CZ20004494A3 - 2-aminopyridines containing condensed cyclic substituents as nitrogen oxide synthase inhibitors - Google Patents

Abstract

The solution includes 2-aminopyridine derivatives of formula I, wherein R ', R2, n and m are of particular importance, pharmaceutical compositions containing said compounds and their use in the treatment of a prevention of central nervous system diseases and others diseases.

Description

Technical field

The invention relates to certain 2-aminopyridines containing fused cyclic substituents which act as inhibitors of nitric oxide synthase (NOS), pharmaceutical compositions containing said compounds, and their use in the treatment of central nervous system diseases, inflammatory diseases, septic shock and other diseases of mammals (e.g. and animals accompanying humans).

BACKGROUND OF THE INVENTION

There are three known isoforms of NOS, an inducible form (I-NOS) and two constitutive forms called neuronal NOS (N-NOS) and endothelial NOS (E-NOS). Each of these enzymes, in response to various stimuli, converts arginine to citrulline to form a nitric oxide (NO) molecule. It is believed that the excess nitric oxide (NO) produced by NOS plays a role in the pathology of multiple mammalian diseases and conditions. For example, NO produced by I-NOS is believed to play a role in diseases manifested by systemic hypotension such as toxic shock and therapy 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 shock-induced cytokines and NO-induced hypotension produced by macrophages, i.e. inducible NOS (I-NOS), Chemical & Engineering News, Dec.20, p.33 (1993). I-NOS inhibitors can reverse this pattern. I-NOS is also believed to play a role in the pathology of central nervous system diseases such as ischemia. For example, it has been shown

that inhibition of I-NOS ameliorates cerebral ischemic injury in rats, see Am.J.Physiol., 268, p. R 286 (1995).

Eur. J. Pharmacol., 273, pp. 15-24 (1995) reported suppression of adjuvant-induced arthritis by selective inhibition of I-NOS.

It is believed that NO produced by N-NOS is implicated in diseases such as cerebral ischemia, pain, and opioid tolerance. For example, inhibition of N-NOS reduces infarct size in a rat model of proximal middle cerebral artery occlusion, see J. Cerebr.Blood Flow Metab., 14, 924-929 (1994). Inhibition of N-NOS has also been shown to be effective in antinociception, which was found in the second phase of the formalin-induced paw licking test and in the acetic acid-induced abdominal constriction test, see Br. J. Pharmacol, 110, 219-224 (1993). In addition, Freund's adjuvant administered to rats by subcutaneous injection results in an increase in NOS-positive neurons in the spinal cord, which is manifested by increased pain sensitivity, and this phenomenon can be treated with NOS inhibitors, see Japanese Journal of Pharmacology, 75, 327-335 (1997). . Finally, rodent opioid withdrawal has a milder course of NNOS inhibition, see Neuropsychopharmacol., 13, pp. 269-293 (1995).

SUMMARY OF THE INVENTION

The invention includes compounds of formula (I)

NH • 3 <

·>

wherein in the bridged rings independently represent 1, 2 or 3 and the carbon atom in one of said bridged rings may be replaced by a heteroatom selected from the group consisting of O, S and N, provided that the top carbon can only be replaced by nitrogen, and R ¹ and R ² each independently represent a C 4 -C 8 alkyl group, which may have a straight, branched or cyclic chain, or may comprise both straight and cyclic chains or branched and cyclic chains, and each R ¹ and R ² may independently be optionally substituted with one to two three substituents, preferably back to two substituents representing a group independently selected from halogen (e.g. chlorine, fluorine, bromine, iodine), nitro, hydroxy, cyano, amino, (C 1 -C 4) alkoxy and (C 1 -C ₄ ) alkylamino;

or R ¹ and R ² together with the nitrogen atom to which they are attached a piperazine, azetidine, piperidine or pyrrolidine ring, or an azabicyclic ring containing 6-14 members in the ring of which 1 to 3 are nitrogen and the remainder are carbon atoms where the distal nitrogen atom said piperazine or azabicyclic ring is optionally substituted with R ³ and R ⁴ wherein R ³ and R ⁴ are independently selected from hydrogen, C 4 -C 6 alkyl, phenyl, naphthyl, C 1 -C 6 alkyl-C (= O) -, HC (= O) -, up to C6 alkoxy- (C = O) -, phenyl-C (= O) -, naphthyl-C (= O) -, and R ⁶ R ⁷ NC (= O) -, where R ⁵ and R ⁷ each independently represent hydrogen or a C 1 -C 6 alkyl group, with the proviso that when said azabicyclic ring is a spirocyclic ring, the distal nitrogen in said spirocyclic ring is optionally substituted with R ⁵ wherein R ⁵ represents a group selected from hydrogen C ₄ -C ₆ alkyl, phenyl, naphthyl, phenyl-C 1 -C 8 alkyl-, and naphthyl-C 1 -C ₅ alkyl-;

9

And wherein said piperazine, azetidine, piperidine and pyrrolidine ring may be optionally substituted with one or more substituents, preferably no to two substituents, representing a group independently selected from the group consisting of C 1 -C ₆ alkyl, amino, C; to C ₆ alkylamino, [di-C 1 -C 6 alkyl] amino, phenyl substituted with 5- to 6-membered heterocyclic rings containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, wherein the phenyl moieties of any of the preceding groups may be optionally substituted with one or more substituents, preferably no to two groups independently selected from halogen, C 1 -C ₃ alkyl, C 1 -C ₃ alkoxy, nitro, amino, cyano,

CF ₃ and OCF ₃ ;

with the proviso that no carbon atom is substituted with more than one substituent representing a group selected from hydroxy, amino, alkoxy, alkylamino and dialkylamino;

and pharmaceutically acceptable salts of said compounds.

Examples of azabicyclic rings that may arise from ΝΡ / ρ ² include

 t »t»

wherein R ³ and R ⁴ are independently selected from the group consisting of H, Ci-alkyl, phenyl, naphthyl, Ci to _C6 alkyl-C (= 0) -, HC (= O) -, Cl to _C6 alkoxy- ( C = O) -, phenyl-C (= O) naphthyl-C (= O) -, and R ⁶ R ⁷ NC (= O) -, wherein R ⁶ and R ⁷ each independently represent hydrogen or a C 1 -C 6 alkyl group ; and wherein ^R5 is selected from the group consisting of H, Ci-Cg alkyl, phenyl, naphthyl, phenyl-C to _C6 alkyl- and naphthyl-Ci-C ₆ alkyl · -.

