C -? - C4); or R1 and R2 form together with the nitrogen to which they are attached, a piperazine ring, azetidine, piperidine or pyrrolidine, or an azabicyclic ring containing from 6 to 14 links, from one to three of which are nitrogen and the remainder are carbon; and where they can be examples of such rings azabicyclics the following: c * ^ ^ ^ ^ ^ ^ ^ ^ k ^ ¿Ak R1 and R2 can also join a group (CH2) n to form a ring of 4 to 7 links; wherein R3 and R4 may be selected from hydrogen, (C6) alkyl, phenyl, naphthyl, (C1-C6) alkyl -C = 0, HC (= 0) -, (C6) alkoxy -5C = 0-, phenyl- (C = 0) -, naphthyl- (C = O) - and R6R7NC (= 0) - in which R6 and R7 are independently selected from hydrogen and alkyl (Ci-Cß); R5 is selected from hydrogen, alkyl (C-i-Ce), phenyl, naphthyl, phenylalkyl (d-Cß) -, and naphthylalkyl (C? -C6) -; and wherein said rings of piperazine, azetidine, piperidine or pyrrolidone may be optionally substituted with one or more substituents, preferably with zero to two substituents which are selected, independently, from alkyl (C? -C6), amino, alkylamino (CrC6), dialkylamino (Ci-C?), phenyl substituted with 5-6 membered heterocyclic rings containing from 1 to 4 nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl and phenoxycarbonyl, and wherein the phenyl radical of any of the above substituents may be optionally substituted with one or more substituents, preferably with zero to two substituents, which are selected independently from each other. halo groups, (C1-C3) alkyl, (C1-C3) alkoxy, nitro, amino, cyano, CF3 and OCF3; and the pharmaceutically acceptable salts of said compounds. The following compounds are NOS inhibitors of formula I: ¡8 ^ ^ ^ 2 -6- [4- (2-dimethylamino-ethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-pyrrolidin-1-yl-ethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- (4- { 2-Benzo [1,3] dioxol-5-ylmethyl) amino-ethoxy} -naphthalen-1-yl] -pyridin-2-ylamine; 6- { 4- [2- (6,7-dimethoxy-3,4-dihydro-1 H-isoquinolin-2-yl) -ethoxy ?} -naftalen-1-il} -pyridin-2-ylamine; 3-. { 2- [4- (6-Amino-pyridin-2-yl) -naphthalen-1-yloxy] -et? L} -3-aza-bicyclo [3.1.0] hex-6-ylamine; 6- { 4- [2- (4-phenethyl-piperazin-1-yl-ethoxy] -naphthalen-1-yl}. -pyridin-2-ylamine; 6- { 4- [2- (3- amine-pyrrolidin-1-yl-ethoxy] -naphthalen-1-yl.} - pyridin-2-lamel; 6- [4- (1-benzyl-piperidin -4 -loxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-benzyl-pyrrolidin-3-yloxy) -naphthalene; 1-yl] -pyridn-2-ylamine; 6- [4- (piperidin-4-yloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 4- (pyrrolidin-3-yloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (pyrrolidin-3-yloxy) -naphthalen-1-yl] -pyridin- 2-ylamine 6- [4- (1-isobutyl-piperidin-4-yloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-furan-2-ylmethyl-piperidine 4-yloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-isobutyl-pyrrolidin-3-yloxy) -naphthalen-1-yl] -pyridin-2 -amine; 6- [4- (1-furan-2-ylmethyl-lyrrolidin-3-yloxy) -naphthalen-1-yl] -pyridin-2-ylamin; 6- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -pyridin-2-amlamine; 6- [4- (2-diisopropylamino-ethoxy) -naphthalen-1-yl] -pyridn-2-ylamine; 6- [4- (1-methyl-piperidn-4-loxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-methyl-pyrrolidin-3-yloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (3-dimethyl-propoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-aza-bicyclo [2.2.2] oct-3-yloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-pperidin-1-yl-ethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- { 4- [2- (3,4-D-Hydro-1 H -soquinolin-2-yl-ethoxy] -naphthalen-1-yl.} - pyridin-2-ylamine; {4- [2- (4-dimethylamino-p-perpent-1-yl-ethoxy] -naphthalen-1-yl} -pyridin-2-lamin; 6- [4- (2-t-butyl-methyl-amino) -ethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- { 4- [2- (4-methyl-piperazin-1-yl ) -ethoxy] -naphthalene-1-yl.}.-pyridin-2-ylamine; 6- { 4- [2- (4-pheny1-piperid-1-yl) - ethoxy] -naphthalen-1-yl.}. pyridin-2-ylamine; 6- { 4- [2- (7,8-dihydro-5H- [1,3] dioxolo [4,5- g] isoquinolin-6-yl) -ethoxy] -naphthalen-1-yl.} - pyridin-2-ylamine; 6- [4-pyrimidin-2-ylmethoxy] -naphthalene-1 - l] -pyridin-2-ylamine; 6- [4- (1-methyl-piperidin-2-ylmethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-methyl-piperidin-3-ylmethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-aminocyclohexyloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (piperidin-3-ylmethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-isobutyl-azetidin-3-yloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-furan-2-methyl-azetidin-3-yloxy) -naphthalen-1-yl] -pyridin-2-ylamin; 6- [4- (8-methyl-8-aza-bicyclo [3.2.1] oct-3 -loxy) -naphthalen-1-yl] -pyridin-2-ylamin; 6- 6- [4- (azetidin-3-yloxy) -naphthalen-1-yl-pyridin-2-ylamine; 6- [4- (1-methyl-pyrrolidin-2-ylmethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (azetidin-2-ylmethoxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [7- (2-dimethylamino-ethoxy) -indan-4-yl] -pyridin-2-ylamine; 6- [7- (2-pyrrolidin-1-yl-ethoxy) -indan-4-yl] -pyridin-2-ylamine; 10 6- [7- (2-benzyl-methyl-amino-ethoxy) -indan-4-yl] -pyridin-2-ylamine; 6- { 7- [2- (4-phenethyl-piperazin-yl-ethoxy) -indan-4-yl] -pyridin-2-ylamine; 6- { 7- [2- (4-isobutyl-piperazin-1-yl-ethoxy] -indan-4-yl] -pyridin-2-ylamine; 6- [7- (2-morpholin-4-yl-ethoxy) -indan-4-yl] -pyridin-2-ylamine; 6- [7- (2-disopropylamino-ethoxy) -indan-4-yl] -pyridin-2-ylamine; 7- [2- (7,8-dihydro-5H- [1,3] dioxolo [4,5-g] isoquinolin-6-yl) -ethoxy] -indan-4-yl] -pyridin-2 -allamine: 6- {7- [2- (4-methyl-piperazin-1-yl-ethoxy] -ndan-4-yl} -pyridin-2-ylamine; [7- (2-t-butyl-metho-amino) -ethoxy) -indan-4-yl] -pyridin-2-ylamine; 6-. {7- [2- (4-dimethylamino-piperidine -1-yl) -ethoxy] -indan-4-yl.}. -pyridin-2- * 20-lamel; 6- [8- (2-dimethylamino-ethoxy) -1, 2,3,4-tetrahydro -1,4-methano-naphthalen-5-yl] -pyridin-2-ylamine; 6- [8- (2-pyrrolidin-1-yl-ethoxy) -1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl] -pyridin-2-ylamine; 6- [4- (2-dimethylamino-ethoxy) -5,6,7,8-tetrahydro-naphthalen-5-yl] -pyridin-2-ylamine; 6- [4- (2-pyrrolidin-1-yl-ethoxy) -5,6,7,8-tetrahydro-naphthalen-5-yl] -pyridin-2-ylamine; 6- { 4- (2-t-Butyl-methyl-amino-ethoxy) -5,6,7,8-tetrahydro-naphthalen-5-yl} -pyridin-2-ilamine; 6- { 4- [2-diisopropylamino-ethoxy) -5,6,7,8-tetrahydro-naphthalen-5-yl} -pyridin-2-ilamine; 6- [4- (2-D-methylamino-ethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-alamine; 6- { 4- [2- (3,4-dihydro-1 H -soquinolin-2-yl) -ethoxy] -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-piperidin-1-yl-ethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-morpholin-4-yl-ethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- { 4- [2- (7,8-dihydro-5H- [1,3] dioxolo [4,5-g] isoquinolin-6-yl) -ethoxy] -5,6,7,8-tetrahydro-naphthalene-1 -l] -pyridin-2-ylamine; 6- { 4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- { 4- [2- (4-dimethylamino-piperidin-1-yl) -ethoxy] -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- { 4- [2- (7,8-dihydro-5H- [1,3] dioxolo [4,5-g] isoquinolin-6-yl) -ethoxy] - 5,6,7,8-tetrahydro-naphthalene-1 -l] -pyridin-2-ylamine; 6- 6- [4- (1-Isobutyl-piperidin-3-ylmethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (1-methyl-pperidin-3-ylmethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- { 4- [2- (2-dimethylamino-ethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -10-pyridin-2-ylamine; 6- [4- (piperidin-3-ylmethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-alamine; 6- [4- (2-amino-cyclohexyl) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 15 6- [4- (pyrrolidin-2-ylmethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-dimethylamino-ethoxy) -5,6,7,8-tetrahydro-5H-benzocyclohepten-1-yl] -pyridin-2-ylamine; and the pharmaceutically acceptable salts thereof. * 20 The following are additional examples of NOS inhibitor compounds of formula I: 6- [4- (2-amino-cyclopentyloxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-amino-cyclobutyloxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-Amino-cyclopropyloxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine, 6- [4- (3-amino-cyclohexyloxy ) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (3-amino-cyclopentyloxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (3-Amino-cyclobutyloxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (4-amino-cyclohexyloxy) -5,6,7,8-tetrahydro-naphthalen-1-yl-pyridin-2-ylamine; 6- [4- (2-amino-cyclopentyloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (2-amino-cyclobutyloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 15 6- [4- (2-amino-cyclopropyloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (3-amino-cyclohexyloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (3-amino-cyclopentyloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (3-amino-cyclobutyloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 6- [4- (4-amino-cyclohexyloxy) -naphthalen-1-yl] -pyridin-2-ylamine; 20 6- [4- (2-amino-cyclopentyloxy) -ndan-1-yl] -pyridin-2-ylamine; 6- [4- (2-amino-cyclobutyloxy) -indan-1-yl] -pyridin-2-ylamine; 6- [4- (2-amino- cyclopropyloxy) -indan-1-yl] -pyridin-2-ylamine; 6- [4- (3-amino-cyclohexyloxy) -indan-1-yl] -pyridin-2-ylamine; s ^^^ sS ^ s ^ j ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -1-yl] -pyridin-2-ylamine; 6- [4- (3-amino-cyclobutyloxy) -ndan-1-yl] -pyridin-2-ylamine; 6- [4- (4-Amino-cyclohexyloxy) -indan-1-yl] -pyridin-2-alan, 6- [4-piperidin-3-ylmethoxy) -6,7,8,9-tetrahydro -5H-benzocyclohepten-5 1-yl] -pyridin-2-ylamine; 6- [4- (2-pyrrolidin-3-ylmethoxy) -6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl] pyridin-2-ylamine; 6- [4- (2-amino-cyclohexyloxy) -6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl] pyridin-2-ylamine; 10 6- [4- (2- (4-dimethylamino-piperidin-1-l) ethoxy) -6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl] pyridin-2-ylamine; 6- [4- (2- (4-methyl-piperazin-1-yl) -6,7,8) 9-tetrahydro-5H-benzocyclohepten-1-yl] pyridin-2-ylamine. Other examples of NOS inhibitor compounds that can be used in the methods and pharmaceutical compositions of this invention are compounds of the formula: I &r *. ^ SSE- ^ - * & -f-5-l and the pharmaceutically acceptable salts thereof, wherein R1 and R2 are independently selected from alkyl (CrC6), tetrahydronaphthalene, and aralkyl, wherein the aryl radical of said aralkyl is phenyl or naphthyl and the alkyl radical is a straight or branched chain of 1 to 6 carbon atoms; and wherein said alkyl (CrC6), tetrahydronaphthalene and the aryl radical of said aralkyl can be optionally substituted with one to three substituents, preferably with zero to two substituents, which are independently selected from halo groups (chloro , fluorine, bromine or iodine, for example), nitro, hydroxy, cyano, amino, alkoxy (C4), and alkylamino (C4); or R1 and R2 form together with the nitrogen to which they are attached, a piperazine ring, azetidine, piperidine or pyrrolidine, or an azabicyclic ring containing from 6 to 14 links, from 1 to 3 of which are nitrogen and the remainder are carbon; and wherein the following can be examples of said azabicyclic rings: wherein R3 and R4 may be selected from hydrogen, alkyl (C6), phenyl, naphthyl, alkyl (C6) C = 0-, HC (= 0) -, alkoxy (C6-6) -C = 0 -, phenyl- (C = 0) -, naphthyl- (C = 0) - and R6 and R7 are independently selected from hydrogen and alkyl (Ci-Cß); R5 is selected from hydrogen, alkyl (CrC6), phenyl, naphthyl, phenylalkyl (C-i-Cß) -, and naphthylalkyl (CrC6) -; and wherein said piperazine, azetidine, piperidine or pyrrolidine rings can be optionally substituted with one or more substituents, preferably with from zero to two substituents which are independently selected from alkyl (Ci-Cß), amino, alkylamino (C Ce), dialkylamino (Ci-Cß), phenyl substituted with 5-6 membered heterocyclic rings containing from 1 to 4 nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the Phenyl radical of any of the above substituents may be optionally substituted with one or more substituents, preferably with from zero to two substituents, which are independently selected from halo groups, (C1-C3) alkyl, (C1-6) alkoxy, C3), nitro, amino, cyano, CF3, and OCF3; n is = 0, 1 or 2; and m is 0, 1 or 2; each R8 and R9 is independently selected from alkyl (C -? - C), arylalkyl (CrC4), wherein said aryl is selected from phenyl and naphthyl; allyl and phenylalyl; i ^ ^^^ r ^ ^^^ X and Y are independently selected from methyl, methoxy, hydroxy and hydrogen; and R10 is alkyl (C6); provided that R8 is absent when n is zero and that R9 is absent when m is zero. Examples of preferred compounds of formula II are those in which NR1R2 is: 4-enoxycarbonylpiperazin-1-yl; 4- (4-fluorophenylacetyl) piperazin-1-yl; 4-phenylethylpiperazin-1-yl; 4-phenoxymethylcarbonylpiperazin-1-yl; 4-phenylaminocarbonylpiperazin-1-yl; 4-benzoylmethylpiperazin-1-yl; 4-benzylcarbonylpiperazin-1-yl; Other preferred compounds of formula II are those in which NR1R2 is a group of formula: wherein NR3R4 is NH2. Other preferred compounds of formula II are those in which it is a group of the formula: AaaáááiiaÉs = wherein R is an aralkyl, benzyl, for example, and R is 4-fluorophenylacetyl. Preferred specific compounds of formula II include: 1- (4- {2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} -piperazin-1 - l) -ethanone; 1- (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -etyl} -piperazin-1-yl) -2-methoxy-ethanone; * 1- (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} -piperazin-1-yl) -2-phenoxy-20-ethanone; (4- {2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} -piperazin-1-yl) -cyclopentyl-methanone; 1- (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} - piperazin-1-yl) -2-phenyl-ethanone; 3-. { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} -3-azabicyclo [3.1.0] hex-6-ylamine; 2- (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} - piperazin-1-yl) -2-phenyl-ethanone; 5 1 - (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} -piperazin-1-yl) -2- (4- fluoro- phenyl) -ethanone; 6- { 4- [2- (4-phenyl-piperazin-1-yl) -ethyl] -phenyl} -pyridin-2-ilamine; 2- (4-. {2- [4- (6-Amino-pyridin-2-yl) -phenyl] -etyl} -piperazin-1-yl) -1-phenyl-ethanol; 10 { 2- [4- (6-Amino-pyridin-2-yl) -phenyl] -ethyl} - (3-oxa-9-azabicyclo [3.3.1] non-7-yl) -amine; 6- (4- { 2- [4- (2-amino-2-phenyl-ethyl) -piperazin-1-yl] -ethyl} -phenyl] -pyridin-2-ylamine; 6- { 4- [4-amino-2,6-dimethyl-p-peridin-1-yl) -ethyl] -phenyl} -piridin-2- 15 laminate; 6- { 4- [2- (4-methyl) -piperazin-1-yl) -ethyl] -phenyl} -p¡r¡din-2-¡la! 3-. { 2- [4- (6-Amino-pyridin-2-yl) -phenyl] -ethyl} 3-azabicyclo [3.1.0] hex-6-yl) -dimethyl-amine; 6- [4- (2-Amino-ethyl) -phenyl] -pyridin-2-ylamine; 20 6-. { 4- [2- (8-aza-spiro [4.5] dec-8-yl) -ethyl] -phenyl} -pyridin-2-ylamine; 6- { 4- [2- (4-isobutyl) -piperazin-1-yl) -ethyl] -phenyl} -pyridin-2-amine; 2- (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -etyl} -piperazin-1-yl) -N-isopropyl- acetamide; 4- p-tolylamide. { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -etl} -piperazin-1-yl) -1-carboxylic acid; 6- (4- { 2- [4- (3-phenyl-propyl) -piperazin-1-yl] -ethyl} -phenyl) -pyridin-2-ylamine; 1 - (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} - piperazin-1-yl) -2- (4-chloro-phenyl) ) -etanone; 8-. { 2- [4- (6-amino- pyridin-2-yl) -phenyl] -ethyl} -3-benzyl-1, 3,8-triaza-spiro [4.5] decane-2,4-dione; N- (1- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl.