CZ183999A3 - Compound, pharmaceutical composition containing thereof and prevention or treatment method - Google Patents

Abstract

This invention involves compounds having structure (I) wherein: a) R1 is hydrogen; or alkyl; b) R2 is hydrogen; alkyl or nil; c) R3 is selected from hydrogen; unsubstituted C1-C3 alkanyl; amino, hydroxy, mercapto; C1-C3 alkylthio or alkoxy; C1-C3 alkylamino or C1-C3 dialkylamino; cyano; and halo; d) R4, R5 and R7 are each independently selected from hydrogen; unsubstituted C1-C3 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstitued C1-C3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C1-C3 alkylamino or C1-C3 dialkylamino and halo; e) when R2 is nil, bond (a) is a double bond; f) the compound is not 7-bromo-6-(2-imidazolinylamino)indazole; and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers, addition salts, biohydrolyzable amides and esters, and pharmaceutical compositions containing such novel compounds, and the use of such compounds for preventing or treating disorders modulated by alpha-2 adrenoceptors.

Description

The invention relates to certain types of substituted (2-imidazolinylamino) indazole compounds. The compounds have been found to be α-2-adrenergic receptor agonists and are useful for the treatment of diseases modulated by α-2-adrenergic receptors.

BACKGROUND OF THE INVENTION

Therapeutic indications of α-2-adrenergic receptor agonists have been discussed in the literature; Ruffolo, RR, AJ Nichols, JM Stadel & JP Hieble, "Pharmacologic and Therapeutic Applications of α-2-adrenoceptor Subtypes", Annual Review of Pharmacology & Toxicology and toxicology), Vol. 32 (1993), pp. 243-279. Information regarding α-adrenergic receptors, agonists and antagonists, in general, and concerning compounds structurally related to the compounds of this invention is disclosed in the following cited sources: Timmermans , PBMWM, AT Chiu & MJMC Thoolen, "12.1 α-Adrenergic Receptors", Comprehensive Medicinal Chemistry, vol. 3, Membranes & Receptors, PG Sammes & JB Taylor et al., Pergamon Press (1990), pp. 133-185; Timmermans, PBMWM & PA van Zwieten, " aAdrenoceptor Agonist and Antagonist ", Drugs ofthe Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, AAHP, Leysen JE, FHL Awouters & CJE Niemegeers, "Futher Validation of In Vivo and In Vitro Pharmacologic Procedures for Assessing the a! aa ₂ -Selectivity of Test Compounds: (2) α-Adrenoceptor Agonists (Further validation of in vivo and in vitro pharmacological procedures for the evaluation process and and ₂ selectivity of test compounds: (2) α-Adrenergic receptor agonists) ", European Journal of Pharmacology ( European Journal of Pharmacology), Vol. 129 (1986), pp. 57-64; Timmermans, PBMWM, A. de Jonge. MJMC Thoolen, B. Wilffert, H. Batink, and PA van Zwieten, "Quantitative Relationships Between α-Adrenergic Activity and Binding Affinity of α-Adrenoceptor Agonists and Antagonists" · · · · · · · · · · · · · · · ·

α-adrenergic receptor agonist and antagonist binding), Journal of Medicinal Chemistry, Vol. 27 (1984), pp. 495-503; van Meel JCA, A. de Jonge, PBMWM Timmermans & PA van Zwieten, "Selectivity of Some aAdrenoceptor Agonists for Peripheral α, α and ₂ Adrenoceptors in the Normotensive Rat (Selective α-ardenergic receptor agonists for peripheral α _per and α ₂ adrenergic receptors in normotensive rats), The Journal of Pharmacology and Experimental Therapeutics, Volume 219, No. 3 (1981), pp. 760-767; Chapleo, CB, JC Doxey, PL Myers, M. Myers, CFC Smith & MR Stiliings, "Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard α-Adrenoreceptor Agents" the activity of some standard α-adrenergic receptor agents), European Journal of Medicinal Chemistry, Vol. 24, pp. 619-622; CB Chapleo, RCM Butler, DC England, PL Myers, AG Roach, CFC Smith, MR Stiliings & IF Tulloch, "Heteroaromatic Analogues of the ₂ -Adrenoreceptor Partial Agonist Clonidine" (Heteroaromatic analogues and _2- adrenoreceptor partial agonist "clonidine)" Journal of Madicinal Chemistry, Volume 32 (1989), pp. 1627-1630; Clare, KA, MC Scrutton & NT Thompson, "Effects of a ₂ -adrenoceptor Agonists and of Related Compounds on Aggregation of and on adenylate cyclase activity in Human Platelets (Effects and ₂ adrenergic receptor agonists and related compounds and to their grouping on the activity adenylate cyclase in human platelets), British Journal of Pharmacology, Volume 82 (1984), pp. 467-476; U.S. Patent 3,890,319, issued to Danielewicz, Snarey & Thomas, June 17, 1975; and US Patent 5,091,528, issued to Gluchowski, February 25, 1992. However, many compounds structurally related to the compounds of the present invention do not provide the activity and specificity required to treat disorders modulated by α-2-adrenergic receptors.

E.g. many of the compounds that have been found to be effective as agents for reducing nasal congestion often have undesirable side effects, such as inducing hypertension and insomnia at systemically effective doses. There is a need for new medicaments for releasing nasal congestion that do not cause these undesirable side effects.

SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds and compositions useful in the treatment of disorders modulated by α-2-adrenergic receptors.

It is an object of the present invention to provide novel compounds having significant effects in preventing or treating nasal congestion, otitis media and inflammation of the paranasal sinuses, without undesirable side effects.

It is also an object of the invention to provide novel compounds for the treatment of cough, chronic obstructive pulmonary disease (COPD) and / or asthma.

It is also an object of the invention to provide novel compounds for the treatment of disorders and diseases associated with the functioning of the sympathetic nervous system, including benign prostatic hypertrophy, cardiovascular diseases including myocardial ischemia, cardiac reperfusion (cardiac tremor), angina, cardiac arrhythmia, heart failure and hypertension. It is also an object of the present invention to provide novel compounds for the treatment of ocular diseases such as intraocular hypertension, glaucoma, hyperemia, conjunctivitis and uveal tract inflammation. It is also an object of the present invention to provide novel compounds for the treatment of gastrointestinal disorders such as diarrhea, irritable bowel syndrome, hyperchlorhydria (increased acidity) and peptic ulcer (ulcer).

It is also an object of the invention to provide novel compounds for the treatment of migraine.

It is also an object of the invention to provide novel compounds for the treatment of pain, substance abuse or substance deletion.

It is a further object of the invention to provide compounds which have good effects at oral, parenteral, intranasal and / or topical dosing.

The invention compounds having the following structure: Formula okecne to _about 1 ·.

a) R 1 is hydrogen or alkyl;

b) R ₂ is hydrogen; alkyl or absent;

c) R ₃ is selected from the group consisting of hydrogen, unsubstituted _Ci-C3 alkanyl amino, hydroxy, mercapto, _Ci-C3 alkylthio or alkoxy, _Ci-C3 alkylamino or _Ci-C3 dialkylamino; cyano; and halogen;

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·················

d) R ₄ , R ₅ and R ₇ are each independently selected from hydrogen; unsubstituted C 1 -C 3 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C 1 -C 3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C 1 -C ₃ alkylamino or C 1 -C ₃ dialkylamino; and halogen;

e) when R ₂ is absent (no), bond (a) is a double bond;

f) the compound is not 7-bromo-6- (2-imidazolinylamino) indazole;

and enantiomers, optical isomers, stereoisomers, diastereoisomers, tautomers, additional salts, biohydrolyzable amides and esters; pharmaceutical compositions comprising said novel compounds and the use of said compounds for the prevention or treatment of disorders modulated by α-2 adrenergic receptors.

The term "alkanyl" as used herein refers to a saturated hydrocarbon substituent having a straight or branched chain, substituted or unsubstituted.

The term "alkenyl" as used herein refers to a single double bonded hydrocarbon substituent having a straight or branched chain, unsubstituted or substituted.

The term "alkylthio" as used herein refers to a substituent having the structure Q-S-, wherein Q is alkanyl or alkenyl.

The term "alkoxy" as used herein refers to a substituent having the structure Q-Ο-, wherein Q is alkanyl or alkenyl.

The term "alkylamino" as used herein refers to a substituent having the structure Q-NH-, wherein Q is alkanyl or alkenyl.

The term "dialkylamino" as used herein refers to a substituent having the structure Q _r N (Q ₂ ) -, wherein each Q independently represents alkanyl or alkenyl.

"Halo", "halogen" or "halide" means chloro, bromo, fluoro or iodo.

The term "pharmaceutically acceptable salt" refers to a cationic salt formed in any acidic (eg, carboxyl) group or an anionic salt formed in any basic (eg, amino) group. Many of these salts are known in the art, described in World Patent 87/05297, Johnston et al., Published September 11, 1987, the disclosure of which is incorporated herein by reference. Preferred cationic salts include alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium), and organic salts. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates and the like. Of course, additional salts are contemplated in the group of salts mentioned, which may provide an optical center where nothing was previously present. E.g. a chiral tartrate salt can be prepared from the compounds of the invention and this definition includes such chiral salts.

The compounds of the invention are sufficiently basic to form acid addition salts. The compounds are useful both in free base form and in acid addition salt form, and both forms are within the scope of the invention. Acid additional ··································· Salts are in some cases a more suitable form for use. In practice, it is the use of the salt forms contained in the amounts according to the use of the base form of the active substance. The acids used to prepare the acid additional salts preferably include those which produce, when combined with the free base, a medically acceptable salt. These salts contain anions that are relatively harmless to an animal organism, such as a mammal, in medical doses such that the beneficial properties included in the base base are not impaired by any side effects attributed to acid anions.

Examples of suitable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, hydrosulfate, acetate, trifluoroacetate, nitrate, maleate, citrate, fumarate, formate, stearate, succinate, malate, malonate, adipate, glutarate Lactate, propionate, butyrate, tartrate, methanesulfonate, trifluoromethanesulfonate, ptoluenesulfonate, dodecyl sulfate, cyclohexanesulfamidate and the like. Other suitable medically acceptable salts within the scope of the invention are those derived from other mineral acids and organic acids. The acid addition salts of the parent compounds are prepared by several methods. For example, the free base may be dissolved in an aqueous alcoholic solution containing a suitable acid and the salt isolated by evaporation of the solution. The salts may optionally be prepared by reacting the free base with an acid in an organic solvent such that the salt is precipitated directly. If salt exclusion is difficult, the salt may be precipitated by a second organic solvent or may be obtained by concentrating the solution.

Although medically acceptable salts of the parent compounds are preferred, all acidic additional salts are included within the scope of the present invention. All acid addition salts are useful as sources of the free base form, even if the individual salt itself is only required as an intermediate. For example, if a salt is prepared solely for purification or identity purposes, or when the salt is used as an intermediate in the preparation of a medically acceptable salt by ion exchange procedures, these salts are, of course, contemplated as part of this invention.

