SK69699A3 - 2-imidazolinylaminoindazole compounds useful as alpha-2 adrenoceptor agonists - 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

Technical field

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 in the treatment of diseases modulated by α-2-adrenergic receptors.

BACKGROUND OF THE INVENTION

The 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, Volume 32 (1993), p. 243 to 279.

Information relating to α-adrenergic receptors, agonists and antagonists, generally, regarding 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 (12.1 α-Adrenergic Receptors), Comprehensive Medicinal Chemistry, Volume 3, Membranes & Receptors,

I, (Membranes and Receptors), P. G. Sammes & J. B. Taylor et al., Pergamon Press (1990), p. 133 to 185; Timmermans, P. B. M. W. M. & P. A. van Zwieten, α-Adrenoceptor Agonist over Antagonist (α-adrenergic receptor agonists and antagonists), Drugs of the Future, Vol. 9, no. 1, (January 1984), p. 41 to 55; Megens, A.A.H. P., J.E. Leysen, F.H. Awouters & C. J.

E. Niemegeers, Futher Validation of in vivo and in vitro Pharmacological Procedures for the assesing αχ and a2-Selectivity of Test Compounds: (2) α-Adrenoceptor Agonists (more validation of in vivo and in vitro pharmacological treatments of the evaluation and ₂ a and ₂ selectivity of test compounds: (2) α-Adrenergic receptor agonists), European Journal of Pharmacology, Volume 129 (1986), p. 57 to 64; Timmermans, P.

B. M. W. M., A. de Jonge. Quantitative Relationships between α-Adrenoceptor Agonists and Antagonists (Quantitative relationships between α-adrenergic activity and chemical affinity of α-adrenergic receptor agonist and antagonist linkages) MJMC Thoolen, B. Wilffert, H. Batink & PA van Zwieten , Journal of Medicinal Chemistry, Vol. 27 (1984), p. 495 to 503; van Meel JC A., A. de Jonge, P.

BMWM Timmermans & PA van Zwieten, Selectivity of Some α-Adrenoceptor Agonists for Peripheral and _x AA ₂ Adrenoreceptors in the Normotensive Rat (selectivity of some α-adrenergic receptor agonists for the peripheral and _x AA ₂ adrenergic receptors in normotensive rats), The Journal of Pharmacology and Experimental Therapeutics, vol. 219, no. 3 (1981) p. 760 to 767; Chapleo, CB, JC Doxey, PL Myers, M. Myers, CFC Smith & MR Stillings, Effect of

1,4-Dioxanyl substitution on the Adrenergic Activity of Some Standard α-Adrenoreceptor Agents, Volume 24, p. 619 to 622; C. B. Chapleo, R. C. M. Butler, D.

C. England, PL Myers, AG Roach, CFC Smith, MR Stillings & IF Tulloch, Heteroatomic Anologues of the -Adrenoreceptor and ₂ Partial Agonist Clonidine (Heteroaromatic analogs and ₂ -adrenoreceptor agonist clonidine partial), Journal of Medicinal Chemistry (Journal of pharmacological chemistry) 32 (1989), p. 1627 to 1630; Lines, KA, MC Scrutton & NT Thompson, Effects of a ₂ Adrenoreceptor Agonists and Related Compounds on Aggregation of and on Adenylate Cyclase Activity in Human Platelets (Effects of ₂ -adrenergic receptor agonists and related compounds on their aggregation and on adenylate cyclase activity in human platelets), British Journal of Pharmacology, Volume 82 (1984), p. 467 to 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.

For example, many of the compounds that have been found to be effective in reducing nasal congestion often have undesirable side effects, such as inducing hypertension and insomnia when delivering systemically effective doses. There is a need for new drugs that provide nasal congestion that do not cause these unwanted 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 invention to provide novel compounds which have significant effects in preventing or treating nasal congestion, otitis media and paranasal sinusitis, 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 prostate hypertrophy, cardiovascular diseases including myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, and heart failure.

It is also an object of the 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 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 present invention provides compounds having the following structure of Formula I:

a) R ¹ is hydrogen or alkyl;

b) R ² is hydrogen; alkyl or absent (nothing);

c) R ³ is selected from the group consisting of hydrogen, unsubstituted C 1 -C 3 alkanyl, amino, hydroxy, mercapto, C 1 -C ₃ alkylthio or alkoxy, C 1 -C 3 alkylamino or C 1 -C 3 dialkylamino; cyano; and halogen

d) R ⁴ , R ⁵ and R ⁷ are each independently selected from the group consisting of hydrogen, unsubstituted C 1 -C 6 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C 1 -C 3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C -C alkylamino or C _x -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, diastereomers, tautomers, supplemental salts, biohydrolyzable amides and esters; pharmaceutical compositions comprising said novel compounds, and the use of said compounds for preventing or treating disorders modulated by α-2 adrenergic receptors.

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

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

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

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

The term alkylamino, as used herein, denotes 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 ¹ -N (Q ² ) -, wherein each Q independently represents alkanyl or alkenyl.

Halo, halogen or halide represents chlorine, bromine, fluorine or iodine.

The term pharmaceutically acceptable salt refers to a cationic salt formed in any acidic (e.g. carboxyl) group or an anionic salt formed in any basic (e.g. amino) group. Many of these salts are known in the art, described in world patent 87/05297, Johnston et al., Published Sep. 11, 1987, the text 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, in the group of salts mentioned, complementary salts are contemplated which may provide an optical center where nothing was previously present. For example, 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 the free base form and in the acid addition salt form, and both forms are within the basic scope of the invention. Acid supplemental salts are more suitable for use in some cases. In practice, it is the use of salt forms which are found in amounts according to the use of the base form of the active substance. The acids used to prepare the acid addition salts preferably include those which produce, when combined with the free base, a medically acceptable salt. These salts contain anions which are relatively harmless to the animal organism, such as mammals, in medical doses such that the beneficial properties included in the base base are not impaired by any side effects attributed to the acid anions.

Examples of suitable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, hydrosulfate, acetate, trifluoroacetate, nitrate, ¹ maleate, citrate, fumarate, formate, stearate, succinate, malate, malonate , adipate, glutarate, lactate, propionate, butyrate, tartrate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, 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 precipitates directly. If precipitation of the salt is difficult, the salt may be precipitated by a second organic solvent or may be obtained by concentration of the solution.