A preferred embodiment of the invention comprises a compound of formula (I) wherein NR ¹ R ² is an optionally substituted piperidine, azetidine, piperazine or pyrrolidine ring or a 3-aza-bicyclo [3.1.0] hex-6-ylamine ring;

• · · • 1

And wherein said piperazine, azetidine, piperidine, pyrrolidine ring and 3-aza-bicyclo [3.1.0] hex-6-ylamine ring is optionally substituted with one or more substituents, preferably none to two substituents representing a group independently selected from the group consisting of C1- _C6 alkyl, amino, C1-C6 alkylamino, [di-C1-C6 alkyl] amino, phenyl substituted with 5- to 6-membered heterocyclic rings containing 1 to 4 ring nitrogen atoms, benzoyl , benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, wherein the phenyl portions of any of the foregoing groups may be optionally substituted with one or more substituents, preferably no to two groups independently selected from halogen, C 1 -C ₃ alkyl, C 1 -C ₃ alkoxy , nitro, amino, cyan,

CF ₃ and OCF ₃ ;

and pharmaceutically acceptable salts of said compound.

Preferred compounds of the invention include the following compounds:

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;

• 4 • 4 t · * · · · · · ·

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

6- [8- (4- (2-Phenethyl) -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 compounds:

6- [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-tetrahydro-isoquinol-2-yl) -ethoxy) -1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl] -pyridine- 2-ylamine; and

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

The invention also includes pharmaceutically acceptable acid addition salts of the compounds of formula (I). The acids used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of the invention are acids forming non-toxic acid addition salts thereof, i.e. salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, acid tartrate, succinate, maleat, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, 9 p-toluenesulfonate and pamoate (i.e. 1.1) -methylene-bis (2-hydroxy-3-naphthoate).

The alkyl groups referred to herein and the alkyl portions of the other groups referred to herein are, unless otherwise indicated, saturated monovalent hydrocarbon radicals containing straight, branched or cyclic groups or combinations thereof.

The term one or more substituents used in this specification includes the number of substituents in an amount from one to the maximum possible number of substituents as permitted by the number of available binding sites.

The term halo or halogen, unless otherwise indicated, is chlorine, fluorine,

Examples of more specific embodiments

and) compounds common formulas (AND) (b) compounds common formulas (AND) C) compounds common formulas (AND) (d) compounds common formulas (AND) E) compounds common formulas (AND) F) compounds common formulas (AND)

independently represent a C 1 -C ₆ alkyl group;

in this specification means bromine and iodine.

Inventions include:

wherein n is 1;

wherein n is 2;

wherein m is 1;

wherein m is 2;

wherein X is oxygen;

where R ¹ and R ² each * ·

g) compounds of formula (I) wherein R ¹ and R ² do not form together with the nitrogen atom to which they are attached a ring structure;

h) compounds of formula (I) wherein R ¹ and R ² together with the nitrogen atom to which they are attached form a piperazine, azetidine, piperidine or pyrrolidine ring; and

i) compounds of formula (I) wherein R ¹ is C 1 -C 6 alkyl and R ² is cyclopropyl.

The present invention also includes a pharmaceutical composition for 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 (eg Parkinson's disease), neuronal toxicity, Alzheimer's disease, addictions and chemical habits (eg drug, alcohol and nicotine dependence), vomiting, epilepsy, anxiety, depression, psychosis, trauma headache, adult respiratory distress syndrome (ARDS), morphine tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, widespread cardiomyopathy, acute spinal cord injury, Huntington's disease, eye diseases (such as glaucoma and macular degeneration), diabetic neuro patina, diabetic nephropathy, and cancer (e.g., leukemia) of mammals including humans, wherein said composition comprises an amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof that is effective for treatment, or

IV for the prevention of the above conditions, together with a pharmaceutically acceptable carrier.

The invention also includes 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, dementia associated AIDS, neurodegenerative diseases (eg Parkinson's disease), neuronal toxicity, Alzheimer's disease, drug addictions and addictions (eg drug, alcohol and nicotine addiction), vomiting, epilepsy, anxiety, depression, psychosis, head trauma, respiratory distress syndrome adult (ARDS), morphine tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, widespread cardiomyopathy, acute spinal cord injury, Huntington's disease, eye diseases (e.g. glaucoma and macular degeneration), diabetic neuropathy, diabetic nephropathy cancer (e.g. such as leukemia) of a mammal, including a human, comprising administering to said mammal an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is effective for treating or preventing said condition.

The invention also includes a pharmaceutical composition for inhibiting nitric oxide synthase (NOS) in a mammal, including a human, comprising an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof that is effective for inhibiting NOS and a pharmaceutically acceptable carrier.

The invention also includes a method of inhibiting NOS in a mammal, including a human, comprising administering to said mammal an amount

A compound of formula (I) or a pharmaceutically acceptable salt thereof, which is effective for inhibiting NOS.

The invention also includes a pharmaceutical composition for 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, dementia associated with AIDS, neurodegenerative diseases (eg Parkinson's disease), neuronal toxicity, Alzheimer's disease, drug addictions and habits (eg drug, alcohol and nicotine addiction), vomiting, epilepsy, anxiety, depression, psychosis, head trauma, syndrome adult respiratory distress (ARDS), morphine tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, widespread cardiomyopathy, acute spinal cord injury, Huntington's disease, eye diseases (such as glaucoma and macular degeneration), diabetic neuropathy nephropathy and cancer (e.g., leukemia) of a mammal, including a human, comprising an amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof that is effective to inhibit NOS and a pharmaceutically acceptable carrier.

The invention also includes 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, dementia associated AIDS, neurodegenerative diseases (such as Parkinson's disease), neuronal toxicity, Alzheimer's disease, addictions and drug habits (such as drug, alcohol and nicotine dependence), vomiting •

Epilepsy, anxiety, depression, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, advanced cardiomyopathy, acute spinal cord injury, Huntington's disease, ophthalmic diseases (e.g., glaucoma and macular degeneration), diabetic neuropathy, diabetic nephropathy, and cancer (e.g., leukemia) of mammals, including humans, comprising administering an amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof effective to inhibit NOS.

The invention also includes compounds of formula (VI)

wherein n, m, R ¹ , and R ² are as defined above for compounds of formula (I). Compounds of formula (VI) are useful as intermediates in the preparation of compounds of formula (I).