} - pyrrolidin-3-yl) -2- (4-fluoro) phenyl) -acetamide: 8-. { 2- [4- (6-Amino-pyridin-2-yl) -phenyl] -ethyl} -8-azabicyclo [3.2.1] oct-3-ylamine; 3-. { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -etl} 3-azabicyclo [3.2.1] oct-8-ylamine; 2-amino-1- (4-. {-2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} -piperazin-1-yl) - 3-phenyl-propan-1 -one; 6- { 4- [2- (4-amino-piperidin-1-yl) -etl] -phenyl} -pyridin-2-ilamine; 6- { 4- [2- (4-Benzylhydrol-piperazin-1-yl) -ethyl] -phenyl} -pyrene-2-ylamine; 6- { 4- [2- (4-benzhydryl-piperidin-1-yl) -ethyl] -phenyl} -pyridin-2-ylamine; 6- { 4 - [(cyclohexyl-methyl-amino) -methyl] -phenyl} -pyridin-2-ilamine; 6- { 4 - [(cyclohexyl-methyl-amino) -methyl] -2-methoxy-phenyl} -pyridin-2-ilamine; 6- [4- (phenethylamino-methyl) -phenyl] -pyridin-2-ylamine; ,, '> - * - 6- [2-methoxy-4- (phenethylamino-m thi) -phenyl] -pyridin-2-ylamine; 6- [4- (4-amino-piperidin-1-ylmethyl) -phenyl]} -pyridin-2-ilamine; 6- { 4 - [(cyclohexyl-methylene-amino) -methyl] -2-fluoro-phenyl} -pyridin-2- ilamine; Other preferred compounds of formula II include: 1- (4-. {2- [4- (6-amino-pyridin-2-yl) -2-methoxy-phenyl] -etyl} - piperazin-1-yl) -2-phenyl-ethanone; 6- { 4- [2- (4-isobutyl-piperazin-1-yl) -ethyl] -2-methoxyphenyl} -pyridin-2- ilamine; 10 3-. { 2- [4- (6-Amino-pyridin-2-yl) -2-methoxy-phenyl] -ethyl} -3-azabicyclo [3.1.0] hex-6-ylamine; . { 2- [4- (6-Amino-pyridin-2-yl) -2-methoxy-phenyl] -ethyl} - (3-oxa-9-azabicyclo [3.3.1] non-7-yl) -amine; 6- (4-. {2- 2- (4- (2-amino-2-phenyl-ethyl) -piperazin-1-yl] -ethyl.} -2-methoxy-phenyl) - 15 pyridin-2-ylamine; 6- { 4- [2- (4-amino-2-methoxy-piperidin-1-yl) -ethyl] -2-methoxy-phenyl} - pyridin-2-ylamine; 2- (4-. {2- [4- (6-amino-pyridin-2-yl] -2-methoxy-phenyl] -ethyl} -piperazin-1-yl) -N- isopropyl acetamide: 6- [4- (4-amino-piperidn-1-ylmethyl) -2-methoxy-phenyl] -pyridin-2-ylamine; 1- (4-. {2 - [4- (6-amino-pyridin-2-yl) -2-methyl-phenyl] -ethyl] -piperazin-1-yl) -2-phenyl-ethanone; 6- { 4- [2- (4-isobutyl-piperaz? N ^ C-1) -ethyl] -2-methyl-phenyl} -p¡r¡din-2- ilamine; 3-. { 2- [4- (6-Amino-pyridin-2-yl) -2-methyl-pheny] -ethyl} -3-azabicyclo [3.1.0] hex-6-ylamine; 2- (4- { 2- [4- (6-Amino-pyridin-2-yl) -2-methyl-phenyl] -ethyl} -piperazin-1-yl) -2-phenyl -etanone; 1- (4- { 2- [4- (6-Amino-pyridin-2-yl) -2-methy1-phenyl] -ethyl}. Piperazin-1-yl) -2- (4- fluoro-phenyl) -ethanone; 6- { 4- [2- (4-phenethyl-piperazin-1-yl) -ethyl] -2-methyl-phenyl} -pyridin-2-ylamine, 2- (4- { 2- [4- (6-Amino-pyridin-2-yl) -2-methyl-phenyl] -ethyl} -piperazin-1-yl ). Phenyl ethanol;:. { 2- [4- (6-Amino-pyridin-2-yl) -2-methyl-phenyl] -ethyl} - (3-oxa-9-azabicyclo [3.3.1] non-7-yl) -amine; 6- (4- { 2- [4- (2-amino-2-phenyl-ethyl) -piperazin-1-yl] -ethyl.} -2-methyl-phenyl) -15-pyridin-2-ylamine; 6- (4-. {2- (4-amino-2,6-dimethyl-p-peridin-1-yl) -ethyl] -2-methyl-phenyl) -pyridin-2-ylamine; 2- (4- { 2- [4- (6-Amino-pyridin-2-yl] -2-methyl-phenyl] -ethyl} -piperazin-1-yl) -N-isopropyl- acetamide: 6- [4- (4-amino-piperidin-1-ylmethyl) -2-methyl-phenyl] -pyridin-2-ylamine; N- (1- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl.} - pyrrolidin-3-yl) -2-phenyl-acetamide; SlÍ - Att »- i ^^^ ^^ ___ ^^^^^^^^^^^^^^^^ N- (1- { 2- [4- (6-amino-pyridin-2 -fl) -phenyl] -ethyl.} - pyrrolidin-3-yl) -2- (3-trifluoromethylphenyl) -acetamide; N- (1- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl.} - pyrrolidin-3-yl) -2- (4-tolyl) -acetamide; 5 N- (1- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl.} - pyrrolidin-3-yl) -2- (4-methoxyphenyl) -acetamide; 2- (4- { 2- [4- (6-Amino-pyridin-2-yl) -2-methoxy-phenyl] -ethyl} -piperazin-1-yl) -1-phenyl-ethanone; 1- (4-. {2- 2- [4- (6-amino-pyridin-2-yl) -2-methoxy-phenyl] -ethyl} -piperazin-1-yl) -10 2- (4-fluoro-phenyl) -ethanone; N- (1- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} - pyrrolidin-3-yl) -2-cyclohexyl-acetamide; 2- (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} -piperazin-1-yl) -1- (4-tolyl) - ethanone; 2- (4- { 2- [4- (6-Amino-pyridin-2-yl) -phenyl] -ethyl} -piperazin-1-yl) -1 - (4-methoxyphenyl) -ethanone; 2- (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} - piperazin-1-yl) -1- (4-chlorophenyl) -ethanone; 2- (4- { 2- [4- (6-Amino-pyridin-2-yl) -phenyl] -ethyl.} - piperazin-1-yl) -1- (4-fluorophenyl) -ethanone; 2- (4- { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -etyl} -piperazin-1-yl) -1- cyclohexyl-ethanone; . 1- (4-. {2- 2- [4- (6-Amino-pyridin-2-yl) -2-fluoro-phenyl] -ethyl} -piperazin-1-yl) -2-phenyl- ethanone; 6- { 4- [2- (4-Isobutyl-p-piperazin-1-yl) -ethyl] -2-fluoro-phenyl} -pyridin-2-ylamine; 3-. { 2- [4- (6-Amino-pyridin-2-yl) -2-fluoro-pheny] -ethyl} -3-aza-bicyclo [3.1.0] hex-6-ylamine; 2- (4- { 2- [4- (6-amino-pyridin-2-yl) -2-fluoro-phenyl] -ethyl} - piperazin-1-yl) -1-phenyl-ethanone; 1- (4- { 2- [4- (6-amino-pyridin-2-yl) -2-fluoro-phenyl] -ethyl} -piperazin-1-yl) -2- (4-fluoro-phenyl) -ethanone; 6- { 4- [2- (4-phenethyl-piperazin-1-yl) -etl] -2-fluoro-phenyl} -pyridin-2-ilamine; 2- (4-. {2- [4- (6-amino-pyridin-2-yl) -2-fluoro-phenyl] -ethyl} -piperazin-1-yl) -1- phenyl ethanol; . { 2- [4- (6-amino-pyridin-2-yl) -2-fluoro-phenyl] -ethyl} - (3-oxa-9-aza-bicyclo [3.3.1] non-7-yl) -amine; 6- (4- { 2- [4- (2-amino-2-phenyl-ethyl-piperazin-1-yl] -ethyl} -2-fluoro-phenyl}. Pyridin-2-ylamine 6- {4- [2- (4-amino-2-fluoro-piperidin-1-yl) -ethyl} -2-fluoro-phenyl} -pyridin-2- Ilamine; 2- (4- { 2- [4- (6-Amino-pyridin-2-yl] -2-fluoro-phenyl] -ethyl} -piperazin-1-yl) -N-isopropyl- acetamide: 6- [4- (4-amino-piperidin-1-ylmethyl) -2-fluoro-phenyl] -pyridin-2-ylamine; 6- { 4- [2- (4-amino-2,6-dethyl-piperidin-1-yl) -ethyl] -phenyl} -pyridin-2-ylamine; 6- { 4- [2- (4-amino-2,6-dibenzyl-piperidin-1-yl) -ethyl] -phenyl} -pyridin-2- ilamine; . { 2- [4- (6 { Amino-pyridin-2-yl) -phenyl] -ethyl} - (9- (4-fluoro) -benzyl- (3-oxa-9-aza-bicyclo [3.3.1] non-7-yl) -amine; {. 2- [4- (6-amino-py ? din-2-yl) -phenyl] -etyl.} - (9- (4-chloro) -benzyl- (3-oxa-9-aza-bicyclo [3-3-1] non-7- il) -amine; {. 2- [4- (6-amino-pyridin-2-yl) -phen?] -ethyl.} - - (9- (4-methyl) -benzyl- (3 -oxa-9-10 aza-bicyclo [3.3.1] non-7-yl) -amine; . { 2- [4- (6-amino-pyridin-2-yl) -phenyl] -ethyl} - (9- (4-methoxy) -benzyl- (3-oxa-9-aza-bicyclo [3-3-1] non-7-yl) -amine, other examples of NOS inhibitory compounds that can be Use in the methods and pharmaceutical compositions of this invention are compounds of the formula: ^, - cy. ^ and & ^ & ^ ^^ and. ^. wherein X is CHOH, CH &, or CHR10 wherein R10, together with X, the CH2 group adjacent to X and the nitrogen of NR1R2 form a saturated ring of 5 or 6 links; R1, R2, R3 and R4 are independently selected from alkyl (d-Cß), tetrahydronaphthalene, aryl and aralkyl, wherein said aryl and the aryl radical of said aralkyl is phenyl or naphthyl and the alkyl radical is a chain, linear or branched, of 1 to 6 carbon atoms; and wherein said (C -? - C6) alkyl, tetrahydronaphthalene and the aryl radical of said araalkyl can be optionally substituted with one to three substituents, preferably with zero to two substituents, which are independently selected from between halo groups (chloro, fluoro, bromo or iodo, for example), nitro, hydroxy, cyano, amino, alkoxy (CrC4), and alkylamino (C4); or R1 and R2 form together with the nitrogen to which they are attached, a piperazine ring, azetidine, piperidine or pyrrolidine, or an azabicyclic ring containing from 6 to 14 links, from 1 to 3 of which are nitrogen and the remainder are carbon; and wherein the following can be examples of said azabicyclic rings: wherein R5 can be selected from hydrogen (C? -C6) alkyl, phenyl, naphthyl, alkyl (C6) -C = O-, HC (= 0), (C6) alkoxy - C = 0-, phenyl- (C = O) -, naphthyl- (C = 0) - and R8R9NC (= O) - wherein R8 and R9 are independently selected from hydrogen and alkyl (C C6); R7 is selected from hydrogen, alkyl (CrC6), phenyl, naphthyl, phenylalkyl (C? -C6) -, and naphthylalkyl (C? -C6) -; and wherein said piperazine, azetidine, piperidine or pyrrolidine rings can be optionally substituted with one or more substituents, preferably with from zero to two substituents which are independently selected from (C6) alkyl, amino, alkylamino (C? -C6), dialkylamino (CrC6), phenyl substituted with 5-6 membered heterocyclic rings containing from 1 to 4 nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the Phenyl radical of any of the above substituents may optionally be substituted with one or more substituents, preferably with zero to two substituents, which are independently selected from halo groups, (C1-C3) alkyl, (C1) alkoxy -C3), nitro, amine, cyano, CF3 and OCF3; and wherein R3 and R4, together with the carbon to which they are attached, form a carbocyclic ring of 3 to 8 links optionally substituted; and the pharmaceutically acceptable salts thereof. Other specific configurations of the compounds of formula III include: (a) compounds of formula III in which R1, R2, R3 and R4 are independently selected from alkyl (C-i-Cß); (b) compounds of formula III in which R3 and R4 are independently selected from alkyls (C? -C6); and 1 and R2, along with the nitrogen to which they are attached, form a ring; (c) compounds of formula III in which one of the groups R1 and R2 is independently selected from alkyl (C -? - C6), and the other of phenyl and phenylalkyl (C? -C6); (d) compounds of formula III wherein R1 and R2 together with the nitrogen to which they are attached, form a piperazine, piperidine or pyrrolidine ring; and (e) compounds of formula II in which R1 and R2 is independently selected from alkyl (C? -C6); and R3 and R4, together with the carbon to which they are attached, form a ring; Preferred compound examples of formula III are: 6- [2-isopropoxy] -4 - ((4-phenethylpiperazin-1-yl) -ethyl) -phenyl] -pyridin-2-ylamine; 6- [2-isobutoxy-4 - ((4-phenethylpiperazin-1-yl) -etl] -phenyl] -pyridin-2-ylamine; 6- [2-isobutoxy-4 - ((4-dimethylaminoetyl) -phenyl] -pyridin-2-ylamine; 6- 6- [2-isopropoxy] - (N- (2-methyl) propi l-4- (pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine; 1- [4- (6-amino-pyridin-2-yl) -3-ylpropoxy-phenyl] -2- (4-phenethyl-piperazin-1-yl) -ethanol; 6- [2-Cyclopentylloxy-4 - ((4-dimethylaminoethyl) -phenyl] -pyridin-2-ylamine; 6- [2-cyclopentyloxy] -4 - ((4-phenethylpiperazin-1-yl) -ethyl) -phenyl] -pyridin-2-ylamine; and the pharmaceutically acceptable salts of the above compounds. Other examples of specific compounds of formula III are: 6- [2-cyclopentyloxy-4 - ((4-phenethyl-1-piperazin-1-yl) -ethyl) -phenyl] -pyridin-2-ylamine; 6- [2-cyclobutyloxy-4 - ((4-phenethylpiperazin-1-yl) -ethyl) -phenyl] -pyridin-2-ylamine; 6- [2-cyclopropyloxy-4 - ((4-phenethylpiperazin-1-yl) -ethyl) -phenyl] -pyridin-2-ylamine; 6- [2-pentyloxy-4 - ((4-phenethylpiperazin-1-yl) -ethyl) -phenyl] -pyridin-2-ylamine; 6- [2-isohexyloxy-4 - ((4-phenethylpiperazine-1-l) -ethyl) -phenyl] -pyridin-2-ylamine; 6- [2-cyclopentyloxy- (N- (2-methyl) propyl-4- (pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine; 6- [2-cyclohexyloxy- ( N- (2-methyl) propyl-4- (pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine; 6- [2-cyclobutyloxy- (N- (2-methyl) propyl; -4- (pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine; • -.... To M -, - ^ «a .-. I. -.... - - '. ,,, ^^ ^, ^ fe ^ ^^^^ S ^^^ fcga ^^^^^ g JftA? »^^ jA ^^ A * ^^ _ 8f 6- [ 2-cyclopropyloxy- (N- (2-methyl) propyl-4- (pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine; 6- [2-pentyloxy- ( N- (2-methyl) propyl-4- (pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine; 5-6- [2-isohexyloxy- (N- (2-methyl) propyl) -4- (pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine; 1- [4- (6-amino-pyridin-2-yl) -3-isobutoxy-phenyl] -2- (4 -phenethyl-piperazin-1-yl) -ethanol; 1- [4- (6-amino-pyridin-2-yl) -3-isopropoxy-pheny] -2- (6,7-dimethoxy-10-tetrahydroisoquinoline) -2-yl) -ethanol; 1- [4- (6-amino-pyridin-2-yl) -3-isobutoxy-phenyl] -2- (4-dimethylamine-piperazine-1 - il) -ethanol: 1- [4- (6-amino-pyridin-2-yl) -3-isopropoxy-phenyl] -2- (dimethylamino) -ethanol, and 15 1 - [4- (6-amino-p Ridn-2-yl) -3-cyclopentyloxy-phenyl] -2- (4-phenethyl-piperazin-1-yl) -ethanol, and the pharmaceutically acceptable salts of the above compounds. Examples of NOS inhibitor compounds that can be used in the methods and pharmaceutical compositions of this invention are compounds of formula: wherein R1 and R2 are independently selected from hydrogen, halo, hydroxy, alkoxy (CrC6), (C1-C7) alkyl, (C2-C6) alkenyl, and (C2-C10) alkoxyalkyl; and G is selected from hydrogen, alkyl (Ci-Cß), alkoxy (Cr C6) alkyl (d-Cs), aminocarbonylalkyl (C1-C3), alkylaminocarbonylalkyl (C1-C3), di (alkyl (CrC3)) aminocarbonylalkyl ( C1-C3), and alkyl (Co-C) N (R3) (R4), wherein R3 and R4 are independently selected from hydrogen, (C -? - C7) alkyl, tetrahydronaphthalene and aralkyl, wherein the aryl radical of said aralkyl is phenyl or naphthyl and the alkyl radical is a straight or branched chain of 1 to 6 carbon atoms; and wherein said (d-C7) alkyl, aryl, tetrahydronaphthalene and the aryl radical of said araalkyl can be optionally substituted with one to three substituents, preferably with zero to two substituents, which are independently selected from between halo, nitro, hydroxy, cyano, amino, alkoxy (CrC), and alkylamino groups or R3 and R4 form, together with the nitrogen to which they are attached, a piperazine ring, azetidine, piperidine or pyrrolidine, or an azabicyclic ring containing from 6 to 14 links, from 1 to 3 of which are nitrogen, from zero two of which are oxygen and the rest are carbon; _ • «- _fe_fey * •" - • - aSfc. and wherein said piperazine, azetidine, piperidine or pyrrolidine rings and said azabicyclic ring systems may be optionally substituted with one or more substituents, preferably with from zero to two substituents which are independently selected from alkyl (Ci). -Cß), amino, alkylamino (C? -C6), dialkylamino (CrC6), phenyl substituted with 5- to 6-membered heterocyclic rings containing from 1 to 4 nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl , and wherein the phenyl radical of any of the above substituents may be optionally substituted with one or more substituents, preferably with zero to two substituents, which are independently selected from halo groups, (C1-C3) alkyl ), (C-1-C3) alkoxy, nitro, amino, cyano, CF3 and OCF3; and wherein said piperazine, azetidine, piperidine or pyrrolidine rings and said azabicyclic ring systems can be attached to an -alkyl (Co-C4) -O- group (wherein the oxygen of said -alkyl group (C0-C4) ) -O- is the oxygen atom represented in structural formula I), a nitrogen atom of the NR3R4 ring or any other atom of said ring possessing an available binding site; or G is a group of formula A wherein Z is nitrogen or CH, n is zero or one, q is zero, one, two or three and p is zero, one or two; and wherein the 2-aminopiperidine ring represented in the above structure I can be optionally substituted with: and the pharmaceutically acceptable salts of said compounds. Examples of compounds of formula IV are those in which G is (C0-C4) alkyl N (R3) (R4) and N (R3) (R4) is amino, dimethylamino, methylbenzylamino, (C? -C4) amino alkyl, dialkyl (C? -C4) amino or one of the following groups: H fifteen The compounds of formula IV preferably include those in which R 2 is hydrogen and R 1 is (C 1 -C 3) alkoxy, and is in the ortho position with respect to the pyridine ring of formula IV. Other compounds of formula IV are those in which G is a group of formula A, as defined above, wherein Z is nitrogen. Other compounds of formula IV are those in which R1 and R2 are independently selected from (C1-C2) alkoxy groups. Other compounds of formula IV are those in which G is a group of formula A, as defined above, wherein Z is nitrogen, p and n are 1 and q is two.