While preferred are the medically acceptable salts of the parent compounds, all acid addition salts are included within the scope of the present invention. All acid addition salts are useful as sources of the free base form, although the individual salt itself is only required as an intermediate. For example, if a salt is prepared solely for purification or identification purposes, or if the salt is used as an intermediate in the preparation of a medically acceptable salt by ion exchange procedures, these salts are, of course, considered as part of the 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 into an active compound of the invention.

The terms optical isomer, stereoisomer, enantiomer, diastereoisomer, as used herein, have standard meanings recognized in the art (cf. Hawleys Condensed Chemical Dictionary, 11th edition). For example, a chiral tartrate salt can be prepared from the compounds of the invention, and this definition includes such chiral salts. It will be understood by those skilled in the art that the explanation of the racemic mixture itself reveals any enantiomers of the invention. one compound.

The term animal, as used herein, includes mammals, which include human.

One of skill 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, where R ³ is oxo and the bond (a) is a single bond, although not specifically described. Thus, the explanation of one tautomeric form in this specification discloses each and all tautomers. Similarly, when the 2-iminoimidazolidinyl form of the molecule is shown, 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 useful protecting groups, salt forms, etc., is within the skill of the skilled artisan.

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

I I ‘

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

6- (2-imidazolinylamino) -

compounds

The invention includes the 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; thiol; cyano and halogen. R ^{7 is} more preferably methyl or ethyl or cyclopropyl, most preferably ethyl. ^R7 which is alkylthio or alkoxy is preferably saturated, also preferably C _x and C _2, most preferably methylthio or methoxy. R ⁷ , when halogen, is preferably chlorine or bromine. R ¹ preferably represents hydrogen. R ³ is preferably selected from the group consisting of 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; an unsubstituted alkylthio or alkoxy group 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:

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

Compound No. R ⁴ R ⁷ 1 H et 2 H Me

ι

Methods for preparing compounds of the invention

Compounds of the invention are synthesized using the following procedures. R ¹ 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 the 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 example synthetic procedures:

SnCI ₂

N H

1) CIjCS

2) NaOH

h ₂ nch _{2 and 2} nh ₂

Hg (OAc) ₂

These compounds are preferably prepared from nitro or amino compounds, for example the compounds mentioned above.

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

Alkylation reaction:

8'2

R ²

NQz

Chlorination is preferably performed using Cl 2 and iodination using IC 1, using the same reactions.

Halogen Exchange Reactions:

1) HNO2

2) NaNOa

Z = O, S, NR

R ⁹ SnL ³ R® Pd (Ol clay -nc> 2 'R ⁹

Z »O, S, NR

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

In the above schemes, when R is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are derived from the final compounds using a standard dealkylation procedure (Bhatt et al., Cleavage of Ethers, Synthesis, 1983, p. 249). to 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 manipulations without further guidance, i. j. to carry out these manipulations is the experience and practice of the trained worker. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic nucleus substitutions, both electrophilic and nucleophilic, etherifications, esterifications and saponifications, and the like. These steps are discussed in common texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (2 parts) and Trost and Fleming, Comprehensive Organic Synthesis organic synthesis) (part 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, thereby avoiding any unwanted side reactions and / or increasing the efficiency of the reaction. Often, the skilled artisan uses 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 steps are provided, 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-imidazolinylaminoindazoles.

Example of compound 1

7-Ethyl-6- (2-imidazolinylamino) indazole

A) 7-Ethyl-6-nitroindazole. 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 with 5.5 ml of 1.0 M magnesium 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 was continued at room temperature for 24 hours. The mixture was diluted with 5 mL of methanol and 20 mL of water. The emulsion mixture was subjected to extraction with ethyl acetate (3 x 100 mL) and the emulsion was 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 was purified by aspiration vacuum filtration through silica gel, eluting with 50% ethyl acetate in hexane to give 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 was added 250 mg of palladium on carbon (10%). The resulting suspension is stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 6 hours. The reaction mixture was filtered through celite, washed with ethyl acetate and rotary evaporated. The residue was 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 was rotary evaporated and the residue was purified by aspiration vacuum filtration through silica gel, eluting with 30% ethyl acetate in hexane to give 130 mg of 7-ethyl-6-isothiocyanatoindazole.

D) 7-Ethyl-6- (2-imidazolinylamino) indazole. Suspension of 126 mg

7-Ethyl-6-isothiocyanatoindazole in 15 ml toluene is added dropwise to a stirred mixture of 186 mg ethylenediamine and 5 ml toluene. After stirring at room temperature for 48 hours, the reaction mixture was rotary evaporated. The residue is dissolved in 20 ml of methanol, 267 mg of mercuric acetate are added. The mixture was stirred at room temperature for 4.5 hours, then rotary evaporated. The residue is filtered on silica gel, methylene chloride: methanol: The purified compound is treated with a solution of 87 methanol for 5 minutes at room temperature.

Purify the aspirate extract with 7.5: 2.5 concentrated hydroxide dissolved in 1.5 ml mg of fumaric acid vacuum: 0.15 ammonium.

The product was 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 of compound 2

6- (2-imidazolinylamino) -7-methyl-indazol

A) 2,6-Dimethyl-3-nitroaniline. 2.86 g of fuming nitric acid are added dropwise to a cold (ice / water bath) mixture of 5 g of 2,6-dimethylaniline and 34 ml of concentrated sulfuric acid while maintaining the internal reaction temperature below 15 ° C. After stirring for 10 minutes at room temperature, the resulting solution was 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 was filtered and washed with water. The material was dissolved in 100 mL of methanol and decolorized with charcoal. The material was further purified by aspiration vacuum filtration on silica gel, eluting with 20% ethyl acetate in hexane and then recrystallized from ethyl acetate / hexane to afford 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 was added 415 mg of sodium nitrite in 2 ml of water at once. The reaction mixture is stirred at room temperature for 48 hours on a rotary evaporator to a small volume. The residue is suspended in 20 ml of 50% ethanol / water, heated to boiling 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 was added 200 mg of palladium on carbon (10%). The resulting suspension is stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 2 hours. The mixture was 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 di-2-pyridylsulfonate and 31 mg of 4-dimethylaminopyridine in 35 ml of methylene chloride is stirred at room temperature for 4 hours. The mixture was rotary evaporated and the residue was 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-Imidazolinyl) -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, and the resulting mixture is stirred at room temperature for 24 hours. The precipitate was filtered and washed with toluene. The solid was dissolved in 30 mL of methanol and 397 mg of mercuric acetate was added. The mixture was stirred at room temperature for 5 hours, then filtered through ¹ celite and the solid was washed with methanol. The filtrate was rotary evaporated and the residue was purified by aspiration vacuum filtration on silica gel, eluting with 8: 2: 0.1 methylene chloride: methanol: concentrated ammonium hydroxide. The purified compound was ml of methanol and treated with 70% acetic acid for 5 hours. The product was precipitated with ether, dissolved in 5 mg of ice, filtered, washed with ether and dried under vacuum to give 199 mg of 6 (2-imidazolinylamino) -7-methylindazole as the acetic acid salt as a light yellow-brown solid.

