HK1035189A - 2-aminopyridines containing fused ring substituents as nitric oxide synthase inhibitors - Google Patents

Description

2-aminopyridines containing fused ring substituents as nitric oxide synthase inhibitors

Background

The present invention relates to certain fused ring substituent-containing 2-aminopyridines that exhibit Nitric Oxide Synthase (NOS) inhibitor activity, to pharmaceutical compositions containing them, and to their use in the treatment of central nervous system disorders, inflammatory disorders, septic shock, and other disorders in mammals, such as humans and pets.

There are three known isomeric forms of NOS: one inducible form (I-NOS) and two constitutive forms, referred to as neuronal NOS (N-NOS) and endothelial NOS (E-NOS), respectively. In response to a variety of stimuli, these enzymes all undergo the conversion of arginine to citrulline, with the production of Nitric Oxide (NO) molecules. Excess Nitric Oxide (NO) produced by NOS is believed to play a role in the pathology of certain diseases and conditions in mammals. For example, it is believed that NO produced by I-NOS plays a role in diseases associated with systemic hypertension, such as toxic shock, and in treatment with certain cytokines. Cancer patients treated with cytokines such as interleukin 1(IL-1), interleukin 2(IL-2) or Tumor Necrosis Factor (TNF) have been shown to suffer from cytokine-induced shock and hypertension due to the production of NO from macrophages, inducible NOS (I-NOS), see Chemical & Engineering News,12 months and 20 days, p.33. (1993). I-NOS inhibitors can reverse this. It is also believed that I-NOS plays a role in the pathology of diseases of the central nervous system such as ischemia. For example, inhibition of I-NOS has been shown to ameliorate ischemic injury in rat brain, see am.j.physiol.,268, p.r286 (1995). Inhibition of adjuvant-induced arthritis by selective inhibition of I-NOS is reported in eur.j.pharmacol, 273, p.15-24 (1995).

It is believed that NO produced by N-NOS plays a role in diseases such as cerebral ischemia, pain, and narcotic tolerance. For example, inhibition of N-NOS reduces infarct volume following occlusion of the proximal middle cerebral artery in rats, J.Cerebr.blood Flow Meteb., 14, p.924-929 (1994). N-NOS inhibition has also been shown to be effective in antinociception as evidenced by activity in the late phase of the formalin-induced paw licking and acetic acid induced abdominal contraction experiment, see br.j. pharmacol, 110, p.219-224 (1993). In addition, subcutaneous injection of Freund's adjuvant into rats caused an increase in NOS-positive neurons in the spinal cord, as evidenced by increased sensitivity to pain, which can be treated with NOS inhibitors, see Japanese journal of pharmacy, 75, p.327-335 (1997). Finally, it has been reported that opioid withdrawal brain syndrome is reduced in rodents by inhibition of N-NOS, see neuropsychopharmacol, 13, p.269-293 (1995).

Summary of The Invention

The present invention relates to compounds of the formula and pharmaceutically acceptable salts of said compoundsWherein

At the bridge ringWherein N and m are independently 1,2 or 3 and the carbon atom in one of said bridged rings may be substituted with a heteroatom selected from O, S and N, provided that the bridgehead carbon atom is substituted by a nitrogen atom only, and R¹And R²Independently selected from C₁To C₆An alkyl group which may be linear, branched or cyclic, or contain both linear and cyclic or branched and cyclic moieties, wherein each R is¹And R²May be independently optionally substituted with 1 to 3, preferably 0 to 2 substituents independently selected from halogen (e.g., chloro, fluoro, bromo, iodo), nitro, hydroxy, cyano, amino, (C)₁-C₄) Alkoxy and (C)₁-C₄) An alkylamino group;

or R¹And R²Together with the nitrogen atom to which they are attached form a piperazine, azetidine, piperidine or pyrrolidine ring or a 6-to 14-membered azabicyclo ring of which 1 to 3 are nitrogen atoms and the remainder are carbon atoms,

wherein the distal nitrogen atom of said piperazine or azabicyclo is optionally substituted by a group R³And R⁴Is substituted in which R³And R⁴Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, C₁-C₆Alkyl- (= O) -, HC (= O) -, C₁To C₆Alkoxy- (C = O) -, phenyl C (= O) -, naphthyl-C (= O) -and R⁶R⁷NC (= O) -, wherein R⁶And R⁷Independently selected from hydrogen atom and C₁To C₆Alkyl, with the proviso that the azabicyclo is spirocycle, the distal nitrogen atom of the spirocycle being optionally substituted by R⁵Is substituted in which R⁵Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, phenyl-C₁To C₆Alkyl-and naphthyl C₁To C₆Alkyl-;

and the piperazine, azetidine, piperidine and pyrrolidine rings may be optionally substituted with one or more substituents, preferably 0 to 2 substituents, independently selected from C₁To C₆Alkyl, amino, C₁To C₆Alkylamino, [ di-C ]₁-C₆Alkyl radical]Amino, phenyl-substituted 5-to 6-membered heterocyclic ring containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moiety of any of the above substituents may be optionally substituted by one or more substituents, preferably 0 to 2 substituents, independently selected from halogen, at C₁To C₃Alkyl radical, C₁To C₃Alkoxy, nitro, amino, cyano, CF₃And OCF₃；

Provided that none of the carbon atoms is substituted with one or more substituents selected from the group consisting of hydroxy, amino, alkoxy, alkylamino and dialkylamino.

Can be prepared from NR¹R²Examples of azabicycles formed areWherein

R³And R⁴Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, C₁To C₆Alkyl C (= O) -, HC (= O) -, C₁To C₆Alkoxy- (C = O) -, phenyl-C (= O) -, naphthyl-C (= O) -and R⁶R⁷NC (= O) -, wherein R⁶And R⁷Independently selected from hydrogen atom and C₁To C₆An alkyl group; while

R⁵Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, phenyl-C₁To C₆Alkyl-and naphthyl C₁To C₆An alkyl group-.

A preferred embodiment of the present invention relates to compounds of formula I, wherein NR is¹R²Is an optionally substituted piperidine, azetidine, piperazine or pyrrolidine ring or 3-aza-bicyclo [3.1.0]A hex-6-ylamine ring;

and wherein said piperazine, azetidine, piperidine, pyrrolidine and 3-aza-5-bicyclo [3.1.0]The hex-6-ylamine ring may be optionallyIs substituted with one or more substituents, preferably 0 to 2 substituents, independently selected from C₁To C₆Alkyl, amino, C₁To C₆Alkylamino, [ di-C ]₁To C₆Alkyl radical]Amino, phenyl-substituted 5 to 6 membered heterocyclic ring containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moiety of any of the above substituents may be optionally substituted by one or more substituents, preferably 0 to 2 substituents, independently selected from halogen, at C₁To C₃Alkyl radical, C₁To C₃Alkoxy, nitro, amino, cyano, CF₃And OCF₃。

The following compounds are preferred compounds of the invention:

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- [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- (4-methylpiperazin-1-yl-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl ] -pyridin-2-ylamine and

6- [8- (4- (2-phenylethyl) -piperazin-1-yl-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl ] pyridin-2-ylamine.