The invention also includes compounds of formula (VIII)

Wherein n, m, R ¹ , and R ² are as defined above for compounds of formula (I), and wherein R ⁸ is an aryl group such as phenyl or naphthyl. Compounds of formula (VIII) are useful intermediates for the preparation of compounds of formula (I).

The term treatment as used herein and unless otherwise indicated is meant to include prevention.

The compounds of formula (I) may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. The present invention encompasses all optical isomers and all stereoisomers of the compound of formula (I) and mixtures thereof, and all pharmaceutical compositions and methods of treatment described above containing them or in which they are used.

The above formula (I) also includes compounds identical to those shown by this formula except that one or more hydrogen, carbon, or other atoms are replaced by their isotopes. These compounds may be useful in research and as a diagnostic means in monitoring metabolism in pharmacokinetic studies and in binding assays.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula (I) may be prepared according to the following schemes and the accompanying description. Unless otherwise indicated, n, m, R ¹ and R ² have the meanings given above in the reaction schemes and in the appended description.

• · · ·

Scheme 1

1. BuLi, B (OEt) ₃

1. LiOH H, O. THF / MeOH / H ₂ O

1. NH ₄ * O ₂ CH-, Pd / C

- _—>

2, BrCH ₂ CO ₂ Et, K ₂ CO ₃

2. EDAC. R ² R ² NH

1, LiAlH ₃ , aici ₃

2. NH ₂ OH HCl

In Scheme 1, a compound of formula (II) is prepared by reacting norbornylene and 2-hydroxypyrone followed by palladium (II) aromatization as described in Syn.Commun 5, 461 (1975). This compound is then reacted with tetrabutylammonium tribromide in 1,2-dichloroethane at about room temperature for about 10 minutes to 10 hours. The reaction product is then reacted with benzyl bromide and potassium carbonate in a solvent such as acetonitrile at

0 0 9 9 0 0 9 9

1 * 5 * ** about the reflux temperature of the reaction mixture for about 1 to 48 hours to prepare a 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 ° C in dry tetrahydrofuran (THF) followed by butyllithium. The resulting solution was then treated with triethylborate with warming to room temperature over a reaction time of 1 to 48 hours to give 5-benzyloxy-1,2,3,4-tetrahydro-1,4-methano-naphthalene-8-boronic acid. Reaction of 5-benzyloxy-1,2,3,4-tetrahydro-1,4-methano-naphthalene-8-boronic acid with 6-bromo-2- (2,5-dimethylpyrrolyl) pyridine in an ethanol solvent in the presence of sodium carbonate and tetrakistriphenylphosphine palladium, at about the reflux temperature of the reaction mixture and a reaction time of 1 to 48 hours, yields a compound of formula (IV).

The compound of formula (IV) can be converted to the compound of formula (V) by the following two-step method. The compound of formula (IV) is reacted with ammonium formate and 10% palladium on carbon in an ethanolic solvent at about the reflux temperature of the reaction mixture and reaction time from about 10 minutes to about 10 hours to give a compound analogous to the compound of formula (IV) however, the benzyloxy group of compound (IV) is replaced by a hydroxy group. The compound of formula (V) is then prepared by reacting the above hydroxy derivative with

2-bromoethyl acetate and potassium carbonate in acetonitrile at about the reflux temperature of the reaction mixture and a reaction time of 1 to 48 hours.

Alkaline hydrolysis of the compound of formula (V) followed by reaction with N-ethyl-N-3-dimethylaminopropylcarbodiimide (EDAC) and the corresponding compound of formula R ¹ R ² NH gives the desired compound of formula (VI). The alkaline hydrolysis is usually carried out with an alkali metal or alkaline earth metal hydroxide in a mixture of THF, methanol and water at a temperature of about room temperature and a reaction time of 1 to 48 hours. The reaction of the compound of formula (VI) with the corresponding compound of formula R ¹ R ² NH and with N-ethyl-N-3-dimethylaminopropylcarbodiimide (EDAC) is carried out in the presence of a base. Examples of suitable bases include compounds 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 from about room temperature to about 100 ° C, preferably at about room temperature for about 1 to 48 hours. Preferably, this reaction is carried out in the presence of a catalyst additive such as N-hydroxy succinamide or hydroxybenzotriazole.

The compound of formula (VI) can then be converted to the desired compound of formula (I) as follows. The compound of formula (VI) is reduced to the corresponding compound wherein the carbonyl compound is replaced with a methylene group, i.e.

after which the 2,5-dimethylpyrrolyl protecting group is removed. This reduction is accomplished by methods known in the art, for example, with lithium aluminum hydride in tetrahydrofuran, with or without aluminum chloride, or with methylsulfidoborane in tetrahydrofuran at a temperature in the range of &lt; RTI ID = 0.0 &gt;

It is about -78 ° C to about reflux temperature, preferably at about -70 ° C to room temperature and a reaction time of about 1 to 24 hours.

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

Compounds of formula (I) identical to compounds of formula (VII), except that one of the bridged rings contains a heteroatom, is prepared by a method analogous to that shown in Scheme 1 by using a compound similar to the compound of formula (II) as starting material. wherein the unsubstituted bridged ring in compound (II) is replaced by a heteroatom-containing bridged ring.

A compound of formula (I) identical to a compound of formula (VII), except that the bridged ring contains more or less atoms (which formula (I) allows) may be prepared in an analogous manner to that shown in Scheme 1 except that as a starting compound An analogous compound of formula (II) containing the appropriate number of atoms is used.

An analogous compound of formula (II) may be prepared as shown in Scheme 1 above, using a compound having the general formula

• · • ·

Compounds of formula (I) wherein n is 2 and m is 1 can also be prepared using 5-methoxy-1,4-dihydro-1,4-ethano-naphthalene (J. Med. Chem., 30, 2191 (1987)). 5-methoxy-1,4-dihydro-1,4-ethano-naphthalene can be converted to 5-hydroxy-1,2,3,4-tetrahydro-1,4-ethano-naphthalene (analogue of compound of formula (II) ) according to Scheme 1 wherein n = 2) hydrogenation and subsequent demethylation Compounds 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-ethano -naphthalene according to the remainder of Scheme 1 following the synthesis of the compound of formula (II).