Alternative preparation of imidazolinylamine from arylamines:

H /

H

KjCO, Γ SCHj

-------------.

^{30 '35} ° θ ^ ΟΟΗ »

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

B) N-Carbomethoxy-2-thiomethyl-2-imidazoline. (10.1 g) is added to methyl chloroformate and the reaction is filtered off.

The filtrate (a)

Potassium carbonate to mixture A above, followed by addition (4.2 mL) with stirring.

warmed to 55 ° C, washed (washed) was collected

After 45 and insoluble 10 ml of pure cooled to t

in Buchner minutes of salt with ethanol.

-20 ° C and funnel.

mixture

The ethanol recrystallized product is washed with 10 ml of cold (-20 ° C) pure ethanol. The product was dried overnight under vacuum at room temperature to give N-carbomethoxy-2-thiomethyl-2-imidazoline.

C) 7-Ethyl-6- (2-imidazolinylamino) indazole. thiomethyl-2-imidazoline is combined with the amine (1B)% acetic acid in ethanol and heated

N-carbomethoxy-2 of Example 1 in 10 reflux heat. Once all of the initial amine was consumed, the mixture was decolorized with carbon. The mixture was cooled, filtered and rotary evaporated. After recrystallization and drying, the compound (1D) of Example 1 is obtained as the acetic acid salt.

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

Example R ³ R ⁴ R ^s R ⁷ 3 H Cl H Me 4 H br H Me 5 H I H Me 6 H F H Me 7 H OMe H Me 8 H CN H Me 9 H Me H Cl 10 H Cl H Cl 11 H br H Cl 12 H I H Cl '13 - H 'F H Cl 14 H OMe H Cl 15 H CN H Cl 16 H H H Cl 17 H Me H br 18 H Cl H br 19 H br H br 20 H I H br

21 Η F H br 22 Η OMe H br 23 Η CN H br 24 Η Me H I 25 Η Cl H I 26 Η br H I 27 Η I H I 28 Η F H I 29 Η OMe H I 30 Η CN H I 31 Η H H I 32 Η Me H et 33 Η Cl H et 34 Η br H et 35 Η I H et 36 Η F H et 37 Η OMe 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 I Me 43 Η H F Me 44 , Η H Cl i Cl 45 Η Me Me Me 46 Η Me Cl Me 47 Η Me br Me 48 Η Me I Me 49 Η H Me et 50 Η H br et 51 Η H Me H

52 H H br H 53 H H C1 H 54 H H I H 55 H H et H 56 H Me Me H 57 H br Me H 58 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 76 CN Me H br 77 CN br H 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 the treatment conditions, but low enough to prevent serious side effects (at a reasonable benefit / risk ratio) in a reliable medical decision. The safe and effective amount of a compound of the invention will vary according to the age and physical condition of the patient to be treated, the severity of the conditions, the duration of treatment, the nature of the concomitant therapy, the particular pharmaceutically acceptable carrier used and similar factors within the physician's knowledge and expertise.

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, and it is further contemplated that one skilled in the art can prepare the possibilities of the claimed compositions.

The compositions of the invention preferably contain from about 0.0001% to about 99% by weight. the compound of the invention, more preferably from about 0.01% to about 90% of the compound of the invention. Depending on the route 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 depends on the pharmacokinetic properties of each specific agent (e.g., biological half-life) and can be determined by one skilled in the art.

The compositions of the invention contain, in addition to the 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 suitable for administration to a mammal. Compatible as used herein means that the ingredients of the composition are capable of being mixed 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 use cases. The compounds of the invention, when preferably used in liquid dosage forms, are soluble in the formulation ingredients. Of course, pharmaceutically acceptable carriers must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the mammal to be treated.

Some examples of substances that can be used as pharmaceutically acceptable carriers or ingredients thereof include sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl sodium cellulose, 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, corn oil and cocoa oil; polyhydric alcohols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifying agents such as Tweens ^R ; wetting agents such as sodium lauryl sulfate (sodium lauryl sulfate); coloring agents; fragrances; tableting agents; stabilizers; antioxidants; protective equipment; water-free pyrogen; isotonic saline; and phosphate buffers. The choice of a pharmaceutically acceptable carrier to be 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 a sterile saline solution with a blood-compatible suspending agent which has been adjusted to a pH of about 7.4.

When the preferred route of administration of the compound of the invention is oral administration, 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, when used for 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 compatible excipients such as inert solvents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants 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 the flow characteristics of the bulk composition. Dyes, such as FD&C dyes, can be added to enhance aesthetic appearance. Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint extract and fruit flavors are adjuvants to chewable tablets. The capsules typically 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 those skilled in the art.

Compositions intended for oral administration also contain 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,

Also polyethylene glycol, liquid sucrose, sorbitol and water. Typical suspension suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel® RC-591, tragacanth and sodium alginate; conventional humectants, polysorbate 80; and the usual protective methyl paraben and sodium benzoate. Liquids include lecithin, and compositions comprising compositions 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 resin, microcrystalline cellulose, carboxymethylcellulose and hydroxymethylcellulose. Flow control agents, lubricants, sweeteners, colorants, antioxidants and flavors mentioned above can also be used.

The compositions may be used to deliver the compound to a site where activity is desired; intranasal dosage to relieve the nose, inhalers 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, containing 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 in an intranasal manner. 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 comprise safe and effective amounts of preservatives such as benzalkonium chloride and thimerozal 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 metahydrosulfate 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 necessary. The compositions may also contain local 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% of a compound of the invention; the amount may, of course, vary according to the condition of the patient being considered and the packaging. Said compositions are usually packaged in containers with attached sprayers. Said compositions also usually contain accelerating agents such as CFCs 12/11 and 12/114 and environmentally compatible fluorocarbons 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. The present compositions are useful for the treatment of respiratory disorders such as asthma and the like.

Other preferred compositions of the invention include aqueous solutions containing 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 adjusting 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 necessary.