* The term "biohydrolyzable amide" refers to an amide of a compound of the invention that is readily converted in vivo (in a living organism) by a mammalian subject to obtain an active compound of the invention.

The term "biohydrolyzable ester" refers to an ester of a compound of the invention that is readily converted by a mammalian subject to obtain an active compound of the invention.

The terms "optical isomer", "stereoisomer", "anantiomer", "diastereoisomer" as used in the text have standard meanings recognized in the art (cf. Hawleys Condensed Chemical Dictionary, 11th edition). Of course, the additional salt may provide an optical center if there is nothing present in the dogwood. From compounds

of the invention, for example, a chiral tartrate salt may be prepared and this definition includes such chiral salts. It will be clear to those skilled in the art that an explanation of the racemic mixture per se reveals any enantiomers of the invention. Thus, more than one compound is described by this one explanation.

The term "animal" as used herein includes "mammalian", which includes "human".

One skilled in the art will appreciate the existence of tautomeric forms in certain compounds of the invention. For example, when R ₃ is hydroxy and the bond (a) is a double bond, it will be clear to include the keto form of the molecule wherein R ₃ is oxo and the bond (a) is a single bond, although not specifically described. Thus, an explanation of one tautomeric form in this disclosure discloses each and all tautomers. Similarly, when depicting the 2-iminoimidazolidinyl form of a molecule, it is clear to include the 2-imidazolinylamino form of the molecule, although not specifically depicted.

An illustration of an example of specific protected forms and other derivatives of the compounds of Formula I is not intended to be limiting. The application of other usable protecting groups, salt forms, etc., is within the skill of the skilled artisan.

The substituent groups, as defined above and used in the invention, may themselves be substituted. Said substitution may be made by one or more substituents. Said substituents include those mentioned in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated by notes in aunt. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (eg, aminomethyl, etc.), cyano, halogen, carboxy, alkoxyacetyl (eg, carboethoxy, etc.), thioalcohol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g. piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

For the purposes of nomenclature, indazole numbering respects IUPAC rules. Thus, according to the following example, the location of the imidazolinylamino radical is indicated:

6- (2-imidazolinylamino) 4 4 4 4 4 4

4 4 4 4 4 4

4 4 4

Compounds

The invention includes compounds described in the Summary of the Invention.

R ₇ is preferably selected from the group consisting of unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy; thioalcohol; cyano and halogen. More preferably, R ₇ is methyl or ethyl or cyclopropyl, most preferably ethyl. R ₇ , when alkylthio or alkoxy, is preferably saturated, also preferably C 1 or C ₂ , most preferably methylthio or methoxy. R ₇ , when halogen, is preferably chloro or bromo. R 1 preferably represents hydrogen. R ₃ is preferably selected from hydrogen; methyl; halogen; and cyano. More preferably, R ₃ is hydrogen. R ₄ is preferably selected from hydrogen; unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; cyano; and halogen. R ₄ is preferably hydrogen, methyl, methoxy, cyano or halogen. Most preferably, R ₄ is hydrogen.

Preferred compounds of the invention have the following structure:

wherein R ₄ and R ₇ represent the groups indicated in the following table:

Compound No. R4 r ₇ 1 H Et 2 H Me

• 444444 44 44 • 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 444 · 4 · 4 · 44 44 · 4 4 · 4

Methods for preparing the compounds of the invention

The compounds of the invention are synthesized using the following procedures. R! to R ₇ radicals are omitted for clarity, unless otherwise prepared according to this specific scheme. A person skilled in the art will appreciate the delivery of omitted radicals using techniques known in the art. One skilled in the art will also appreciate the possibility of using the described methods with protecting groups and the like, as appropriate. Imidazolinylamino groups are conveniently prepared from nitro and amino compounds using the following exemplary synthetic sequences:

These compounds are preferably prepared from nitro or amino compounds, such as those listed above.

The above-mentioned starting nitro and amino compounds are obtained through one or more steps of synthetic reactions including alkylations, halogenations (usually accumulation) and halogen exchange reactions. These types of reactions are summarized as follows:

• 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 999 9 9 9 99 · 9 9 • 9 9 9 · 99 99

Alkylation reactions:

RMgX

DDQ

Fluorination:

κι ^Μ < ^{θ) RaSnSnRa}

I3r

SnRg

CHaCOaF

1 =

Halogenation, preferably accumulation:

Br

Br

Chlorination is preferably performed using Cl ₂ and iodination using ICI, using the same reactions.

Halogen Exchange Reactions:

1) HNO2

2) NaNO2

Z = O, S, NR * 999 · ^Λ

II · <

• · · · 1 · * 9 · 4 · · 4 · · · 4 · 4 4 · 4 * 44 4 · <

• 4 · 4 · · 4 4

999 999 ·

4 9 9

ReSnLj

Pd (Ο) .A ⁿ ° 2 ¹ * · N \\

CuCN

RjZH Base

RgSnL3

XioZH \ Base

It will be clear to those skilled in the art that the reactions illustrated above are known reactions. More, it is within the skill of the art to vary these reactions for the preparation of the compounds within the scope of the claims.

• 4 ····

4 4 · 4 9 444 444 44 99 4 99 4 99 9 * 9

In the above schemes where R is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are derived from the final compounds using the standard dealkylation procedure (Bhatt et al., "Cleavage of Ehters", Synthesis, 1983, p. 249-281).

The starting materials used to prepare the compounds of the invention are known, prepared by known methods or are commercially available as starting material.

It is understood that a person skilled in the art of organic chemistry can easily carry out the manipulations without further guidance, i.e. to carry out such manipulations is within the experience and practice of the trained worker. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic nucleus substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification, and the like. These steps are discussed in common texts such as March, “Advanced Organic Chemistry” (Wiley), Carey and Sundberg, “Advanced Organic Chemistry” (Volume 2) and Tost and Fleming, Comprehensive Organic Synthesis (Volume 6). The skilled artisan will clearly appreciate the ability to carry out some reactions if other functional groups are hidden or protected within the molecule, thus preventing any unwanted side reactions and / or increasing the reaction efficiency. The skilled worker will often use protecting groups to supplement these enhanced effects or to prevent adverse reactions. These reactions are described in the literature and are also within the skill of the art. Examples of many such manipulations are given, for example, in T. Greene, Protecting Groups in Organic Synthesis.

Examples of compounds

The following non-limiting examples provide details of the synthesis of 6-imidazolinylamino-indazoles.

Example compound 1: 7-Ethyl-6- (2-imidazolinylamino) indazole

A. 7-Ethyl-6-nitroindazole. To a solution of 200 mg of 6-nitroindazole in 9 mL of dry tetrahydrofuran maintained at 15-20 ° C (ice / water bath) is added dropwise 5.5 mL of 1.0 M magnesium ethyl bromide, followed by stirring for 90 minutes. To this mixture is added 292 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and stirring is continued at room temperature for 24 hours. The mixture is diluted with 5 mL of methanol and 20 mL of water. The emulsion mixture is subjected to extraction with ethyl acetate (3 x 100 mL) and the emulsion vacuum filtered through a short strip of silica gel. The organic layers are compounds, dried over sodium sulfate, filtered, and rotary evaporated. The unpurified material is purified by aspiration vacuum filtration through silica gel, eluting with 50% ethyl acetate in hexane to afford 60 mg of 7-ethyl-6-nitroindazole as a yellow soft solid.

B. 6-Amino-7-ethylindazole. To a solution of 400 mg of 7-ethyl-6-nitroindazole in 20 mL of ethyl acetate is added 250 mg of palladium-carbon (10%). The resulting suspension is stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 6 hours. The reaction mixture is filtered through celite, washed with ethyl acetate and rotary evaporated. The residue is purified by aspiration vacuum filtration on silica gel, eluting with 50% ethyl acetate in hexane to afford 145 mg of 6-amino-7-ethylindazole.

C. 7-Ethyl-6-isothiocyanatoindazole. A mixture of 140 mg of 6-amino-7-ethylindazole, 215 mg of di-2-pyridylthiocarbonate and 22 mg of 4-dimethylaminopyridine in 30 ml of methylene chloride is stirred at room temperature for 2 hours. The reaction mixture is rotary evaporated and the residue is purified by aspiration vacuum filtration through silica gel, eluting with 30% ethyl acetate in hexane to afford 130 mg of 7-ethyl-6-isothiocyanatoindazole.

D. 7-Ethyl-6- (2-imidazolinylamino) indazole. A suspension of 126 mg of 7-ethyl-6-isothiocyanatoindazole in 15 ml of toluene is added dropwise to a stirred mixture of 186 mg of ethylenediamine and 5 ml of toluene. After stirring at room temperature for 48 hours, the reaction mixture is rotary evaporated. The residue is dissolved in 20 ml of methanol, 267 mg of mercuric acetate are added. The mixture is stirred at room temperature for 4.5 hours, then rotary evaporated. The residue is purified by aspiration vacuum filtration on silica gel, eluting with 7.5: 2.5: 0.15 methylene chloride: methanol: concentrated ammonium hydroxide. The purified compound is dissolved in 1.5 ml of methanol and treated with a solution of 87 mg of fumaric acid in 3.5 ml of methanol for 5 minutes at room temperature. The product is precipitated with ether, filtered, washed with ether and dried under vacuum to give 178 mg of 7-ethyl-6- (2-imidazolinylamino) indazole as a fumaric acid salt.

Example compound 2: 6- (2-imidazolinylamino) -7-methylindazole

A. 2,6-Dimethyl-3-nitroaniline. To a cold (ice / water bath) mixture of 5 g of 2,6-dimethylaniline and 34 ml of concentrated sulfuric acid is added dropwise 2.86 g of fuming nitric acid while maintaining the internal reaction temperature below 15 ° C. After stirring for 10 minutes at room temperature, the resulting solution is poured into 400 ml of ice / water and neutralized with 50% aqueous sodium hydroxide while maintaining the temperature below 25 ° C. The reddish-brown precipitate is filtered and washed with water. The material is dissolved

in 100 ml of methanol and decolourised with charcoal. The material is further purified by aspiration vacuum filtration on silica gel, eluting with 20% ethyl acetate in hexane followed by recrystallization from ethyl acetate / hexane to give 3.25 g of 2,6-dimethyl-3-nitroaniline as a yellow solid.

B. 7-Methyl-6-nitroindazole. To a cold (ice / water bath) mixture of 1 g of 2,6-dimethyl-3-nitroaniline and 42 ml of glacial acetic acid is added simultaneously 415 mg of sodium nitrite in 2 ml of water. The reaction mixture is stirred at room temperature for 48 hours and rotary evaporated to a small volume. The residue is suspended in 20 ml of 50% ethanol / water, heated to quark for 15 minutes, and filtered. The procedure is repeated three times with solid material to remove the undesired isomer (7-methyl-4-nitroindazole), the purity of the desired isomer is monitored by proton NMR (nuclear magnetic resonance). This purification yielded 327 mg of 7-methyl-6-nitroindazole as a tan solid.