Compounds of formula (I) may also be prepared from compounds of formula (VIII) as shown in Scheme 2:

Scheme 2

The group R ⁸ in Scheme 2 represents a group selected from the group consisting of aryl and C 1 -C ₆ alkyl, wherein aryl preferably represents phenyl or naphthyl. The compound of formula (I) is obtained by hydrolyzing the compound of formula (VIII) with an acid or a base. Examples of acids that can be used include, but are not limited to, mineral acid and sulfonic acid. Examples of bases that may be used include alkali metal hydroxide and alkaline earth metal hydroxide. The hydrolysis of the compounds of formula (VIII) may be carried out in an alcoholic or aqueous solvent.

at a temperature of about 0 ° C to about 100 ° C, at a reaction time of about 1 to 24 hours.

The preparation of other compounds of formula I not specifically described in the foregoing description of the preparation methods can be accomplished by combining the reactions described above as will be apparent to those skilled in the art.

In all of the reactions described and illustrated above, pressure is not a critical parameter. In general, pressures from about 0.5 atmospheres to about 5 atmospheres are acceptable, and from a practical standpoint it is preferred to use ambient pressures, i.e., about 1 atmosphere.

The compounds of formulas I (i.e., active compounds of the invention) which are naturally basic are capable of forming various salts with various inorganic and organic acids. Although said salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to first isolate the compound of formula (I) from the reaction mixture in the form of a pharmaceutically unacceptable salt, then simply convert it back to the free base thereof by treatment with an alkaline agent and subsequently convert this free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the active basic compounds of the invention can be readily prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. Careful evaporation of the solvent then readily affords the desired salt in solid form.

The active compounds of the 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 can therefore act as therapeutic agents in the treatment of the above-mentioned diseases and disorders of the affected mammals.

The active compounds of the invention and their pharmaceutically acceptable salts can be administered by either oral, parenteral or topical routes. In general, it is most convenient to administer the compounds of the invention in doses ranging from about 0.01 to about 250 mg per day, in single or divided doses (i.e., from 1 to 4 doses per day), although some variations depending on the species, weight and the condition of the patient being treated and the particular mode of administration. However, the most suitable dosage used is in the range of about 0.07 mg to about 21 mg per kg body weight per day. Deviations from this dosage may occur depending on the species of animal being treated and its individual response to the drug, the type of dosage form chosen and the duration of administration and intervals of administration.

In some cases, doses below the lower limit of the above range will be more than adequate, while in other cases even higher doses will be used without harmful side effects, provided that the higher doses are initially divided into several smaller doses intended for during the day.

The active compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the three routes of administration mentioned above, wherein said administration may be by single or multiple doses. More specifically, the novel therapeutic compositions of the invention can be administered in various dosage forms, i. can be combined with various pharmaceutically acceptable inert carriers for tablets, capsules, lozenges, pills, candies, powders, sprays, creams, balms, suppositories, jellies, gels, pastes, lotions, ··· ·

ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, sweetening and / or flavoring agents may be suitably added to the oral pharmaceutical compositions. In general, the compounds of the invention are present in said dosage forms at concentrations from about 5.0% to about 70% by weight.

For oral administration, tablets containing various ingredients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine may be used together with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, glidants such as magnesium stearate, sodium lauryl sulfate and talc are often added from the viewpoint of the tabletting process. Solid compositions of a similar type may be employed as fillers in gelatin capsules; preferred compositions in this context include lactose or milk sugar as well as high molecular weight polyethylene glycols. If it is desired to prepare aqueous suspensions and / or elixirs for oral administration, the active ingredient may be combined with various sweetening or flavoring, coloring or coloring agents and, if desired, emulsifying or suspending agents together with diluents such as is water, ethanol, propylene glycol, glycerin and the like.

For parenteral administration, solutions of the active compound of the invention may be used either in sesame oil or in peanut oil or in aqueous propylene glycol. The aqueous solutions should be suitably buffered (preferably to a pH greater than about 10% by weight).

8) and liquid diluents should first be isotonized. The aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The preparation of all said solutions under sterile conditions is readily accomplished by standard pharmaceutical preparation procedures known to those skilled in the art.

In addition, for the treatment of inflammatory skin conditions, the active compounds of the invention may be administered topically in the form of creams, jellies, pastes, patches, ointments and the like prepared by standard pharmaceutical methods.

The ability of compounds of formula (I) to inhibit NOS can be determined by methods known in the literature. The ability of the compounds of formula (I) to inhibit endothelial NOS can be determined by the methods described by Schmidt et al. In Proc. Nati.Acad.Sci. USA,

88, pp.365-369 (1991) and Pollock et al., Proc. Nati.Acad.Sci. USA, 88, pp. 1080-10484 (1991). The ability of the compounds of formula (I) to inhibit inducible NOS can be determined by the methods described by Schmidt et al. In Proc. Nati.Acad.Sci. USA,

88, pp.365-369 (1991) and Garvey et al., In J. Biol. Chem., 269, pp. 26669-26676 (1994). The ability of compounds of formula (I) to inhibit neuronal NOS can be determined as described by Bredt and Snyder in Proc. Nati.Acad.Sci. USA, 87, pp. 68-685 (1990). Of the two compounds of formula (I) that were tested, both exhibited an IC ₅ of <10 µΜ when inhibiting either inducible or neuronal NOS.

The following examples further illustrate the invention. However, the specific details set forth in the individual examples do not limit the invention in any way. Melting points are uncorrected. Proton spectra ·· »· ·· ·· '· *

- ·;; »» »»;;;; · · · ·

Nuclear magnetic resonance ( ¹ H NMR) and ¹³ C nuclear magnetic resonance were measured in solutions in deuterochloroform (CDCl ₃ ) or in CD ₃ OD or in CD ₃ SOCD ₃ and the position of the plots are expressed in parts per million (ppm) relative to tetramethylsilane (TMS). The peak shapes are indicated as follows: s, singlet; d, duplet; t, triplet; q, quartet; m, multiplet; b, wide.

DETAILED DESCRIPTION OF THE INVENTION

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

Norbornylene (18.1 g, 190 mmol) is reacted with a known compound (Syn.Commun., 5, 461, (1975))

2-hydroxypyron (5.38 g, 48 mmol) undiluted in a sealed tube at 125 ° C for 2 days to give a mixture of 1,2a 1,4-, 5,6,7,8-octahydro-5,8 -methano-naphth-1-one in the corresponding yields of 45% and 4%, and the product is converted to the desired phenol in 71% yield by heating at reflux for 48 hours with palladium oxide (0.5 g) and magnesium sulfate (1, 0 g) in toluene (80 mL).

¹ H-NMR (δ, CDCl ₃ ): 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).