Other compounds of the invention include the following:

6- [8- (2- (4-dimethylamino-piperidin-1-yl) -ethoxy) -1,2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridin-2-ylamine;

6- [8- (2- (6, 7-dimethoxy-tetrahydroisoquinolin-2-yl ] -ethoxy) -1,2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridin-2-ylamine and

6- [8- (2- (4-methylpiperazin-1-yl) -ethoxy) -1,2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridin-2-ylamine.

The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the present invention described above are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, glucarate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ i.e., 1-methylene-bis- (2-hydroxy-3-naphthoic acid) salt ].

Alkyl groups and the alkyl portion of other groups herein, unless otherwise specified, include saturated monovalent hydrocarbon groups containing straight, branched, or cyclic moieties or combinations thereof.

The term "one or more substituents" as used herein means that the number of possible substituents is equal to 1 to the maximum number of substituents based on the number of bonding sites that can be provided.

The terms "halogen" and "halogen atom" as used herein, unless otherwise specified, include chlorine, fluorine, bromine and iodine.

Examples of more specific embodiments of the present invention include:

(a) compounds of formula (I) wherein n is 1;

(b) compounds of formula (I) wherein n is and;

(c) compounds of formula (I) wherein m is 1;

(d) compounds of formula (I) wherein m is 2;

(e) compounds of formula (I) wherein X is an oxygen atom;

(f) wherein R is¹And R²Independently selected from C₁To C₆Alkyl compounds of formula I;

(g) wherein R is¹And R²Compounds of formula I wherein the nitrogen atom to which they are not attached form a ring;

(h) wherein R is¹And R²A compound of formula I which together with the nitrogen atom to which they are attached forms a piperazine, azetidine, piperidine or pyrrolidine ring; and

wherein R is¹Is selected from C₁To C₆Alkyl radical and R²A compound of formula i which is cyclopropyl.

The invention also relates to a pharmaceutical composition for the treatment of a disease selected from the group consisting of: migraine, inflammatory diseases (e.g., asthma and psoriasis), stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS-related dementia, neurodegenerative diseases (e.g., Parkinson's disease), neuronal intoxication, Alzheimer's disease, chemical dependence and addiction (e.g., drug, alcohol and nicotine dependence), emesis, epilepsy, anxiety, depression, psychosis, brain trauma, Adult Respiratory Distress Syndrome (ARDS), morphine-induced tolerance and withdrawal from brain syndrome, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, ocular diseases (e.g., glaucoma and macular degeneration), diabetic neuropathy, diabetic nephropathy and cancer (e.g., leukemia), which comprises a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent such disorders, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating a condition selected from the group consisting of: migraine, inflammatory diseases (e.g., asthma and psoriasis), stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS-related dementia, neurodegenerative diseases (e.g., Parkinson's disease), neuronal intoxication, Alzheimer's disease, chemical dependence and addiction (e.g., drug, alcohol and nicotine dependence), emesis, epilepsy, anxiety, depression, psychosis, brain trauma, Adult Respiratory Distress Syndrome (ARDS), morphine-induced tolerance and withdrawal from brain syndrome, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, ocular diseases (e.g., glaucoma and macular degeneration), diabetic neuropathy, diabetic nephropathy and cancer (e.g., leukemia), which comprises administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat or prevent such a condition.

The invention also relates to a pharmaceutical composition for inhibiting Nitric Oxide Synthase (NOS) in mammals including humans, comprising an NOS inhibitory effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also relates to a method of inhibiting NOS in a mammal, including a human, comprising administering to said mammal an NOS inhibiting effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention also relates to pharmaceutical compositions for treating a condition selected from: migraine, inflammatory diseases (e.g., asthma and psoriasis), stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS-related dementia, neurodegenerative diseases (e.g., Parkinson's disease), neuronal intoxication, Alzheimer's disease, chemical dependence and addiction (e.g., drug, alcohol and nicotine dependence), emesis, epilepsy, anxiety, depression, psychosis, brain trauma, Adult Respiratory Distress Syndrome (ARDS), morphine-induced tolerance and withdrawal from brain syndrome, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, ocular diseases (e.g., glaucoma and macular degeneration), diabetic neuropathy, diabetic nephropathy and cancer (e.g., leukemia), which comprises a compound of formula I or a pharmaceutically acceptable salt thereof with an effective NOS inhibiting effect and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating a condition selected from the group consisting of: migraine, inflammatory diseases (e.g., asthma and psoriasis), stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS-related dementia, neurodegenerative diseases (e.g., Parkinson's disease), neuronal intoxication, Alzheimer's disease, chemical dependence and addiction (e.g., drug, alcohol and nicotine dependence), emesis, epilepsy, anxiety, depression, psychosis, brain trauma, Adult Respiratory Distress Syndrome (ARDS), morphine-induced tolerance and withdrawal from brain syndrome, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, ocular diseases (e.g., glaucoma and macular degeneration), diabetic neuropathy, diabetic nephropathy and cancer (e.g., leukemia), comprising administering to said mammal a NOS inhibitory effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof.

The invention also relates to compounds of the formulaWherein

n,m,R¹And R²As defined above for the compounds of formula I. The compounds of formula VI are useful as intermediates in the preparation of compounds of formula I.

The invention also relates to compounds of the formulaWherein

n,m,R¹And R²As defined above for compounds of formula I, and R⁸Is aryl such as phenyl or naphthyl. The compounds of formula VIII are useful as intermediates in the preparation of the compounds of formula I.

The term "treatment" as used herein is to be understood as including "prevention" unless otherwise indicated.

The compounds of formula i may contain chiral centers and may therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of the compounds of formula (I) and mixtures thereof, and to all pharmaceutical compositions containing them and all the above-mentioned methods of treatment using them.

The above formula i includes compounds which are the same as the compounds described, but in which one or more hydrogen, carbon or other atoms have in fact been replaced by their isotopes. These compounds can be used as research and diagnostic tools in metabolic pharmacokinetics and binding assays.

Detailed Description

The compounds of formula i can be prepared as described in the reaction schemes and discussion below. Unless otherwise stated, n, m, R are used in the subsequent reaction schemes and discussions¹And R²As defined above. Scheme 1

Referring to scheme 1, compounds of formula ii were prepared by the reaction of norbornene and 2-hydroxypyrone followed by aromatization with palladium oxide according to the procedure described in syn. It is then reacted with tetrabutylammonium tribromide in 1, 2-dichloroethane at about room temperature for about 10 minutes to about 10 hours. The reaction product is then treated with benzyl bromide and potassium carbonate in a solvent such as acetonitrile at about the reflux temperature of the reaction mixture for about 1 to 48 hours to form the compound of formula iii.

The compound of formula iii is then converted to 5-benzyloxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene-8-boronic acid by cooling the compound of formula iii to about-70 ℃ in dry Tetrahydrofuran (THF) and adding a solution of n-butyllithium thereto. The resulting solution is then treated with triethyl borate and warmed to room temperature for 1 to 48 hours to form 5-benzyloxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene-8-boronic acid. 5-benzyloxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene-8-boronic acid is reacted with 6-bromo-2- (2, 5-dimethylpyrrolyl) pyridine in an alcohol solvent in the presence of sodium carbonate and tetrakis (triphenylphosphine) palladium at about the reflux temperature of the reaction mixture for about 1 to 48 hours to provide the compound of formula IV.