Other compounds of formula IV are those in which the 2-aminopiperjdine ring represented in the above formula VI is present. Other examples of NOS inhibitor compounds that can be used in the methods and pharmaceutical compositions of this invention are compounds of the formula: Wherein R1 and R2 are independently selected from hydrogen, hydroxy, methyl and methyloxy; and G is a group of formula (A) (B) where n is zero or one; Y is NR3R4, alkyl (CrCß), or aralkyl, wherein the aryl radical of said aralkyl is phenyl or naphthyl and the alkyl radical is a straight or branched chain of 1 to 6 carbon atoms; and wherein said (C -? - C6) alkyl and the aryl radical of said aralkyl alkyl can be optionally substituted with ¿^^^^^ á ^ A ^ a & * ^. ^ Fj - ^. one to three substituents, preferably with zero to two substituents, which are independently selected from halo groups (chloro, fluoro, bromo or iodo, for example), nitro, hydroxy, cyano, amino, alkoxy (d) -C4), and alkylamino (C -? - C4); 5 X is N when Y is alkyl (d-Cß), aralkyl, or substituted (d-Cß) alkyl, and X is CH when Y is NR3R4; q is zero, one or two; m is zero, one or two; R3 and R4 are independently selected from alkyl (CrC6), tetrahydronaphthalene and aralkyl, wherein the aryl radical of said aralkyl is phenyl or naphthyl and the alkyl radical is a straight or branched chain of 1 to 6 carbon atoms; and wherein said alkyl (d-Cß), tetrahydronaphthalene and the aryl radical of said araalkyl can be optionally substituted with one to three substituents, preferably with zero to Two substituents, which are independently selected from halo groups (chloro, fluoro, bromo or iodo, for example), nitro, hydroxy, cyano, amino, alkoxy (d-d), and alkylamino (C C); or R3 and R4 form together with the nitrogen to which they are attached, a piperazine ring, azetidine, piperidine or pyrrolidine, or an azabicyclic ring which contains from 6 to 14 links, from 1 to 3 of which are nitrogen and the remainder are carbon, in which an example of said azabicyclic rings is the 3-aza-bicyclo [3.1.0] hex-6- ring ilamine; Aria «« BHfefc Mia e »*, - ..A _ _ -_ _.T and wherein said piperazine, azetidine, pyperidine or pyrrolidine rings can be optionally substituted with one or more substituents, preferably with zero to two substituents which are independently selected from amino, alkylamino (Ci-Cd), dialkylamino (d-Ce), phenyl substituted with 5- to 6-membered heterocyclic rings containing from 1 to 4 nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl radical of any of the above substituents may be optionally substituted with one or more substituents, preferably with zero to two substituents, which are independently selected from between halo groups, (C 1 -C 3) alkyl, (C 1 -C 3) alkoxy, nitro, amino, cyano, CF 3 and OCF 3; and the pharmaceutically acceptable salts of said compounds. Examples of preferred compounds of formula V are those in which NR3R4 is: 4-phenylethylpiperazin-1-yl; 4-methylpiperazin-1-yl; phenethylamino; or 3-aza-bicyclo [3.1.0] hex-6-ylamine. Other preferred compounds of formula V are those in which NR3R4 is a group of formula wherein NR5R6 is NH2. Other examples of NOS inhibitor compounds that can be used in the methods and pharmaceutical compositions of this invention are compounds of the formula: where n and m in the bridge rings are, independently, 1, 2 or 3, and a carbon atom in one of said bridge rings can be substituted by a heteroatom selected from O, S and N, provided that the carbon bridgehead can be replaced only by nitrogen, and R1 and R2 are independently selected from alkyl (d-C6), which may be a branched or cyclic linear chain, or may contain linear and cyclic radicals or radicals branched or cyclical; and in each of the groups R1 and R2 can be optionally substituted, independently, with one to three substituents, preferably with zero to two substituents, which are independently selected from , _?; * 3fri &'; if _Si__itat¿fc _' .. «-« R = -. halo groups (chloro, fluoro, bromo or example), nitro, hydroxy, cyano, amino, alkoxy (d-C4), and alkylamino or R1 and R2 form, together with the nitrogen to which they are attached, a piperazine ring, azetidine, piperidine or pyrrolidine, or an azabicyclic ring containing from 6 to 14 links, from 1 to 3 of which are nitrogen and the remainder are carbon, wherein the distal nitrogen of said piperazine ring or azabicyclic ring is optionally substituted with groups R3 and R4 which can be selected from hydrogen, alkyl (CrC6), phenyl, naphthyl, alkyl (d-C6) -C (= 0) -, CH (= O) -, alkoxy (d-C6) -C = O -, phenyl-C (= O) -, naphthyl- (C = 0) - and R6R7NC (= 0) - wherein R6 and R7 are independently selected from hydrogen and alkyl (d-C6); provided that when the azabicyclic ring is a spirocyclic ring, the distal nitrogen in said spirocyclic ring is optionally substituted with R5, wherein R5 is selected from hydrogen, alkyl (d-C6), phenyl, naphthyl, alkyl (C? C6) phenyl, alkyl (d-Cβ-naphthyl, and wherein said piperazine, azetidine, piperidine or pyrrolidine rings can be optionally substituted with one or more substituents, preferably with from zero to two substituents is selected independently of alkyl (d-Ce), phenyl substituted with 5- to 6-membered heterocyclic ring containing from 1 to 4 nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl radical of any of the ^^^^? ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ fe ^^^^^^^^^^^^ ^^^^^^^^ previous substituents can optionally be substituted with one or more substituents, preferably with zero to two substituents, which are independently selected from halo groups, (C1-C3) alkyl, alkoxy ( C1-C3), nitro, amino, cyano, CF3 and OCF3; provided that a carbon atom with more than one substituent selected from hydroxy, amino, alkoxy, alkylamino and dialkylamino is not substituted; and the pharmaceutically acceptable salts of said compounds. The examples of azabicyclic rings that can form the group NR1R2 in the above compound formulas VI are: > - ° £ j a * ¿_ < í. »_. __ »- e r * - ^" faith * -_. ~ ^ • $ * & __ "_ < *% * .. g __ .YES. _? Á_ wherein R3 and R4 which may be selected from hydrogen, alkyl (d-C6), phenyl, naphthyl, alkyl (d-C6) -C (= 0) -, CH (= 0) -, alkoxy (C? - C6) -C = 0-, phenyl-C (= 0) -, naphthyl- (C = 0) - and R6R7NC (= 0) - wherein R6 and R7 are independently selected from hydrogen and alkyl (d- 5 C6); and wherein R5 is selected from hydrogen, alkyl (C Cd), phenyl, naphthyl, alkyl (d-C6) phenyl, alkyl (CrC6) naphthyl. Preferred formula IV compounds include those in which NR1R2 is a piperidine, azetidine, piperazine or pyrrolidine ring, or is a 3-aza-bicyclo [3.1.0] hex-6-ylamine ring; and wherein said piperazine ring, azetidine, piperidine, pyrrolidine and 3-aza-bicyclo [3.1.0] hex-6-ylamine can be optionally substituted with one or more substituents, preferably with zero to two substituents are independently selected from alkyl (C? -C6), amino, alkylamino (d-C?), dialkylamino (CrC6), phenyl substituted with heterocyclic ring to 6 links containing from 1 to 4 nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl radical of any of the above substituents may be optionally substituted with one or more substituents, preferably with zero to two substituents, which are independently selected from halo groups, (C1-C3) alkyl, (C1-C3) alkoxy, nitro, amino, cyano, CF3, and OCF3; and the pharmaceutically acceptable salts of said compounds. The following compounds are the preferred compounds of formula VI: 6- [8- (2-dimethylamino-ethoxy) -1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl] -pyridin- 2-ylamine; 6- [8- (2-pyrrolidin-1-yl-ethoxy) -1, 2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl] -pyridin-2-ylamine; Other compounds of formula VI are the following; 10 6- [8- (2-dimethylamino-ethoxy) -1,2,3,4-tetrahydro-1,4-ethano-naphthalen-5-yl] -pyridin-2-ylamine; 6- [8- (2-pyrrolidin-1-yl-ethoxy) -1, 2,3,4-tetrahydro-1,4-ethano-naphthalen-5-yl] -pyridin-2-ylamine; 6- [8- (2- (4-dimethylamino-piperidin-1-yl-ethoxy) -1, 2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl] -pyridin-2- Laminate: 6- [8- (2- (6,7-dimethoxy-tetrahydroisoquinol-2-yl) -ethoxy) -1,2,3,4-tetrahydro-1,4-methano-naphthalene-5-yl ] -pyridin-2-alamine; 6- [8- (2- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-1,4-methano-naphthalene-5-yl ] -pyridin-2-ylamine: The compounds of formulas I to VI can have chiral centers and, therefore, can exist in various enantiomeric and distereoisomeric forms The invention relates to the above methods of treatment by using the compositions pharmaceuticals that they include all optical isomers and all stereoisomeric compounds of the compounds of formulas I to VI, and mixtures thereof. The term "alkyl", as used herein, includes, unless otherwise indicated, monovalent radicals of saturated hydrocarbons with a linear, branched or cyclic radical, or with combinations thereof. The term "one or more substituents", as used herein, refers to a number of substituents ranging from one or a number of available linkage sites. The terms "halo" and "halogen", as used herein, unless otherwise indicated, include chlorine, fluorine, bromine and iodine. The preceding formulas I to VI include identical compounds to those represented except for the fact that one or more hydrogens, carbons or other atoms are replaced by isotopes thereof. Said compounds can be useful as research and diagnostic instruments in pharmacokinetic studies of metabolism and in agglutination tests. > and ^ DETAILED DESCRIPTION OF THE INVENTION X * In the discussion that follows, formulas I, II, III, IV, V and VI are defined as set forth above in the summary of the invention. The compounds of formula I and the pharmaceutically acceptable salts thereof can be prepared as described below, and as described in the provisional application E.U.A. 60/057094, filed on August 27, 1997- and entitled "2-Aminopyridines Containing Fused Ring Substituents", and in the PCT application of the same title registered on May 5, 1998, which designates the United States and which claims the priority of the provisional application 60/057094. In schemes 1 to 3 and in the discussion of schemes 1 to 3 below, all substituents as defined above for the compounds of formula I are defined. faith »áte.i_i.? ^ s y.