¹³ C-NMR ((δ, CDCl ₃ ): 26.4, 27.0, 39.2, 43.9, 49, 0, 113, 1,

113.4, 126.7, 132.4, 148.6, 150.65.

• · · · · · · ·

24 '

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

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

To a 250 ml round-bottomed flask equipped with an addition funnel and an N ₂ inlet was added 2.9 g (18 mmol) of 5,6,7,8-tetrahydro-1,4-methano-naphthalen-1-ol and 50 mL of 1 mL. A solution of 8.7 g (18 mmol) of tributylammonium tribromide in 30 ml of 1,2-dichloroethane is added dropwise over 10 minutes with stirring. The reaction mixture was stirred at room temperature for 10 minutes, then the solution was washed with water, diluted with aqueous sodium bisulfite 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 3.2 g (74%) of an oil.

¹ H-NMR (δ , CDC1 _3): 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, J = 9) 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 50 mL of acetonitrile and treated with 1.7 mL (14.4 mmol) of benzyl bromide and 3.6 g (26.4 mmol) of potassium carbonate, and then the reaction mixture was refluxed for 14 h. On TLC showed a major spot at _Rf = 0.3 using a mobile phase of 10% methylene chloride / hexane (with benzyl bromide at R _f = 0.4). The reaction mixture was cooled, poured into dilute aqueous hydrochloric acid / ethyl acetate, the organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride / hexane as eluent to give 4.1 g (94%) of an oil.

¹ H-NMR (δ, CDCl ₃ ): 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).

¹³ C-NMR ((δ, CDCl ₃ ): 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 / Br ⁸¹ , 100).

D. 5-Benzyloxy-1,2,3,4-tetrahydro-1,4-methano-naphthalene-8-boronic acid

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

• ·

e. 1 H-NMR (δ, CDCl ₃ ): 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 (singlets, 2H for mono- and di-arylboronic acid), 6.77 and 6.83 (duplets,

J = 8, 1H), 7.2-7.5 (m, 5H), 7.8 and 7.92 (duplets, J = 9, 1H).

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

To a 500 ml round bottom flask equipped with a condenser and an N ₂ inlet was added 3.1 mg (12.2 mmol) of 2- (2,5-dimethylpyrrolyl) -6-bromo-pyridine, 3.2 mg (12.2 mmol). 5-benzyloxy-1,2,3,4-tetrahydro-1,4-methano-naphthalene-8-boronic acid, 5.2 g (48.8 mmol) sodium carbonate, 282 mg (0.24 mmol) tetrakistriphenylphosphine palladium, 135 ml ethanol and 15 ml water, and the reaction mixture is heated at 80 ° C for 13 hours. On TLC showed a major spot at R _f = 0.4 in 20% ethyl acetate in hexane, and LCMS showed a major peak at P + l = 421. The reaction mixture was then 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 was chromatographed on silica gel using hexane / ethyl acetate as eluent to give 4.8 g (94%) of a white solid.

^ -NMR (δ, CDC1 _3): 1.33 (m, 2H), 1.50 (m, IH) 1.75 (m, 1H), 1.98 (m, 2H), 2.22 (s, 6H), 3.73 (bs, 1H), 3.85 (bs, 1 H), 5.15 (s, 2H). 5.92 (s, 2H). 6.81 (d, J = 8.5, 1H). 7.10 (d, J = 7.5, 1H) , 2-7.5 (m. 7H) 7.845 (t, J = 8, 1H). ¹³ C-NMR ( : (Δ, CDC1 _3): 13 , 2, 3, 4, 5, 6, 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.

· R V V V V V V V V V V V V 9 · * 9 V V V V V

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

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

A 250 ml round bottom flask equipped with a condenser and an N ₂ inlet was charged with 4.8 g (11.4 mmol) of 2- (2,5-dimethylpyrrolyl) -6- [8-benzyloxy-1,2,3,4] -tetrahydro-1,4-methano-naphthalen-5-yl] pyridine, 3.0 g (47.6 mmol) of ammonium formate, 130 mg of 10% palladium on carbon and 100 ml of ethanol. The reaction mixture was heated at reflux for 4 hours, at which time additional catalyst and formate were added at 2 and 3 hours, then the reaction mixture was cooled and filtered through diatomaceous earth (Celite trademarks) with ethanol and methylene chloride. The filtrate was evaporated and the residue was taken up in ethyl acetate / aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to a light brown solid. 3.9 g (about 100%).

¹ H-NMR (δ, CDCl ₃ ): 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).

¹³ C-NMR ((δ, CDCl ₃ ): 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 (one carbon atom not indicated)

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

• • • •

(t z?

i:. :::

and «· · · ······ · · ···

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

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

¹ H-NMR (δ, CDCl ₃ ): 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).

¹³ C-NMR ((δ, CDCl ₃ ): 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).

H. 2- (2,5-Dimethylpyrrolyl) -6- [8-carboxymethoxy-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl] -pyridine

29 · · ’

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

2.4 g (65%). ¹ H-NMR (δ, CDCI3 / 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 ÍH), 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, ÍH). ¹³ C-NMR ( (δ, CDC1 _3): 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).

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

In a 100 mL round bottom flask equipped with a condenser and N ₂ inlet was added 200 mg (0.52 mmol) of 6- (4-carboxymethyl-naphthalen-1-yl) -pyridin-2-ylamine, 85 mg (1.04 mmol). )

N, N-dimethylamine hydrochloride, 397 mg (2.1 mmol) of N-ethyl-N-3-dimethylaminopropylcarbodiimide, 381 mg (3.1 mmol):

3β ·

4-dimethylaminopyridine and 10 ml dry acetonitrile. The reaction mixture was stirred at room temperature for 12 hours (LCMS showed P + 1 = 416 and TLC Rf = 0.2 using 5% methanol / methylene chloride), then the mixture was evaporated and the residue was chromatographed on silica gel using methanol / methylene chloride. eluent to give 202 mg (93.5%) of the product as a foam.

¹ H-NMR (δ, CDCl ₃ ): 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).