The compound of formula IV can be converted to the compound of formula V in the following two-step process. The compound of formula iv is reacted with ammonium formate and 10% palladium on carbon in an alcohol solvent at about the reflux temperature of the reaction mixture for about 10 minutes to about 10 hours to provide a compound similar to the compound of formula iv wherein the benzyloxy group of formula iv is replaced by a hydroxyl group. The compound of formula v is formed by reacting the above hydroxy derivative with 2-bromoethyl acetate and potassium carbonate in acetonitrile at about the reflux temperature of the reaction mixture for about 1 to 48 hours.

The compound of formula V is subjected to basic hydrolysis and then reacted with N-ethyl-N-3-dimethylaminopropylcarbodiimide (EDAC) and a compound of formula R¹R²The appropriate compound of NH to give the desired compound of formula vi. This basic hydrolysis is typically carried out with an alkali or alkaline earth metal hydroxide in a compound of THF, methanol and water at about room temperature for about 1 to 48 hours. Compounds of formula VI and formula R¹R²The reaction of a suitable compound of NH with N-ethyl-N-3-dimethylaminopropylcarbodiimide (EDAC) is carried out in the presence of a base. Examples of suitable bases are selected from trialkylamines, alkali metal carbonates and alkaline earth metal carbonates. The reaction is generally carried out in a solvent such as acetonitrile, dichloromethane or N, N-Dimethylformamide (DMF) at about room temperature to about 100 ℃, preferably at about room temperature, for about 1 to 48 hours. Preferably, the reaction is carried out in the presence of a catalyst such as N-hydroxysuccinamide or hydroxybenzotriazole.

Compounds of formula VI may be converted to the desired compounds of formula I by the following method. Reduction of a compound of formula VI to form the corresponding compound with the carbonyl group replaced by a methylene group, i.e.

Thereafter the 2, 5-dimethylpyrrolyl protecting agent is removed. This reduction may be carried out by methods known to those skilled in the art, for example, with lithium aluminum hydride in tetrahydrofuran, with or without the addition of aluminum chloride, or with borane methyl sulfide in tetrahydrofuran at about-78 ℃ to about reflux temperature, preferably at about-70 ℃ to room temperature, for about 1 to about 24 hours.

Removal of the 2, 5-dimethylpyrrolyl protecting agent can be accomplished by reaction with hydroxylamine hydrochloride. The reaction is generally carried out in an alcoholic or aqueous alcoholic solvent (preferably ethanol is used as the alcohol) at about room temperature to about the reflux temperature of the reaction mixture, preferably at reflux temperature, for about 8 to about 72 hours.

Compounds of the formula I which are identical to the compounds of the formula VII but in which a heteroatom is actually present in one of the bridged rings can be prepared in a manner analogous to that described in scheme 1, starting with suitable compounds analogous to the compounds of the formula II in which the unsubstituted bridged ring of the formula II is replaced by a heteroatom-containing bridged ring.

Compounds of formula I which are identical to those of formula VII except that they contain more or fewer atoms per bridged ring (provided formula I permits) may be prepared in a manner analogous to that described in scheme 1, starting with an analogue of formula II bearing a bridged ring containing the appropriate number of atoms.

Analogous compounds of formula II can be prepared as described in scheme 1 and the reaction starts with compounds of the formulaCompounds of formula I wherein n is 2 and m is 1 may also be prepared using 5-methoxy-1, 4-dihydro-1, 4-ethano-naphthalene as starting material (J.Med.chem.,30,2191 (1987)). 5-methoxy-1, 4-dihydro-1, 4-ethano-naphthalene can be converted into 5-hydroxy-1, 2,3, 4-tetrahydro-1, 4-ethano-naphthalene (n =2 analogue in the compound of formula II of scheme 1) by hydrogenation followed by demethylation. The compound of formula 1, wherein n is 2 and m is 1, can then be prepared from 5-hydroxy-1, 2,3, 4-tetrahydro-1, 4-ethanonaphthalene following the remaining steps of scheme 1, followed by synthesis of the compound of formula ii.

The compounds of formula I can also be prepared from formula VIII according to the process described in scheme 2 belowScheme 2 for the preparation of compounds of

Reference scheme 2, R⁸Selected from aryl and C₁To C₆Alkyl, wherein aryl is preferably phenyl or naphthyl. The compound of formula I is obtained by hydrolysis of the compound of formula VIII with an acid or a base. Examples of acids that may be used include, but are not limited to, mineral acids and sulfonic acids. Examples of the base that can be used include alkali metal hydroxides and alkaline earth metal hydroxides. The hydrolysis of the compound of formula viii may be carried out in an alcohol or aqueous solvent at about 0 to about 100 c for about 1 to 24 hours.

The preparation of other compounds of formula I, which are not specifically described in the experimental section above, can be accomplished by a combination of the above reactions, as will be apparent to those skilled in the art.

In each of the reactions discussed and illustrated above, unless otherwise indicated, the pressure is not critical. Pressures of about 0.5 to about 5 atmospheres are generally acceptable, with atmospheric pressure, i.e., about 1 atmosphere, being preferred for convenience.

The compounds of formula i ("active compounds of the invention") are basic in nature and form a large number of different salts with different inorganic and organic acids. Although these salts must be pharmaceutically acceptable salts for animal use, it is often necessary in practice to isolate the compound of formula i from the reaction mixture in the form of a non-pharmaceutically acceptable salt, and then to simply convert the latter back to the free base compound by treatment with an alkaline agent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the active base compounds of this invention can be readily prepared by treating the basic compound with substantial equivalents of the selected inorganic or organic acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. The desired solid salt is readily obtained by carefully evaporating the solvent.

The active compounds of the present invention and their pharmaceutically acceptable salts are useful as NOS inhibitors, i.e., they have the ability to inhibit the NOS enzyme in mammals and are therefore useful as therapeutic agents in the treatment of such disorders and diseases in mammalian patients.

The active compounds of the invention and their pharmaceutically acceptable salts can be administered by oral, parenteral or topical routes. Although variations will be required depending on the species, weight and condition of the patient, and the particular route of administration chosen, in general these compounds will most desirably be administered in a dosage range of from about 0.01 to about 250mg per day, in single or divided doses (i.e., 1 to 4 doses per day). However, dosage levels of about 0.07mg to 21mg per kilogram of body weight per day are most preferred. Nevertheless, variations may be made depending on the species of animal being treated and its individual response to the drug, as well as the type of pharmaceutical formulation selected and the time and interval of administration. In some cases, dosage levels below the lower limit of the aforesaid range may be more suitable, while in other cases larger doses may be employed which do not cause any harmful side effects, provided that the larger dose is first divided into several small doses to be administered throughout the day.

The active compounds of the present invention may be administered alone or with pharmaceutically acceptable carriers or diluents by any of the three routes of administration described above, and such administration may be in the form of single or multiple doses. More particularly, the novel therapeutic agents of the present invention may be administered in a wide variety of different dosage forms, i.e., they may be combined with a wide variety of pharmaceutically acceptable inert carriers to form tablets, capsules, lozenges, troches, powders, sprays, creams, ointments, suppositories, jellies, coacervates, pastes, lotions, salves, aqueous suspensions, injections, elixirs, syrups, and the like. The carrier includes solid diluents or fillers, sterile inclusion media and various sterile organic solvents and the like. In addition, oral pharmaceutical compositions may be suitably sweetened and/or flavored. Generally, the therapeutically effective compounds of the present invention are present in these dosage forms at concentration levels of from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycerol may be employed, as may disintegrating agents such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, and as may particulate binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for preparing tablets. Solid compositions in similar form may also be used as fillers in gelatin capsules; preferred materials in this regard also include lactose and high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or pigments, and, if desired, emulsifying and/or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various mixtures thereof.