Other preferred compositions of the invention useful for oral administration include non-unitary solid units such as tablets and capsules, and liquids such as solutions, suspensions and emulsions (preferably in soft gelatin shells) that contain 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 digestive 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® finish, waxes, and shellac.

Any of the compositions of the invention may optionally contain other active drugs. Unrestricted examples of active drugs that can be incorporated into these compositions include:

Antihistamines, which include:

Hydroxizine, 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 1 to about 24 mg; phenindamine, preferably at a dosage range of from about 6.25 to about 150 mg; dexchloropheniramine, preferably, at a dosage range of from about 0.5 to about 12 mg; dexbromopheniramine, preferably at a dosage range of from about 0.5 to about 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 1680 pg (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 administered 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; dimenydrinate, 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 2 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; tonzylamine, 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, which include:

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 180 mg; benzonatate, 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; chlorophedianol, 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; 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; caramifene, 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, preferably non-steroidal anti-inflammatory agents (NSAIDS), which include:

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 1500 mg; naproxen sodium, preferably at a dosage range of from about 110 to about 1650 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 1500 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 in the range

Dosages 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 1200 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 1500 mg; nabumetone, preferably at a dosage range of from about 250 to about 200 mg; phenylbutazone,

I 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 1800 mg; and other.

Analgesics, including:

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

Medicines that facilitate coughing / mucolytics, which include:

Guafenezine, preferably at a dosage range of from about 50 to about 2400 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; terpinhydrate, preferably at a dosage range of from about 100 to about 1200 mg; potassium iodide, preferably at a dosage range of from about 50 to about 250 mg; and other.

Anticholinergics (e.g. atropines), preferably intranasally or orally administered anticholinergics, comprising:

Ipratropium (preferably intranasal), preferably at a dosage range of from about 42 to about 252 gg; atropine sulfate (preferably oral), preferably at a dosage range of from about 100 to about 1000 gg; 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, metobromide, preferably at a dosage range of from about

2.5 to about 20 mg; homatropin, metobromide, 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 1000 gg; isopropramide (preferably oral), preferably at a dosage range of from about 5 to about 20 mg; orfenadrine (preferably oral), preferably at a dosage range of from about 50 to about 400 mg; benzalkonium chloride (preferably intranasal), preferably at a dosage range of from about 0.005% to about 0.1% solution; and other.

Fat ointment stabilizers, preferably intranasally or orally administered fat ointment stabilizers, comprising:

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 gg; and other.

Leukotriene antagonists, including zileuton and others.

Methylxanthines which include:

Caffeine, 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 1200 mg; enprophylline, pentoxifylline, preferably at a dosage range of from about 400 to about 3600 mg; aminophylline, preferably at a dosage range of from about 50 to about 800 mg; dyphylline, preferably at a dosage range of from about 200 to about 1600 mg; and other.

Antioxidants or radical buffering agents, 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, comprising:

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 1008 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, comprising:

Albuterol, preferably at a dosage range of from about 90 to about 1080 gg; from about 2 to about 16 mg (when dosed orally); epinephrine, preferably at a dosage range of from about 220 to about 1320 gg; ephedrine, preferably at a dosage range of from about 15 to about 240 mg (when dosed orally), from about 250 to about 1000 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 dosed orally); terbutaline, preferably at a dosage range of from about 200 to about 2400 gg, from about 2.5 to about 20 mg (when dosed orally); isoetarin, preferably at a dosage range of from about 340 to about 1360 µg; pirbuterol, preferably at a dosage range of from about 200 to about 2400 pg; bitolterol, preferably at a dosage range of from about 370 to about 2220 gg; phenoterol, preferably at a dosage range of from about 100 to about 1200 gg; from about 2.5 to about 20 mg (when dosed orally);

rimeterol, preferably at a dosage range of from about 200 to about 1600 gg; ipratropium, preferably at a dosage range of from about 18 to about 216 µg (inhalation); and other.

Antivirus agents that include:

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; enviroxime, nonoxinol, preferably at a dosage range of from about 2 to about 20 mg (preferably in an intranasal form of administration); acyclovir, preferably at a dosage range of from about 200 to about 2000 mg (oral), from about 1 to about 10 mg (preferably intranasal form); α-interferon, preferably at a dosage range of from about 3 to about 36 MIU; β-interferon, preferably at a dosage range of from about 3 to about 36 MIU; and other.

Ophthalmic Active Drugs: acetylcholinesterase inhibitors, such as echothiophate, from about 0.03% to about 0.25% in a solution administered topically; and

Gastrointestinal active agents, anti-diarrheal agents, for example, 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, the above description contemplates and includes acidic and basic additive salts, esters, metabolites, stereoisomers, and enantiomers of these preferred active agent combinations, as well as analogues of these active agents that are safe and effective. It is also understood that the active ingredient can be used for more than one of the above uses, and these uses are undoubtedly also contemplated. This interconnection is recognized in the art and appropriate dosage adjustments and the like according to the indication are entirely at the discretion of the skilled practitioner.

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 an intervention in the biological cascade that causes the disorder (s) and / or their manifestation (s). . There may be no deficiency in the activity of α-2-adrenergic receptors; said activity may be normal. However, administration of α-2-agonists can be an effective way of treating diseases, conditions or symptoms thereof.

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

The disorders described by the terms modulated by α-2-adrenergic receptors or modulated by the action of α-2-adrenergic receptors as used herein refer to a disorder, condition or disease where the action of the α-2-adrenergic receptor is an effective means of alleviating the disorder. or one or more biological manifestations of the disease or disorder; or bothers at one or more stages in the biological cascade that results in the failure or responsible for the underlying disorder; or ameliorates one or more symptoms of the disorder. Disorders thus caused by modulation include disorders 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, intrinsic stimulus, or some other cause;

the disease or disorder or observable manifestation (s) 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;

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

In particular, the compounds of the invention are 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, which is not limited to a single mechanism of action, provide advantages in treating nasal relief with the corresponding compounds through their ability to interact with α-2 adrenoceptors (adrenergic receptors).

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 moieties, although this is not essential for their activity or efficacy. The compounds of the invention differ in their ability to penetrate the central nervous system and thus elicit effects mediated through central α-2-adrenergic receptors. Thus, for example, a compound that exhibits a higher degree of activity on the central nervous system is advantageous for indications compared to other central nervous system compounds as described below.