C. 6-Amino-7-methylindazole. To a solution of 295 mg of 7-methyl-6-nitroindazole in 16 mL of ethyl acetate is added 200 mg of palladium-carbon (10%). The resulting suspension is stirred at room temperature under a carbon atmosphere at atmospheric pressure for 2 hours. The mixture is filtered through celite, washed with ethyl acetate and rotary evaporated to give 236 mg of 6-amino-7-methylindazole.

D. 6-Isothiocyanato-7-methylindazole. A mixture of 174 mg of 6-amino-7-methylindazole, 293 mg of di2-pyridylsulfonate and 31 mg of 4-dimethylaminopyridine in 35 ml of methylene chloride is stirred at room temperature for 4 hours. The mixture is rotary evaporated and the residue is purified by aspiration vacuum filtration on silica gel, eluting with 50% ethyl acetate in hexane to afford 218 mg of 6-isothiocyanato-7-methylindazole.

E. 6- (2-Imidazolinylamino) -7-methylindazole. A suspension of 253 mg of 6-isothiocyanato-7-methylindazole in 60 ml of toluene is added dropwise to a stirred mixture of 402 mg of ethylenediamine in 25 ml of toluene, the resulting mixture is stirred at room temperature for 24 hours. The precipitate is filtered and washed with toluene. The solid is dissolved in 30 mL of methanol and 397 mg of mercuric acetate is added. The mixture is stirred at room temperature for 5 hours, then filtered through celite and the solid is washed with methanol. The filtrate is rotary evaporated and the residue is purified by aspiration vacuum filtration on silica gel, eluting with 8: 2: 0.1 methylene chloride: methanol: concentrated ammonium hydroxide. The purified compound is dissolved in 5 ml of methanol and treated with 70 mg of glacial acetic acid for 5 minutes. The product is precipitated with ether, filtered, washed with ether and dried from vacuum to give 199 mg of 6- (2-imidazolinylamino) -7-methylindazole as the acetic acid salt as a light tan solid.

····· · · · ·· · ·

Alternative preparation of imidazolinylamine from arylamines:

H>

\

Abs. EtOH CH3 -

- 35OC

O

OCHj r- ^N

K2CO, Γ y-scw

-—— * ^ -N

- 35 OC θΛ-oCH

AcOH, Reflux

A. 2-Methylthio-2-imidazoline. 2-Imidazolidinethione (5.0 g) is added to pure ethanol (40 mL) during stirring. Methyl iodide (4.3 mL) is added rapidly. The reaction mixture is heated at 30-35 ° C for 45 minutes. This solution is used directly in the next reaction.

B. N-Carbomethoxy-2-thiomethyl-2-imidazoline. Potassium carbonate (10.1 g) is added to mixture A of the step above, followed by addition of methyl chloroformate (4.2 mL) with stirring. After 45 minutes, the reaction mixture is heated to 55 ° C and the insoluble salts are filtered off. These salts are washed with 10 ml of pure ethanol. The filtrate (and the ethanol wash) is cooled to -20 ° C and the recrystallized product is isolated by a Buchner funnel. The product is washed with 10 ml of cold (-20 ° C) pure ethanol. The product is dried overnight under vacuum at room temperature to give N-carbomethoxy-2-thiomethyl-2-imidazoline.

C. 7-Ethyl-6- (2-imidazolinylamino) indazole. The N-carbomethoxy-2-thiomethyl-2-imidazoline is combined with the amine (1B) of Example 1 in 10% acetic acid in ethanol and heated to reflux. Once all of the starting amine is consumed, the mixture is bleached with carbon. The mixture is cooled, filtered and rotary evaporated. After recrystallization and drying, the compound (1D) of Example 1 is obtained as the acetic acid salt.

• eee • eee and a·· · <<<ee ee ee ee ee ee ee ee ee ee ee ee ee ee ee ee ee ··· · ee

Using the methods outlined above and exemplified, the following examples are prepared:

VL

Exampl · * 3 «4 Re Rr 3 H Cl H Me 4 H Br H Me 5 H AND H Me 6 H F H Me .7 H About me H Me 8 H CN H Me 9 H Me H Cl 10 H Cl H Cl 11 H Br H Cl 12 H AND H Cl 13 H F H Cl 14 H About me H Cl 15 Dec H CN H Cl 16 H H H Cl

• · · · · · · · · · ·

16 1 Η 1 Me Br 1 Br 18 ί - Η WHOSE H | Br 19 ί Βγ Br 1 Br 20 May Η 1 Br ί Br 21 Η F Br 1 Br 22nd Η About me H Br 23 Η CN H Br 24 Η Me H 1 25 Η Cf H 1 26 Η Br H 1 27 Mar: Η 1 H 1 28 Η F H 1 29 Η About me H 1 30 Η CN H 1 31 Η H H 1 32 Η Me H Et 33 Η Cl H Et 34 Η Br H Et 35 Η 1 H Et 36 Η F H Et 37 Η About me H Et 38 Η CN H Et 39 Η H Me Me 40 Η H Cl Me 41 Η H Br Me 42 Η H 1 Me 43 Η H F Me 44 Η H Cl Cl 45 Η Me Me Me 46 Η Me Cl Me 47 Η Me Br > Me 48 Η Me 1 Me 49 Η H Me Et 50 Η H Br Et 51 Η H Me H

· · «« «« «· * * * * * * * * * * · · · · · ·

52 H I H I Br I H 53 H ί H Cl H 54 H H I H 55 H H ί Et I H 56 H Me Me H 57 H Br Me H 5Θ H F Me H 59 H Me Br H 60 Me H H Me 61 CN H H Me 62 Me ~ Me H Me 63 Me Br H Me 64 CN Me H Me 65 CN Br H Me 66 Me H H Et 67 CN H H Et 68 Me Me H Et 69 Me Br H Et 70 CN Me H -Et- 71 CN Br H Et 72 Me H H Br 73 CN H H Br 74 Me Me H Br 75 Me Br H Br 78 CN Me H Br 77 CN Br TO Br

Resources

Another aspect of the invention are compositions comprising a safe and effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · ·

The term "safe and effective amount" as used herein refers to an amount of the subject compound high enough to induce a significant positive modification under treatment conditions, but low enough to prevent serious side effects (at reasonable benefit / risk ratio) within a reliable medical decision. . The safe and effective amount of the compound of the invention will vary according to the age and physical condition of the patient being treated, the severity of the conditions, the duration of treatment, the nature of the concurrent therapy, the particular pharmaceutically acceptable carrier used and similar factors within the knowledge and judgment of the supervising physician.

Preparation of the dosage form is based on the experience and perspective of the skilled worker. The examples are given to those skilled in the art but are not limiting, it is further contemplated that one skilled in the art can prepare the possibilities of the claimed compositions.

The compositions of the invention preferably comprise from about 0.0001% to about 99% by weight. of the compound of the invention, more preferably from about 0.01% to about 90% of the compound of the invention. Depending on the mode of administration and the concomitant bioavailability, solubility, and insolubility properties of the dosage form, the dosage form preferably comprises from about 10% to about 50%, also preferably from about 5% to about 10%, further preferably from about 1% to about 5% and further preferably from about 0.01% to about 1% of a compound of the invention. The frequency of dosing of a compound of the invention is dependent upon the pharmacokinetic properties of each specific agent (eg, biological half-life) and can be determined by a skilled artisan.

The compositions of the invention contain, in addition to a compound of the invention, a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein refers to one or more compatible solid or liquid soluble fillers or encapsulating substances that are suitable for administration to mammals. The term "compatible" as used herein means that the components of the composition are capable of mixing with the compound of the invention and with each other in such a way that no internal reaction occurs that would substantially reduce the pharmaceutical efficacy of the composition in normal situations of use. The compounds of the invention, when preferably used in liquid dosage forms, are soluble in the ingredients of the composition. Of course, pharmaceutically acceptable carriers must be sufficiently pure and not sufficiently toxic to be suitable for administration to the mammal being treated.

Some examples of substances that can be used as pharmaceutically acceptable carriers or their components are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; loose tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil,

4 4 4

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4 4 4 4

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4 4 4 corn oil and cocoa oil; polyhydric alcohols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifying agents such as Tweens®; wetting agents, such as sodium lauryl sulfate (sodium lauryl sulfate); dyes; scent; tableting agents; stabilizers; antioxidants; protective equipment; pyrogen-free water; isotonic saline; and phosphate buffers. The choice of a pharmaceutically acceptable carrier used in conjunction with a compound of the invention is essentially limited to the mode of administration of the compound. When the compound of the invention is to be administered by injection, the preferred pharmaceutical carrier is sterile saline with a blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.

When the preferred route of administration of the compound of the invention is oral, preferred units of this dosage form are tablets, capsules, lozenges, chewable tablets and the like. Said dosage units comprise a safe and effective amount of a compound of the invention, which is preferably from about 0.01 mg to about 350 mg, more preferably from about 0.1 mg to about 35 mg, based on a 70 kg person. Pharmaceutically acceptable carriers suitable for the preparation of dosage unit forms for oral administration are well known in the art. Tablets usually contain conventional pharmaceutically acceptable excipients such as inert solvents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrating agents such as starch, alginic acid and "cross-linked caramelose; lubricants such as magnesium stearate, stearic acid and talc. Flow control agents, such as silica, can be used to adjust flow characteristics of the bulk composition. Dyes, such as FD&C dyes, can be delivered to enhance aesthetic appearance. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint extract and fruit flavors are adjuvants for chewable tablets. The capsules usually contain one or more of the solid solvents described above. The choice of carrier component depends on secondary considerations, such as taste, cost and degree of stability, which are not critical for the purposes of the invention and can be readily adjusted by the skilled artisan.

Formulations for oral administration also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Said liquid oral compositions preferably comprise from about 0.001% to about 5% of a compound of the invention, more preferably from about 0.01% to about 0.5%. Common components of syrup carriers, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. Typical suspending agents for suspensions include methylcellulose, sodium carboxymethylcellulose, and the like.

999 99 99

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Avicel® RC-591, tragacanth and sodium alginate; common humectants include lecithin and polysorbate 80; and conventional preservatives include methylparaben and sodium benzoate. Liquid compositions intended for oral administration may also contain one or more of the ingredients such as sweeteners, flavors and colorants described above.

Other means useful for achieving systemic administration of a compound of the invention include sublingual and buccal dosage forms. Said compositions typically comprise one or more soluble filler materials, such as sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxymethylcellulose. Flow control agents, lubricants, sweeteners, colorants, antioxidants and flavors disclosed above may also be used.

The compositions may also be used to deliver the compound to a site where activity is desired; intranasal dosage for nasal relief, inhalants for asthma and eye drops, gels and creams for eye diseases.