SCHEME 1 (2. 3) (5) (6) (7) IA (X = link, ring A = benzene co) i ^^^ mMHfrftft »SCHEME 2 (10) (eleven) (12) - n &jtf &t ** "TÉ J XÍ- 1. LiAIH4, AICI3 NH2OH? CI R1 (13) 10 IB (X = O, ring, A = benzene) SCHEME 3 (16) (17) IB (ring A = benzene, X = O) Scheme 1 illustrates a method of preparing compounds of formula I wherein X is a bond and ring A is benzene. Schemes 2 and 3 illustrate methods of preparing compounds of formula I wherein X is an oxygen and ring A is benzene. The starting materials used in the procedures of Schemes 1 and 2 are commercially available, are known in the art, or can be readily prepared from known compounds by procedures that are apparent to those skilled in the art. technique. 10 With reference to scheme 1, the compound of formula (2) is cooled to about -70 ° C in tetrahydrofuran (THF), and then a solution of n-butyllithium is added thereto. The resulting solution is treated with triethyl borate and allowed to warm to room temperature to form the compound of formula (3). The compound of formula (3) is then reacted with a compound of formula (4) to form the compound of formula (5). This reaction is usually carried out in a solvent of ethanol in water and in the presence of sodium carbonate and tetrakis (triphenylphosphine) palladium, at reflux temperature. The compound of formula (6) can be obtained in the following manner. First, the compound of formula (5) is reacted with N-bromosuccinimide (NBS) and with bis- (1-cyano-1-aza) -cyclohexane in carbon tetrachloride, then maintained under reflux for 8 hours, and adding additional portions of the initiator after 1, 2 and 4 hours. Once the solvent has evaporated, the product of A * reaction is reacted with triethylammonium cyanide in methylene chloride at room temperature to form the compound of formula (6) The saturation of the solution of the compound of formula (6). ) in ethanol with hydrogen chloride, followed by refluxing the mixture and heating, then, in aqueous hydrochloric acid, gives a compound of formula (7). The compound of formula (7) obtained in the previous step can be converted into the compound of formula IA in the following manner: First, the compound of formula (7) is reacted with the appropriate compound of formula R2R1NH and with N-ethyl-N-direthylaminopropylcarbodiimide (EDAC) in the presence of a base. Suitable bases are those selected from trialkylamines, alkali metal carbonates and alkaline earth metal carbonates.This reaction is usually carried out in a solvent such as acetonitrile, sodium chloride, ethylene or N, N-dimethylformamide (DMF), at a temperature ranging from room temperature to * about 100 ° C (preferably at room temperature). It is also preferred to carry out the reaction in the presence of a catalytic additive such as N-hydroxysuccinamide or hydroxybenzotriazole. The product of the above reaction is then reduced by methods well known in the art. The reduction can be done, for example, using lithium aluminum hydride in tetrahydrofuran, with or without aluminum chloride, or using borane methylsulfide in tetrahydrofuran, at a temperature of about -78 ° C to about 0 ° C (preferably -70 ° C), to give the desired compound of formula IA. With reference to scheme 2, the compound of formula (8) is reacted with tetrabutylammonium tribromide in 1,2-dichloroethane at room temperature. The product of this reaction is then treated with benzyl bromide and with potassium carbonate in a solvent such as acetonitrile, at reflux temperature to give the compound of formula (9). The compound of formula (9) is converted to 1-benzyloxy-naphthalene-4-boronic acid by the procedure described above to prepare the boronic acid derivative of formula (3) in scheme 1. The reaction of 1-benzyloxy acid Naphthalene-4-boronic acid with the compound of formula (10) in ethanol solvent, in the presence of sodium carbonate and tetrakis (triphenylphosphine) palladium, at reflux temperature gives the compound of formula (11). The compound of formula (11) can be converted to the compound of formula (13) by following the following two-step process. The compound of formula (11) is reacted with ammonium formate and with 10% palladium on carbon, in ethanol solvent, at the reflux temperature of the reaction mixture, to give the analogous compound to that of formula (11) , wherein the benzyloxy group of the formula (11) is substituted with a hydroxy group. The compound of formula (12) is then formed by reacting the above X.sub.2, X.sub.2, X.sub.x.sup.-, hydroxy derivative with 2-bromoethylacetate and potassium carbonate in acetonitrile at the reflux temperature of the reaction mixture. The basic hydrolysis of the compound of formula (12), followed by reaction with N-ethyl-N-dimethylaminopropylcarbodimide (EDAC) and the appropriate compound of formula R2R1NH gives the desired compound of formula (13). Basic hydrolysis is usually carried out using an alkali metal or alkaline earth metal hydroxide in a mixture of THF, methanol and water at room temperature. The reaction with R2R1NH and (EDAC) is usually carried out using the procedure described above to prepare the compound of formula IA from the compound of formula (7) of scheme 1. The compound of formula (13) can be converted to the compound of formula IB as follows. The compound of formula (13) is reduced to form the corresponding compound in which the carbonyl group is replaced by a methylene group, after which the protecting group, 2,5-15 dimethylpyrrolyl, is removed. The reduction can be carried out using procedures well known in the art, using, for example, lithium aluminum hydride in tetrahydrofuran, with or without aluminum chloride, or using borane methylsulfide in tetrahydrofuran, at a temperature of about -78 ° C (preferably -70 ° C). The removal of the 2,5-dimethylpyrrolyl protecting group can be completed by reaction with hydroxylamine hydrochloride. This reaction is usually carried out in alcoholic solvent, or in aqueous alcoholic solvent at a temperature ranging from room temperature to temperature »Faith _- ^ • > * .. reflux (preferably at reflux temperature), for a period of 8 to 72 hours. The compounds of formula I, which are identical to those of formula IB except for the fact that ring A is a group other than benzene, can be prepared analogously, starting with the appropriate compound which is analogous to that of formula (8). ), in which the unsubstituted benzene ring of formula (8) is replaced by another ring other than benzene which is within the definition of ring A. With reference to scheme 3, 1-fluoronaphthalene (14) which is Well known, bromine is brominated in acetic acid at a temperature ranging from about room temperature to about the reflux temperature of the reaction mixture for a period of 1 to 48 hours. The bromide is then cooled to about -70 ° C in anhydrous tetrahydrofuran (THF) and a solution of n-butyllithium is added thereto. The The resulting solution is treated with triethyl borate and allowed to warm to room temperature to form the compound of formula (15). The compound of formula (15) is then reacted with a compound of formula (4) to form the compound of formula (16). This reaction is usually carried out in an ethanol solvent in water and in the presence of sodium carbonate and tetrakis (triphenylphosphine) palladium, at reflux temperature. The compound of formula (16) is then treated with an alkali metal alkoxide prepared from a compound of the formula HO (CH2) NR1R2 and sodium hydride in a polar solvent such as dimethylformamide, at a temperature ranging from room temperature to 140 ° C for a period of 1 to 48 hours. This reaction produces the corresponding compound of formula (17), which is then deblocked to remove the 2,5-dimethylpyrrolyl protecting group by reaction with hydroxylamine hydrochloride. This reaction is usually carried out in an alcoholic solvent, or in an aqueous alcoholic solvent at a temperature ranging from about room temperature to about the reflux temperature (preferably at reflux temperature), for a period of about 8 to about 72 hours. . The compounds of formula I, which are identical to those of formula IA and IB except for the fact that ring A is a group other than benzene, can be prepared analogously, starting with the appropriate compounds which are analogous to those of formulas (2), (8) and (14), Schemes 1, 2 and 3, respectively, wherein the unsubstituted benzene ring of said starting products is replaced by another ring other than benzene which is within the definition of ring A. The preparation of other compounds of formula I which they have not been specifically described in the above experimental section can be performed using combinations of the reactions described above, which are obvious to those skilled in the art. In each of the reactions discussed or illustrated above, the pressure is not critical, unless otherwise indicated. Pressures of about 50.65 kPa to about 506.5 kPa are usually acceptable, although, as a matter of convenience, the ambient pressure, that is, about 101.3 kPa, is preferred. The compounds of formula II and pharmaceutically acceptable salts thereof can be prepared as described in the published PCT patent application WO 97/36871, which designates the United States and that was published on October 9, 1997. The previous application has been incorporated here in its entirety as a reference. The compounds of formula III and the pharmaceutically acceptable salts thereof can be prepared as described below and in the provisional application of US Pat. No. 60/057739 by John A. Lowe, Ill, entitled "6-Phenylpyridin-2-. yl-amine Derivates ", which was registered on August 28, 1997. The previous application has been incorporated here in its entirety as a reference. Schemes 4 and 5 presented below illustrate processes for preparing compounds of formula III.
SCHEME 4 (18) (19) (twenty) SCHEME 4 (COIW-UATION.
HCl, H20, EtOH (23) (24) (X = CH2) (25) SCHEMES (27) (X = CH2) With reference to scheme 47, the compound of formula (18) is reacted with a compound of formula CHR3R4Br or CHR3R4I and potassium carbonate, in a solvent such as acetonitrile, at about the reflux temperature of the mixture of reaction, in order to convert the hydroxy group of the formula (18) to a group of the formula -OCHR3R4. The resulting compound is then reduced to about room temperature using hydrogen gas in the presence of 10% palladium on carbon, in ethanol solvent, to form 3-OCHR3R4-4-aminotoluene. This is reacted, in turn, with sodium nitrite and with cuprous bromide in concentrated sulfuric acid to form 3-OCHR3R4-4-bromotoluene. The 3-OCHR3R4-4-bromotoluene obtained in the above reaction is cooled to about -70 ° C in anhydrous tetrahydrofuran (THF), and then a solution of n-butyllithium is added. The resulting solution is treated with triethyl borate and allowed to warm to room temperature to form the compound of formula (19): The compound of formula (19) is then reacted with a compound of formula (20) to form the compound of the formula (21).
This reaction is usually carried out in an ethanol solvent in water and in the presence of sodium carbonate and tetrakis (triphenylphosphine) palladium, at about the reflux temperature of the reaction mixture. The compound of formula (23) can be obtained in the following manner. First, the compound of formula (21) is reacted with N-bromosuccinimide (NBS) and with bis- (1-c-ano-1-aza) -cyclohexane (formula f * ^^ i «j £ i? ^ f ü g (22)) in carbon tetrachloride, then refluxing for 8 hours, and adding additional portions of the initiator after 1, 2 and 4 hours. Once the solvent has evaporated, the reaction product is reacted with triethylammonium cyanide in methylene chloride at room temperature to form the compound of formula (23). Saturation of the solution of the compound of formula (23) in ethanol with hydrogen chloride, followed by refluxing the mixture and heating, then, in aqueous hydrochloric acid, gives a compound of formula (24). Basic hydrolysis is usually carried out using an alkali metal or alkaline earth metal hydroxide in a mixture of ethanol and water at a temperature ranging from about room temperature to about the reflux temperature of the solvent. The compound of formula (25) obtained in the previous step can be converted into the compound of formula () (wherein X is CH 2) in the following manner. First, the compound of formula (25) is reacted with the appropriate compound of formula R2R1NH and with N-ethyl-N-dimethylaminopropylcarbodiimide EDAC) in the presence of a base. Examples of suitable bases are those selected from trialkylamines, alkali metal carbonates and alkaline earth metal carbonates. This reaction is usually carried out in a solvent such as acetonitrile, methylene chloride or N, N'-dimethylformamide (DMF), at a temperature ranging from about room temperature to about 100 ° C (preferably at about room temperature). It is also preferred to carry out the reaction in the presence of a catalytic additive such as N-hydroxysuccinamide or hydroxybenzotriazole. The product of the above reaction is then reduced by methods well known in the art. The reduction can be performed, for example, using lithium aluminum hydride in tetrahydrofuran, with or without aluminum chloride, or using borane methylsulfide in tetrahydrofuran, at a temperature of about -78 ° C to about 0 ° C (preferably about 70 ° C), to give the compound of formula III (where X is CH2) desired. Referring to Scheme 5, 4-bromo-3-fluorotoluene is first converted into a boronic acid derivative and then coupled to 6-bromo-2- (t-butylcarbonylamino) pyridine to form a compound of formula (26) as follows. A halogen-metal exchange reaction is carried out in 3-fluoro-4-bromotoluene in tetrahydrofuran, ether, dimethoxyethane, hexane or other suitable ethereal or hydrocarbon solvent, at a temperature ranging from -100 ° C to about room temperature, using butyl lithium or any other suitable alkyl-lithium type reagent, followed by reaction with borate triesters , such as triethyl borate or triisopropyl borate, for a period of about 1 to about 48 hours, and at a temperature ranging from about -100 ° C to about the reflux temperature. The boronic acid intermediate is then converted to the compound of formula (26) in an ethanol solvent in water and in the presence of sodium carbonate and tetrakis triphenylphosphine, palladium, at about the reflux temperature of the reaction mixture, using 6-bromo-2-t-butylcarbonylamino) pyridine as the coupling component. The compound of formula (26) is then converted to the compound of formula (27) by displacement of the fluoro group of the alcohol with the appropriate alcohol, which is formed in a solvent such as dimethylformamide, tetrahydrofuran or dioxane, and a metal hydride as the sodium hydride, at a temperature ranging from about room temperature to about the reflux temperature, for a period of about 5 minutes to approximately 5 hours. The reaction with the compound of formula (26) is carried out in a reaction system, at a temperature ranging from about room temperature to about the reflux temperature, for a period of about 1 to about 48 hours. The compound of formula (27) can be converted in the compound of formula (25) corresponding as follows. First, the compound of formula (27) is reacted with N-bromosuccinimide (NBS) and with bis- (1-cyano-1-aza) -cyclohexane (formula (22)) in carbon tetrachloride, maintaining it after reflux for about 8 hours, and adding additional ingredients of the initiator to the After 1, 2 and 4 hours, to bromide the methyl group of said compound. Once the solvent has evaporated, the reaction product is reacted with triethylammonium cyanide in methylene chloride at about room temperature to form the compound aaibJh .. * »S» ltafaJS - * • «• *«. * «; _. % Jf * t? S? TdSjM corresponding in which the bromo substituent is replaced by a cyano group. The resulting derivative is then hydrolyzed to form the corresponding compound of formula (25). Basic hydrolysis is usually carried out using an alkali metal or alkaline earth metal hydroxide in a mixture of 5 ethanol and water at a temperature ranging from about room temperature to about the reflux temperature of the solvent. The compound of formula (25) obtained in the previous step can be converted into the compound of formula I in the following manner. First, the compound of formula (25) is reacted with the appropriate compound of formula R2R1NH and with N-ethyl-N-dimethylaminopropylcarbodiimide (EDAC) in the presence of a base. Examples of suitable bases are those selected from trialkylamines, alkali metal carbonates and alkaline earth metal carbonates. This reaction is usually carried out in a solvent such as acetonitrile, methylene chloride or N, N'-dimethylformamide.
(DMF), at a temperature ranging from about room temperature to about 100 ° C (preferably at about room temperature). It is also preferred to carry out the reaction in the presence of a catalytic additive such as N-hydroxysuccinamide or hydroxy benzotriazole. The product of the above reaction is then reduced by methods well known in the art. Reduction can be performed, for example using lithium aluminum hydride in tetrahydrofuran, with or without aluminum chlorine, or using borane methylsulfide in tetrahydrofuran, at a temperature of about -78 ° C to about 0 ° C (preferably about -70 ° C). The compounds of formula III wherein X is CHOH can be prepared using procedures analogous to those described in Example 1 of this request. Compounds of formula I in which X is part of a 5- or 6-membered saturated ring can be prepared using procedures analogous to those described in example 2. The starting materials used in the procedures of schemes 4 and 5 are available in the market, they are known in the The technique can be easily prepared from the known compounds by methods that are obvious to those skilled in the art. The preparation of other compounds of formula III that have not been specifically described in the above experimental section can be performed using combinations of the reactions described above, which are apparent to those skilled in the art. In each of the reactions that have been discussed or illustrated above, the pressure is not critical, unless otherwise indicated. Pressures of about 50.65 kPa to 20 about 506.5 kPa are usually acceptable, although, as a matter of convenience, the ambient pressure, that is, about 101.3 kPa, is preferred. The compounds of formula IV and the pharmaceutically acceptable salts thereof can be prepared as described in the application of the patent PCT / IB98 / 00112, entitled "4-amino-6- (2-substituted-4-phenoxy) - substituted-pyridines", which is designated to the United States and which was filed on January 29, 1998. The application above has been incorporated here in its entirety as a reference. The schemes 6 to 14 presented below illustrate processes for preparing compounds of formula IV.