However, even for compounds that primarily exhibit marginal activity, central activity may be induced by increasing the compound dosage, the action of these compounds may be achieved by the body part in which activity is required by the nervous system. 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. Centrally effective means that the compounds have some action on the 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, the treatment of respiratory diseases, ocular diseases, migraine, certain cardiovascular diseases and certain other gastrointestinal disorders are marginally active. Marginally active means that these compounds primarily act on α-2-adrenoceptors in the marginal portion rather than in the central nervous system. Methods are available in the art for determining compounds that are primarily marginally active and which are primarily centrally active.

Thus, the compounds of the invention are also useful in the treatment of 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 the suppression of gastrointestinal disorders such as diarrhea, irritable bowel syndrome, hyperchlorohydria and peptic ulcer.

The compounds of the invention are also effective against diseases and disorders associated with the functioning of the sympathetic nervous system, including hypertension, myocardial ischemia, damage to cardiac reperfusion (heart tremor), angina, cardiac arrhythmia, heart failure, and benign prostatic hypertrophy. Due to their sympatholytic effects, the compounds are also useful as an adjuvant in anesthesia during surgical procedures.

T

The compounds of the invention are also effective in relieving pain associated with various disorders. The compounds are administered by oral, parenteral and / or direct injection of 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 drug withdrawal syndromes.

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

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

The pharmacological effects and selectivity of these compounds can be determined using published assay methods. α-2 selectivity is determined by measuring the binding chemical relationship of receptors and in vitro functional efficacy in various tissues known to include α-2 and / or α-1 receptors. (See, for example, The Alpha-2 Adrenergic Receptor (α-2-adrenergic receptors), L. E. Limbird, ed. Humana Press, Clifton, NJ). The following in vitro tests are usually performed in rodents or other species. Central nervous system activity is determined by measuring physical activity as an index of silence. (See, e.g., Spyraki, C & H. Fibiger, Clonidine-induced Sedation in Rats): Evidence of F or Mediation by Postsynaptic Alpha-2 Adrenoreceptors, Journal of Neural Transmission, Vol. 54 (1982), pp. 153-163. The effects of a substance that reduces nasal congestion are measured using rhinomanometry to determine the nasal passage. (See, e.g., Salem, S. & E. cavities), Archives of Otolaryngology, Vol. 96 (1972), pp. 524-529. Effects against glaucoma are determined by measuring internal pressure. (See, e.g., Potter, D., Adrenergic Pharmacology of Aqueous Human Dynamics), Pharmacological

Reviews, Volume 13 (1981), p. 133 to 153). Anti-diarrhea effects are determined by measuring the ability of the compounds to suppress prostaglandin-induced diarrhea. (See, e.g., Thollander, M., P. Hellstrom & T. Svensson, Suppression of Castor Oil-Induced Diarrhea by α-2 Adrenoceptor Agonist, Alimentary Pharmacology and Therapeutics, Alimentary Pharmacology and Therapeutics) devices and therapeutics), Volume 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, for example, Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro & H. Ormsbee III, Coldrestraint stress increases rat pellet output and colonic transit. in rats and rectal transition), American Journal of Physiology, Volume 258 (1990), pp. G329 to G337). The efficacy against ulcers and the reduction of hyperchlorohydria 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. Roze, Effect of α-2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat. secretion of gastric pepsin and acid 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 responses such as inhalation of substances that induce formation

I antibodies. (See. E.g., Chang, J. J. Musser & J. Hand, Effects of a Novel Leukotriene D ₄ Antagonist with 5Lipoxygenase and Cyclooxygenase Inhibitors Activity, W -45 911 _s, on Leukotriene-D ₄ - and Antigen-Induced Bronchoconstriction in Guinea Pig (the effects of the new leukotriene D ₄ antagonists 5lipoxygenázovým with a cyclooxygenase depressants, W -45 911 _s, on the bronchoconstriction induced by leukotriene D ₄ - and antigens in guinea pigs), International Archives of Allergy and Applied Immunology (International Archives of disorders associated with allergies and applied Immunology), Vol. 86 (1988), pp. 48-54;

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 Review of Respirators) American Review of Respiratory Diseases), Volume 130 (1984), p. 748-754). Cough effects are determined by measuring the number and symptom-free periods of cough response diseases to induce a respiratory response, such as inhaled citric acid. (See. Eg Callaway, J. & R. King, Effects of Inhaled alpha-2 adrenoceptor agonists and GABA B Receptor Agonists on Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigs (The impact of inhaled alpha-2 adrenoceptor agonist and GABA _b receptor agonists for cough induced by 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. Urban, B. Szabo & K. Starké, Involvement of peripheral presynaptic inhibition in sympathetic tone reduction by moxonidine, rilmenidine and UK 14 304 (Inclusion of marginal presynaptic depressant in reducing sympathetic state by moxonidine, rilmenidine and UK 14 304), European Journal of Pharmacology, Volume 282 (1985), pp. 29-37) or reduction of renal activity sympathetic nerve (see, e.g., Feng, QS Carlsson, P. Thoren & Effects of clonidine on renal sympathetic nerve activity, natriuresis and diuresis in rats with chronic venous heart failure, Journal of Pharmacology and Experimental Pharmacology and experimental therapeutics), Volume 261 (1992), p. 1129 to 1135), which provides the 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, e.g., Timmermans,

P. & P. Van Zwieten, Central and peripheral α-adrenergic effects of some imidazolidines, European Journal of Pharmacology, vol. 45 (1977), p. 229-236). Clinical studies have shown the beneficial effects of α-2 agonists in preventing myocardial ischemia during surgery (see, for example, Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg & D. Mangano, Effects of Perioperative Dexmedetomidine Infusion in Patients undergoing Vascular Surgery, the effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery, Anesthesiology, Vol. 82 (1995), pp. 620-633, and in the prevention of angina (see, e.g., Wright, RA, P. Decroly, T. Kharkevitch & M. Oliver, Exercise Tolerance in Angina is Improved by Mivazerol α-2-Adrenoceptor Agonist (Cardiovascular Drugs and Therapy (Cardiovascular Drugs and Therapy) Cardiovascular Drugs and Therapy, Volume 7 (1993), pp. 929-934). The efficacy of these compounds in damaging cardiac reperfusion (heart tremors) 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 (Role of L-arginine in the treatment of reperfusion after cat myocardial ischemia), Circulation, Vol. 86 (1992), pp. 279-288. The anti-cardiac arrhythmia activity of these compounds is demonstrated by measuring ouabain-induced arrhythmias (see, e.g., Thomas, G., P., Stephen, Effects of Two Imidazolines (ST-91 and ST-93) on Cardiac Arrhytmias and Lethality Induced by Ouabain) in Guinea-Pig (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, Volume 8 (1993), pp. 109 to 113, and Samson, R., J. Cai, E. Shibata, J. Martins & H. Lee, Electrophysiological effects of α-2-adrenergic stimulation in canine cardiac Purkinje fibers (Electrophysiological effects of α-2-adrenergic stimulation to canine heart Purkinje fibers), American Journal of Physiology, Volume 268 (1995), pp. H2024 to H 2035). The vasoconstrictive effects of these compounds are demonstrated by measuring the contractile properties on isolated arteries and veins in vitro (see, e.g., Flavahan, NT Rimele, J. Cooke & M. Vanhoutte, Characterization of Postfunctional Alpha-1 and Alpha-2 Adrenoceptors Activated by Exogenous or Nerve- Saphenous Vein (Characterization of complementary functional α-1 and α-2 adrenoceptors activated by exogenous or nerve-released norepinephrine on canine vein), Journal of Pharmacology and Experimental Therapeutics, Volume 230 (1984) , pp. 699 to 705). The efficacy of these compounds to reduce intracranial pressure is demonstrated by measuring this property in a canine model in subarachnoid haemorrhage (see, for example, McCormick, J.,