For parenteral administration, solutions of the active compounds of the invention in sesame or peanut oil or aqueous propylene glycol may be used. The aqueous solution should be suitably buffered (preferably to a pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. All of these solutions are readily prepared under sterile conditions by standard pharmaceutical techniques well known to those skilled in the art.

Furthermore, when treating inflammation of the skin, the active compounds of the invention may also be administered topically, and they may be accomplished by creams, jellies, gels, pastes, patches, ointments and the like in accordance with standard pharmaceutical practice.

The ability of the compounds of formula I to inhibit NOS can be determined by methods described in the literature. The ability of compounds of formula I to inhibit endothelial NOS can be determined by the methods described by Schmidt et al Proc. Natl. Acad. Sci. U.S.A.,88, pp.365-369(1991) and Pollock et al Proc. Natl. Acad. Sci. U.S.A.,88, pp.10480-10484 (1991). The ability of compounds of formula I to inhibit inducible NOS can be determined by the methods described by Schmidt et al, Proc.Natl.Acad.Sci.U.S.A.,88, pp.365-369(1991) and Garvey et al, J.Bio1.chem.,269, pp.26669-26676 (1994). The ability of compounds of formula I to inhibit neuronal NOS can be determined using Bredt and Snyder in Proc. Natl.Acad.Sci.U.S.A.,87,682-685 (1990). Two compounds of formula I were tested, both of which showed IC for inhibition of inducible or neuronal NOS₅₀＜10μM。

The invention is illustrated by the following examples. It should be understood, however, that the invention is not limited by the specific details of these examples. The melting point is uncorrected. Proton nuclear magnetic resonance spectrum (¹H NMR) and¹³nuclear magnetic resonance spectroscopy in deuterated chloroform (CDCl)₃) Or in CD₃OD or CD₃SOCD₃And peak positions are expressed in parts per million (ppm) below the magnetic field of Tetramethylsilane (TMS). The peak shape is represented as follows: s, singlet; d, doublet; t, triplet; q, quartet, m, multiplet, b, broad.

Example 1

6- [8- (2-dimethylamino-ethoxy) -1,2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridin-2-ylamine:

a.5-hydroxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene

Norbornene (18.1g,190mmol) was reacted with known (syn. commun.,5,461, (1975)) 2-hydroxypyrone (5.38g,48mmol) and heated in a sealed tube at 125 ℃ for 2 days to give 1, 2-and 1,4-5,6,7, 8-octahydro-5, 8-methano-naphthalen-1-one in yields of 45% and 4%, respectively, which was converted to the desired phenol in 71% yield by refluxing with palladium oxide (0.5g) and magnesium sulfate (1.0g) in toluene (80mL) for 48 hours.

¹H-NMR(δ,CDCl₃):1.20(m,2H),1.50(m,1H),1.75(m,1H),1.90(m,2H),3.355(m,1H),3.55(m,1H),5.28(bs,1H),6.59(d,J=8,1H),6.79(d,J=7,1H),6.95(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃):26.4,27.0,39.2,.43.9,49.0,113.1,113.4,126.7,132.4,148.6,

150.65。

MS (%): 160 (parent, 100).

B.5-hydroxy-8-bromo-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene

To a 250mL round bottom flask equipped with an addition funnel and nitrogen inlet was added 2.9g (18mmol) of 5,6,7, 8-tetrahydro-1, 4-methano-naphthalen-1-ol and 50mL of 1, 2-dichloroethane, and a solution of 8.7g (18mmol) of tributylammonium tribromide in 30mL of 1, 2-dichloroethane was added dropwise over 10 minutes with stirring. After stirring for a further 10 minutes at room temperature, the solution is washed with water, dilute aqueous sodium hydrogen sulfite solution and water, dried over sodium sulfate and evaporated. The mixture of product and tributylammonium bromide was chromatographed on silica gel using hexane/ethyl acetate as eluent to give 3.2g (74%) of an oil.

¹H-NMR(δ,CDCl₃):1.20(m,2H),1.50(m,1H),1.75(m,1H),1.90(m,2H),3.53(m,1H),3.58(m,1H),4.80(bs,1H),6.46(d,J9,1H),7.04(d,J=9,1H)。

C.5-benzyloxy-8-bromo-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene

The above oil was dissolved in 50ml acetonitrile and treated with 1.7ml (14.4mmol) of benzyl bromide and 3.6g (26.4mmol) of potassium carbonate and then refluxed for 14 hours. TLC showed in R in 10% dichloromethane/hexane_f=0.3 having one major spot (benzyl bromide at R)_f= 0.4). The reaction was cooled, poured into dilute hydrochloric acid/ethyl acetate and the organic layer was separated, washed with water and brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using dichloromethane/hexane as eluent to give 4.1g (94%) of an oil.

¹H-NMR(δ,CDCl₃):1.21(m,2H),1.50(m,1H).1.76(m,1H),1.940(m,2H),3.57(m,1H),3.77(m,1H),5.08(s,2H),6.61(d,J=9,1H),7.14(d,J=9,1H),7.3-7.5(m,5H)。

¹³C-NMR(δ,CDCl₃):26.0,26.2,41.0,44.7,48.5,70.6,107.6,112.6,127.3,127.9,128.8,129.1,137.2,137.6,149.5,151.5。

MS (%): 327/327 (parent, Br)⁷⁹/Br⁸¹,100)。

5-benzyloxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene-8-boronic acid

To a 125ml round bottom flask equipped with a nitrogen inlet was added 4.1g (12.5mmol) of 5-benzyloxy-8-bromo-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene and 20ml of dry tetrahydrofuran. The solution was cooled to-70 ℃ and 6.5ml (16.2ml) of a 2.5M solution of n-butyllithium in hexane were added over 5 minutes, and the reaction mixture was stirred at-70 ℃ for 10 minutes. The solution was then treated with 2.8ml (16.2mmol) of triethyl borate, stirred at-70 ℃ for 5 minutes, then warmed to room temperature and stirred for 40 hours. The reaction was stopped with aqueous ammonium chloride solution, poured into 0.5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give 3.6g (100%) of a white foam after trituration with hexane.

¹H-NMR(δ,CDCl₃) 1.2-1.4(m,2H),1.55(m,1H),1.84(m,1H),1.92(m,2H),3.72(m,2H),5.15 and 5.17 (singlet, 2H of mono-and diarylboronic acids), 6.77 and 6.83 (doublet, J =8,1H),7.2-7.5(m,5H),7.8 and 7.92 (doublet, J =9, 1H).