¿J ^ g g? Iás ^ g ^? Jgarf SCHEME 6 (30) SCHEME 6 (continued) (32) Pd (PPh3) 4Na2CO3 EtOH / H2O / heat (3. 4) VAT ^. ^. 2§ari? Haa_ ~ _. _ & .A. ^ < _aJ SCHEME 7 VAT K2C03 / heat GX / K2CO3 GX \ DMF or acetone DMF or acetone (G = CH2C (= 0) NR3R4) IVC SCHEME 8 (36) (37) (Bn = benzyl) (32A) (32B) CONTINUE AS WITH COMPOUND 20 (32) OF SCHEME 1 mSdjfaa. < , SCHEME 9 (38) SCHEME 10 WE IVG SCHEME 11 (42) 15 (43) (44) SCHEME 12 IVJ 10% Pd / C23 ° C 3515k / cm2H / EtOH IVL SCHEME 12 CONTINUED IVL 10 SCHEME 13 (45) (46) Pd ° (47) IVN SCHEME 14 IVP VAT Scheme 6 illustrates a process for preparing compounds of formula I wherein G is hydrogen, R1 is OR where R is an alkyl (d-C6) and R2 is hydrogen. In scheme I, these compounds are referred to as compounds of formula "IA". With reference to scheme 6, the compound of formula (28) is reacted with excess potassium carbonate and with one equivalent of tosyl chloride in acetone, at a temperature ranging from about 0 to about 80 C (preferably at the temperature of reflux of the reaction mixture). A compound of formula RX is then added to the reaction mixture, wherein R is an alkyl (d-Cß) and X is iodine, chlorine or bromine and this mixture is allowed to react at a temperature ranging from about 0 to about 80 C (preferably at the reflux temperature of the mixture). This reaction gives a compound of formula (29) which will then be converted to the corresponding compound of formula (30) by reaction with potassium hydride in ethanol, using water as solvent. This reaction can be carried out at a temperature ranging from about room temperature to about the reflux temperature of the reaction mixture. It is preferred to heat the reaction mixture to reflux and allow it to react at said temperature. The compound of the formula of formula (30) is reacted with potassium carbonate and benzyl bromide in acetone, at a temperature ranging from about room temperature to about 80 C, to form the corresponding compound of formula (31). The reaction preferably carried out at about reflux temperature. Reaction of the resulting compound of formula (31) with n-butyl lithium in tetrahydrofuran (THF) at about 78 C, followed by the addition of triethyl borate leaving the reaction mixture quenched at room temperature, gives the corresponding acid derivative phenylboronic of formula (32). Reacting the phenylboronic acid derivative of formula (32) with 2-bromo-6 (2,5-dimethyl-pyrrol-1-yl) -pyridine (33), with sodium carbonate and with tetrakis (triphenylphosphine) palladium (0) , in ethanol / water or THF / water, at a temperature ranging from about room temperature to about the reflux temperature of the reaction mixture (preferably at about the reflux temperature), gives the corresponding compound of formula (34) . Alternatively, the reagent of formula (33) can be replaced by another wherein P is a nitrogen protecting group such as trityl, acetyl, benzyl, trimethylacetyl, t-butoxycarbonyl, benzyloxycarbonyl, trichloroethyloxycarbonyl and other suitable nitrogen protecting groups; and wherein the hydrogen bonded to the nitrogen protecting group is absent when P is a protecting group that forms a ring with the protected nitrogen, as in the case of P = 2,5-dimethylpyrrolyl. Said protecting groups are well known in the practice of the art. The above compounds of formula (33) are commercially available, are well known in the scientific literature or can be obtained using known methods and reagents. The benzyl substituent can be removed from the compound of formula (34) by reacting said compound with ammonium formate in water or in a lower alcohol solvent, or in a mixture of one or more such solvents, at a temperature which is about the temperature environment at about the reflux temperature of the reaction mixture. It is preferred to carry out this reaction at reflux temperature in presence of 20% palladium hydroxide on carbon. The resulting compound of formula (35) is then converted to the desired compound of formula IV A by reacting it with hydroxylamine in a solvent selected from water, lower alcohols and mixtures of said solvents, at a temperature ranging from about the temperature at about the reflux temperature of the reaction mixture (preferably at about reflux temperature). The method of scheme 6 can also be used to prepare compounds of formula IV in which R1 and R2 are different from those specified and represented in the above scheme. This can be done by the use of a compound of the formula: as a starting product, carrying out the series of reactions, as described above, which are represented in scheme 6 as reactions (30) - »(31) -» (32) - »(33) - (34 ) - »(35) -» (IV A). Scheme 7 illustrates a process for preparing compounds of formula IV wherein G is hydrogen in the corresponding compounds of formula IV in which G is a group other than hydrogen. With reference to scheme 7, a compound of formula IV A can be converted into the corresponding compound of formula IV C by reacting it with the compound of formula GX, wherein X is iodo, chloro or bromo, G is CH2CH2NR3R4, and with potassium carbonate in dimethylformamide (DMF) or in acetone, at a temperature ranging from about room temperature to about the reflux temperature of the reaction mixture (preferably at about reflux temperature). The compounds of formula IV C can also be obtained, as illustrated in scheme 7, by first preparing the corresponding compounds of formula IV B and then converting them, if desired, into the compounds of formula IV C. of formula IV B can be formed by reacting the corresponding compounds of formula IV A with a compound of formula GX, wherein X is defined as above and G is CH2C (= 0) NR3R4, and with potassium carbonate in DMF or in acetone, at a temperature ranging from about room temperature to about the reflux temperature of the reaction mixture . It is preferred to carry out this reaction at about the reflux temperature. The resulting compounds of formula IV B can be converted into the corresponding compound of formula IV C by reacting them with lithium aluminum hydride and with aluminum chloride in THF, or with borane in THF. Also, other reducing agents of the aluminum hydride type, such as diisobutyl hydride and aluminum, can be used, although diborane can also be used. This reaction is usually carried out at a temperature ranging from room temperature to about the reflux temperature of the reaction mixture (preferably at the reflux temperature). Other suitable solvents are the organic ethers such as: ethyl ether, dioxane and glyme. The solvent THF is particularly preferred. Scheme 8 illustrates the mode of preparation of certain compounds of formula IV whose substituents R1 and R2 are different from those represented in the method of scheme 6. Said compounds can be prepared by a procedure similar to that shown in scheme 6, with the exception of that the procedure of scheme 6 related to the synthesis of compound (32) is replaced by that represented in scheme 8. More specifically, and with reference to scheme 8, in which R2 is hydrogen and R1 is fluorine in the ortho position, the compound of formula (36) is converted into the corresponding phenylboronic acid analogously to that of the conversion of the compounds of formula (31) into those of formula (32) of scheme 6. In scheme 8, 9 reference to the resulting phenylboronic acid derivative as compound (32A). Analogously, as shown in scheme 8, the compounds of formula IV, wherein both R 1 and R 2 are methyl groups in the ortho position to the pyridine ring, can be prepared by converting the compound of formula (37), as shown in scheme 8, in the corresponding phenylboronic acid derivative designated as compound (32 B), analogously to the conversion of the compounds of formula (31) to those of formula (32) of scheme 6. The compounds of formula (32 A) and (32 B) can be transformed into the corresponding compounds of formula IV following procedures analogous to those shown in scheme 6. Scheme 9 exemplifies methods for preparing compounds of formula IV wherein G is NR3R4, and NR3R4 forms a ring of N-methylpyrrolin-2-yl. The compounds of formula IV in which G is NR3R4, and NR3R4 forms other nitrogen-containing rings, can be prepared analogously. With reference to scheme 9, a compound of formula IV D is allowed to react with the 3-methanesulfonyloxy-pyrrolidin-1-carboxylic acid t-butyl ester to form a compound of formula (38). Nitrogen protecting groups such as -C (= 0) OCH 2 C 6 H 5 and COOR (wherein R is a benzyl group, phenyl, t-butyl or a similar group) which can be used to protect the nitrogen from pyrrolidine can be used. Also, the leaving mesylate group can be substituted by other appropriate leaving groups. It preferred > Ht (.? _ • »_» _. add, in addition, a catalytic amount of tetrabutylammonium iodide (TBAI) to the reaction mixture. This alkylation reaction is usually carried out in the presence of an alkali metal alkoxide, preferably potassium t-butoxide, in a polar high-boiling solvent such as dimethylsulfoxide (DMSO) or DMF, preferably with the DMSO. The reaction temperature ranges from about 50 ° to about 100 ° C, preferably at a temperature of about 100 ° C. The reduction of the compound of formula XII gives the compound of formula IV F. It is preferred to carry out this reduction using hydride of lithium and aluminum as a reducing agent and tetrahydrofuran (THF) or another organic ether (ethyl ether or glyme, for example) as a solvent. Also, other reducing agents of the aluminum hydride type, such as diisobutyl hydride and aluminum, can be used, although diborane can also be used. This reaction is usually carried out at a temperature ranging from about room temperature to about the reflux temperature of the reaction mixture (preferably at about the reflux temperature). As illustrated in scheme 10, the alkylation of the compound of formula IV with 1- (2-chloroethyl) -pyrrolidine gives a compound of formula IV E. This reaction is usually carried out in the presence of a base such as sodium carbonate. cesium, potassium carbonate or sodium carbonate (preferably cesium carbonate), in a solvent such as acetone, DMSO or acetonitrile (preferably acetone), at a temperature ranging from about room temperature to about the reflux temperature of the reaction mixture (preferably at about reflux temperature). The compounds of formula IV, in which NR3R4 does not form a ring, can be prepared by the process illustrated in the scheme and described above to form the compound of formula IV E. The structural formula IV G, represented in scheme 5 includes said compounds. Scheme 11 illustrates the process for the preparation of benzeneboronic acid intermediates used in the synthesis described above in Schemes 6 and 8 in which the benzene ring of benzeneboronic acid contains a cycloalkyl substituent. Said intermediates can be used in the processes of schemes 6 and 8 to form compounds of formula IV in which one of the groups R1 or R2, or both, are cycloalkyl groups. With reference to scheme 11, the compound of formula (39) is refluxed in the presence of metallic magnesium, in THF or in ethyl ether for about 8 hours, after which cyclobutanone is added to the reaction mixture. This reaction gives the compound of formula (40). By reduction of this compound of formula (40) using, for example, hydrogen gas in the presence of 10% palladium on carbon, in a lower alcohol solvent such as ethanol, at a temperature close to room temperature, the composed of corresponding formula (41).
The reaction of the compound of formula (41) with benzyl bromide in the presence of a base such as cesium carbonate, sodium or potassium, in a solvent such as acetone, dichloroethane, chloroform or methylene chloride, at a temperature ranging from about room temperature to about the reflux temperature of the reaction mixture (preferably at about reflux temperature), gives the corresponding compound of formula (42). The compound of formula (42) obtained in the previous step is then joke by making it react with N-bromosuccinimide (NBS) and gel of silica in a chlorinated hydrocarbon solvent such as carbon tetrachloride, methylene chloride or chloroform. This reaction is usually carried out at room temperature. The compound of formula (43) obtained in this reaction can then be converted to a benzeneboronic acid derivative of formula (44) in the following manner. The compound of The formula (43), in a solvent such as THF, is cooled to a temperature between about -78 ° C and about -70 ° C and a solution of n-butyllithium is then added thereto. After stirring the reaction mixture for about 1 hour, triethyl borate is added and the mixture is stirred for an additional period of 1 to 3 hours. The intermediate product of acid The benzeneboronic acid can be isolated by methods well known in the art (buffering with ammonium chloride, adding water and then concentrated hydrochloric acid, and extracting it with ethyl acetate, for example).
Scheme 12 exemplifies a process for preparing compounds of formula IV in which G is an alkenyl group, as well as for preparing compounds of formula IV in which G is hydrogen and R 2 is an alkyl or alkenyl group. With reference to scheme 12, the compound of formula IV A can be converted into the corresponding compound of formula IV H, by an alkylation reaction analogous to the conversion reaction of the compound of formula IV D into the compound of formula IV of scheme 11 Heating the resulting compound of formula IV H to about 230 ° C gives the corresponding compounds of formula IV J and IV K. Hydrogenation of the compounds of formula IV J and IV K, by methods well known in the art (using hydrogen gas in ethanol at 344.7 kPa, in the presence of 10% palladium on carbon at room temperature, for example) the corresponding alkylated derivatives of formulas IV L and IV M, respectively. The alkylation of the compounds of formulas IV L and IV M (in which G is hydrogen), using any of the alkylation processes described in schemes 7, 9 and 10, and the appropriate alkylating agent, gives the desired corresponding compounds, where G is a group other than hydrogen. Scheme 13 illustrates an alternative procedure for preparing compounds of formula IV wherein G is alkyl (Co-C4) NR3R4. Referring to scheme 13, a compound of formula (45) is reacted with bromine in acetic acid at a temperature between about 0 ° and about 60 ° C (preferably at about 20 ° C). - _ *? ambient). By means of this reaction, the corresponding compound is obtained with a bromo substituent in position para to the fluorine substituent, which can be converted into the corresponding boronic acid derivative of formula (46) as described above for the synthesis of the compounds of formula (32) (in scheme 6) and in (44) (in scheme 11). The addition of a 2,5-dimethylpyrrolyl protecting group as described above for the synthesis of the compounds of formula (34) (in scheme 6) gives the corresponding compound of formula (47). This compound of formula (47) is then reacted with a compound of formula R3R4NOH and with an alkali metal hydride, preferably sodium hydride, in a polar organic solvent such as DMSO or DMF, preferably DMF, at a temperature between about -50 ° C and about -110 ° C, preferably at about 100 ° C, to form a compound that is identical to the corresponding compound of formula IV N desired, except for the presence of a 2,5-dimethylpyrrolyl protecting group. Removal of the protecting group, as described above for the preparation of compounds of formula IV A (from scheme 6), gives the desired compound of formula IV N. Scheme 14 illustrates a method of synthesizing compounds of formula I in which G is an optionally substituted pyrrolidi-2-yl or pyrrolidi-3-yl group. With reference to scheme 14, a compound of formula IV A is reacted with a compound of formula: triphenylphosphine or diethylazodicarboxylate, or other water-soluble azodicarboxylate, in THF under the standard Mitsunobo reaction conditions. The reagents are usually combined, at a temperature of about 0 ° C, to leave them then temper to room temperature. (If a substituent on the pyrrolidine nitrogen other than methyl is desired in the final product of formula IV P, it can be obtained by substituting the BOC group of formula (49) with a group of formula -C (= 0) R , wherein R is the desired alkyl group). The compound of formula (48) obtained in the above reaction (or the corresponding compound protected with C (= 0) R) can be converted to the desired product of formula IV P (or a similar compound in which the methyl substituent represented in structure IV P has been replaced by another alkyl group) by reduction. This reduction can be carried out by reacting the product of the above reaction with lithium aluminum hydride and with aluminum chloride in THF or borane, as described above for the formation of compounds of formula IV C. The compound of formula IV corresponding, in which the alkyl substituent on the nitrogen of the pyrrolidine of formula IV P is replaced by a hydrogen, can be obtained by reacting the compound of formula (48) as indicated above, with trifluoroacetic acid or hydrochloric acid in a solvent such as dioxane or ether, preferably dioxane, at a temperature ranging from about 0 ° C to about the reflux temperature of the reaction mixture, preferably at the reflux temperature. The starting materials used in the procedures of schemes 6 to 14 whose synthesis is not described above, are commercially available, are known in the art, or can be easily prepared from known compounds by procedures that are evident for those who are specialized in the technique. The preparation of other compounds of formula IV that have been specifically described in the above experimental section can be performed using combinations of the reactions described above, which are apparent to those skilled in the art. In each of the reactions discussed or illustrated above, the pressure is not critical unless otherwise indicated. Pressures of approximately 50.65 kPa to approximately are acceptable 506-5 kPa, although, as a matter of convenience, the ambient pressure, that is, approximately 101.3 kPa, is preferred. The compounds of formula V and the pharmaceutically acceptable salts thereof can be prepared as described in the PCT patent application PCT / IB97 / 01446, entitled "6-Phenylpyridyl-2-amine Derivates", which designates the United and that was submitted on November 17, 1997. The previous application has been incorporated herein in its entirety as a reference. The schemes 15 to 19 presented below illustrate processes for preparing compounds of formula V.
^^^^^^^^^^ "SCHEME 15 (51) SCHEME 16 (56) NH2OH "HCI Going to G = A n = 1, q = 0 SCHEME 17 VA-b G = A, X = N n = 1, q = 1. Yes benzyl * 3 * ._ ._ & - i-i SCHEME 18 (60) (61) VA-c G = A, q = 1 X = CH, Y = NR3R4 -. < A «_r .y ^ = gSto. ^ .. ^ ¿¿_» «'» jai > .- »-. J-- > : ^ A ^ - «_..- ^ í - ^. < ^ at-. & £ * ', .- ¿-j ^ _ ^ ¿já £ »f *.