Preferred compositions of the present invention include solutions or emulsions, preferably aqueous solutions or emulsions comprising a safe and effective amount of a compound of the invention intended for topical intranasal administration. Such compositions preferably comprise from about 0.001% to about 25% of a compound of the invention, more preferably from about 0.01% to about 10%. Similar compositions are preferred for the systematic administration of the compounds of the invention by the intranasal route. Compositions intended to deliver a compound systemically by intranasal doses preferably contain similar amounts of a compound of the invention that are intended to be safe and effective for oral or parenteral administration. Said compositions used for intranasal administration also usually include safe and effective amounts of preservatives such as "benzalkonium chloride" and "thimerosal" and the like; chelating agents such as "sodium edeinate" and the like; buffers, such as phosphate, citrate and acetate; tonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcystine, sodium metabisulphate and others; aromatic agents; viscosity modifying agents, such as polymers, including cellulose and its derivatives and polyvinyl alcohol; and acids and bases to adjust the pH of these aqueous compositions as desired. The compositions may also contain topical anesthetics or other active agents. These compositions can be used in the form of sprays, spray formulations, drops and the like.

Other preferred compositions of the invention include aqueous solutions, suspensions and dry bulk compositions containing a safe and effective amount of a compound of the invention intended to be sprayed and inhaled. Said compositions preferably comprise from about 0.1% to about 50% of a compound of the invention, more preferably from about 1% to about 20%; the amount may, of course, be varied according to the condition of the patient being considered and the package. Said compositions are usually packaged in containers

4 4

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4 * 4 4 4 4 with sprayers attached. Said compositions also typically contain accelerating agents such as CFCs 12/11 and 12/114 and more environmentally compatible fluorinated hydrocarbons or other nontoxic volatiles; solvents, such as water, glycerol and ethanol, include co-solvents as needed to solvate or suspend the active agent; stabilizers such as ascorbic acid, sodium metabisulphite; preservatives such as cetylpyridinium chloride and benzalkonium chloride; tonicity agents such as sodium chloride; buffers; and flavoring agents such as sodium saccharin. Said compositions are useful for treating respiratory disorders such as asthma and the like.

Other preferred compositions of the invention include aqueous solutions comprising a safe and effective amount of a compound of the invention for topical intraocular administration. Said compositions preferably comprise from about 0.0001% to about 5% of a compound of the invention, more preferably from about 0.01% to about 0.5%. Said compositions usually also include one or more preservatives such as "benzalkonium chloride", "thimerosal", mercuric phenylacetate; binders such as "poloxamers", modified cellulose derivatives, "povidone" and purified water; tonicity agents such as sodium chloride, mannitol and glycerin; buffers, such as acetate, citrate, phosphate and borate; antioxidants such as sodium metabisulphite, butylated hydroxytoluene and acetylcysteine; acids and bases can be used to adjust the pH of these formulations as desired.

Other preferred compositions of the invention useful for oral administration include unitary solid units such as tablets and capsules, and liquids such as solutions, suspensions and emulsions (preferably in soft gelatin shells) containing a safe and effective amount of a compound of the invention. Said compositions preferably comprise from about 0.01 mg to about 350 mg per dose, more preferably from about 0.1 mg to about 35 mg per dose. Said compositions may be coated with protective layers using conventional methods, usually with pH or time-dependent layers, so that the compounds of the invention are released in the gastrointestinal tract at different times to achieve the desired effects. Said dosage forms usually include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudravit® coating, waxes, and shellac. Any of the compositions of the invention may optionally contain other active drugs. Non-limiting examples of active drugs that can be incorporated in these compositions include:

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Antihistamines, including:

"Hydroxyzine", preferably at a dosage range of from about 25 to about 400 mg; "Doxylamine", preferably at a dosage range of from about 3 to about 75 mg; Pyrilamine, preferably at a dosage range of from about 6.25 to about 200 mg; "Chlorpheniramine", preferably at a dosage range of from about to about 24 mg; "Phenindamine", preferably at a dosage range of from about 6.25 to about 150 mg; "Dexchlorpheniramine", preferably at a dosage range of from about 0.5 to about 12 mg; "Dexbrompheniramine", preferably at a dosage range of from 0.5 to 12 mg; "Clemastine", preferably at a dosage range of from about 1 to about 9 mg; "Diphenhydramine", preferably at a dosage range of from about 6.25 to about 300 mg; "Azelastine", preferably at a dosage range of from about 140 to about 1,680 gg (when dosed intranasally); from about 1 to about 8 mg (when dosed orally); "Acrivastine", preferably at a dosage range of from about 1 to about 24 mg; "Levocarbastine" (which may be dosed as an intranasal or ophthalmic drug), preferably at a dosage range of from about 100 to about 800 mg; "Mequitazine", preferably at a dosage range of from about 5 to about 20 mg; "Astemizole", preferably at a dosage range of from about 5 to about 20 mg; "Ebastine", preferably at a dosage range of from about 5 to about 20 mg; "Loratadine", preferably at a dosage range of from about 5 to about 40 mg; "Cetirizine", preferably at a dosage range of from about 5 to about 20 mg; "Terfenadine", preferably at a dosage range of from about 30 to about 480 mg; terfenadine metabolites; "Promethazine", preferably at a dosage range of from about 6.25 to about 50 mg; "Dimenhydrinate", preferably at a dosage range of from about 12.5 to about 400 mg; "Meclizine", preferably at a dosage range of from about 6.25 to about 50 mg; "Tripelennamine", preferably at a dosage range of from about 6.25 to about 300 mg; "Carbinoxamine", preferably at a dosage range of from about 0.5 to about 16 mg; "Cyproheptadine", preferably at a dosage range of from about to about 20 mg; "Azatadine", preferably at a dosage range of from about 0.25 to about 2 mg; "Brompheniramine", preferably at a dosage range of from about 1 to about 24 mg; "Triprolidine", preferably at a dosage range of from about 0.25 to about 10 mg; "Cyclizine", preferably at a dosage range of from about 12.5 to about 200 mg; "Thonzylamine", preferably at a dosage range of from about 12.5 to about 600 mg; "Pheniramine", preferably at a dosage range of from about 3 to about 75 mg; and others.

Antitussives, including:

"Codeine", preferably at a dosage range of from about 2.5 to about 120 mg; "Hydrocodone", preferably at a dosage range of from about 2.5 to about 40 mg; "Dextromethorphan", preferably at a dosage range of from about 2.5 to about 120 mg; Noscapine, preferably at a dosage range of from about 3 to about 4 to about 4 to about 9 to about 9 to about 9 to about 9 to 9

9 9 9 9 9

9 99 9 9 9 9 9 9 9 about 180 mg; Benzonate, preferably at a dosage range of from about 100 to about 600 mg; "Diphenhydramine", preferably at a dosage range of from about 12.5 to about 150 mg; "Chlofedianol", preferably at a dosage range of from about 12.5 to about 100 mg; "Clobutinol", preferably at a dosage range of from about 20 to about 240 mg; "Fominoben", preferably at a dosage range of from about 80 to about 480 mg; 'Glaucine'; Pholcodine, preferably at a dosage range of from about 1 to about 40 mg; "Zipeprol", preferably at a dosage range of from about 75 to about 300 mg; A "Hydromorphone", preferably at a dosage range of from about 0.5 to about 8 mg; "Carbetapentane", preferably at a dosage range of from about 15 to about 240 mg; "Caramiphen", preferably at a dosage range of from about 10 to about 100 mg; "Levopropoxyphene", preferably at a dosage range of from about 25 to about 200 mg; and other;

Anti-inflammatory agents, preferably non-steroidal anti-inflammatory agents (NSAIDS), including:

"Ibuprofen", preferably at a dosage range of from about 50 to about 3200 mg; "Naproxen", preferably at a dosage range of from about 62.5 to about 1,500 mg; "Naproxen sodium", preferably at a dosage range of from about 110 to about 1,650 mg; "Ketoprofen", preferably at a dosage range of from about 25 to about 300 mg; "Indoprofen", preferably at a dosage range of from about 25 to about 200 mg; "Indomethacin", preferably at a dosage range of from about 25 to about 200 mg; "Sulindac", preferably at a dosage range of from about 75 to about 400 mg; "Diflunisal", preferably at a dosage range of from about 125 to about 1,500 mg; "Ketorolac", preferably at a dosage range of from about 10 to about 120 mg; "Piroxicam", preferably at a dosage range of from about 10 to about 40 mg; "Aspirin", preferably at a dosage range of from about 80 to about 4000 mg; "Meclofenamate", preferably at a dosage range of from about 25 to about 400 mg; "Benzydamine", preferably at a dosage range of from about 25 to about 200 mg; "Carprofen", preferably at a dosage range of from about 75 to about 300 mg, "Diclofenac", preferably at a dosage range of from about 25 to about 200 mg; "Etodolac", preferably at a dosage range of from about 200 to about 1,200 mg; "Fenbufen", preferably at a dosage range of from about 300 to about 900 mg; "Phenoprofen", preferably at a dosage range of from about 200 to about 3200 mg; "Flurbiprofen", preferably at a dosage range of from about 50 to about 300 mg; "Mefenamic acid", preferably at a dosage range of from about 250 to about 1,500 mg; "Nabumetone", preferably at a dosage range of from about 250 to about 2000 mg; "Phenylbutazone", preferably at a dosage range of from about 100 to about 400 mg; "Pirprofen", preferably at a dosage range of from about 100 to about 800 mg; "Tolmetin", preferably at a dosage range of from about 200 to about 1,800 mg; and other.

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Analgesics, including:

"Acetaminophen", preferably at a dosage range of from about 80 to about 4000 mg; and other.

Expectorants / mucolytics, including:

"Guaifenesin", preferably at a dosage range of from about 50 to about 2,400 mg; "N-acetylcysteine", preferably at a dosage range of from about 100 to about 600 mg; "Ambroxol", preferably at a dosage range of from about 15 to about 120 mg; "Bromhexin", preferably at a dosage range of from about 4 to about 64 mg; "Terpin hydrate", preferably at a dosage range of from about 100 to about 1,200 mg; "Potassium iodide", preferably at a dosage range of from about 50 to about 250 mg; and other.

Anticholinergics (eg Atropines), preferably intranasally or orally administered anticholinergics, including:

"Ipratropium" (preferably intranasally), preferably at a dosage range of from about 42 to about 252 pg; "Atropine sulfate" (preferably oral), preferably at a dosage range of from about 10 to about 1,000 pg; "Belladonna" (preferably in the form of an extract), preferably at a dosage range of from about 15 to about 45 mg equivalents; "Scopolamine", preferably at a dosage range of from about 400 to about 3200 pg; "Scopolamine, methobromide", preferably at a dosage range of from about 2.5 to about 20 mg; "Homatropin, methobromide", preferably at a dosage range of from about 2.5 to about 40 mg; Hyoscyamine (preferably oral), preferably at a dosage range of from about 125 to about 1,000 pg; Isopropramide (preferably oral), preferably at a dosage range of from about 5 to about 20 mg; "Orphenadrine" (preferably oral), preferably at a dosage range of from about 50 to about 400 mg; "Benzalkonium chloride" (preferably intranasally), preferably at a dosage range of from about 0.005% to about 0.1% solution; and other.