E.2- (2, 5-dimethylpyrrolyl) -6- [ 8-benzyloxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine

To a 500ml round bottom flask equipped with a condenser and nitrogen inlet was added 3.1mg (12.2mmmol)2- (2, 5-dimethylpyrrolyl) -6-bromo-pyridine, 3.2mg (12.2mmol) 5-benzyloxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene-8-boronic acid, 5.2g (48.8mmol) sodium carbonate, 282mg (0.24mmol) tetrakis (triphenylphosphine) palladium, 135ml ethanol and 15ml water and the reaction mixture was heated at 80 ℃ for 13 hours. TLC in 20% ethyl acetate in hexane at R_fThe major spot is shown at =0.4, while LCMS shows a major peak at P +1= 421. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated. The residue is washed with hexane on silica gelPurification by chromatography with ethyl acetate as eluent gave 4.8g (94%) of a white solid.

¹H-NMR(δ,CDCl₃):1.33(m,2H),1.50(m,1H),1.75(m,1H),1.98(m,2H),2.22(s,6H),3.73(bs,1H),3.85(bs,1H),5.15(5,2H),5.92(5,2H),6.81(d,J=8.5,1H),7.10(d,J=7.5,1H),7.2-7.5(m,7H),7.845(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃):13.5,26.4,26.7,39.7,43.1,48.9,70.1,106.7,107.6,110.65,119.0,120.3,121.0,126.3,126.4,127.3,127.5,127.8,128.5,128.7,136.3,137.4,138.0,148.4,151.6,152.7,158.0。

MS (%): 421 (parent +1,100).

2- (2, 5-dimethylpyrrolyl) -6- [ 8-hydroxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine

To a 250ml round bottom flask equipped with a condenser and nitrogen inlet was added 4.8g (11.4mmol)2- (2, 5-dimethylpyrrolyl) -6- [ 8-benzyloxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine, 3.0g (47.6mmol) ammonium formate, 130mg 10% palladium on carbon and 100ml ethanol. The reaction mixture was refluxed for 4 hours, and the catalyst and formate were added at 2 and 3 hours, then cooled and filtered through Celite (trade mark Celite) with ethanol and dichloromethane. The filtrate was evaporated and the residue was dissolved in ethyl acetate/aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give 3.9g (about 100%) of a light brown solid.

¹H-NMR(δ,CDCl₃):1.30(m,2H),1.49(m,1H),1.72(m,1H),1.95(m,2H),2.215(s,6H),3.59(bs,1H),3.81(bs,1H),5.93(s,2H),6.59(d,J=8.5,1H),7.11(d,J=8,1H),7.38(d,J=8.5,1H),7.50(d,J=8,1H),7.855(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃) 13.4,26.4,26.6,3.3,43.0,48.9,106.8,107.2,113.9,119.2,121.4,127.6,128.8,133.5,138.3,148.6,150.0,158.4 (with one carbon atom not indicated).

MS (%): 329 (parent +1,100).

G.2- (2, 5-dimethylpyrrolyl) -6- [ 8-ethoxycarbonylmethoxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine

To a 250ml round bottom flask equipped with a condenser and nitrogen inlet was added 3.9g (11.9mmol)2- (2, 5-dimethylpyrrolyl) -6- [ 8-hydroxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl]Pyridine, 1.6ml (14.2mmol) of ethyl bromoacetate, 2.0g (14.2mmol) of potassium carbonate and 80ml of acetonitrile. The mixture was refluxed for 12 hours and cooled (TLC R)_f=0.4 in 1/3 ethyl acetate/hexane), poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluent to give 3.95g (80%) of an oil.

¹H-NMR(δ,CDCl₃):1.29(t,J=7,3H),1.30(m,2H),1.49(m,1H),1.75(m,1H),1.97(m,2H),2.20(s,6H),3.73(bs,1H),3.82(bs,1H),4.25(q,J=7,2H),4.67(s,2H),5.89(s,2H),6.63(d,J=9,1H),7.09(d,J=8,1H),7.49(m,2H),7.835(t,J=8,1H).

¹³C-NMR(δ,CDCl₃):13.4,14.1,26.25,26.5,39.7,43.0,48.8,61.2,65.8,106.6,106.9,110.1,119.0,120.9,122.0,127.4,128.6,136.4,137.9,148.5,149.1,151.8,157.8,169.0。

MS (%): 415 (parent +1, 100).

2- (2, 5-dimethylpyrrolyl) -6- [ 8-methoxycarbonyl-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine

To a 125ml round bottom flask equipped with a condenser and nitrogen inlet was added 3.95g (9.5mmol)2- (2, 5-dimethylpyrrolyl) -6- [ 8-ethoxycarbonylmethoxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine, 30ml tetrahydrofuran and 1.2g (28.6mmol) lithium hydroxide hydrate in 30ml water, methanol was added to maintain the solution state. The reaction mixture was stirred at room temperature for 12 hours, (LCMS P +1=389), poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to a solid 2.4g (65%).

¹H-NMR(δ,COCl₃/CD₃OD):1.28(m,2H),1.51(m,1H),1.70(m,1H),1.95(m,2H),2.13(s,6H),3.715(bs,1H),3.76(bs,1H),4.67(s,2H),4.81(S,2H),6.70(d.J=8.5,1H),7.16(d,J=8,1H),7.38(d,J=8.5,1H),7.55(d,J=8,1H),7.95(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃ ):12.3,25.9,26.3.39.6,42.85,65.0,110.0,119.7,121.8,126.5,127.2,128.15,136.0,138.7,148.4,151.6,152.1,158.1,171.4。

MS (%): 389 (parent +1,100).

2- (2, 5-dimethylpyrrolyl) -6- [8- (N, N-dimethylcarboxamido) methoxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine

To a 100ml round bottom flask equipped with a condenser and nitrogen inlet was added 200mg (0.52mmol)6- (4-carboxymethylnaphthalen-1-yl) -pyridin-2-ylamine, 85mg (1.04mmol) N, N-dimethylamine hydrochloride, 397mg (2.1mmol) N-ethyl, N-3-dimethylaminopropylcarbodiimide, 381mg (3.1mmol) 4-dimethylaminopyridine and 10ml dry acetonitrile. The reaction mixture was stirred at rt for 12 h (LCMS showed P +1=416 and TLC showed R_f=0.2 in 5% methanol/dichloromethane) then evaporation and chromatographic purification of the residue on silica gel with methanol/dichloromethane as eluent gives 202mg (93.5%) of product as a foam.

¹H-NMR(δ,CDCl₃):1.32(m,2H),1.50(m,1H),1.73(m.1H),1.97(m,2H),2.21(s,6H),2.98(s,3H),3.10(s,3H),3.71(bs,1H),3.85(bs,1H),4.74(s,2H),5.90(s,2H),6.76(d,J=9,1H),7.09(d,J=8,1H),7.49(m,2H),7.84(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃):13.42,26.36,26.54,35.65,36.57,39.61,42.99,45.85,67.75,106.62,110.01,118.99,120.90,126.90,127.52,128.58,135.97,138.00,148.43,151.52,151.78,157.87,167.93。

MS (%); 416 (mother +1, 100).