McCormick, J. Zabramski & R, Spetzler, Intracranial pressure reduction by a central alpha-2 adrenoreceptor agonist after subarachnoid haemorrhage (Neurosurgery, Volume 32 (1993)) ). Str. 974-979). Suppression of menopausal release is shown by measuring the reduction of facial blood flow in the rat (see, e.g., Escott, K., D. Beattie, H. Connor & S. Brain,

The modulation of the increase in rat facial skin flow observed after trigenimal ganglion stimulation (Modulation of the increase in facial skin blood flow in rats observed following stimulation of the trigeminal nerve node), European Journal of Pharmacology, Volume 284 (1995) , p. 69 'to 76), which is shown for α-2 adrenergic agonists on the cutaneous blood flow at the tail (see, e.g., Redfem, WM MacLean, R. Clague & J. McGrath, The role of alpha-2 adrenoceptors in the vasculature of the rat tail (Role of α-2 adrenoceptors in 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 increased pain threshold in rodent superhelical winding and in fresh (still warm) platelets of antinociceptive models (see, e.g., M. Millan, K. Bervoets, J. Rivet, R. Widdowson) A. Renouard, S. Marouille-Girardon & A. Gobert, Multiple Alpha-2 Adrenergic Receptor Subtypes II Evidence for a Role of Rat Alpha-2A Adrenergic Receptors in Control of Nociception, Motor Behavior and Hippocampal Synthesis of Noradrenaline (Numerous α-2 adrenergic receptor subtypes.

II. Evidence for the role of α-2A rat adrenergic receptors in controlling pain response, motor behavior, and hippocampal noradrenaline synthesis), Journal of Pharmacology and Experimental Therapeutics, Volume 270 (1994), p. 958-972). The effects of these compounds against migraine are 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 the dura mater by the functional mechanisms (UK 14 304, R (-) - α-methylhistamine and loss of SMS 201 995 block plasma protein within the brain's diaper by puncture mechanisms), European Journal of Pharmacology (European Journal of Pharmacology), Volume 224 (1992), pp. 145-150. The ability of these compounds to suppress opioid omission is demonstrated by measuring suppression of increased sympathetic nerve activity (see, e.g., D. Franz, D. Hare & K. McCloskey, Switched sympathetic neurons: possible sites of opioid-withdrawal suppression by lonidine) suppression of opioid omission by clonidine), Science, vol. 215 (1982), pp. 1643-1645). The anti-epileptic effects of these compounds are demonstrated by measuring attenuation induced 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 (α-2 agonist clonidine suppresses seizures, while α-2 antagonist indazoxan promotes seizures - microinfusion study in kittens with tonsillitis), Brain Research , Vol. 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 deficiency hyperactivity disorder 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 Tourette's syndrome: preliminary clinical experience (Journal of American Academy of Child and Adolescent Psychiatry ( 34 (1995), pp. 1140-1146), cognitive disorders (see, for example, J. Coull, Pharmacological manipulations of the α-2-noradrenergic system. Effects on cognition.) on the α-2 noradrenergic system (effects on consciousness), Drugs and aging, Volume 5 (1994), pp. 116-126, and convulsions (see, for example, M. Eyssette, F. Rohmer, G. Serratrice, J. Warter & D. Boisson, Multicenter, double-blind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple sclerosis) Novel Antispatic, Tizanidine, for convulsions associated with multiple sclerosis), Current Medical Research & Opinion, Volume 10 (1988), p. 699-708).

Another aspect of the invention encompasses 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 viral infection, paranasal sinusitis, persistent nasal mucosa, and allergic rhinitis. Additionally, other disorders (e.g., otitis media and paranasal sinusitis) may also be associated with mucosal congestion. 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 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 preferred for the treatment of other conditions of the respiratory system such as cough, chronic obstructive pulmonary disease (COPD) and asthma. Said dosages and frequency are also preferred for the treatment of conditions 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 a test mammal or at risk of ocular opacity in the 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 (e.g. 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% compound. Determining the exact dosage and method is within the skill and expertise 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 encompasses methods for 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 a test mammal or at risk of gastrointestinal disorders in test subjects. 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 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 for preventing or treating migraine by administering a safe and effective amount of a compound of the invention to a test mammal or at risk of migraine in a test mammal. 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, more preferably from about one to about four doses per day or infusions up to the desired effect. The intranasal dosage frequency 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 for preventing or treating disorders related to sympathetic nervous system activity such as hypertension, myocardial ischemia, cardiac reperfusion disorder (cardiac tremor), angina, cardiac arrhythmia and benign prostate hypertrophy, by administration of

A safe and effective amount of a compound of the invention to the test mammal or at risk of such diseases and disorders in the test subjects. Each administration of a dose 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 from about one to about four doses per day or by infusion to the desired effect.

Another aspect of the invention includes methods of preventing or treating pain by administering a safe and effective amount of a compound of the invention to a test mammal or at risk of pain in the test mammal. 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. The frequency of oral administration of a compound of the invention in accordance with the invention is preferably from about one to about six times a day, more preferably about one to 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 withdrawal of such agents, such as alcohol and opioid, by administering a safe and effective amount of a compound of the invention to a test mammal or at risk of substance abuse or withdrawal syndrome. 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, 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 PH102 ^r Middle calcium phosphate 96.0 Pyrogenic silica 1.0 Cab-O-Sil ^R Magnesium stearate 3.0 Pretty 200.0 mg

The patient with nasal congestion took one tablet. The congestion has been substantially reduced.