Mast ointment stabilizers, preferably intranasally or orally administered mast ointment stabilizers, including:

"Cromalyn", preferably at a dosage range of from about 10 to about 60 mg; "Nedocromil", preferably at a dosage range of from about 10 to about 60 mg; "Oxatamide", preferably at a dosage range of from about 15 to about 120 mg; "Ketotifen", preferably at a dosage range of from about 1 to about 4 mg; "Lodoxamide", preferably at a dosage range of from about 100 to about 3000 pg; and other.

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Leukotriene antagonists, including "Zileuton" and others.

Methylxanthines, including:

"Caffein", preferably at a dosage range of from about 65 to about 600 mg; "Theophylline", preferably at a dosage range of from about 25 to about 1,200 mg; 'Enprophyllin'; "Pentoxifylline", preferably at a dosage range of from about 400 to about 3,600 mg; "Aminophylline", preferably at a dosage range of from about 50 to about 800 mg; "Dyphylin", preferably at a dosage range of from about 200 to about 1,600 mg; and other.

Antioxidants or free radical depressants, including:

"Ascorbic acid", preferably at a dosage range of from about 50 to about 10,000 mg; "Tocopherol", preferably at a dosage range of from about 50 to about 2000 mg; "Ethanol", preferably at a dosage range of from about 500 to about 10,000 mg; and other.

Steroids, preferably intranasally administered steroids, including:

"Beclomethasone", preferably at a dosage range of from about 84 to about 336 gg; "Fluticasone", preferably at a dosage range of from about 50 to about 400 gg; "Budesonide", preferably at a dosage range of from about 64 to about 256 gg; "Mometasone", preferably at a dosage range of from about 50 to about 300 mg; "Triamcinolone", preferably at a dosage range of from about 110 to about 440 gg; "Dexamethasone", preferably at a dosage range of from about 168 to about 1,008 gg; "Flunisolide", preferably at a dosage range of from about 50 to about 300 gg; "Prednisone" (preferably oral), preferably at a dosage range of from about 5 to about 60 mg; "Hydrocortisone" (preferably oral), preferably at a dosage range of from about 20 to about 300 mg; and other.

Bronchodilators, preferably for inhalation, include:

"Albuterol", preferably at a dosage range of from about 90 to about 1,080 gg, from about 2 to about 16 mg (if dosed orally); "Epinephrine", preferably at a dosage range of from about 220 to about 1,320 gg; "Ephedrine", preferably at a dosage range of from about 15 to about 240 mg (when dosed orally), from about 250 to about 1,000 gg (when dosed intranasally); "Metaproterenol", preferably at a dosage range of from about 65 to about 780 gg, or from about 10 to about 80 mg (when *).

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Π dosed orally); "Terbutaline", preferably at a dosage range of from about 200 to about 2,400 gg, from about 2.5 to about 20 mg (when dosed orally); "Isoetharin", preferably at a dosage range of from about 340 to about 1,360 gg; "Pirbuterol", preferably at a dosage range of from about 200 to about 2,400 gg; "Bitolterol", preferably at a dosage range of from about 370 to about 2,220 gg; "Phenoterol", preferably at a dosage range of from about 100 to about 1,200 gg; from about 2.5 to about 20 mg (when dosed orally); "Rimeterol", preferably at a dosage range of from about 200 to about 1,600 gg; "Ipratroprium", preferably at a dosage range of from about 18 to about 216 gg (inhalation); and other.

Antiviral agents, including:

"Amantadine", preferably at a dosage range of from about 50 to about 200 mg; "Rimantadine", preferably at a dosage range of from about 50 to about 200 mg; 'Enviroxim'; "Nonoxinol", preferably at a dosage range of from about 2 to about 20 mg (preferably in intranasal form); "Aciclovir", preferably at a dosage range of from about 200 to about 2000 mg (oral), from about 1 to about 10 mg (preferably intranasal form); "Alpha-interferon", preferably at a dosage range of from about 3 to about 36 MIU; "Beta-interferon", preferably at a dosage range of from about 3 to about 36 MIU; and other.

Ophthalmic active drugs: acetylcholinesterase inhibitors, e.g., echothiophate from about 0.03% to about 0.25% in a solution administered topically and others; and

Gastrointestinal active agents: anti-diarrheal agents such as "loperamide" from about 0.1 mg to about 1.0 mg per dose and bismuth basic salicylate from about 25 mg to about 300 mg per dose and others.

Of course, acid and base addition salts, esters, metabolites, stereoisomers and enantiomers of these preferred active agent combinations, as well as analogues thereof, which are safe and effective, are undoubtedly contemplated and included in the above description. It is also understood that the active agent may be useful for more than one of the above uses, and these uses are undoubtedly also contemplated. Such interconnection is recognized in the art and appropriate adjustment of dosages and the like according to the indication is entirely at the discretion of the skilled practitioner.

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Methods of use

Without being bound by theory, it has been found that the primary mechanism by which α-2-agonists induce action is based on the intervention in the biological cascade causing the disorder (s) and / or their manifestation (s). There may be no deficiency in α-2-adrenergic receptor activity; said activity may be normal. However, administration of an α-2-agonist may be an effective way of treating the disease, condition or symptoms thereof.

The terms &quot; disease &quot;, &quot; disorder &quot; and &quot; condition &quot; as used herein are used interchangeably and refer to diseases related to or modified by the action of α-2 adrenergic receptors.

The disorders described by the terms "α-2-adrenergic receptor modulated" or "α-2-adrenergic receptor modulated" as used herein refer to a disorder, condition or disease in which α-2-adrenergic receptor action is an effective agent a mitigating disorder or one or more biological manifestations of the disease or disorder; or 'annoys' at one or more stages in the biological cascade leading to or responsible for the underlying disorder; or alleviates one or more symptoms of the disorder. Disorders thus caused by "modulation" include those in which:

• Lack of α-2 activity is the "cause" of the disorder or one or more biological manifestations, regardless of whether the activity has been altered genetically, infection, irritation, internal stimulus or any other cause;

The disease or disorder or observable manifestation or symptoms of the disease or disorder are alleviated by α-2 activity. The lack of α-2 activity may not be causally related to the disease or disorder or its observable manifestations.

Α-2 activity disrupts the portion of the biochemical or cellular cascade that results in or is associated with the disease or disorder; α-2 activity, in this regard, transforms the cascade and thereby suppresses the disease, condition or disorder.

The compounds of the invention are particularly effective in treating nasal congestion associated with allergies, colds and other nasal diseases, as well as the consequences of mucosal congestion (e.g., paranasal sinusitis and otitis media). It has been found that undesirable side effects can be suppressed with effective dosing.

It is believed that the compounds of the invention, not limited to a single mechanism of action, provide advantages in the treatment of nasal relief with the corresponding compounds through their ability to interact with α-2 "adrenoceptors" (adrenergic receptors).

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The compounds of the invention have been found to be α-2-adrenergic receptor agonists that induce the constriction of the peripheral vascular layers in the nasal spirals.

α-2- "adrenoceptors" are dispersed both inside and outside the central nervous system. Certain disorders are thus preferably treated with compounds that act on α-2-adrenergic receptors in only one of these portions, although this for their activity or efficiency is not essential. The compounds of the invention vary in their ability to penetrate the central nervous system and thus elicit effects mediated through central α-2-adrenergic receptors. E.g. thus, a compound that exhibits a higher degree of activity on the central nervous system is advantageous for indications of the central nervous system over other compounds as described below. However, even for compounds that primarily exhibit marginal activity, central nervous system activity can be induced by increasing the compound dosage. Additional specificity of action of these compounds can be achieved by delivering the agent to the part of the body in which the activity is desired (eg, topical administration to the eye, nasal mucosa or respiratory tract).

Compounds preferred for, but not limited to, the treatment of certain cardiovascular diseases, pain, substance misuse and / or omission, ulcer and increased acidity include those compounds that are centrally active. The term "centrally active" indicates that the compounds have some action on α-2-adrenoceptors in the central nervous system in addition to their action on the peripheral α-2-adrenoceptors.

Compounds preferred for, but not limited to, treatment of respiratory diseases, eye diseases, migraine, certain cardiovascular diseases, and certain other gastrointestinal disorders are regionally active. The term "marginally active" indicates that these compounds primarily act on α-2-adrenoceptors in the marginal part, rather than in the central nervous system. Methods are available in the art to determine compounds that are primarily marginally active and which are primarily centrally active.

Thus, the compounds of the invention are also useful for treating ocular diseases such as intraocular hypertension, glaucoma, congestion, conjunctivitis and uveal tract inflammation. The compounds are administered either orally or topically in the form of drops, sprays, sprays, gels or creams directly to the outside of the mammalian eye.

The compounds of the invention are also useful for suppressing gastrointestinal disorders such as diarrhea, irritable bowel syndrome, hyperchlorhydria and peptic ulcer. The compounds of the invention are also effective against diseases and disorders associated with the activity of the sympathetic nervous system, including hypertension, myocardial ischemia, damage to cardiac reperfusion (heart tremor), angina, cardiac arrhythmia, heart failure, and benign hypertrophy

• Prostate. Because of their sympatholytic effects, the compounds are also useful as an adjuvant in anesthesia during surgical procedures.

The compounds of the invention are also effective for relieving pain associated with various disorders. The compounds are administered orally, parenterally and / or by direct injection of the cerebrospinal fluid.

The compounds of the invention are also useful for the prophylactic or acute treatment of migraine. The compounds are administered orally, parenterally or intranasally.

The compounds of the invention are also useful for the treatment of substance abuse, in particular alcohol and narcotic drug abuse, and the alleviation of withdrawal syndromes caused by the omission of these substances.

The compounds of the invention are also useful for the treatment of other diseases and disorders in which vascular constriction, particularly veins, including septic or cardiogenic shock, elevated intracranial pressure, hemorrhoids, venous insufficiency, varicose veins and menopausal release would provide advantages.

The compounds of the invention are also useful for the treatment of neurological diseases and disorders including convulsion, epilepsy, hyperactive disorder deficiency treatment, Tourette's syndrome and cognitive disorders.