J.2- (2, 5-dimethylpyrrolyl) -6- [8- (N, N-dimethylaminoethoxy) -1,2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine

To a 100ml round bottom flask equipped with a condenser and nitrogen inlet was added 196mg (1.5mmol) of aluminium chloride and 10ml of dry tetrahydrofuran. The solution was cooled to 0 ℃ and 3.40ml (3.40mmol) of a 1.0M solution of lithium aluminum hydride in tetrahydrofuran were added. Stirring is continued for 20 min at room temperature, after which the solution is cooled to-70 ℃ and 202mg (0.49mmol) of 2- (2, 5-dimethylpyrrolyl) -6- [8- (N, N-dimethylformamidomethoxy) -1,2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine in 10ml of dry tetrahydrofuran are added. Stirring was continued at-70 ℃ for 1 hour, then at room temperature for 2 hours (LCMS showed P +1=402) and then carefully stopped with 5ml of 1N hydrochloric acid. After stirring for 20 minutes, the reaction was treated with 6ml of 6N aqueous sodium hydroxide solution and extracted with several portions of dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give 152mg (77%) of an oil.

¹H-NMR(δ,CDCl₃):1.28(m,2H),1.48(m,1H),1.72(m,1H),1.96(m,2H),2.22(s,6H),2.37(s,6H),2.78(t,J=6,2H),3.67(bs,1H),3.85(bs,1H),4.15(t,J=6,2H),5.91(s,2H),6.76(d,J=9,1H),7.09(d,J=8,1H),7.52(m,2H),7.83(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃):13.52,26.42,26.66,30.35,39.69,43.10,46.13,48.91,58.32,66.89,106.68,110.21,118.93,120.94,125.55,126.28,127.48,128.66,136.12,137.98,148.29,15 1.63,152.78,158.10。

MS (%): 402 (parent +1, 100).

K.6- [8- (N, N-dimethylamino-ethoxy) -1,2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridin-2-ylamine

Into a 100ml round bottom flask equipped with a condenser and nitrogen inlet was added 152mg (0.36mmol)2- (2, 5-dimethylpyrrolyl) -6- [8- (N, N-dimethylaminoethoxy) -1,2,3, 4-tetrahydro-1, 4-methano-naphthalen-5-yl ] -pyridine, 506mg (7.6mmol) hydroxylamine hydrochloride, 10ml ethanol and 1ml water. The solution was refluxed for 40 hours (LCMS P +1=324), cooled, poured into dilute hydrochloric acid, and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 12 with 6N aqueous sodium hydroxide solution and extracted with several portions of dichloromethane. The organic layer was converted to the hydrochloride salt in ether, dried over sodium sulfate and evaporated to give 129mg (78%) of a solid (mp 130 ℃ C.) (decomposed).

¹H-NMR(δ,CDCl₃):1.25(m,2H),1.42(m,1H),1.67(m,1H),1.89(m,2H),2.34(s,6H),2.74(t,J=6,2H),3.615(bs,1H),3.74(bs,1H),4.11(t,J=6,2H),4.52(bs,2H),6.35(d,J=8,1H),6.70(d,J=8,1H),6.80(d,J=7.5,1H),7.36(d,J=8,1H),7.42(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃):26.5,26.7,39.8,42,9,46.1,48.8,58.3,66.9,105.9,110.2,113.2,126.9,127.5,135.8,137.8,148.0,152.2,156.9,158.2。

MS (%): 324 (parent +1, 100).

Elemental analysis, calculation of (C)₂₀H₂₅N₃O₂HCl3/2H₂O1/2(C₄H₁₀O)):C 57.39,H 7.66,N 9.13。

Found C57.58, H7.47, N9.09.

Example 2

6- [8- (2-pyrrolidin-1-yl-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl ] -pyridin-2-ylamine

Prepared as in example 1, but replacing N, N-dimethylamine hydrochloride in step 1I above with pyrrolidine to give a tan solid in 45% yield as the hydrochloride salt from diethyl ether, mp 80 deg.C (decomposed).

¹H-NMR(δ,CDCl₃):1.25(m,2H),1.44(m,1H),1.70(m,1H),1.80(m,4H),1.91(m,2H),2.65(m,4H),2.92(t,J=6,2H),3.62(bs,1H),3.75(bs,1H),4.16(t,J=6,2H),4.46(bs,2H),6.38(d,J=8,1H),6.72(d,J=8,1H),6.82(d,J=7.5,1H),7.37(d,J=8,1H),7.45(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃):23.5,26.4,26.6,39.7,42.8,48.7,54.8,55.0,67.7,105.8,110.2,113.2,126.9,135.7,137.7,147.9,152.2,156.9,158.0。

MS (%): 350 (parent +1, 100).

Elemental analysis, calculation of (C)₂₂H₂₇N₃O₂HC19/4H₂O1/2(C₄H₁₀O)):C57.65,H7.76,N8.40。

Measured value: c57.65, H7.43, N8.34.

Example 3

6- [8- (2-dimethylamino-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl) -pyridin-2-ylamine: prepared according to example 1, starting with (instead of 5-hydroxy-1, 2,3, 4-tetrahydro-1, 4-methano-naphthalene) 5-hydroxy-1, 2,3, 4-tetrahydro-1, 4-ethano-naphthalene, which is known as 5-methoxy-1, 4-dihydro-1, 4-ethano-naphthalene (j.med.chem.,30,2191(1987)), hydrogenated in dichloromethane with palladium on carbon as catalyst, followed by demethylation with boron tribromide. 5-hydroxy-1, 2,3, 4-tetrahydro-1, 4-ethano-naphthalene¹H-NMR data: 1.36(m,4H),1.75(m,4H),2.95 (singlet with good coupling, 1H),3.28 (singlet with good coupling, 1H),4.62(bs,1H),6.66(d, J =7,1H),6.76(d, J =7,1H),7.01(t, J =7,1H), mass spectrometry data: p =174 (60%, maternal). The remaining steps were carried out as in example 1 to give the product as a tan solid in 74% yield as the hydrochloride salt from diethyl ether, mp130 (decomposition).

¹H-NMR(δ,CDCl₃):1.33(m,4H),1.67(m,4H),2.32(s,6H),2.75(t,J=5,2H),3.35(m,1H),3.52(m,1H),4.09(t,J=5.2H),4.55(bs,2H),6.38(d,J=8,1H),6.64(d,J=8,1H),6.77(d,J=8,1H),7.26(d,J=8,1H),7.405(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃):25.49,25.72,29.88,45.83,50.21,53.37,58.11,63.44,66.85,105.96,109.15,114.29,126.87,129.90,132.35,137.54,143.23,152.76,157.24,158.06。

MS (%): 338 (parent +1, 100).

Elemental analysis, calculation of (C)₂₂H₂₇N₃O₂HC15/4H₂O):C 57.66,H 7.37,N 9.61。

Measured value: c57.89, H7.26, N9.21.

Example 4

6- [8- (2-pyrrolidin-1-yl-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl ] -pyridin-2-ylamine: prepared according to the method of example 3 in 78% yield as a tan solid, from ether to give the hydrochloride salt, mp 200 ℃ (decomposed).

¹H-NMR(δ,CDCl₃):1.345(m,4H),1.69(m,4H),1.78(m,4H),2.63(m,4H),2.91(t,J=6,2H),3.38(m,1H),3.54(m,1H),4.14(t,J=6,2H),4.49(bs,2H),6.38(d,J=8,1H),6.67(d,J=7,1H),6.79(d,J=8,1H),7.27(d,J=8,1H),7.41(t,J=8,1H)。

¹³C-NMR(δ,CDCl₃):23.44,25.52,25.75,26.09,29.88,46.00,54.71,54.88,63.40,67.90,105.79,109.30,114.30,126.89,129.91,132.36,137.45,143.18,152.81,157.43,157.99。

MS (%): 364 (parent +1, 100).