SCHEME 19 (Y = benzyl) (Y = benzyl) (62) (63) (Y = benzyl) 15 (64) VA-d G = A, q = 0, X = N Y = H The starting materials used in the processes of schemes 15 to 19 are commercially available, are known in the art, or can be readily prepared from known compounds by procedures that are evident to those who are specialized in the art. With reference to scheme 15, a compound (50) is prepared by reaction of 1,4-dibromobenzene with an organic lithium derivative, preferably butyl lithium, at a temperature of -100 ° to about 0 ° C, followed by the addition of 2- (2,5-dimethylpyrrolyl) -pyrirdine at a temperature from about 0 ° C to about 50 ° C in an ethereal solvent, preferably ethyl ether, for a period of about 1 to 24 hours. The compound (51) is prepared by reacting the compound (50) with a boronic acid derivative of the formula p-OHC (CH2) m-2 (C6H3R1R2) B (OH) 2 in a solvent composed of alcohol, preferably Ethanol, optionally mixed with water and with a halogenated hydrocarbon, at a temperature of about 25 ° C to about 150 ° C, for a period of about 1 to 24 hours, using a palladium catalyst whose oxidation state is Pd (0). ) or Pd (ll) and with phosphines as usual ligands, preferably tetrakis (triphenylphosphine) palladium. The compound (52) is prepared by reacting the compound (51) with tosylmethyl isocyanide in the presence of t-butoxide and of ethanol, in an ethereal solvent such as 1,2-dimethoxyethane, at a temperature of from about 100 ° C to about 100 ° C, over a period of approximately 1 to 24 hours. The compound (53) is prepared from the compound (52) by basic hydrolysis of the nitrile group using an alkali metal alkoxide is an alcohol solvent in water, such as aqueous ethanol, at a temperature of about 25 ° C to 125 ° C, for a period of approximately 30 minutes to 48 hours. The compound (54) is prepared from the compound (53) by dehydrating coupling as ammonia or with a primary or secondary amine of the formula R3R4NH which will carry out a dehydrating agent such as a carbodiimide, N-ethyl-N-dimethylaminopropylcarbodiimide, by example, in a solvent such as a halogenated hydrocarbon or an N, N-dialkylamide, such as dimethylformamide, for example, at a temperature from about 0 ° C to about 100 ° C, for a period of about 1 to 48 hours. The compound (55) is prepared from the compound (54) by deblocking using hydroxylamine hydrochloride in an alcoholic or aqueous solvent, preferably aqueous ethanol, at a temperature of about 25 ° C to 100 ° C, for a period of about 1 hour. at 48 hours, which may include the release of a protective group such as t-butoxycarbonyl by reaction with trifluoroacetic acid, with a similar polyhalogenated acetic acid or with a gaseous hydrogen halide such as HCl, in a halogenated hydrocarbon, ethereal solvent or ethyl acetate, at a temperature of about -70 ° C to about 100 ° C, for a period of about 10 minutes to 24 hours.
«R-if AC, ^ L ____ A The final compound of the 15 VB scheme, in which G = B, is prepared by reduction of (55) with borane, trialkylborane, alane or lithium aluminum hydride, in an ethereal solvent such as ether ethyl or tetrahydrofuran, at a temperature of about 100 ° C to about 100 ° C, for a period of about 30 minutes to 24 hours, either using, optionally, cesium fluoride and an alkali metal or alkaline earth metal carbonate in alcoholic solvent aqueous, at a temperature of about 125 ° C to about 125 ° C, for a period of 1 to 72 hours. With reference to scheme 16, compound (56) is prepared from compound (50) by reaction with 3-pyridylboronic acid using a palladium catalyst whose oxidation state is Pd (0) or Pd (ll) and with phosphines as usual ligands, preferably tetrakis (tp-phenylphosphine) palladium, in aqueous alcoholic solvent at a temperature of about 25 ° C to about 125 ° C, for a period of about 1 to 48 hours. The compound (57) is prepared from the compound (56) by alkylation with an alkyl or aralkyl halide or sulfonate, in ethereal, alcoholic, aqueous alcoholic, or dialkylamide-based solvent such as dimethylformamide, at a temperature of about 0 ° C at about 125 ° C, for a period of about 30 minutes to 72 hours, followed by reduction with a reagent based on a gold or aluminum hydride, such as sodium borohydride, in an ethereal, alcoholic or aqueous alcoholic solvent, preferably ethanol, at a temperature from about 0 ° C to about 125 ° C, for a period of 1 to 72 hours. The final compound of scheme 16, VA-a, wherein G = A, n = 1 and q = 0, is prepared from the compound (57) by deblocking using hydroxylamine hydrochloride in an alcoholic solvent or aqueous alcoholics, preferably ethanol water, at a temperature of about 25 ° C to about 125 ° C, for a period of about 1 to 72 hours. In the method of scheme 16, the preferred value of Y in formulas (57) and V A-a is benzyl. The compounds of formula V Aa in which Y is a benzyl group can be converted to the corresponding compounds in which Y is a non-benzyl group by debenzylation, using hydrogen or ammonium formate in the presence of a noble metal catalyst, such as palladium , in an ethereal solvent, of halogenated hydrocarbon, alcoholic or aqueous alcohol, at a temperature of 0 ° C to 100 ° C, for a period of 30 minutes to 24 hours, followed by reductive amination with an alkyl or aralkyl aldehyde in the presence of a reagent based on a boron hydride, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in an ethereal solvent, of halogenated hydrocarbon, alcoholic or aqueous alcohol, at a temperature of 0 ° C to 100 ° C, for a period of 1 hour. to 72 hours. With reference to scheme 17, compound (58) is prepared for reductive amination of 2- (4-bromophenylmethyl) -piperidine with benzaldehyde and with a reagent based on a boron hydride, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in an ethereal solvent, of halogenated hydrocarbon, alcoholic or aqueous alcohol, at a temperature of from about 0 ° C to about 100 ° C, for a period of about 1 to 72 hours. The compound (59) is prepared from the compound (58) by reaction of the compound (589 with an organic lithium derivative, preferably butyllithium, followed by the addition of the resulting organolithium reagent to the 2- (2,5- dimethylpyrrolyl) -pyridine in an ethereal solvent, preferably ethyl ether, at a temperature of from about -70 ° C to about 100 ° C for a period of 30 hours. minutes to 48 hours. The final compound of scheme 17, I AB, wherein G = A, n = 1, q = 1, and Y is benzyl is prepared from compound (59) by deblocking using hydroxylamine hydrochloride in an alcoholic or aqueous solvent , preferably aqueous ethanol, at a temperature from about 25 ° C to about 125 ° C, over a period of approximately 1 to 72 hours. The compounds of formula I A-b can be converted into the corresponding compounds in which Y is a non-benzyl group by the process described above for converting compounds of formula I A-a to analogous compounds in which Y is a group other than benzyl. With reference to scheme 18, compound (60) is prepared from 6-bromo-2 (2,5-dimethyl-pyrrolyl) -pyridine and 4-formylphenylboronic acid in the presence of a palladium catalyst whose state of oxidation is Pd (0) or well Pd (ll) and with phosphines as typical ligands, preferably tetrakis (triphenylphosphine) palladium, in an aqueous alcoholic solvent, at a temperature of about 25 ° C to about 125 ° C, for a period of about 1 to 48 hours. The compound (61) is prepared from the compound (60) by reacting the compound (60) with the enamine of a ketone or an aldehyde, usually the enamine of the morpholine or the pyrrolidine, in a hydrocarbon, hydrocarbon solvent. aromatic or halogenated hydrocarbon, preferably toluene, at a temperature of about 25 ° C to about 150 ° C, for a period of about 1 to 72 hours, followed by an aqueous hydrolysis process, usually with aqueous hydrochloric acid, and then a reduction process with hydrogen or with ammonium formate in the presence of a noble metal catalyst, such as palladium, in an ethereal solvent, of halogenated hydrocarbon, alcoholic or aqueous alcohol, at a temperature of from about 0 ° C to about 100 ° C, for a period of about 30 minutes to 24 hours. The final compound of scheme 18, VA, in G = A, q = 1, X = CH and Y = NR3R4, is prepared from compound (61) by reductive amination of compound (61) with ammonia or with an amine primary or secondary, in the presence of a reagent based on a boron hydride, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in an ethereal solvent, of halogenated hydrocarbon, alcoholic or aqueous alcohol, at a temperature of about 0 ° C to about 100 ° C, for a period of 1 to 72 hours, followed by a deblocking using hydroxylamine hydrochloride in an alcoholic or aqueous solvent, preferably aqueous ethanol, at a temperature of about 25 ° C to about 125 ° C, for a period of about 1 to 72 hours. With reference to scheme 19, compound (62) is prepared from 3- (4-bromophenyl) glutaric acid by dehydration with acetic anhydride or a similar dehydrating reagent, followed by reaction with benzylamine in a hydrocarbon solvent, aromatic hydrocarbon or halogenated hydrocarbon, at a temperature of about 25 ° C to about 180 ° C, for a period of about 1 to 48 hours followed by dehydration of acetic anhydride or a similar dehydrating reagent at a temperature from about 25 ° C to about reflux for about 1 to 48 hours. The compound (63) is prepared by reduction of the compound (64) with borane, borane methylsulfide, alane or lithium aluminum hydride, in an ethereal or hydrocarbon solvent, at a temperature from about 0 ° C to about 100 ° C , for a period of approximately 30 minutes to 48 hours. The compound (64) is prepared from the compound (63) by reaction of the compound (63) with an organic lithium derivative, preferably butyllithium, followed by the addition of the resulting organolitiate reagent to the 2- (2,5- methylmethylpyrrolyl) -pyridine in an ethereal solvent, preferably ethyl ether, at a temperature of about -70 ° C to about 100 ° C for a period of 30 minutes to 48 hours. He final compound of scheme 19, V Ad, in which G = A, Y = H, q = 0 and X = N, is prepared by debenzylation of the compound (64), using hydrogen or ammonium formate in the presence of a metal catalyst noble, such as palladium, in an ethereal solvent, of halogenated hydrocarbon, alcoholic or aqueous alcohol, at a temperature of 0 ° C to 100 ° C, for a period of 30 minutes to 24 hours, followed by unblocking using hydroxylamine hydrochloride in an aqueous alcoholic or alcoholic solvent, preferably aqueous ethanol, at a temperature of about 25 ° C to about 125 ° C, for a period of about 1 to 72 hours. Compounds of formula V Ad, which can be prepared using the methods of scheme 19, can be converted to the analogous compounds wherein Y is alkyl or aralkyl, by reductive amination with an alkyl or aralkyl aldehyde in the presence of a reagent based on a boron hydride, such as sodium cyanoborohydride or sodium tracethoxyborohydride, in an ethereal solvent, of halogenated hydrocarbon, alcoholic or aqueous alcohol, at a temperature of 0 ° C to 100 ° C, for a period of 1 to 72 hours. The preparation of other compounds of formula V that have not been specifically described in the above experimental section can be performed using combinations of the reactions described above, which are apparent to those skilled in the art.
In each of the reactions discussed or illustrated above, the pressure is not critical, unless otherwise indicated. Pressures of approximately 50.65 kPa to approximately are acceptable 506. 5 kPa, although, as a matter of convenience, the ambient pressure is preferred, that is, approximately 101.3 kPa. The compounds of formula VI can be prepared as described below and in the provisional application of the patent E.U.A. by John A. Lowe, Ill, entitled "2-aminopyridines Containing Fused Rings Substituents", which was filed on June 3, 1998. The above application has been incorporated herein in its entirety as a reference. Scheme 20 is presented below illustrates a process for preparing compounds of formula VI.
SCHEME 20 With reference to Scheme 20, a compound (65) is prepared by reaction of the norbinylene and the 2-hydroxypyrone followed by aromatization with palladium oxide, according to the procedure described in Syn. Commun. 5, 461, (1975). The tetrabutylammonium tribromide is then reacted in 1,2-dichloroethane at room temperature for a period of about 10 minutes to about 10 hours. Next, the product of this reaction is treated with benzyl bromide and with potassium carbonate in in solvent such as acetonitrile, at about reflux temperature of the reaction mixture during About 1 to 48 hours to give the compound of formula (66). The compound of formula (66) is converted to 5-benzyloxy-1, 2,3,4-tetrahydro-1,4-methano-naphthaleneboronic acid by cooling the compound of formula III to about -70 ° C in dry tetrahydrofuran (THF) ), then adding a solution of n-butyl-lithium. The resulting solution is It is treated with triethyl borate and allowed to warm to room temperature over a period of about 1 to 48 hours to form 5-benzyloxy-1, 2,3,4-tetrahydro-1,4-methano-naphthalene boronic acid. By the reaction of the pacido 5-benmciloxy-1, 2,3,4-tetrahydro-1,4-methano-naphthaleneboronic acid with 6-bromo-2- (2,5-dimethylpyrrolyl) -pyridine in a solvent of ethanol, in the presence of sodium carbonate and of tetrakis (triphenylphosphine) palladium, at the reflux temperature of the reaction mixture, over a period of 1 to 48 hours, gives the compound of formula (67).
The compound of formula (67) can be converted to the compound of formula V by following the following two-step process. The compound of formula (67) is reacted with ammonium formate and with 10% palladium on carbon, in ethanol solvent, at the reflux temperature of the reaction mixture, for a period of from about 10 minutes to about 10 hours, to give the compound analogous to that of formula (67) with a hydroxy group. The compound of formula (68) is then formed by reacting the above hydroxy derivative with 2-bromoethylacetate and potassium carbonate in acetonitrile at the reflux temperature of the mixture of reaction, over a period of about 1 to 48 hours. Basic hydrolysis of the compound of formula (68), followed by reaction with N-ethyl-N-dimethylaminopropylcarbodiimide (EDAC) and the compound of formula R2R1NH gives the desired compound of formula (69). Basic hydrolysis is usually carried out using an alkali metal or metal hydroxide Alkaline earth in a mixture of THF, methanol and water at room temperature for a period of about 1 to 48 hours. The reaction with the appropriate compound of the formula R2R1NH and with N-ethyl-N-dimethylaminopropylcarbodiimide (EDAC) is carried out in the presence of a base. As examples of suitable bases are those selected from among trialkylamines, alkali metal carbonates and alkaline earth metal carbonates. This reaction is usually carried out in a solvent such as acetonitrile, methylene chloride or N, N-dimethylformamide (DMF), at a temperature ranging from about room temperature to about 100 ° C (preferably at about room temperature), for a period of about 1 to 48 hours. It is also preferred to carry out the reaction in the presence of a catalytic additive such as N-hydroxysuccinamide or hydroxybenzotriazole. The compound of formula (69) can be converted to the compound of formula I as follows. The compound of formula (69) is reduced to form the corresponding compound wherein the carbonyl group is replaced by a methylene group, after which the 2,5-dimethylpyrrolyl protecting group is removed. The reduction can be carried out using procedures well known in the art, using, for example, lithium aluminum hydride in tetrahydrofuran, with or without aluminum chloride, or using borane methylsulfide in tetrahydrofuran, at a temperature ranging from about -78 ° C at about reflux temperature (preferably about -70 ° C at room temperature) for a period of about 1 to 24 hours. The removal of the 2,5-dimethylpyrrolyl protecting group can be completed by reaction with hydroxylamine hydrochloride. This reaction is usually carried out in alcoholic solvent. Or in aqueous alcoholic solvent (preferably using ethanol as alcohol) at a temperature ranging from about room temperature to about reflux temperature (preferably at reflux temperature), for a period of about 8 to about 72 hours.
Compounds of formula VI, in which there is a heteroatom in one of the bridging rings, can be prepared analogously, starting with the appropriate compound which is analogous to that of formula (65), in which the unsubstituted bridging ring of formula (65) is replaced by another bridge ring that includes a heteroatom. The preparation of other compounds of formula VI that have not been specifically described in the above experimental section can be performed using combinations of the reactions described above, which are apparent to those skilled in the art. In each of the reactions discussed or illustrated above, the pressure is not critical, unless otherwise indicated. Pressures of about 50.65 kPa to about 506.5 kPa are usually acceptable, although, as a matter of convenience, the ambient pressure, that is, about 101.3 kPa, is preferred. The compounds of formulas I to VI are basic in nature, being able, therefore, to form a wide variety of salts with various organic and inorganic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is desirable to initially isolate a compound of formula I, II, II, IV, V or VI, in the form of a pharmaceutically unacceptable salt, from a reaction mixture initially, for then simply converting this end to the free base compound by treatment with an alkyl reagent, and subsequently converting this free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of the active base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol. or ethanol. By careful evaporation of the solvent, the desired solid salt can easily be obtained. The compounds of formulas I, II, II, IV, V or VI and the pharmaceutically acceptable salts thereof are useful as NOS inhibitors, that is, they possess the ability to inhibit the NOS enzyme in mammals and, therefore, are capable of of acting as therapeutic agents in the treatment of the disorders and diseases mentioned above in the mammals that suffer them. The ability of the compounds of formulas I to VI to inhibit the NOS enzyme can be determined by methods described in the literature. The ability of the compounds of formula I to inhibit the endothelial NOS enzyme can be determined by the methods described by Schmidt et al., Proc. Nati Acad. Sci. E.U.A., 88, pp. 365-369 (1991), and by Pollock et al., Proc. Nati Acad. Sci. E.U.A .. 88, pp. 10480-10484 (1991). The ability of the compounds of formula I to inhibit the inducible NOS enzyme can be determined by the methods described by Schmidt et al., Proc. Nati Acad. Sci. E.U.A., 88, pp. 365-369 (1991), and by Garvey et al., J. Biol. Chem., 269, pp.26669-26676 (1994). The capacity of ¥ »The compounds of formula I for inhibiting the neuronal NOS enzyme can be determined by the methods described by Bredt and Snyder, Proc. Nati Acad. Sci. U.S.A .. 87 pp. 682-685 (1990). The compounds of formulas I to VI and pharmaceutically acceptable salts thereof can be administered parenterally or by topical routes. When used as simple active agents in the treatment of psoriasis, sleep disorders and deficits or cognitive disorders, it is preferred to administer these compounds, generally in dosages of approximately 250 mg per day, in single or divided doses (from 1 to 4 doses per day, for example), although with possible variations depending on the spice, weight and condition of the subject to be treated, and the particular administration route chosen. However, it is preferred to employ a dosage level of 0.07 mg per kg of body weight per day. However, variations may occur depending on the species of the animal to be treated and its individual response to said medication, as well as the type of pharmaceutical formulation chosen and the period of time and interval in which said medication is carried out. administration. In some cases, lower dosage levels may be more suitable, whereas in other cases higher doses may be used without causing any harmful side effects, provided that said higher doses are divided into several lower doses for administration throughout the day.