¹³ C-NMR ((δ, CDCl ₃ ): 13.42, 26.36, 26.54, 35.65, 36, 57, 39.61, 42.99, 48.85, 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 (parent + 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 100 mL round bottom flask equipped with a condenser and N ₂ inlet was added 196 mg (1.5 mmol) of aluminum chloride and 10 mL of dry tetrahydrofuran. The prepared solution was cooled to 0 ° C and 3.40 mL (3.40 mmol) of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 20 minutes, then cooled to -70 ° C and a solution of 202 mg (0.49 mmol) of 2- (2,5-dimethylpyrrolyl) -6- [8 - (N, N-) was added. dimethylcarboxamidomethoxy) -1,2,3,4-tetrahydro-1,4-1,4-methano-naphthalen-5-yl] -pyridine in 10 ml dry

3ř * ..

and tetrahydrofuran. Stirring was then continued for an additional 1 hour at -70 ° C and then for 2 hours at room temperature (LCMS showed P + 1-402), after which the reaction mixture was carefully quenched with 5 mL of 1 N hydrochloric acid. The reaction mixture was stirred for 20 minutes and then treated with 6 ml of 6N aqueous sodium hydroxide solution and extracted with several portions of methylene chloride. The organic phase is then dried over sodium sulphate and evaporated

yield 152 mg (77%) of an oil. ¹ H-NMR (δ, CDC1 _3): 1.28 (m, 2H), 1.48 (m, 1 H), 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, 1 H), 3.85 (bs, 1 H) , 4.15 ( t, J = 6, 2H) , 5.91 (s, 2H) , 6.76 (d, J = 9, 1 H), 7.09 (d, J = 8, 1 H) 7.52 (m, 2H), 7.83 (t, J = 8, 1H).

¹³ C-NMR ((δ, CDCl ₃ ): 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, 151.63, 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

In a 100 mL round bottom flask equipped with a condenser and N ₂ inlet was added 152 mg (0.36 mmol) of 2- (2,5-dimethylpyrrolyl) -6- [8- (N, N-dimethylaminoethoxy) -1 2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl] -pyridine, 506 mg (7.6 mmol) of hydroxylamine hydrochloride, 10 ml of ethanol and 1 ml of water. The resulting solution was heated at reflux (LCMS P + 1 = 324) for 40 hours, cooled, poured into aqueous dilute hydrochloric acid and washed with ethyl acetate. PH value τ · · »* .. .. _# . . . The aqueous layers were adjusted to 12 with 6 N aqueous sodium hydroxide solution and the layer was extracted with several portions of methylene chloride. The organic layer was then dried over sodium sulfate and evaporated to give 129 mg (78%) of a solid, mp after conversion to the hydrochloride salt in ether at 130 ° C (dec.).

¹ H-NMR (δ, CDCl 3): 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 (s. 2H); 6.35 (d, J = 8, 1 H), 6.70 (d, J = 8, 1 H) 6.80 (d, J = 7) Δ, 1H), 7.36 (d, J = 8, 1 H), 7.42 (t, J = 8, 1 H)

¹³ C-NMR ((δ, CDCl ₃ ): 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).

Calc'd for C20H25N3O.2 HCI.3 / 2 H ₂ OI / 2 (C ₄ H ₁₀ O): C 57.39, H 7.66, N 9.13;

Found: C 57.58, H 7.47, N 9.09.

Example 2

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

It was prepared as described in Example 1 except that pyrrolidine was used in place of N, N-dimethylamine hydrochloride in Step II and the product was obtained in 45% yield as a light brown hydrochloride salt from ether, m.p. 80 ° C (dec.).

···· · · ··

1 H-NMR (δ, CDCl ₃ ): 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, 1 H) , 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, 1Ή), 7.45 (t, J = 8, 1H). ¹³ C-NMR ((δ, CDCl ₃ ): 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).

Analysis: calculated for C 22 H 27 N 3 O 2 HCl. 9/4 H ₂ O / 2 (C 4 H 10 O): C 57.65, H 7.76, N 8.40; Found: C 57.65, H 7.43, N 8.34.

Example 3

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

Prepared as described in Example 1, substituting 5-hydroxy-1,2,3,4-tetrahydro-1,4-methano-naphthalene for 5-hydroxy-1,2,3,4 -tetrahydro-1,4-ethano-naphthalene, which is prepared by hydrogenation with palladium on carbon catalyst and subsequent demethylation with boron tribromide in methylene chloride of the known compound,

5-methoxy-1,4-dihydro-1,4-ethano-naphthalene (J. Med. Chem., 30, 2191 (1987)). 5-hydroxy-1,2,3,4-tetrahydro-1,4-ethano-naphthalene shows the following 1 H NMR spectra: 1.36 (m, 4H), 1.75 (m, 4H), 2.95 (finely divided singlet, 1H), 3.28 (finely divided singlet, 1H), 4.62 (bs, 1H), 6.66 (d, J = 7, 1H), 6.76 (d, J) = 7, 1H), 7.01 (t, J = 7, 1H) and the following mass spectrometry values: P = 174 (60%, parent). The other steps are carried out in the manner described above. according to Example 1 to give a light brown solid product in 74% yield as the hydrochloride salt from ether of m.p. 130 ° C (dec.).

¹ H-NMR (δ, CDCl ₃ ): 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).

¹³ C-NMR ((δ, CDCl ₃ ): 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).

Calcd. For C ₂₁ H ₂₇ N ₃ 0.2 HCl / 2 H ₂ O:

C 57.66, H 7.37, N 9. 61; Found: C 57.89, H 7.26, N 9.21.

Example 4

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

Prepared as in Example 3 as the hydrochloride salt from ether as an oil in 87% yield.

¹ H-NMR (δ, CDCl ₃ ): 1.355 (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).

··· * · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

¹³ C-NMR ((δ, CDCl ₃ ): 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).

Calcd for C ₂₂ H ₂₇ N ₃ 0.2 HCl / 4H ₂ O:

C 60.19, H 7.36, N 9.16; Found: C 60.15, H 7.01, N 8.95.

Example 5

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

Prepared as in Example 3 as a light brown solid hydrochloride salt from ether in 78% yield, m.p. 200 ° C (dec.).

³ H-NMR (δ, CDC1 _3): 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).

¹³ C-NMR ((δ, CDCl ₃ ): 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).

Anal. Calcd for C ₂₂ H ₂₇ N ₃ 0.3 HCl. 3/2 H ₂ O:

· 9 · · ·

J »» ··· ···

C 54.50, H 7.24, N 10.59;

Found: C 54.83, H 7.27, N 10.29.

Example 6

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

Prepared as in Example 3 as a light brown solid hydrochloride salt from ether in 73.5% yield, m.p. 130 ° C (dec.).

¹ H-NMR (δ, CDCl ₃ ): 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).