Elemental analysis, calculation of (C)₂₂H₂₇N₃O₂HCl5/4H₂O):C 60.19,H 7.36,N 9.16。

Measured value: c60.15, H7.01, N8.95.

Example 5

6- [8- (4-methylpiperazin-1-yl-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl ] -pyridin-2-ylamine: prepared according to the method of example 3 in 78% yield as a tan solid, providing the hydrochloride salt from diethyl ether, mp 200 ℃ (decomposed).

¹H-NMR(δ,CDCl₃):1.33(m,4H),1.68(m,4H),2.26(s,3H),2.4-2.8(m,10H),2.81(t,J=6,2H),3.37(m,1H),3.51(m,1H),4.12(t,J=6,2H),4.48(bs,2H),6.38(d,J=8,1H),6.66(d,J=7,1H),6.77(d,J=8,1H),7.26(d,J=8,1H),7.41(t,J=7,1H)。

¹³C-NMR(δ,CDCl₃):25.59,25.80,26.16,29.95.45.88,46.03,53.55,55.12,57.17,66.92,105.91,109.42,114.40,126.97,130.05,132.49,137.55,143.29,152.80,157.45,158.07。

MS (%): 393 (parent +1,100).

Elemental analysis, calculation of (C)₂₂H₂₇N₃O₃HCl3/2H₂O):C 54.50,H 7.24,N 10.59。

Measured value: c54.83, H7.27, N10.29.

Example 6

6- [8- (4- (2-phenylethyl) -piperazin-1-yl-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl) -pyridin-2-ylamine: prepared according to the method of example 3, yield 73.5% as a tan solid, hydrochloride salt from ether, mp130 ℃ (decomposed).

¹H-NMR(δ,CDCl₃):1.36(m,4H),1.70(m,4H),1.84(m,2H),2.5-2.9(m,12H),3.365(m,1H),3.54(m,1H),4.18(t,J=8,2H),4.79(bs,2H),6.38(d,J=-8,1H),6.65(d,J=7,1H),6.79(d,J=8,1H),7.2-7.4(m,6H),7.42(t,J=7,1H)。

¹³C-NMR(δ,CDCl₃):25.61,25.83,26.17,30.00,31.71,32.59,33.49,53.06,53.47,57.17,60.50,66.69,106.15,109.25,114.36,126.06,127.08,128.40,128.72,129.76,132.35,137.70,140.24,143.26,152.82,156.33,157.27,158.26。

MS (%): 483 (parent +1, 100).

Claims (12)

1. A compound of the formula and pharmaceutically acceptable salts of said compoundWherein

N and m in the bridged ring are independently 1,2 or 3, and the carbon atom in one of said bridged rings may be substituted by a heteroatom selected from O, S and N, provided that the bridgehead carbon atom is substituted by a nitrogen atom only, and R¹And R²Independently selected from C₁To C₆An alkyl group which may be linear, branched or cyclic, or contain both linear and cyclic or branched and cyclic moieties, each of whichR is¹And R²May be independently optionally substituted with 1 to 3, preferably 0 to 2 substituents independently selected from halogen, nitro, hydroxy, cyano, amino, (C)₁-C₄) Alkoxy and (C)₁-C₄) An alkylamino group;

or R¹And R²Together with the nitrogen atom to which they are attached form a piperazine, azetidine, piperidine or pyrrolidine ring or a 6-to 14-membered azabicyclo ring of which 1 to 3 are nitrogen atoms and the remainder are carbon atoms,

wherein the distal nitrogen atom of said piperazine or azabicyclo is optionally substituted by a group R³And R⁴Is substituted in which R³And R⁴Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, C₁-C₆Alkyl- (= O) -, HC (= O) -, C₁To C₆Alkoxy- (C = O) -, phenyl C (= O) -, naphthyl-C (= O) -and R⁶R⁷NC (= O) -, wherein R⁶And R⁷Independently selected from hydrogen atom and C₁To C₆Alkyl, with the proviso that the azabicyclo is spirocycle, the distal nitrogen atom of the spirocycle being optionally substituted by R⁵Is substituted in which R⁵Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, phenyl-C₁To C₆Alkyl-and naphthyl C₁To C₆Alkyl-;

and the piperazine, azetidine, piperidine and pyrrolidine rings may be optionally substituted with one or more substituents, preferably 0 to 2 substituents, independently selected from C₁To C₆Alkyl, amino, C₁To C₆Alkylamino, [ di-C ]₁-C₆Alkyl radical]Amino, phenyl-substituted 5-to 6-membered heterocyclic ring containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moiety of any of the above substituents may be optionally substituted by one or more substituents, preferably 0 to 2 substituents, independently selected from halogen, at C₁To C₃Alkyl radical, C₁To C₃Alkoxy, nitro, amino, cyano, CF₃And OCF₃；

Provided that none of the carbon atoms is substituted with one or more substituents selected from the group consisting of hydroxy, amino, alkoxy, alkylamino and dialkylamino.

2. Preferred compounds according to claim 1, selected from the group consisting of:

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- [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- (4-methylpiperazin-1-yl-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl ] -pyridin-2-ylamine and

6- [8- (4- (2-phenylethyl) -piperazin-1-yl-ethoxy) -1,2,3, 4-tetrahydro-1, 4-ethano-naphthalen-5-yl ] pyridin-2-ylamine.

3. The compound of claim 1, wherein NR¹R²Is an optionally substituted piperidine, azetidine, piperazine or pyrrolidine ring or 3-aza-bicyclo [3.1.0]A hex-6-ylamine ring;

and wherein said piperazine, azetidine, piperidine, pyrrolidine and 3-aza-bicyclo [3.1.0]The hex-6-ylamine ring may be optionally substituted with one or more substituents, preferably 0 to 2 substituents, independently selected from C₁To C₆Alkyl, amino, C₁To C₆Alkylamino, [ di-C ]₁To C₆Alkyl radical]Amino, phenyl-substituted 5-to 6-membered heterocycles having 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl of any of the above substituentsThe moiety may be optionally substituted with one or more substituents, preferably 0 to 2 substituents, independently selected from halogen, at C₁To C₃Alkyl radical, C₁To C₃Alkoxy, nitro, amino, cyano, CF₃And OCF₃。

4. The compound of claim 1, wherein NR¹R²To form an azabicyclo of the formulaWherein

R³And R⁴Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, C₁To C₆Alkyl C (= O) -, HC (= O) -, C₁To C₆Alkoxy- (C = O) -, phenyl-C (= O) -, naphthyl-C (= O) -and R⁶R⁷NC (= O) -, wherein R⁶And R⁷Independently selected from hydrogen atom and C₁To C₆An alkyl group; while

R⁵Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, phenyl-C₁To C₆Alkyl-and naphthyl C₁To C₆An alkyl group-.

5. A pharmaceutical composition for the treatment and prevention of a condition selected from the group consisting of: migraine, inflammatory diseases, psoriasis, asthma, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS-related dementia, neurodegenerative diseases including Parkinson's disease, neuronal intoxication, Alzheimer's disease, chemical dependencies and addiction, emesis, epilepsy, anxiety, depression, psychosis, cerebral trauma, Adult Respiratory Distress Syndrome (ARDS), morphine-induced tolerance and withdrawal syndromes, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, ocular diseases, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer, comprising a compound of claim 1 in an amount effective to treat or prevent such disorders, and a pharmaceutically acceptable carrier.