The compounds of the formulas I to VI can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by one of the three previously indicated routes, said administration being possible in single or multiple doses. In particular, said therapeutic agents can be administered in a wide variety of dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers of tablet, capsule, tablet, tablet, dragee, powder, spray, cream, balsam, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. On the other hand, oral pharmaceutical compositions can be conveniently sweetened or flavored. The therapeutically effective compounds of this invention are, in general, in said dosage forms with concentration levels between about 0.5 to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, calcium acid phosphate and glycine can be used together with various disintegrants such as starch (preferably corn starch, potato starch or of tapioca), alginic acid, and certain complex silicates, as well as granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Also, in the manufacture of tablets, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are frequently used. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this relation include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are preferred for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, colorants or dyes and, optionally, emulsifying and dispersing agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions of a compound of formulas I may be used, II, III, IV, V or VI or the pharmaceutically acceptable salts thereof in peanut or sesame oil or in aqueous propylene glycol. If necessary, the aqueous solutions should be suitably buffered (preferably at a pH higher than 8), as well as the liquid diluents should be made isotonic. Aqueous solutions are suitable for use in intravenous injections. Oily solutions are suitable for use in intraarticular, intramuscular and subcutaneous injections. The preparation of all these solutions under sterile conditions is easily carried out by conventional pharmaceutical techniques well known in the art. It is also possible to administer the compounds of formulas I to VI topically in the treatment of inflammatory skin conditions, by the use of creams, gelatine, gels, pastes, patches, ointments and the like, in accordance with conventional pharmaceutical practice. This invention relates to methods for the treatment of inflammatory disorders in which the antiinflammatory compound and the NOS inhibitor compound are administered together, as part of a pharmaceutical composition, as well as methods in which these two active agents are administered separately as part of a pharmaceutical composition. of a convenient dosing regimen designed to reap the benefits of a combination therapy. The convenient dosage regimen, the amount of each dose administered, and the specific intervals between doses of each active agent depend on the subject to be treated, as well as the origin and severity of the condition. Generally, and following all the methods of this invention, the NOS inhibitor compound will be administered to an adult, of an average weight of 70 kg, in an amount of about 0.01 about 10 mg per kg of body weight of the subject being removed. to be treated and per day in individual or divided doses, preferably 1 to about 3 mg / kg, and the anti-inflammatory compound in an amount of about 0.2 to about 30 mg per kg of body weight of the subject to be treated and per day, in individual or divided doses. Variations may occur, however, depending on the species of the animal to be treated and its individual response to said medicament, as well as the type of pharmaceutical formulation chosen and the period of time and interval in which said medication is carried out. administration.
In some cases, dosage levels may be more suitable, while in other cases higher doses may be employed without causing any harmful side effects, provided that said higher doses are divided into several lower doses for administration throughout the course of administration. day. This invention relates to methods for the treatment of acute or chronic pain in which the analgesic compound and the NOS inhibitor compound are administered together, as part of a pharmaceutical composition, as well as methods in which these two active agents are administered separately as part of a convenient dosage regimen designed to obtain the benefits of a combination therapy. The convenient dosage regimen, the amount of each dose administered, and the specific intervals between doses of each active agent depend on the subject to be treated, as well as the origin and severity of the condition. Generally, and following the methods of this invention, the NOS inhibitor compound will be administered to an adult, of an average weight of 70 kg, in an amount from about 0.01 to about 10 mg per kg of body weight of the subject being removed. to treat and per day, in individual or divided doses, preferably from approximately 1 to about 3 mg / kg, and the analgesic compound in an amount of about 0.01 to about 0.01 to about 1 mg per kg of body weight of the subject to be treated and per day, in individual doses or divided, preferably approximately 1 ^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Variations may occur, however, depending on the species of the animal to be treated and its individual response to said medicament, as well as the type of pharmaceutical formulation chosen and the period of time and interval in which said medication is carried out. administration. In some cases, lower dosage levels may be more suitable, while in other cases higher doses may be used without causing any harmful side effects, provided that said higher doses are divided into several lower doses for administration throughout the administration. day. This invention refers to procedures for the treatment of migraines, recurrent headache and other headaches in which the 5H-? D agonist and the NOS inhibitor compound are administered together, as part of a pharmaceutical composition, as well as methods in which these two active agents are administered separately as part of a convenient dosing regimen designed to reap the benefits of a combination therapy. The convenient dosage regimen, the amount of each dose administered, and the specific intervals between doses of each active agent depend on the subject to be treated, as well as the origin and severity of the condition. Generally, and following the methods of this invention, the NOS inhibitor compound will be administered to an adult, of an average weight of 70 Kg, in an amount of about 0.01 to about 10 mg per kg of body weight of the subject being removed. to try . . ^ _ ^ &mm. sdéé ^ * -! £ __! and per day, in single or divided doses, preferably from ~ X approximately 1 to approximately "3 mg / kg, and the agonist 5H-T- | D in an A amount of approximately 1 to approximately 100 mg per kg of body weight of the subject to be treated and per day, in individual or divided doses, preferably from approximately 5 to approximately 50 mg per day Variations may occur, however, depending on the species of the animal to be treated and its individual response to said medicament, as well as the type of pharmaceutical formulation chosen and the period of time and interval in which said administration is carried out.In some cases, lower dosage levels may be more suitable, while in other cases they may be employing higher doses without causing any harmful side effects, provided that said higher doses are divided into several lower doses for administration throughout the day. it is illustrated with the following examples. It is understood, however, that this invention is not limited to the specific details of these examples. The melting points are uncorrected. The proton nuclear magnetic resonance (1H NMR) and 13C nuclear magnetic resonance (13C NMR) spectra have been measured for solutions in deuterated chloroform (CDI3) or in CD3OD or CD3SOCD3, and the positions of the peaks are expressed in parts per million (ppm) in fields lower than that of tetramethylsilane (TMS). The shapes of the peaks are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, wide.
EXAMPLE 1 1-r4- (6-Amino-pyridin-2-yl) -3-isopropoxy-phen-2- (4-phenethyl-piperazin-1-yl) -ethanol A. Nt-Butylcarbonyl-6- (2-isopropoxy-4-formylphenyl) -pyridin-2-ylamine. To a 100 ml round bottom flask, equipped with a condenser and with a nitrogen inlet, 4.85 g were added. (11, 97 mmol) of Nt-butylcarbonyl-6- (2-isopropoxy-4-bromometyl-phenyl) -pyridin-2-ylamine (from the previous example 1 E), 3.35 g (23.95 mmol) of hexamethylenetetramine and 30 ml of acetic acid: water ( 1: 1) and refluxed for 5 hours. The reaction was then cooled, adjusted to pH 10 with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel using hexane / ethylene acetate as eluent gave 2.995 g (74%) of a white solid. 1 H NMR (d, CD13): 1.32 (m, 15H); 4.68 (septet, J = 6.1 H); 7.47 (s, 1 H); 7.51 (d, J = 8, 1 H); 7.64 (m, 1 H); 7.72 (t, J = 8, 1 H); 8.05 (bs, 1 H); 8.20 (d, J = 8, 1 H); 9.99 (s, 1 H) MS (%): 341 (M + 1, 1009 E Ntb carbonyl-6- (2-isopropoxy-4-oxiranylphenyl-pyridin-2-ylamine) 2.99 g were added to a 100 ml round, equipped with a condenser and with a nitrogen inlet. (8.79 mmol) of N-5 t-butylcarbonyl-6- (2-iopropoxj-4-formylphenyl) -pyridin-2-ylamine, 1.79 g (8.79 mmol) of trimethylisulfonium iodide, 0, 98 g (17.59 mmol) of potassium hydroxide powder, 44 ml of acetonitrile and 0.5 ml of water The reaction was heated to 60 ° C for 2.5 hours, then cooled, filtered and evaporated. The yellow oil obtained (3.3 g, = 100%) was used directly, 10 1 H NMR (d, CDC13): 1.27 (d, J = 6, 6H), 1.32 (s, 9H), 2.76 (m, 1 H); 3. 15 (m, 1 H); 3.87 (m, 1 H); 4.54 (septet, 1H); 6.87 (s, 1 H); 6.97 (d, J = 8, 1 H); 7.58 (m, 1 H); 7.69 8m, 2H); 8.05 (bs, 1 H); 8.13 (d, J = 8, 1 H) MS (%): 355 (M + 1, 100) C. 1- [Nt-Butylcarbonyl-4- (6-amino-pyridin-2-yl) -3-ylpropoxy-phenyl-2-, 4-phenethyl-piperazin-1-yl, -ethanol They were added to a 25 ml round bottom flask, equipped with a condenser and with a nitrogen inlet, 300 mg (0.847 mmol) of Nt-butylcarbonyl-6- (2-orpropoxy-4-oxiranylphenyl) -pyridin-2-ylamine, 193 mg (1, 017 mmol) of N-phenethylpiperazine, 9 ml of acetonitrile and 0.85 ml of water. The reaction was heated to 80 ° C for 20 hours, cooled and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with brine, dried over sodium sulfate and evaporated. Through ^^^^^^^ í »^^^^^^^^^^^ Ei ^^^^^" ^^ chromatography of the residue on silica gel using methanol / methylene chloride / ammonium hydroxide as eluant obtained 283 mg (62%) of a whitish foam. 1 H NMR (d, CD13): 1.27 (d, J = 6, 6H); 1.31 (s, 9H); 2.4-2.9 (m, 15H); 3.15 (m, 1 H); 4.56 (septet, J = 6, 1 H); 4.75 (m, 1H); 6.99 (d, J = 8, 1H); 7.06 (s, 1 H); 7.06 (s, 1 H); 7.1-7.3 (m, 5H); 7.58 (d, J = 8, 1 H); 7.67 (m, 2H); 8.08 (bs, 1 H); 8.13 (d, J = 8, 1 H). 13 C NMR (d, CDCl 3): 22.05; 27.45; 33.53; 39.71; 53.18; 60.36; 65.95; 68.41; 70.99; 111, 54; 112.10; 118.26; 121.18; 126.01; 128.34; 128.61; 130.80; 137.67; 140.09; 144.34; 150.98; 154.29; 155.47; 176.99. MS (%): 545 (M + 1, 100) JD 1-f4- (6-Amino-pyridin-2-yl) -3-isopropoxy-phenyl] -2- (4-phenethyl-piperazin-1-yl) -ethanol. They were added to a 25-ml round bottom flask. ml, equipped with condenser and nitrogen inlet, 283 mg (0.52 mmol) of 1- [Nt-butylcarbonyl-4- (6-am¡no-pyridin-2-yl) -3-isopropoxyphenyl] - 2- (4-phenethyl-piperazin-1-yl) -ethanol, 5 ml of dioxane, and 10 ml of 10% aqueous sodium hydroxide solution. The reaction was refluxed for 3 days, then cooled, poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated. By chromatography of the residue on silica gel using methanol / methylene chloride / ammonium hydroxide as eluent 203 mg (86%) of an oil, which was converted to the hydrochloride salt using HCl in tetrahydrofuran and mp they were obtained: 148-165 ° C. * 1 H NMR (d, CDCl 3): 1.27 (d, J = 6, 6H); 2.6-2.9 (m, 15H); 4.48 (bs, 2H); 4.52 (septet, J = 6, 1 H); 4.74 (m, 1 H); 6.385 (d, J = 8, 1 H); 6.97 (d, J = 8, 1 H); 7.03 (s, 1 H); 7.1-7.3 (m, 6H); 7.41 (t, J = 8, 1 H); 7.70 (d, J = 8, 1 H). 13 C NMR (d, CDCl 3): 22.16; 33.62; 53.03; 53.27; 60.45; 66.04; 68.57; 71.19; 106.47; 112.47; 112.56; 115.62; 118.46; 126.09; 128.42; 128.70; 129.75; 130.97; 137.27; 140.22; 143.81; 154.35; 155.52; 158.01. MS (%): 461 (M + 1, 100). Analysis calculated for C28H36N4? 2-3HCI-2H20: 55.49% C, 7.15% H, 9.24% N. Determined: 55.50% C, 7.38% H, 8.97% EXAMPLE 2 6-f2-iopropoxy- (N- (2-methyl) propyl-4- (pyrrolidin-3-yl) -phene-pyridin-2-ylamine A. N-t-butylcarbonyl-6- (2-fluoro-4-bromomethylphenyl) -pyridin-2-ylamine To a 250 ml round bottom flask, equipped with a condenser and with a nitrogen inlet, 5.0 g (17.48 mmoles) of N-t-butylcarbonyl-6- (2-fluoro-4-methylphenyl) -pyridin-2-ylamine (example 2B), 4.36 g (24.47 mmoles) of N-bromosuccinimide, 10 mg of carbon tetrachloride. The reaction was refluxed under a heating lamp for 30 minutes, MÍAÍ then cooled and filtered. Medianta_cromatografía the residue on silica gel using hexane / ethyl acetate as eluant Cie 5.36 g (52%) of product as an oil, which was crystallized from isopropanol to give m.p .: 97-100 ° C were obtained. 1 H NMR (d, CDCl 3): 1.32 (s, 9 H); 4.46 (s, 2H); 7.18 (d, J = 11.5, 1 HOUR); 7.24 (d, J = 8, 1 H); 7.49 (d, J = 8, 1H); 7.74 (t, J = 8, 1H); 7.88 (t, J = 8, 1 H); 8.06 (bs, 1 H); 8.21 (d, J = 8, 1 H); 13 C NMR (d, CDCl 3): 27.52; 31.90; 39.85; 112.92; 116.82; 117.07; 120.37; 120.47; 124.99; 125.03; 126.75; 131.17; 131.20; 138.87; 140.42; 140.51; 150.80; 151.47; 158.99; 161.48; 177.15. MS (%): 366 (M + 1, 100) Analysis calculated for d7H18H2OFBr: 55.90% C, 4.97% H, 7. 46% N. Determined: 55.57% C, 4.79% H, 7.46% N.
B. Nt-butylcarbonyl-6- (2-fluoro-4-formylphenyl) -pyridin-2-ylamine to a round bottom flask of 125 ml, equipped with a condenser and nitrogen inlet, 5.35 g was added (14.66 mmol) of Nt-butilcarbon¡l-6- (2-fluoro-4-bromomethylphenyl) -pir¡din-2-ylamine, 26 ml of chloroform and 4.10 g (29.32 mmol) of hexamethylenetetramine. The reaction was refluxed for 5 hours, then cooled and evaporated. The residue was taken up in 29 ml of 50% aqueous acetic acid and refluxed for 16 hours. The reaction was cooled and suspended in ethyl acetate, ««. - «f & ¡tsk¡¡ & t • * s¡ &»? Ti »» B < *? washed with aqueous sodium hydroxide solution and with brine, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel using hexane / ethyl acetate as eluent gave 3.49 g (67%) of an oil. 1 H NMR (d, CDCl 3): 1325 (s, 9H); 7.56 (m, 1 H); 7.62 (d, J = 11, 1 H); 7.7-7.8 (m, 2H); 8.10 (m, 2H); 8.26 (d, J = 8, 1 H); 9.99 (s, 1 H). 13 C NMR (d, CDCl 3): 27.41; 39.78; 113.65; 116.41; 116.66; 120.67; 120.77; 125.66; 131.61; 137.84; 138.93; 149.83; 151.60; 159.35; 161.86; 177.14; 190.54. MS (%): 301 (M + 1, 100) Analysis calculated for C17H? 7N202F: 67.99% C, 5.71% H, 9.33% N. Determined: 67.62% C, 5.67% H, 9.50% N.