The pharmacological effects and selectivity of these compounds can be determined using published assay methods, α-2 selectivity of the compounds is determined by measuring receptor binding chemistry and in vitro functional activity in various tissues known to include α-2 and / or α-1 receptors. . (See, e.g., The Alpha-2 Adrenergic Receptors, LE Limbird, Humana Press Edition, Clifton, NJ.). The following in vivo tests are usually performed in rodents or other species. Central nervous system activity is determined by measuring physical activity as an index of sedation. (See, eg, Spyraki, C. & H. Fibiger, "Clonidine-Induced Sedation in Rats": Evidence for Mediation by Postsynaptic Alpha-2 Adrenoreceptors) ", Journal of Neural Transmission, Vol. 54 (1982), pp. 153-163. The effects of the nasal congestion reducing agent are measured using rhinomanometry to determine nasal passage resistance. (See, e.g., Salem, S. & E. Clemente, &quot; A New Experimental Method for Evaluating Drugs in the Nasal Cavity &quot;, Archives of Otolaryngology, Volume 96 (1972) 524-529). Effects against glaucoma are determined by measuring intraocular pressure. (See, e.g., Potter, D., "Adrenergic Pharmacology of Aqueous Human Dynamics", Pharmacological Reviews, Vol. 13 (1981), p. 133 • ·· · · ··· · Up to 153). Anti-diarrhea effects are determined by measuring the ability of compounds to suppress prostaglandin-induced diarrhea. (See, e.g., Thollander, Μ., P. Hellstrom & T. Svensson, "Suppression of Castor Oil-Induced Diarrhea by α-2 Adrenoceptor Agonists", Alimentary Pharmacology and Therapeutics (Digestive Tract Pharmacology and Therapeutics), Vol. 5 (1991), pp. 255-262. Efficacy in the treatment of irritable bowel syndrome is determined by measuring the ability of the compounds to reduce the increased excrement output caused by stress. (See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro, and H. Ormsbee III, "Cold-Restraint Stress Increases Rat Pellet Output and Colonic Transit" excrement in rats and rectal passage) ”, American Journal of Physiology, Volume 258 (1990), pp. G329 to G337). The efficacy against ulcers and the reduction of hyperchlorhydria is determined by measuring the reduction of gastric acid secretion induced by these compounds. (See, e.g., Tazi-Saad, K., J. Chariot, M. Del Tacca & C. Rose, "Effect of α-2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat" agonists for gastric pepsin and acid secretion in rats ", British Journal of Pharmacology, Volume 106 (1992), pp. 790-796). The anti-asthma effects are determined by measuring the effect of the compound on bronchoconstriction associated with induced pulmonary reactions, such as inhalation of antibody-inducing agents. (See, e.g., Chang, J., J. Musser &amp; J. Hand, "Effects of a Novel Leukotriene D ₄ Antagonist with 5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, W _y -45 911, on Leukotriene-D ₄ - and Antigen -lnduced bronchoconstriction in Guinea Pig (Effects of novel leukotriene D ₄ antagonists having a 5-lipoxygenase and cyclooxygenase depressants W _Y 45 911 on the bronchoconstriction induced by leukotriene D ₄ - and antigens in guinea pigs) ", International Archives of Allergy and Applied Immunology (International Archive of Allergy-Related Diseases and Applied Immunology), Volume 86 (1988), pp. 48-54, and Delehunt, J., A. Perruchound, L. Yerger, B. Marchette, J. Stevenson & W. Abraham, "The Role of Slow-Reacting Substance of Anaphylaxis in the Late Bronchial Response After Antigen Challenge in Allergic Sheep", American Reviews of Respirators Disease review of respiratory diseases), Volume 130 (1984), pp. 748-754). Cough effects are determined by measuring the number and symptom-free periods of the cough response to inducing a respiratory response, such as inhaled citric acid. (See, e.g., Callaway, J. & R. King, "Effects of Inhaled and 2-Adrenoceptor and GABA _B Receptor Agonists on Citric Acid-lnduced Cough and Tidal Volume Changes in Guinea Pigs (Influence of inhaled a-2 adrenergic receptor agonist and GABA _b cough-induced cough-agonist-induced cough agonists Citric acid and tidal volume changes in guinea pigs ”, European Journal of Pharmacology, Volume 220 (1992), pp. 187-195 The sympatholytic effects of these compounds are determined by measuring the reduction of plasma catecholamines. (See, e.g., R. Urban, B. Szabo & K. Starke, &quot; Inclusion of marginal presynaptic depressant in reducing sympathetic state by "moxonidine"'Rilmenidine' and UK 14,304 '), the European Journal of Pharmacology, Volume 282 (1985), pp. 29-37) or the reduction of renal sympathetic nerve activity (See, e.g., Feng, Q., S. Carlsson, P. Thoren & T. Hedner, "Effects of clonidine on renal sympathetic nerve activity, natriuresis and diuresis in chronic congestive heart failure rats (Effects of clonidine on renal sympathetic nerve activity, natriuresis and diuresis in rats with chronic congestive heart failure) ", Journal of Pharmacology and Experimental Therapeutics, Volume 261 (1992), pp. 1129-1135), providing a basis for their contribution to heart failure and benign prostatic hypertrophy. The hypotensive effect of these compounds is measured directly as a reduction in mean blood pressure (See, eg, Timmermans, P. & P. Van Zwieten, "Central and peripheral α-adrenergic effects of some imidazolidines") European Journal of Pharmacology, Vol. 45 (1977), pp. 229-236. Clinical studies have shown the beneficial effects of α-2 agonists in preventing myocardial ischemia during surgery (see, e.g., Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg & D. Mangano, "Effects of Perioperative Dexmedetomidine Infusion in Patients Undergoing Vascular Surgery", in Anesthesiology, Vol. 82 (1995), pp. 620-633, and in the prevention of angina (See, e.g., Wright, RA, P. Decroiy, T. Kharkevitch & M. Oliver, "Exercise Tolerance in Angina is Improved by Mivazerol α-2-Adrenoceptor Agonist" adrenoceptor agonist), Cardiovascular Drugs and Therapy, Vol. 7 (1993), pp. 929-934). The efficacy of these compounds in damaging cardiac reperfusion (heart tremor) is demonstrated by measuring cardiac necrosis reduction and neutrophil penetration (See, e.g., Weyrich, A., X. Ma & A. Lefer, "The Role of L-Arginine in Ameliorating Reperfusion Injury After"). Myocardial Ischemia in the Cat (The role of L-arginine in the treatment of reperfusion injury following myocardial ischemia in a cat), Circulation, Volume 86 (1992), pp. 279-288. The anti-cardiac arrhythmia activity of these compounds is shown by measuring the inhibition of ouabain-induced arrhythmias (See, e.g., Thomas, G. & P. Stephen, Effects of Two Imidazolines (ST-91 and ST-93) on the

Effects of two types of imidazoline (ST-91 and ST-93) on cardiac arrhythmias and ouabain-induced mortality in guinea pigs ”, Asia-Pacific Journal of Pharmacology (Asia- Pacific Region Journal of Pharmacology), Volume 8 (1993), pp. 109-113; and Samson, R., J. Cai, E. Shibata, J. Martins, and H. Lee, "Electrophysiological Effects of α-2-Adrenergic Stimulation in Canine Cardiac Purkinje Fibers" Fibers), "American Journal of Physiology, Vol. 268 (1995), pp. H2024 to H2035). The vasoconstrictive effects of these compounds are demonstrated by measuring contractile properties on isolated arteries and veins in vitro (See, e.g., Flavahan, N., T. Rimele, J. Cooke & M. Vanhoutte, &quot; Characterization of Postfunctional Alpha-1 and Alpha-2 Adrenoceptors &quot; Saphenous Vein (Characterization of additionally functional α-1 and α-2 adrenoceptors activated by exogenous or nerve-released norepinephrine on canine saphenous vein), Journal of Pharmacology and Experimental Therapeutics (Journal of Pharmacology and Experimental) 230 (1984), pp. 699-705). The efficacy of these compounds in reducing intracranial pressure is demonstrated by measuring this property in a canine model in subarachnoid haemorrhage (See, e.g., McCormick, J., P. McCormick, J. Zabramski & R. Spetzler, "Intracranial pressure reduction by a central alpha-2"). adrenoreceptor agonist after subarachnoid haemorrhage (Neurosurgery, Vol. 32 (1993), pp. 974-979), reducing the control pressure following subarachnoid hemorrhage by central α-2 adrenoreceptor agonist. Suppression of menopausal release is shown by measuring the reduction of facial blood flow in the rat (See, eg, Escott, K., D. Beattie, H. Connor &amp; S. Brain, "The modulation of the increase in rat facial blood flow observed after trigeminal ganglion"). stimulation (Modulation of an increase in facial skin blood flow in rats observed following stimulation of the trigeminal nerve node), "European Journal of Pharmacology, Volume 284 (1995), pp. 69-76, which is demonstrated for a- 2 adrenergic agonists on the cutaneous blood flow of the arm (See, e.g., Redfem, W., M. MacLean, R. Clague & J. McGrath, "The role of alpha-2 adrenoceptors in the vasculature of rat tail") adrenoceptors for tail blood supply in rats ", British Journal of Pharmacology, Volume 114 (1995), pp. 1724-1730). The antinociceptive and pain-reducing properties of these compounds are demonstrated by measuring the increase in pain thresholds in rodent superhelical winding and in fresh (still warm) platelets of antinociceptive models (See, eg, M. Millan, K. Bervoets, J. Rivet, R. Widdowson, A. Renouard, S. Le Marouille-Girardon, & A. Gobert, "Multiple Alpha-2 Adrenergic Receptor Subtypes. II. Evidence for a Role of Rat Alpha-2A Adrenergic." ·············· · · · · · • · · · · · · · · · · · · ·

(Numerous α-2 adrenergic receptor subtypes. II. Evidence for the role of α-2A adrenergic receptor rats in controlling response to painful stimuli, motor behavior and hippocampal noradrenaline synthesis), Journal of Pharmacology and Experimental Therapeutics, Volume 270 (1994), pp. 958-972. The effects of these compounds against migraine have been demonstrated by measuring the reduction of dural neurogenic inflammation in stimulating the trigeminal nerve node in rats (See, e.g., T. Matsubara, M. Moskowitz & Z. Huang, "UK-14 304, R (-) - alpha-methyl" -histamine and SMS 201-995 block plasma protein leakage within deterioration of material by over-functional mechanisms (UK 14 304, R (-) - α-methyl-histamine and loss of SMS 201 995 block plasma protein within the tube by prefunction mechanisms) ", European Journal of Pharmacology, Volume 224 (1992), pp. 145-150. The ability of these compounds to suppress opioid omissions is demonstrated by measuring suppression of increased activity of sympathetic nerves (See, e.g., D. Franz, D. Hare & K. McCloskey, &quot; Spinal sympathetic neurons: possible sites of opiate-withdrawal suppression by lonidine &quot; suitable sites for opiate omission suppression ("clonidine"), "Science, Vol. 215 (1982), pp. 1643-1645). The antiepileptic effects of these compounds are demonstrated by measuring attenuation of stimulated sensitivity (See, e.g., M. Shouse, M. Bier, J. Langer, O. Alcalde, M. Richkind & R. Szymusiak, "The α-2 agonist clonidine suppresses seizures, the alpha-2 antagonist idazoxan promotes seizures - a microinfusion study in amygdala-kindled kittens (an α-2 agonist clonidine suppresses seizures, while the α-2 antagonist indazoxan promotes seizures - microinfusion studies in kittens with tonsillitis) " 648 (1994), pp. 352-356). The efficacy of other α-2 agonists in the treatment of neurological disorders has been shown, including the treatment of hyperactivity deficiency diseases and Tourette's syndrome (See, e.g., P. Chappell, M. Riddle, L. Scahill, K. Lynch, R. Schultz, A. Amsten, J.Leckman & D. Cohen, "Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourettes syndrome: preliminary clinical experience", Journal of American Academy of Child and Adolescent Psychiatry, Volume 34 (1995), pp. 1140 to 1146), cognitive disorders (See, eg, J. Coull, "Pharmacological manipulations of α-2-noradrenergic system. Child and Adolescent Psychiatry"). Effects on cognition. ", Drugs and aging, Volume 5 (1994), pp. 116-12 6) and spasticity (See, e.g., M. Eyssette, F. Rohmer, G. Serratrice, J. Warter & D. Boisson, &quot; Multicenter, double-blind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple

sclerosis (Multi-center double-blind trial of a novel antispatic agent, "tizanidine", in spasm associated with multiple sclerosis) ", Current Medical Research & Opinion, Volume 10 (1988), pp. 699-708.