6. A method of treating or preventing a disorder selected from the group consisting of: migraine, inflammatory diseases, psoriasis, asthma, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS-related dementia, neurodegenerative diseases including Parkinson's disease, neuronal intoxication, Alzheimer's disease, chemical dependencies and addiction, emesis, epilepsy, anxiety, depression, psychosis, cerebral trauma, Adult Respiratory Distress Syndrome (ARDS), morphine-induced tolerance and withdrawal syndromes, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, ocular diseases, diabetic neuropathy, diabetic nephropathy and cancer, comprising administering to said mammal an amount of a compound of claim 1 effective to treat or prevent such a condition.

7. A pharmaceutical composition for inhibiting Nitric Oxide Synthase (NOS) in a mammal comprising an NOS inhibiting effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

8. A method of inhibiting NOS in a mammal comprising administering to said mammal an NOS inhibiting effective amount of a compound of claim 1.

9. A pharmaceutical composition for treating or preventing a condition selected from the group consisting of: migraine, inflammatory diseases, psoriasis, asthma, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS-related dementia, neurodegenerative diseases including Parkinson's disease, neuronal intoxication, Alzheimer's disease, chemical dependencies and addiction, emesis, epilepsy, anxiety, depression, psychosis, brain trauma, Adult Respiratory Distress Syndrome (ARDS), morphine induced tolerance and withdrawal brain syndrome, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, huntington's disease, ocular diseases, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer comprising an NOS inhibiting effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

10. A method of treating a mammal selected from the group consisting of: migraine, inflammatory diseases, psoriasis, asthma, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS-related dementia, neurodegenerative diseases including Parkinson's disease, neuronal intoxication, Alzheimer's disease, chemical dependencies and addiction, emesis, epilepsy, anxiety, depression, psychosis, cerebral trauma, Adult Respiratory Distress Syndrome (ARDS), morphine-induced tolerance and withdrawal syndromes, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, ocular diseases, diabetic neuropathy, diabetic nephropathy and cancer comprising administering to said mammal an NOS inhibitory effective amount of a compound of claim 1.

11. A compound of the formulaWherein

N and m in the bridged ring are independently 1,2 or 3, and the carbon atom in one of said bridged rings may be substituted by a heteroatom selected from O, S and N, provided that the bridgehead carbon atom is substituted by a nitrogen atom only, and R¹And R²Independently selected from C₁To C₆An alkyl group which may be linear, branched or cyclic, or contain both linear and cyclic or branched and cyclic moieties, wherein each R is¹And R²May be independently optionally substituted with 1 to 3, preferably 0 to 2 substituents independently selected from halogen, nitro, hydroxy, cyano, amino, (C)₁-C₄) Alkoxy and (C)₁-C₄) Alkane (I) and its preparation methodAn amino group;

or R¹And R²Together with the nitrogen atom to which they are attached form a piperazine, azetidine, piperidine or pyrrolidine ring or a 6-to 14-membered azabicyclo ring of which 1 to 3 are nitrogen atoms and the remainder are carbon atoms,

wherein the distal nitrogen atom of said piperazine or azabicyclo is optionally substituted by a group R³And R⁴Is substituted in which R³And R⁴Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, C₁-C₆Alkyl- (= O) -, HC (= O) -, C₁To C₆Alkoxy- (C = O) -, phenyl C (= O) -, naphthyl-C (= O) -and R⁶R⁷NC (= O) -, wherein R⁶And R⁷Independently selected from hydrogen atom and C₁To C₆Alkyl, with the proviso that the azabicyclo is spirocycle, the distal nitrogen atom of the spirocycle being optionally substituted by R⁵Is substituted in which R⁵Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, phenyl-C₁To C₆Alkyl-and naphthyl C₁To C₆Alkyl-;

and the piperazine, azetidine, piperidine and pyrrolidine rings may be optionally substituted with one or more substituents, preferably 0 to 2 substituents, independently selected from C₁To C₆Alkyl, amino, C₁To C₆Alkylamino, [ di-C ]₁-C₆Alkyl radical]Amino, phenyl-substituted 5-to 6-membered heterocyclic ring containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moiety of any of the above substituents may be optionally substituted by one or more substituents, preferably 0 to 2 substituents, independently selected from halogen, at C₁To C₃Alkyl radical, C₁To C₃Alkoxy, nitro, amino, cyano, CF₃And OCF₃；

Provided that none of the carbon atoms is substituted with one or more substituents selected from the group consisting of hydroxy, amino, alkoxy, alkylamino and dialkylamino.

12. A compound of the formulaWherein

N and m in the bridged ring are independently 1,2 or 3, and the carbon atom in one of said bridged rings may be substituted by a heteroatom selected from O, S and N, provided that the bridgehead carbon atom is substituted by a nitrogen atom only, and R¹And R²Independently selected from C₁To C₆An alkyl group which may be linear, branched or cyclic, or contain both linear and cyclic or branched and cyclic moieties, wherein each R is¹And R²May be independently optionally substituted with 1 to 3, preferably 0 to 2 substituents independently selected from halogen, nitro, hydroxy, cyano, amino, (C)₁-C₄) Alkoxy and (C)₁-C₄) An alkylamino group;

or R¹And R²Together with the nitrogen atom to which they are attached form a piperazine, azetidine, piperidine or pyrrolidine ring or a 6-to 14-membered azabicyclo ring of which 1 to 3 are nitrogen atoms and the remainder are carbon atoms,

wherein the distal nitrogen atom of said piperazine or azabicyclo is optionally substituted by a group R³And R⁴Is substituted in which R³And R⁴Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, C₁-C₆Alkyl- (= O) -, HC (= O) -, C₁To C₆Alkoxy- (C = O) -, phenyl C (= O) -, naphthyl-C (= O) -and R⁶R⁷NC (= O) -, wherein R⁶And R⁷Independently selected from hydrogen atom and C₁To C₆Alkyl, with the proviso that the azabicyclo is spirocycle, the distal nitrogen atom of the spirocycle being optionally substituted by R⁵Is substituted in which R⁵Selected from hydrogen atoms, C₁To C₆Alkyl, phenyl, naphthyl, phenyl-C₁To C₆Alkyl-and naphthyl C₁To C₆Alkyl-;

and the piperazine, azetidine, piperidine and pyrrolidine rings may be optionally substituted with one or more substituents, preferably 0 to 2 substituentsThe substituents are independently selected from C₁To C₆Alkyl, amino, C₁To C₆Alkylamino, [ di-C ]₁-C₆Alkyl radical]Amino, phenyl-substituted 5-to 6-membered heterocyclic ring containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moiety of any of the above substituents may be optionally substituted by one or more substituents, preferably 0 to 2 substituents, independently selected from halogen, at C₁To C₃Alkyl radical, C₁To C₃Alkoxy, nitro, amino, cyano, CF₃And OCF₃；

Provided that none of the carbon atoms is substituted with one or more substituents selected from the group consisting of hydroxy, amino, alkoxy, alkylamino, and dialkylamino; and is

Wherein R is⁸Selected from phenyl or naphthyl.