¹³ C-NMR ((δ, CDCl ₃ ): 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 (11)

PATENT CLAIMS A compound of formula (I) wherein in the bridged rings independently represent 1, 2 or 3 and the carbon atom in one of said bridged rings may be replaced by a heteroatom selected from the group consisting of O, S and N, provided that the top carbon atom may be replaced only by nitrogen, and R ¹ and R ² each independently represent a C 1 -C 8 alkyl group which may have a straight, branched or cyclic chain, or may include both straight and cyclic branched and cyclic chains, and each R ¹ and R ² may independently be optionally substituted with one to three substituents, preferably no to two substituents representing a group independently selected from halogen, nitro, hydroxy, cyano, amino, (C 1 -C 4) alkoxy and (C 1 -C 4 alkylamino); or R ¹ and R ² together with the nitrogen atom to which they are attached a piperazine, azetidine, piperidine or pyrrolidine ring, or an azabicyclic ring containing 6-14 members in the ring of which 1 to 3 are nitrogen and the remainder are carbon atoms where the distal nitrogen atom said piperazine or azabicyclic ring is optionally substituted with R ³ and R ⁴ wherein R ³ and R ⁴ are independently selected from 38 'including hydrogen, C 1 -C 6 alkyl, phenyl, naphthyl, C 1 -C ₆ alkyl-C (= O) -, HC (= O) -, C 1 -C ₆ alkoxy- (C = O) -, phenyl-C (= O) -, naphthyl-C (= O) -, and R ⁶ R ⁷ NC (= O) -, wherein R ⁶ and R ⁷ each independently represent hydrogen or a C 1 -C 6 alkyl group, with the proviso that when said azabicyclic ring is a spirocyclic ring, the distal nitrogen in said spirocyclic ring is optionally substituted with R ⁵ , wherein R ⁵ is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, phenyl, naphthyl, phenyl-C 1 -C 8 alkyl-, and naphthyl- C 1 to C 8 alkyl-; and wherein said piperazine, azetidine, piperidine and pyrrolidine ring may be optionally substituted with one or more substituents, preferably no to two substituents, representing a group independently selected from the group consisting of C 1 -C ₆ alkyl, amino, C 1 -C 6 alkylamino, [di-C 1] -C8 alkyl] amino, phenyl substituted with 5- to 6-membered heterocyclic rings containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, wherein the phenyl portions of any of the foregoing groups may be optionally substituted with one or more substituents, preferably no to two groups independently selected from halogen, C 1 -C ₃ alkyl, C 1 -C ₃ alkoxy, nitro, amino, cyano, CF ₃ and OCF ₃ ; with the proviso that no carbon atom is substituted with more than one substituent representing a group selected from hydroxy, amino, alkoxy, alkylamino and dialkylamino; and pharmaceutically acceptable salts of said compound. A compound, preferably a compound 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-Methyl-piperazin-1-yl-ethoxy) -1,2,3,4-tetrahydro-1,4-ethano-naphthalen-5-yl] -pyridin-2-ylamine; and 6- [4- (4- (2-Phenethyl) -piperazin-1-yl-ethoxy) -1,2,3,4-tetrahydro-1,4-ethano-naphthalen-5-yl] -pyridin-2- ylamine. The compound of claim 1, wherein N 1 R ² is an optionally substituted piperidine, azetidine, piperazine or pyrrolidine ring or a 3-aza-bicyclo [3.1.0] hex-6-ylamine ring; and wherein said piperazine, azetidine, piperidine, pyrrolidine ring and 3-aza-bicyclo [3.1.0] hex-6-ylamine ring is optionally substituted with one or more substituents, preferably no to two substituents, representing a group independently selected from C 1 C 1 -C ₆ alkyl, amino, C 1 -C ₆ alkylamino, [di-C 1 -C 6 alkyl] amino, phenyl substituted 40 · ' 5- to β-membered heterocyclic rings containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, wherein the phenyl portions of any of the foregoing groups may be optionally substituted with one or more substituents, preferably no to two groups independently selected from the group consisting of halogen, C 1 -C ₃ alkyl, C 1 -C ₃ alkoxy, nitro, amino, cyano, CF ₃ and OCF ₃ . The compound of claim 1, wherein NR ^X R ² forms an azabicyclic ring having the formula selected from the group consisting of βΊ R ³ R ⁴ N or wherein R ³ and R ⁴ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl, naphthyl, C 1 -C ₆ alkyl-C (= O) -, HC (= O) -, C 1 -C ₆ alkoxy- (C = O) -, phenyl-C (= O) -, naphthyl-C (= O) -, and R ⁶ R ⁷ NC (= O) -, wherein R ⁶ and R ⁷ each independently represent hydrogen or a C 1 to C 8 alkyl group; and R ⁵ represents a group selected from hydrogen, C 1 -C 8 alkyl, phenyl, naphthyl, phenyl-C 1 -C 8 alkyl-, and naphthyl C 1 -C 8 alkyl-. 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, dementia AIDS-related neurodegenerative diseases including Parkinson's disease, neuronal toxicity, Alzheimer's disease, chemical dependence and habits, vomiting, epilepsy, anxiety, depression, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine tolerance and post-symptoms discontinuation, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, widespread cardiomyopathy, acute spinal cord injury, Huntington's disease, eye diseases, macular degeneration, diabetic neuropathy, diabetic nephropathy, and mammalian cancer, wherein said composition comprises an amount of a compound • » A pharmaceutical composition according to claim 1 which is effective for treating or preventing the above conditions and a pharmaceutically acceptable carrier. A method 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, dementia associated with AIDS, neurodegenerative diseases including Parkinson's disease, neuronal toxicity, Alzheimer's disease, chemical dependence and habits, vomiting, epilepsy, anxiety, depression, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, widespread cardiomyopathy, acute spinal cord injury, Huntington's disease, eye diseases, diabetic neuropathy, diabetic nephropathy, and mammalian cancer, said treatment comprising administering to said mammal an amount of a compound of claim 1, which It is effective for treating or preventing the above conditions. A pharmaceutical composition for inhibiting nitric oxide synthase (NOS) in a mammal according to claim 1 comprising an amount of a compound of claim 1 that is effective for inhibiting NOS and a pharmaceutically acceptable carrier. A method of inhibiting nitric oxide synthase (NOS) in a mammal comprising administering to said mammal an amount of a compound of claim 1 that is effective for inhibiting NOS. 4? 