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

Example B

I

Chewable tablets

Compound of the Invention 1 Mannitol Microcrystalline Cellulose (Avicel PH 101 ^R ) Quantity per tablet (mg) 15.0 255.6 100.8

Dextrinated sucrose 199,5 (DiPac ^R ) 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 ^R Pretty 600.0 mg

A patient with nasal congestion pulverized and took one tablet. The congestion has been substantially reduced.

Other compounds having the structure of Formula I were used with substantially similar 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 ^R 1 Menthol flavor 0.25 Sodium saccharin 0.08 Pretty 33.33 mg

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

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

Example D

Intranasal solution

admixture 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. Pretty 100.00

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

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 0.10 benzalkonium chloride 0.02 thimerosal 0,002 Hydroxypropy1mety1ce1u1óza 1.0 (Metolose 65SH4000 ") Aromatic substances 0.06

Sodium chloride (0.65%) Pretty G. S. 100.00

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

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

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 Propeller (F12, F114) G. S. Pretty 100.00

Two aerosol formulations were inhaled from a metered dose inhaler to asthma patients. Asthmatically, ¹ condition was effectively alleviated.

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

Example G

Local eye care

admixture Composition (% w / v) Compound of the Invention 2 0.10 benzalkonium chloride 0.01 EDTA 0.05 hydroxyethyl 0.50 (Natrosol M ^R ) Sodium metabisulphite 0.10 Sodium chloride (0.9%) G. S. Pretty 100.00

One-tenth ml of the formulation 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.

Example H

Oral liquid preparation

admixture Quantity / 15 ml dose Compound of the Invention 1 15 mg chlorpheniramine 6 m g propylene 1/8 g Ethanol (95%) 1.5 ml methanol '12.5 mg Eucalyptus oil 7.55 mg flavorings 0.05 ml sucrose 7.65 g carboxymethylcellulose 7.5 mg (CMC) Microcrystalline cellulose a 187.5 mg

CMC Sodium Avicel RC 591 ^R Polysorbate 80 3.0 mg glycerin 300 mg sorbitol 300 mg FD&C red # 40 dye 3 mg Sodium saccharin 22.5 mg Sodium phosphate 44 mg j ednomocný Sodium citrate monohydrate 28 mg Deionized water G. S. Pretty 15 ml

One 15 ml dose of the liquid formulation was used in patients with nasal congestion and rhinitis due to hay fever. Swallowing and rhinitis were effectively relieved.

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

Example J

Oral liquid preparation

admixture Quantity / 15 ml dose Compound of the Invention 2 30 mg sucrose 8.16 g glycerin 300 mg sorbitol 300 mg methylparaben 19.5 mg Propyl 4.5 mg menthol 22.5 mg Eucalyptus oil 7,5 mg

flavorings 0.07 ml FD&C red # 40 dye 3.0 mg Sodium saccharin 30 mg Deionized water G. S. Pretty 15 ml

One 15 ml dose of alcohol-free liquid medicine was used in patients with nasal congestion. The congestion has been substantially reduced.

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

Example K

Oral tablets

admixture Compound of the Invention 1 Microcrystalline Cellulose, NF Starch 1500, NF Magnesium stearate, USP Total Quantity per tablet (mg) 4 130 100 2 236 mg

A migraine patient took one table. 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 Compound of the Invention 2 Hydroxypropylmethylcellulose USP Magnesium stearate, USP Anhydrous lactose, USP Total Quantity per tablet (mg) 12 12 2 200 226 mg

To relieve pain. An adult older than 12 years took 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. · hydroxypropyl methylcellulose 6 USP Magnesium stearate, USP 2 Povidone, K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF 44 Pretty 300 mg

To relieve the symptoms associated with common cold, paranasal sinusitis or influenza, including nasal congestion, headache, fever, body pain and pain. An adult older than 12 years took two capsules every twelve hours.

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

Example N

Oral tablets

admixture Quantity per tablet (mg) Compound of the Invention 1 6 hydroxypropyl methylcellulose 6 USP Silica, colloidal, NF 30 Pregelatinized starch, NF 50 Magnesium stearate, USP 4 Pretty 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 0

Oral tablets

admixture Quantity per tablet (mg) Compound of the Invention 1 6 Hydroxypropy1mety1ce1ulóza 6 USP Magnesium stearate, USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystalline cellulose 44 Pretty 80 mg

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

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

Example P

Oral tablets

admixture Quantity per tablet (mg) Compound of the Invention 1 6 hydroxypropyl methylcellulose 12 USP Magnesium stearate, USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF 44 Pretty 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 number Compound of the Invention 2 10 mg / ml vehicle carrier Citrate buffer sodium containing (wt% carrier): lecithin 0.48% carboxymethylcellulose 0.53 povidone 0.50 methylparaben 0.11 Propyl 0,011

To reduce disturbances in cardiac reperfusion (heart tremors).

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

Example R

Oral liquid preparation

admixture Quantity / liquid ounce dose (mg) Acetaminophen, USP 1000 Doxy1amine succinate 12.5 Dextrometorfán- 30 hydrobromide, USP Compound of the Invention 2 6 Dow XYS-40010.00 3 resin High corn syrup 16000 fructose Polyethylene glycol, NF 3000 Propylene glycol, USP 3000 Alcohol, USP 2500 Sodium citrate dihydrate, 150 USP Citric acid, anhydrous, 50 USP Sodium saccharin, USP 20 flavor . 3.5 Deionized water, USP 3500 Pretty 29275 mg / liquid. ounce

To relieve light pain, headache, muscle pain, sore throat, and fever associated with cold or flu. To relieve nasal congestion, coughs caused by slight irritation of the throat and bronchi, rhinitis, sneezing associated with the usual cold. Adults over 12 years of age use 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 preparation

admixture Quantity / liquid ounce dose (mg) Sodium naproxen, anhydrous, 220 USP Doxylamine Succinate, USP 12.5 Dextrometorfán- 30 hydrobromide and Compound of the Invention 1 6 Dow XYS-40010.00 3 resin High corn syrup 16000 fructose Polyethylene glycol, NF 3000 Propylene glycol, USP 3000 Alcohol, USP 2500 Sodium citrate dihydrate, 150 USP Citric acid, anhydrous, 50 USP Sodium saccharin, USP 20 flavor 3.5 Deionized water, USP 3800 Pretty 28795 mg / liquid. ounce

To relieve light pain, headache, muscle pain, sore throat, and fever associated with cold or flu. To relieve nasal congestion, cough caused by slight irritation of the throat and bronchi, rhinitis, sneezing associated with the usual cold. Adults over 12 years of age use one ounce of liquid every six hours.