Another aspect of the invention includes methods of preventing or treating nasal congestion by administering a safe and effective amount of a compound of the invention to a test mammal or at risk of nasal congestion in test subjects. Said nasal congestion may be associated with human diseases or disorders, including, but not limited to, seasonal hay fever, acute upper respiratory tract viral infection, paranasal sinusitis, persistent nasal inflammation, and allergic rhinitis. Additionally, other disorders (eg, otitis media and paranasal sinusitis) may be generally associated with mucosal congestion. Each dose administration of a compound of the invention preferably provides a dose ranging from about 0.0001 mg / kg to about 5 mg / kg of the compound, more preferably from about 0.001 mg / kg to about 0.5 mg / kg. Oral administration of said doses is preferred. The frequency of administration of a compound of the invention in accordance with the invention is preferably from about one to about six daily doses, more preferably from about one to about four doses per day. Said dosages and frequency are also useful for treating other conditions of the respiratory system, such as cough, chronic obstructive pulmonary disease (COPD) and asthma. Said dosages and frequency are also useful for treating conditions that are associated with mucosal congestion (e.g., paranasal sinusitis and otitis media).

Another aspect of the invention encompasses methods of preventing or treating glaucoma by administering a safe and effective amount of a compound of the invention to test mammals or at risk of ocular opacity in test subjects. Each administration of a dose of a compound of the invention, when administered systemically, preferably provides a dose ranging from about 0.0001 mg / kg to about 5 mg / kg of the compound, more preferably from about 0.001 mg / kg to about 0.5 mg / kg. When an intraocular dosage is used, then a preferred single dosage provides a conventional volume (eg, 1 or 2 drops) of a liquid composition comprising from about 0.0001% to about 5% of a compound of the invention, more preferably from about 0.01% to about 0.5% compounds. Determining the exact dosage and method is within the skill and skill of the skilled artisan. Intraocular administration of said doses is preferred. The frequency of administration of a compound of the invention in accordance with the invention is preferably from about one to about six doses per day, more preferably from about one to about four doses per day.

Another aspect of the invention includes methods of preventing or treating gastrointestinal disorders such as diarrhea, irritable bowel syndrome and peptic ulcer by administering a safe and effective amount of a compound of the invention to test mammals or at risk of gastrointestinal disorders in test subjects. Each administration of a dose of a compound of the invention preferably provides a dose in the range of about 0.0001 mg / kg to about 5 mg / kg 99. 0 · 0 · 0 · 0 · · 9 · 9 999 999

9 9 9 9 9

More preferably from about 0.001 mg / kg to about 0.5 mg / kg. Oral administration of said doses is preferred. The frequency of administration of a compound of the invention in accordance with the invention is preferably from about one to about six doses per day, more preferably from about one to about four doses per day.

Another aspect of the invention encompasses methods of preventing or treating migraine by administering a safe and effective amount of a compound of the invention to test mammals or at risk of migraine in test mammals. Each administration of a dose of a compound of the invention preferably provides a dose ranging from about 0.0001 mg / kg to about 5 mg / kg of the compound, more preferably from about 0.001 mg / kg to about 0.5 mg / kg. Oral, parenteral or intranasal routes of administration are preferred. The frequency of oral administration of a compound of the invention in accordance with the invention is preferably from about one to about six doses per day, more preferably from about one to about four doses per day. The frequency of parenteral dosing of a compound of the invention in accordance with the invention is preferably from about one to about six doses per day, preferably from about one to about four doses per day, or by infusion to the desired effect. The frequency of intranasal dosing of a compound of the invention in accordance with the invention is preferably from about one to about six doses per day, more preferably from about one to about four doses per day.

Another aspect of the invention includes methods of preventing or treating disorders related to the activity of the sympathetic nervous system, such as hypertension, myocardial ischemia, cardiac reperfusion disorder (cardiac tremor), angina, cardiac arrhythmia and benign prostatic hypertrophy, by administering a safe and effective amount of a compound of the invention to test mammals. or at risk of such diseases and disorders in test subjects. Each dose administration of the subject compound of the invention preferably provides a dose ranging from about 0.0001 mg / kg to about 5 mg / kg of the compound, more preferably from about 0.001 mg / kg to about 0.5 mg / kg. Oral and parenteral administration of said doses is preferred. The frequency of oral administration of a subject compound of the invention in accordance with the invention is preferably from about one to about six doses per day, more preferably from about one to about four doses per day. The frequency of parenteral administration of a compound of the invention in accordance with the invention is preferably from about one to about six doses per day, more preferably about one to about four times a day or by infusion up to the desired effect.

Another aspect of the invention encompasses methods of preventing or treating pain by administering a safe and effective amount of a compound of the invention to test mammals or at risk of pain in test mammals. Each administration of a dose of a compound of the invention preferably provides a dose ranging from about 0.0001 mg / kg to about 5 mg / kg of the compound, more preferably from about 0.001 mg / kg to about 0.5 mg / kg. Oral or parenteral administration of said doses is preferred. Frequency of oral administration of a compound of the invention in accordance with

With the present invention it is preferably about once to about six times a day, more preferably about once to about four times a day. The frequency of parenteral administration of a compound of the invention in accordance with the invention is preferably about one to about six times a day, more preferably about one to about four times a day or by infusion to the desired effect.

Another aspect of the invention encompasses methods of preventing or treating substance abuse and withdrawal syndrome resulting from the denial of such agents, such as alcohol and opiate, by administering a safe and effective amount of a compound of the invention to test mammals or at risk of substance abuse or withdrawal syndromes. Each administration of a dose of a compound of the invention preferably provides a dose ranging from about 0.0001 mg / kg to about 5 mg / kg of the compound, more preferably from about 0.001 mg / kg to about 0.5 mg / kg. Oral administration of said doses is preferred. The frequency of administration of a compound of the invention in accordance with the invention is preferably about one to about six times a day, more preferably about one to about four times a day.

DETAILED DESCRIPTION OF THE INVENTION

Examples of means and methods

The following non-limiting examples illustrate compositions and methods of using the invention.

Example A: Oral tablets

Admixture Quantity per tablet (mg) Compound of the Invention 1 20.0 Microcrystalline cellulose 80.0 (Avicel PH 102) Medium calcium phosphate 96.0 Pyrogenic silica 1.0 (Cab-O-Sil®) Magnesium stearate 3.0 Overall 200.0 mg

A patient with nasal congestion swallowed one tablet. The congestion decreased substantially.

Other compounds having the structure of Formula I were used with substantially similar results.

4

4 4 4

4 4 4

444 444

4

4 · ···· 4 ·

4 «4 4 4 • 43 4

443 4 4

4 4

444 44

4

4

4

4

Example B: Chewable tablets

Admixture Quantity per tablet (mg) Compounds of the invention 15.0 Mannitol 255.6 Microcrystalline cellulose 100.8 (Avicel PH 101®) Dextrinated sucrose 199.5 (Di-Pac®) Imitation of orange flavor 4.2 Sodium saccharin 1,2 Stearic acid 15.0 Magnesium stearate 3.0 FD&C yellow # 6 dye 3.0 Pyrogenic silica 2.7 (Cab-O-Sil®) Overall 600.0 mg

A patient with nasal congestion pulverized and swallowed one tablet. The congestion was substantially reduced.

Other compounds having the structure of Formula I were used with substantially the same results.

Example C: Sublingual tablets

Admixture Quantity per tablet (mg) Compound of the Invention 2 2.00 Mannitol 2.00 Microcrystalline cellulose 29,00 (Avicel PH 101®) Menthol flavor 0.25 Sodium saccharin 0.08 Overall 33.33 mg

Μ · ♦ ··

A patient with nasal congestion placed one tablet under his tongue and allowed it to dissolve. The congestion was rapidly and substantially reduced.

Other compounds having the stricture of Formula I were used with substantially similar results.

Example D: Intranasal solution

Example Composition (% w / v) Compound of the Invention 1 0.20 Benzalkonium chloride 0.02 Thimerosal 0,002 d-Sorbitol 5.00 Glycine 0.35 Aromatic substances 0,075 Deionized water g.s. Overall 100.00

One-tenth ml of the composition was sprayed from a pump-equipped sprayer into each nostril of a patient with nasal congestion. The congestion has substantially decreased.

Other compounds having the structure of Formula I were used with substantially similar results.

Example E: Intranasal Gel

Admixture Composition (% w / v) Compound of the Invention 1 Benzalkonium chloride Thimerosal Hydroxypropylmethylcellulose (Metolose 65SH4000®) Aromatic substances Sodium chloride (0.65%) Overall 0.10 0.02 0,002 1.0 0.06 gs. 100.00

One fifth of the ml of the composition was administered as drops from the dropper bottle to each nostril of a patient with nasal congestion. The congestion was substantially reduced.

Other compounds having the structure of Formula I were used with substantially similar results.

• «« η ········

4 · 4 * 4,444 »

444 44 4 4445

444 4444 4,444 «4»

4 4 4 4

44443 «4 · 44 44

Example F; Inhalation aerosol formulation

Admixture Composition (% w / v) Compound of the Invention 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Sodium saccharin 0.2 Propelant (F12, F124) g.s. Overall 100.00

Two puffs of aerosol formulation were inhaled from a metered dose inhaler by an asthma patient. The asthmatic condition was effectively alleviated.

Other compounds having the structure of Formula I were used with substantially similar results.

Example G: Topical ocular device

Admixture Composition (% w / v) Compound of the Invention 2 0.10 Benzalkonium chloride 0.01 EDTA 0.05 Hydroxyethylcellulose 0.50 (Natrasol M®) Sodium metabisulphite 0.10 Sodium chloride (0.9%) gs. Overall 100.00

One-tenth ml of the composition was administered to a patient with glaucoma directly into each eye. Intraocular pressure decreased significantly.

Other compounds having the structure of Formula I were used with substantially similar results.

• Φ φ φ φ »» φ φ φ φ φ φ

Example Η: Oral liquid composition

Admixture Quantity / 15 ml dose Compound of the Invention 1 15 mg Chlorpheniramine maleate 4 mg Propylene glycol 1,8g Ethanol (95%) 1.5 ml Methanol 12.5 mg Eucalyptus oil 7.55 mg Flavoring 0.05 ml Sucrose 7.65 g Carboxymethylcellulose 7,5 mg (CMC) Microcrystalline cellulose a 187.5 mg CMC Sodium (Avicel RC 591) Polysorbate 80 3.0 mg Glycerine 300 mg Sorbitol 300 mg FD&C red # 40 dye 3 mg Sodium saccharin 22.5 mg Sodium phosphate 44 mg monovalent Sodium citrate monohydrate 28 mg Deionized water g.s. Overall 15 ml

One 15 ml dose of the liquid formulation was ingested by a patient with nasal congestion and a cold due to hay fever. The congestion and runny nose were effectively relieved.