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, dementia AIDS-related neurodegenerative diseases including Parkinson's disease, neuronal toxicity, Alzheimer's disease, chemical dependence and habits, vomiting, epilepsy, anxiety, depression, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine tolerance and post-symptoms discontinuation, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, advanced cardiomyopathy, acute spinal cord injury, Huntington's disease, eye diseases, macular degeneration, diabetic neuropathy, diabetic nephropathy, and mammalian cancer, wherein said composition comprises a plurality of compounds y according to claim 1 which is effective for inhibiting NOS and a pharmaceutically acceptable carrier. A method 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, dementia associated with AIDS, neurodegenerative diseases including Parkinson's disease, neuronal toxicity, Alzheimer's disease, chemical dependence and habits, vomiting, epilepsy, anxiety, depression, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, widespread cardiomyopathy, acute spinal cord injury, Huntington's disease, eye diseases, diabetic neuropathy, diabetic nephropathy and mammalian cancer, characterized in that said treatment comprises administering to said mammal a plurality of compounds y according to claim 1 which is effective for inhibiting NOS. 11. Compound of formula (VI) CH VI wherein in the bridged rings independently represent 1, 2 or 3 and the carbon atom in one of said bridged rings may be replaced by a heteroatom selected from the group consisting of O, S and N, provided that the top carbon can only be replaced by nitrogen, and R ¹ and R ² each independently represent a C 1 -C 6 alkyl group which may have a straight, branched or cyclic chain, or may include both straight and cyclic branched and cyclic chains, and each R ¹ and R ² may independently be optionally substituted with one to three substituents , preferably no to two substituents representing a group independently selected from halogen, nitro, hydroxy, cyano, amino, (C 1 -C 4) alkoxy and (C 1 -C ₄ ) alkylamino; or R and R together with the nitrogen atom to which they are attached a piperazine, azetidine, piperidine or pyrrolidine ring, or an azabicyclic ring containing from 6 to 14 ring members of which 1 to 3 are nitrogen and the remainder are carbon atoms, · · · Wherein the distal nitrogen atom of said piperazine or azabicyclic ring is optionally substituted with R ³ and R ⁴ wherein R ³ and R ⁴ are independently selected from hydrogen, C 1 -C 4 to C6 alkyl, phenyl, naphthyl, C1 to C6 alkyl-C (= O) -, HC (= O) -, C1 to C6 alkoxy- (C = O) -, phenyl-C (= O) -, naphthyl-C (= O) -, and R ⁶ R ⁷ NC (= O) -, wherein R ⁶ and R ⁷ each independently represent hydrogen or a C 1 -C 8 alkyl group, with the proviso that when said azabicyclic ring is a spirocyclic ring, distal nitrogen in said spirocyclic ring is optionally substituted with ^R5 wherein ^R5 is selected from the group consisting of H, Ci-Cg alkyl, phenyl, naphthyl, phenyl-C to _C alkyl and naphthyl-Ci to Cg alkyl; and wherein said piperazine, azetidine, piperidine and pyrrolidine ring may be optionally substituted with one or more substituents, preferably no to two substituents, representing a group independently selected from the group consisting of C 1 -C 8 alkyl, amino, C 1 -C 8 alkylamino, [di-C 1-6] C8 alkyljamino, phenyl substituted with 5- to 6-membered heterocyclic rings containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, wherein the phenyl moieties of any of the preceding groups may be optionally substituted with one or more substituents, preferably zero to two groups independently selected from halogen, C 1 -C ₃ alkyl, C 1 -C ₃ alkoxy, nitro, amino, cyano, CF ₃ and OC F ₃ ; with the proviso that no carbon atom is substituted with more than one substituent representing a group selected from hydroxy, amino, alkoxy, alkylamino and dialkylamino. 9 9 9 • 99 9900 99 o Wherein in the bridged rings independently represent 1, 2 or 3 and the carbon atom in one of said bridged rings may be replaced by a heteroatora selected from the group consisting of 0, S and N, provided that the top carbon can only be replaced by nitrogen, and R ¹ and R ² each independently represent a C 1 to C 8 alkyl group which may have a straight, branched or cyclic chain, or may include both straight and cyclic branched and cyclic chains, and each R ¹ and R ² may independently be optionally substituted with one to three substituents , preferably no to two substituents representing a group independently selected from the group consisting of halogen, nitro, hydroxy, cyano, amino, C 1 -C ₄ alkoxy and C 1 -C ₄ alkylamino; or R ¹ and R ² together with the nitrogen atom to which they are attached a piperazine, azetidine, piperidine or pyrrolidine ring, or an azabicyclic ring containing 6 to 14 ring members of which 1 to 3 are nitrogen and the remainder are carbon atoms where the distal atom the nitrogen of said piperazine or azabicyclic ring is optionally substituted with R ³ and R ³ R ⁴ wherein R ³ and R ⁴ are independently selected from hydrogen, C ₁ -C ₆ alkyl, phenyl, naphthyl, C; to C ₆ alkyl-C (= O) -, HC (= O) -, C ₄ to C 6 alkoxy- (C = O) -, phenyl-C (= O) -, Naphthyl-C (= O) and R ⁶ R ⁷ NC (= O) -, wherein R ⁶ and R ⁷ each independently represent hydrogen or a C 1 -C ₆ alkyl group, with the proviso that when said azabicyclic ring is a spirocyclic ring, the distal nitrogen in said spirocyclic ring is optionally substituted with R ⁵ wherein R ⁵ represents a group selected from hydrogen, C 1 -C 8 alkyl, phenyl, naphthyl, phenyl-C 1 -C 8 alkyl-, and naphthyl -C 1 to C 8 alkyl-; wherein said piperazine, azetidine, piperidine and pyrrolidine ring may be optionally substituted with one or more substituents, preferably no to two substituents, representing a group independently selected from the group consisting of C 1 -C ₆ alkyl, amino, C 1 -C 6 alkylamino, [di-C 1-6] C8 alkyl] amino, phenyl substituted with 5- to 6-membered heterocyclic rings containing 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, wherein the phenyl portions of any of the foregoing groups may be optionally substituted with one or more substituents , preferably no to two groups independently selected from the group consisting of halogen, C 1 -C ₃ alkyl, C 1 -C ₃ alkoxy, nitro, amino, cyano, CF ₃ and OCF ₃ ; with the proviso that no carbon atom is substituted by more than one substituent representing a group selected from hydroxy, amino, alkoxy, alkylamino and dialkylamino, and wherein R ⁸ represents a group selected from phenyl and naphthyl.