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

Example T

According to the invention there is provided a composition for parenteral administration comprising:

component number Compound of the Invention 1 10 mg / ml vehicle carrier Citrate buffer sodium containing (wt% carrier): lecithin 0.48% carboxymethylcellulose 0.53 povidone 0.50 methylparaben 0.11 Propyl 0,011

The above ingredients are mixed to form a solution. About 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

component number Compound of the Invention 2 10 hydroxypropyl 12 USP Magnesium stearate, USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF 44 Pretty 90 mg

For the treatment of cardiac arrhythmia. Use as prescribed.

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

Example V

Oral tablets

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

For the treatment of venostasis of heart failure. Use as prescribed.

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

Modification of the foregoing units is within the scope of the formulation of the skilled artisan, as set forth in the specification guide, in light of the state of the art.

Other examples of active substance combinations are contemplated. Examples of drugs that can be combined with the primary active agent are disclosed in U.S. Patent 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 components 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 (4)

PATENT CLAIMS 1. The comments were made on the following documents: Dl: CH 641 782A (SIEGFRIED AG), March 15, 1984 D2: RICKETTS et al., Journal of Medical Chemistry, vol. 36, no. 2, 1992, p. 372 to 377, XP002058195 D3: US 4,526,898 A (MOLNAR ISTVAN et al.), Jul. 2, 1985 D4: US 5,478,858 (CUPPS THOMAS L. et al.), Dec. 26, 1995 D5: WO 9516449 A (PROCTER & GAMBLE), June 22, 1995 D6: CHAPLEO C. B. et al., Journal of Medical Chemistry, vol. 32, no. 7, July 1989, p. 1627 to 1630, XP000601554 (cited in the application) 1. A 2-imidazolinylaminoindazole compound having the general 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 the group consisting of hydrogen; unsubstituted C 1 -C 3 alkanyl; amino; hydroxy; mercapto; C 1 -C 3 alkylthio or alkoxy; C 1 -C 3 alkylamino or C 1 -C 3 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 I halogen; , · e) when ^R2 is nil, bond (a) it is a double bond; f) the compound is not 7-bromo-6- (2-imidazolinylamino) indazole; and enantiomers, optical isomers, stereoisomers, diastereoisomers, tautomers, supplemental salts, biohydrolyzable amides and esters. 2. Novelty The compound of Example 1 D1 falls within the definition of formula I of claim 1. The compound disclosed in D2 was excluded from claim 1 as an exception. The nature of claim 1 and of dependent claims 2 to 8 of the present application does not appear to be new with respect to D1 (PCT Article 33 (2)). The 2-imidazolinylaminoindazole compound of claim 1, wherein R ⁷ is selected from the group consisting of hydrogen; unsubstituted C 1 -C 3 alkanyl, alkenyl, alkynyl or cycloalkanyl; unsubstituted C 1 -C 3 alkylthio or alkoxy; C 1 -C ₂ alkylamino or C 1 -C ₂ dialkylamino; and halogen; and R ³ is selected from the group consisting of hydrogen; and cyano. The term biohydrolyzable amides and esters in claim 1 is not acceptable, since without examination it is not known which groups are considered for hydrolysis in vivo. «c 3. The inventive step The problem which is the subject of the present application appears to be the benefit of indazole derivatives active in adrenergic receptors. D1, D2 and D3 reveal indazole derivatives that are active at adrenergic receptors. In particular, Formula I D1 includes compounds of the present invention; moreover, D1 illustrates an example of one compound that falls within the definition of Formula I of the present application. D1, D2 and D3 explain that indazole derivatives can act as agonists and antagonists at adrenergic receptors. Because the compounds they exhibit The imidazolinylaminoindazole structure was already known to be active in adrenergic receptors, providing the compounds of the present application does not appear to involve the inventive step (Article 33 (3) PCT). However, the inventive step could be recognized if evidence were provided that would show the unexpected effects of the compounds of the present application as compared to structurally closest to the prior art. These unexpected effects should be shown for the whole group of claimed compounds. In this respect, it is noted that the application does not contain any data concerning effects. 4. In the PCT assessment of the industrial dependent on the industrial compound in the claims due to not presented utility. The formulation of the usability of the medically known uniform criteria with respect to the question of also does not recognize the use provided for by any claim 8 with respect to the patentability of the claims. essence of treatments, compounds For example, the EPO may, however, allow claims for the first time use medical treatment and the use this compound for production medication for new medical treatment • Part VIII International Notes application 1. Definitions of alkanyl they should by provided mark alkyl. Is a question, Why in claim 1, R ¹ is defined as alkyl and R ³ , R ⁴ , R ^p and R ⁷ how alkanyl (Article 6 PCT). 2. It is not entirely clear why v description on the p. 4 (English versions) the terms alkyl, alkenyl, etc. are defined as unsubstituted or substituted, while in claim 1 these terms are defined as unsubstituted. of claim 1 which are contemplated for substitutions, the nature of the substituents indicated in the claim. For groups should be The 2-imidazolinylaminoindazole compound according to any one of the preceding claims, wherein R ⁴ is selected from the group consisting of hydrogen; methyl; methoxy; cyano; iodine; and chlorine; and R ⁵ represents hydrogen. The 2-imidazolinylaminoindazole compound according to any one of the preceding claims, wherein R ⁷ is selected from the group consisting of methyl; ethyl; ethenyl; methoxy; methylthio, cyclopropyl; chloro; and iodine. A 2-imidazolinylaminoindazole compound according to any one of the preceding claims which is 7-ethyl-6- (2imidazolinylamino) indazole or 6- (2-imidazolinylamino) -7-methylindazole. A pharmaceutical composition comprising a safe and effective amount of a compound of any preceding claim and a pharmaceutically acceptable carrier. Use of a 2-Imidazolinylaminoindazole compound or a pharmaceutical composition thereof for the preparation of a medicament for the prevention or treatment of disorders modulated by α-2 adrenergic receptors. - 67 International Interim Survey Report Part 5 The statement of reasons referred to in Article 35 (2) in respect of novelty, inventive step or industrial applicability; citations and explanations that support this statement The term safe and effective amount in claim 6 is not clear.