Other compounds having the structure of Formula I were used with substantially similar results.

· 0 0 0 0 0

0 0 0 ♦ 000 000

0 · 00

0 * 0 0 0

0 0

000 0 0

0 ·· 00

0000 0 0 0 0 0 0

0 0 0 0 0 0

0

Example J: Oral liquid composition

Admixture Quantity / 15 ml dose Compound of the Invention 2 30 mg Sucrose 8.16 g Glycerine 300 mg Sorbitol 300 mg Methylparaben 19.5 mg Propylparaben 4.5 mg Menthol 22.5 mg Eucalyptus oil 7,5 mg Flavoring 0.07 ml FD&C red # 40 dye 3.0 mg Sodium saccharin 30 mg Deionized water gs. Overall 15 ml

One 15 ml dose of alcohol-free liquid drug was ingested by a patient with nasal congestion. The congestion has been substantially reduced.

Other compounds having the structure of Formula I were used with substantially the same results.

Example K: Oral tablets

Admixture Quantity per tablet (mg) Compound of the Invention 1 4 Microcrystalline cellulose, NF 130 Starch 1500, NF 100 ALIGN! Magnesium stearate, USP 2 Overall 236 mg

Patient with migraine swallowed one tablet. Pain and migraine manifestations have decreased significantly.

Other compounds having the structure of Formula I were used with substantially similar results.

• · ·······················

Example L: Oral tablets

Admixture Quantity per tablet (mg) Compound of the Invention 2 12 Hydroxypropylmethylcellulose, 12 USP Magnesium stearate, USP 2 Anhydrous lactose, USP 200 Overall 226 mg

To relieve pain. Adults over 12 years take one tablet every twelve hours.

Other compounds having the structure of Formula I were used with substantially similar results.

Example M: Oral Capsules

Admixture Quantity per tablet (mg) Sodium naproxen, anhydrous, 220 USP Compound of the Invention 2 6 Hydroxypropylmethylcellulose, 6 USP Magnesium stearate, USP 2 "Povidone" K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF 44 Overall 300 mg

To relieve symptoms associated with common cold, paranasal sinusitis or influenza including nasal congestion, headache, fever, body pain and pain. Adults over 12 years take two capsules every twelve hours.

Other compounds having the stricture of Formula I were used with substantially similar results.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · ·· ··

Example N: Oral tablets

Admixture Quantity per tablet (mg) Compound of the Invention 1 6 Hydroxypropylmethylcellulose, 6 USP Silica, colloidal, NF 30 Pregelatinized starch, NF 50 Magnesium stearate, USP 4 Overall 96 mg

For the treatment of benign prostatic hypertrophy. Take one tablet a day.

Other compounds having the structure of Formula I were used with substantially similar results.

Example O: Oral tablets

Example Quantity per tablet (mg) Compound of the Invention 1 6 Hydroxypropylmethylcellulose, 6 USP Magnesium stearate, USP 2 "Povidone" K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF 44 Overall 80 mg

For use in the treatment of alcoholism or opiate dependence. Adults over 12 years take two tablets every twelve hours.

Other compounds having the structure of Formula I were used with substantially similar results.

• · ·

Β · Β · • · Β · · · · · ·

Example Ρ: Oral tablets

Admixture Quantity per tablet (mg) Compound of the Invention 1 6 Hydroxypropylmethylcellulose, 12 USP Magnesium stearate, USP 2 "Povidone" K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF 44 Overall 86 mg

For the treatment of ulcers and increased acidity. Take two tablets as appropriate.

Other compounds having the structure of Formula I were used with substantially similar results.

Example Q: Oral tablets

Admixture Quantity per tablet (mg) Component Amount Compound of the Invention 2 10 mg / ml of carrier Carrier Citrate buffer sodium containing (% by weight of carrier): Lecithin 0.48% Carboxymethylcellulose 0.53 Povidon 0.50 Methylparaben 0.11 Propylparaben 0.011

To reduce cardiac reperfusion (heart tremor).

Other compounds having the structure of Formula I were used with substantially similar results.

Example R: Oral liquid composition

Admixture Quantity / liquid ounce doses (mg) "Acetaminophen", USP 1 000 "Doxylamine Succinate", USP 12.5 'Dextromethorphan' - 30 hydrobromide, USP Compound of the Invention 2 6 Dow XYS-40010.00 3 resin High corn syrup 16 000 fructose Polyethylene glycol, NF 3 000 Propylene glycol, USP 3 000 Alcohol, USP 2 500 Sodium citrate dihydrate, 150 USP Citric acid, anhydrous, 50 USP Sodium saccharin, USP 20 May Flavor 3.5 Deionized water, USP 3 500 Overall 29 275 mg / liquid

For relieving light pain, headache, muscle pain, sore throat and fever associated with colds or flu. To relieve nasal congestion, coughs caused by slight irritation of the neck and bronchi, runny nose, sneezing associated with the usual cold. Adults over 12 years of age take one ounce of liquid every six hours.

Other compounds having the structure of Formula I were used with substantially similar results.

Example S: Liquid oral composition

Admixture Quantity / liquid ounce doses (mg) 'Naproxen sodium', anhydrous, 220 USP "Doxylamine Succinate", USP 12.5 'Dextromethorphan' - 30 hydrobromide, USP Compound of the Invention 1 6 Dow XYS-40010.00 3 resin High corn syrup 16 000 fructose Polyethylene glycol, NF 3 000 Propylene glycol, USP 3 000 Alcohol, USP 2 500 Sodium citrate dihydrate, 150 USP Citric acid, anhydrous, 50 USP Sodium saccharin, USP 20 May Flavor 3.5 Deionized water, USP 3 800 Overall 28 795 mg / liquid

For relieving light pain, headache, muscle pain, sore throat and fever associated with colds or flu. To relieve nasal congestion, coughs caused by slight irritation of the neck and bronchi, runny nose, sneezing associated with the usual cold. Adults over 12 years of age take one ounce of liquid every six hours.

Other compounds having the structure of Formula I were used with substantially similar results.

Example Τ

In accordance with the invention there is provided a composition for parenteral administration comprising:

Component Amount Compound of the Invention 1 Carrier Citrate buffer sodium containing (% by weight of carrier): 10 mg / ml of carrier Lecithin 0.48% Carboxymethylcellulose 0.53 "Povidon" 0.50 Methylparaben 0.11 Propylparaben 0.011

The above ingredients are mixed to form a solution. Approximately 2.0 ml of the solution was intravenously administered to a human subject suffering from septic and cardiogenic shock. Symptoms subsided.

Other compounds having the structure of Formula I were used with substantially similar results.

Example U: Oral tablets

Admixture Quantity per tablet (mg) Compound of the Invention 2 10 Hydroxypropylmethylcellulose, 12 USP Magnesium stearate, USP 2 "Povidone" K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF 44 Overall 90 mg

For the treatment of cardiac arrhythmia. Take as prescribed.

• ···································· · · · · ···

Other compounds having the structure of Formula I were used with substantially similar results.

Examples V: Oral tablets

Admixture Quantity per tablet (mg) Compound of the Invention 1 4 Microcrystalline cellulose, NF 130 Starch 1500, NF 100 ALIGN! Magnesium stearate, USP 2 Overall 236 mg

For the treatment of congestive heart failure. Take as prescribed.

Other compounds having the structure of Formula I were used with substantially similar results.

Modifications to the foregoing units are within the skill of the art, as set forth in the specification specification, in light of the state of the art.

Other examples of active agent combinations are contemplated. Examples of drugs that may be combined with the primary active agent are disclosed in U.S. Pat. No. 4,552,899 to Sunshine et al., Incorporated herein by reference. All other references that apply throughout this specification are hereby incorporated by reference.

While the various units of the invention have been described, it will be apparent to those skilled in the art that various modifications and modifications of the invention may be made without departing from the spirit and scope of the invention. The appended claims are intended to include all such modifications that fall within the scope of the invention.

Claims (8)

PATENT CLAIMS 9 999 9 9 9 9 · ·· * ··· • 9 9 9 9 9 9 99 9 99 99 9 9 9 9 9 \ 6 c 1. Compound in the formula: in which: a) R 1 is hydrogen; or alkyl; b) R ₂ is hydrogen; alkyl; or is absent (nothing); c) R ₃ is selected from hydrogen; unsubstituted _Ci-C3 alkanyl; amino; hydroxy; mercapto; _Ci-C3 alkylthio or alkoxy; C _r C ₃ alkyl amino, or _Ci-C3 dialkylamino; cyano and halogen; d) R ₄ , R ₅ and R ₇ are each independently selected from hydrogen; unsubstituted C 1 -C ₃ alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C 1 -C 3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C _r C ₃ alkyl amino, or _Ci-C3 dialkylamino; and halogen; e) when R ₂ is absent (no), bond (a) is a double bond; f) the compound is not 7-bromo-6- (2-imidazolinylamino) indazole; and enantiomers, optical isomers, stereoisomers, diastereoisomers, tautomers, additional salts, biohydrolyzable amides and esters; pharmaceutical compositions comprising said novel compounds and the use of said compounds for the prevention or treatment of disorders modulated by α-2 adrenergic receptors. A compound according to claim 1, wherein: R y is selected from hydrogen; unsubstituted C 1 -C ₃ alkanyl, alkenyl, alkynyl, or cycloalkanyl; unsubstituted _Ci-C3 alkylthio or alkoxy; C _r C ₂ -alkylamino or C _r C ₂ dialkylamino; and halogen; and R ₃ is selected from hydrogen; and cyano. • 4 4 4 4 4 4 4 4,444 4 4 9 4 4,449,944 • 4 4 9 9 9 4 494 44 49 4 94 94 A compound according to any one of the preceding claims, wherein: R ₄ is selected from hydrogen; methyl; methoxy; cyano; iodo; and chloro; and R ₅ represents hydrogen; A compound according to any one of the preceding claims, which is: Ry is selected from methyl; ethyl; ethenyl; methoxy; methylthio; cyclopropyl; chloro; and jodo. A compound according to any one of the preceding claims, which is: 7-Ethyl-6- (2-imidazolinylamino) indazole; or 6- (2-imidazolinylamino) -7-methylindazole. 6. A pharmaceutical composition comprising: (a) a safe and effective amount of a compound according to any preceding claim; and (b) a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a compound of any one of the preceding claims and one or more active agents selected from the group consisting of antihistamines, antitussives, mast ointment stabilizers, leukotriene antagonists, expectorants / mucolytics, antioxidants or radical depressants, steroids , bronchodilators; antiviral agents, analgesics, anti-inflammatory agents, gastrointestinal and ocular active agents. A method of preventing or treating a disease modulated by α-2 adrenergic receptors comprising administering a safe and effective amount of an α-2 adrenergic receptor agonist of a compound of any preceding claim to a mammal in need of said treatment.