C. Diethyl-2-fluoro-4-.Nt-butylcarbonyl-6-pyridin-2-ylaminal benzylidenemalonate. To a 125 ml round bottom flask, equipped with a condenser and with a nitrogen inlet, 2.65 g ( 8.83 mmoles) of Nt-butylcarbonyl-6- (2-fluoro-4-formyphenyl) -pyridin-2-ylamine, 1.41 g (8.83 mmol) of diethyl malonate, 45 ml of benzene, 40 mg (0.44 mmol) of piperidine and 10 mg of benzoic acid. The reaction was refluxed for 3 days, then cooled, poured into water and extracted with ethyl acetate. The organic phase was washed with 1 N hydrochloric acid, with : & akib *! ¡^ - & .. td && amp; amp; aqueous sodium bicarbonate solution and with brine, dried sodium sulfate and evaporated. By chromatography? fff residue on silica gel using hexane / ethyl acetate as eluent 3.14 g (80%) of a product was obtained as a yellow oil, which was crystallized with 2-propane, m.p .: 97-100 ° C. 1 H NMR (d, CDCl 3): 1.32 (m, 15H); 4.29 (q, J = 7, 2H); 4.34 (q, J = 7, 2H); 7.24 (d, J = 12, 1 H); 7.32 (d, J = 8, 1 H); 7.53 (d, J = 7, 1H); 7.67 (s, 1H); 7.75 (t, J = 8, 1 H); 7.96 (t, J = 8, 1 H); 8.05 (bs, 1 H); 8.22 (d, J = 8, 1 H). 13 C NMR (d, CDCl 3): 13.94; 14.12; 27.51; 39.85; 61.89; 61.97; 113.27; 116.75; 117.00; 120.53; 120.63; 125.66; 131.13; 135.17; 130.95; 139.89; 150.29; 151.53; 159.04; 161.65; 163.76; 166.20; 177.16. MS (%): 443 (M + 1, 100) Analysis calculated for C2 H27N2? 5F: 65.15% C, 6.15% H, 6.33% N. Determined: 64.88% C, 6.18% H, 6.59% N.
D. 3-Cyanopropionate of etl-3-f2-fluoro-4- [Nt-butylcarbonyl-6-pyridin-2-ylaminalphenyl] They were added to a 125 ml round bottom flask, equipped with a condenser and with an inlet of nitrogen, 3.12 mg (7.05 mmol) of benzylidene-2-fluoro-4- [Nt-butylcarbonyl-6-pyridin-2-yl] benzylidenemalonyl] and 100 ml of ethanol. To the stirred solution was added a solution of 460 mg (7.05 mmoles) of potassium cyanide in 1.8 ml of water, and the reaction was stirred at _- • & _ .. w ** - room temperature for 3 days, and then heated at 60 ° C for 38 hours. The reaction was then cooled and buffered with dilute hydrochloric acid. It was then taken up in ethyl acetate and washed with acid and with brine, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel using hexane / ethyl acetate as eluent gave 1.88 g (67%) of an oil. 1 H NMR (d, CDCl 3): 1.24 (t, J = 7, 3H); 1.32 (s, 9H); 2.93 (ABq, J = 8,? V = 58, 2H); 4.17 (m, 2H); 4.33 (t, J = 7, 1 H); 7.19 (d, J = 11, 1H); 7.26 (d, J = 8, 1H); 7.48 (m, 1 H); 7.75 (t, J = 8, 1H); 7.94 (t, J = 8, 1H); 8.05 (bs, 1H); 8.225 (d, J = 8, 1 H). 13 C NMR (d, CDCl 3): 14.0; 27.4; 32.5; 39.6; 39.8; 61.6; 113.0; 115.4; 115.7; 119.2; 120.6; 123.4; 127.6; 127.7; 131.7; 137.0; 138.9; 150.3; 151.4; 159.1; 161.6; 168.7; 177.1 MS (%): 398 (M + 1, 100) E. Nt-butylcarbonyl-6-f2-fluoro-4- (2-fluoro-4 - ('2-oxo-pyrrolidin-3-yl) -fenip-pyridin-2-ylamine To a bottle To 125 ml were added 188 g (4.73 mmoles) of ethyl-3- [2-fluoro-4- [Nt-butylcarbonyl-6-pyridin-2-ylamine-phenyl] -3-cyanopropionate, 35 ml of ethanol, 1 g of 10% palladium on charcoal and 2 ml of 6N hydrochloric acid The reaction was stirred under hydrogen at 275.8 kPa for 20 hours, filtered through celite, washed with aqueous sodium hydroxide, dried over sodium sulfate and evaporated.The residue was suspended in 35 ml. from < aaifeg._, A.
Anhydrous toluene was treated with 3.5 ml of Jcylethylamine and heated to reflux for 18 hours. The reaction was then cooled, washed with dilute hydrochloric acid and with brine, dried over sodium sulfate and evaporated: chromatography of the residue on silica gel using hexane / ethyl acetate as eluent yielded 394 mg (23%) ) of a solid, mp: 162-165 ° C. 1 H NMR (d, CDCl 3): 1.31 (s, 9H); 2.59 (ABq, J = 8,? V = 112, 2H); 3.27 (m, 1 H); 3.68 (m, 2H); 7.01 (d, J = 12, 1 H); 7.10 (d, J = 8, 1 H); 7.19 (s, 1 H); 7.44 (m, 1 H); 7.73 (t, J = 8, 1 H); 7.84 (t, J = 8, 1 H); 8.20 (d, J = 8, 1 H); 8.23 (bs, 1 H). 13 C NMR (d, CDCl 3): 27,465; 39.6; 39.9; 49.2; 112.9; 1 14.6; 114.8; 120.2; 120.3; 122.7; 125.6; 128.2; 129.0; 131.3; 138.9; 145.7; 150.9; 151.6; 15.2; 161.7; 177.3; 177.5. MS (%): 356 (M + 1, 100) Analysis calculated for C20H22N3O2F: 67.59% C, 6.24% H, 11.82% N. Determined: 67.49% C, 6.37% H, 11.76% N.
F. 6-r2-fluoro-4- (2-oxo-pyrrolidin-3-yl) -fenin-pyridin-2-ylamine The above material was deblocked using 6N hydrochloric acid at 90 ° C for 18 hours, and then treated with N-ethyl-N-isopropylcarbodiimide and N-hydroxybenzotriazole, and with triethylamine and 4-dimethylaminopyridine in acetonitrile at room temperature for 2 days. The reaction was treated with ethyl acetate * "? \ * _: and water, dried over sodium sulfate and evaporated by chromatography of the residue on silica gel using meFanol / methylene chloride as eluent 167 mg (47%) of a solid were obtained, mp .: 185-188 ° C. 1 H NMR (d, CDCl 3): 2.94 (Aßq, J = 8,? V = 108, 2H); 3.22 (m, 1 H); J * 3.60 (m, 2H); 4.90 (bs, 2H); 6.38 (d, J = 8, 1 H); 6.87 (m, 2H); 6.97 (d, J = 8, 1 H); 7.35 (t, J = 8, 1 H); 7.59 (t, J = 8, 1H). 13 C NMR (d, CDCl 3): 37.6; 39.3; 49.1; 108.0; 114.1; 114.4; 122.4; 126. 3; 131.0; 138.2; 144.6; 150.6; 158.6; 161.3; 177.9. MS (%): 272 (M + 1, 100) G. 6- [2-Fluoro-4- (pyrrolidin-3-yl) -phenyl-1-pyridin-2-ylamine) To a 25 ml round bottom flask equipped with a nitrogen inlet was added 160 mg ( 0.59 mmole) of 6- [2-fluoro-4- (2-oxo-pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine and 8 ml of anhydrous tetrahydrofuran. The solution was cooled to about -70 ° C and 5.9 ml (5.9 mmoles) of a 1.0M lithium aluminum hydride solution in tetrahydrofuran was added. The reaction was allowed to warm to room temperature and was stirred for 2 days. The reaction was then carefully quenched with dilute aqueous sodium hydroxide solution, taken up in a solution of ethyl acetate and sodium hydroxide in water, and the combined organic phase was washed with water, dried over sodium sulfate and evaporated. , obtaining a crude oil, which was used directly in the next stage. 1 H NMR (d, CDCl 3): 1.8-2.Q and 2.2-2.4 (m, 2H); 2.6-3.7 (m, 5H); 4.80 (bs, 2H); 6.41 (d, J = 8, 1 H); 6.92 (m, 2H); 7.01 (d, J = 8, 1 H); 7.21 (d, J = 8, 1H); 7.395 (t, J = 8, 1H); 7.66 (t, J = 8, 1H); 7.71 (m, 1 H). MS (%): 258 (M + 1, 100) H. 6-f2-fluoro- (N- (2-methyl) propyl) -4- (pyrrolidin-3-yl) -phenyl-Pyridin-2-ylamine. They were added to a round bottom flask of 25 ml. ml, equipped with a nitrogen inlet, 151 mg (0.587 mmol) of 6- [2-fluoro-4- (pyrrolidin-3-yl) -phenyl] -pyridin-2-ylamine, 85 mg (0.587) mmoles) of isobutyraldehyde, 74 mg (1175 mmoles) of sodium cyanoborohydride and 6 ml of methanol. The reaction was stirred at room temperature for 2 hours, poured into dilute hydrochloric acid, and washed with ethyl acetate. The aqueous phase was adjusted to pH 12 with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel using methanol / methylene chloride as eluent gave 25 mg (%) of an oil. 1 H NMR (d, CDCl 3): 0.94 (d, J = 6, 6H); 1.7-1.9 (m, 2H); 2.32 (m, 3H); 2.55 (m, 1 H); 2.74 (m, 2H); 2.98 (m, 1 H); 3.37 (m, 1 H); 4.49 (bs, 2H); 6.44 (d, J = 12, 1H); 7.11 (m, 2H); 7.46 (t, J = 8, 1H), 7.79 (t, J = 8, 1H). 13 C NMR (d, CDCl 3): 21.0; 27.2; 33.0; 42.7; 54.7; 61.9; 64.7; 107.1; 114.6; 114.7; 123.2; 12 * 4; 130.5; 137.9; 148.4; 151.6; 158.1; 159.0; 161.5. MS (%): 314 (M + 1. 100) I. 6-r2-isopropoxy- (N- (2-methyl) propyl) -4- (pyrrolidin-3-yl) -fenin-pyridin-2-ylamine. They were added to a 25 ml round bottom flask, equipped with a nitrogen inlet, 24 mg (0.077 mmol) of 6- [2-fluoro- (N- (2- 10 methyl) propyl) -4- (pyrrolidin-3-yl) -phenyl] -pyridin- 2-ylamine and 3 ml of dimethylformamide. The reaction was heated to 80 ° C and then 46 mg (0.767 mmoles) of 2-propanol and 37 mg (0.920 mmoles) of sodium hydride (60% dispersion in oil) were added. The reaction was stirred at 100 ° C for 18 hours, then cooled and evaporated. The residue was treated with dioxane and with aqueous solution of 1 N sodium hydroxide to be divided into an N-formy by-product at room temperature for 18 hours. The reaction was partitioned between an aqueous 0.5N sodium hydroxide solution and ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and silica gel plate was evaporated using methanol / methylene chloride / ammonium as The eluant was obtained 24 mg (89%) of an oil, which was converted to the hydrochloride salt, m.p .: 1 18-138 ° C. 1 H NMR (d, CDCl 3): 0.96 (d, J = 6, 6H); 1.25 (d, J = 6, 6H); 1.8 (m, 1H); 1.9 (m, 1H); 2.4 (m, 3H); 2/4 (m, 1H); 2.85 (m, 2H); 3.07 (m, 1H); 3.38 (m, 1H); 4.45 (m, 3H); 6,395 (d, J = 8, 1H); 6.92 (m, 2H); 7.22 (T, J = 8, 1H); 7.42 (t, J = 7, 1H), 7.64 (d, J = 8, 1H). 13 C NMR (d, CDCl 3): 21.0; 22.2; 27.2; 33.1; 43.2; 55.0; 62.0; 64.75; 71.2; 106.4; 114.5; 115.6; 119.9; 128.7; 131.0; 137.3; 146.4; 154.4; 157.9. MS (%): 354 (M + 1, 100)

Claims (10)

  1. NOVELTY OF THE INVENTION CLAIMS 5 1. The use of (a) a NOS inhibitor compound of formula I, II, III, or a pharmaceutically acceptable salt thereof; in combination with (b) a compound showing anti-inflammatory activity or a pharmaceutically acceptable salt thereof; for the preparation of a medicament for the treatment of inflammatory disorders in mammals, in which the above active agents "a" and "b" are present in such amounts as to make effective the combination of both agents in the treatment of said disorders.
  2. 2. The use of (a) an inhibitor compound Nos of formula I, II, lili, ; JMiiiiC ^ BSNfac. __.- > _ ^ ¿S_- - or a pharmaceutically acceptable salt thereof; in combination with (b) a narcotic analgesic compound or a pharmaceutically acceptable salt thereof; for the preparation of a medicament for the treatment of pain, acute or chronic, in mammals, in which the above active agents "a" and "b" are present in such amounts as to make effective the combination of both agents in the treatment of acute or chronic pain.
  3. 3. A pharmaceutical composition for the treatment of inflammatory disorders in mammals, comprising: (a) a compound that shows anti-inflammatory activity or a pharmaceutically acceptable salt thereof; (b) a NOS inhibitor compound of formula I, II, III, IV, V or VI, & 15 or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the above active agents "a" and "b" are present in such a composition in amounts that make the combination of both agents effective in the treatment of said disorders.
  4. 4. A pharmaceutical composition for the treatment of pain, acute or chronic, in mammals, including man, and comprising; (a) a NOS inhibitor compound of formula I, II, III, IV, V or VI, * JCll !! L »aS»? -_ * 8 &r-. S j ^ = ¡aA ÉÍfctfc »fc_ or a pharmaceutically acceptable salt thereof; (b) a narcotic analgesic compound or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the above active agents "a" and "b" are present in such composition in amounts that make the combination of both agents effective in the treatment of said disorder:
  5. 5. A pharmaceutical composition for the treatment of selected condition of between migraine, recurrent headache and other vascular headaches in mammals, comprising: (a) an inhibitor compound Nos, or a pharmaceutically acceptable salt thereof; (b) a serotonin-1 D (5H-TID) receptor agonist or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the above active agents "a" and "b" are present in such composition in amounts that make the combination of both agents effective in the treatment of said condition.
  6. 6. The use of (a) a NOS inhibitor compound, or a pharmaceutically acceptable salt thereof; in combination with (b) a serotonin-1 D (5H-Tjp) receptor agonist or a pharmaceutically acceptable salt thereof; for the preparation of a medicament for the treatment of a condition selected from migraine, recurrent headache and other vascular headaches in mammals, in which the above active agents "a" and "b" are present in such composition in amounts which make the combination of both agents effective in the treatment of said condition.
  7. 7 '.- A pharmaceutical composition for the treatment of a condition selected from the group consisting of sleep disorders, psoriasis, and deficits or cognitive disorders in mammals, comprising a quantity of a NOS inhibitor compound of formula I, II, III , IV, V or VI, üi_Étfb_fe. - ^ §S & amp; & amp; amp; & S & amp; & amp; amp; & > : T & - 2 & amp; amp; amp; amp; which is effective to treat said condition, as well as a pharmaceutically acceptable vehicle.
  8. 8. The use of a NOS inhibitor compound of formula I, II, III, IV, V or VI, for the preparation of a medicament for the treatment of a condition selected from the group consisting of sleep disorders, psoriasis, and deficits or cognitive disorders in mammals.
  9. 9. A pharmaceutical composition for the treatment and prevention of a condition selected from the group consisting of sleep disorders, psoriasis, and deficits or cognitive disorders in mammals, comprising an effective amount of a NOS inhibitor compound of formula I, II, III, IV, V or VI, 10 - ^ a »- -. ^ -. & - * * ^ > & ****, - • »& £ - i - 3 * ^^ _jfe? BS_8« .. > r..a '' '* s ^ ". a ^ B¿3« ta »*» "..- > ^ e3 ^^^^^ * a or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier.
  10. 10. The use of a NOS inhibitor compound of formula I, II, III, IV, V or VI, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a condition selected from the group consisting of sleep disorders, psoriasis, and deficits or cognitive disorders in mammals,
MXPA/A/2001/001548A 1998-08-11 2001-02-09 New pharmaceutical uses for nos inhibitors MXPA01001548A (en)

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