CZ20002001A3 - Substituted imidazole derivatives exhibiting activity similar to that of agonists of adrenergic receptors alpha 2B or 2B/2C - Google Patents

Abstract

Compounds with adrenergic activity that are selective agonists for one or both adrenoceptor receptors they prefer the alpha2B and alpha2C subtypes adrenoceptor receptor subtype alpha2A; active the compound is selected from the group consisting of formula I, wherein the dotted lines represent preferred bonds beyond provided that the two double bonds do not need to share the same carbon atom; R is H or lower alkyl; X is S or C (H) R ', wherein R 1 is H or lower alkyl but R 1 is absent if the bond between X and the ring represented by formula (a) is double bond; Y is O, N, S, (CR12) ,, where y is an integer from 1 to 3, -CH = CH- or Υ'ΟΕ-, wherein Y 1 is O, N or S; x is 1 or 2, wherein x is 1 when R2, R3 or R4 are bonded to a saturated carbon atom and x is 2 when R2, R3 or R4 are bonded to a saturated carbon atom, R 2 is H, lower alkyl, halogen, hydroxy, hydroxy or lower alkoxy, or phenyl, or together, are - (C (R 2) x) 2 -; -Y '(C (R2) x) z'; - Y '(C (R2) x) yY'-; -C (R 2) x) Y'-C (R 2) x) -; - (C (R 2) x) -Y '- (C (R 2) x) - (C (R 2) x) -a -Y' - (C (R 2) x) -, z is an integer from 3 to 5, z 'is an integer from 2 to 4 and x and y are as they are as defined above, and further both ends of each of these divalent parts of the molecule may be attached to either R 3 or R 4 and create a condensed circular structure and formed the rings may be fully unsaturated, partially unsaturated, or fully saturated; and are useful for treating muscle spasticity including hyperactive frequent urination, diarrhea, urination, withdrawal syndromes, pain, including neuropathic, neurodegenerative diseases, memory and consciousness disorders, psychoses including manic and anxiety states, hypertension, congestive heart failure, cardiac ischemia and congestion of the nasal mucosa without showing sedation or cardiovascular side effects.

Description

Substituted imidazole derivatives with activity similar to alpha 2B or 2B / 2C adrenergic receptor agonists. ’*

Technical field

and

The invention is directed to a method of treating glaucoma or elevated intraocular pressure and other diseases with a significant reduction in cardiovascular or sedative side effects by administering compounds that are selective agonists of either alpha2B or alpha2B and 2C adrenergic receptors alone and lacking significant activity at the alpha2A receptor subtype. , mammals including humans. The present invention is also directed to novel compounds and pharmaceutical compositions adapted for administration of said compounds to mammals including humans.

AND

BACKGROUND OF THE INVENTION

Compounds with adrenergic activity are well known in the art and are described in numerous patents in the US and abroad, including scientific publications. It is generally known and accepted in the art that adrenergic activity is useful in the treatment of mammalian species, including humans, for treating or ameliorating the symptoms and condition of a patient in a variety of diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions containing an adrenergic compound or compounds as an active ingredient are useful in the treatment of glaucoma, chronic pain, nasal congestion, high blood pressure, congestive heart failure, and induction of anesthesia.

Two major classes of adrenergic receptors are referred to in the art as alpha and beta adrenergic receptors, and each group includes subtypes, which are denoted by the letters o

alphabets such as alpha2A, alpha2B. See Bylund et al., Pharmacol. Roar. 46, 121-136 (1994).

SUMMARY OF THE INVENTION

In accordance with the present invention, it has been found that adrenergic compounds that act selectively and preferentially, specifically, as agonists of the alpha2B or alpha2B / alpha2C (referred to herein as alpha2B or alpha2B / 2C) receptor subtypes on which they act preferentially over the alpha2A subtype receptors, have desirable therapeutic properties consistent with adrenergic agents, but without one or more side effects, such as changes in blood pressure or sedation (sedation). For the purposes of this invention, a compound is defined as a specific, or at least selective, alpha2B or alpha2B / 2C receptor subtype agonist when it is at least ten times more potent as an alpha2B or alpha2C receptor subtype than either the alpha2A receptor subtype or at the alpha2B and alpha2B / 2C receptors compared to the alpha2A receptor is greater than 0.3 and its efficacy at the aifa2A receptors is less than or equal to 0.4.

Accordingly, the invention relates to a method of treating animals of mammalian species, including humans, with a pharmaceutical composition comprising as active ingredient one or more compounds having the effect of specific or selective alpha2B or alpha2B / 2C agonists, used to treat many diseases or conditions for which alpha is useful. adrenergic compounds, including, but not limited to, glaucoma, intraocular pressure reduction, chronic pain, diarrhea and nasal congestion. Further, the compounds of the invention are useful for treating muscle spasticity including hyperactive frequent urination, diarrhea, urination, withdrawal syndromes, pain, including neuropathic,

Neurodegenerative diseases including optic nerve neuropathy, spinal cord ischemia and stroke, memory and consciousness disorders, attention deficit disorder, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion.

This invention also encompasses pharmaceutical compositions used in the above-described method of treatment.

In particular, the present invention relates to a method of treating diseases and conditions in which adrenergic compounds are useful, but their use is limited due to known side effects.

DETAILED DESCRIPTION OF THE INVENTION

The compounds used in the pharmaceutical compositions and method of treatment of the invention are selective or specific agonists of the alpha2B or alpha2B / 2C adrenergic receptor subtype, which they act preferentially as compared to the alpha2A receptor subtype. In accordance with the present invention, a compound is considered to be a selective alpha2B or alpha2C agonist if the difference in its activity as agonists on the alpha2B or alpha2B / 2C receptor subtypes compared to the alpha2A receptor subtype is greater than 0.3 and its activity on the alpha2A receptor subtype is less than or equal to 0.4 and / or is at least ten times smaller. Preferably, the compounds used in accordance with the present invention are specific alpha2B or alpha2B / 2C receptor subtype agonists. Specifically, a specific agonist is defined in this sense in that the specific adrenergic agonist exerts no measurable or biologically significant effect on the alpha2A receptor subtype.

A number of substances have been discovered which are functionally selective for the alpha2B or alpha2B / 2C subtypes of said adrenergic receptors. Their preferential activity can be determined by a series

f- ’· 4 4> ♦

Různých t various functional assays such as cyclic AMP production, Shimizu et al., J.

Neurochem. 16: 1609-1619 (1969); R-SAT (receptor selection and amplification technique), Messier et al., Pharmacol. Toxicol. 76, 308-311 (1995) and a cytosensor microphysiometer, Neve et al, J. Biol. Chem. 267, 25748-25753 (1992), using cells that naturally express individual subtypes, or one of the subtypes is introduced into them. The cells or recombinant receptors used should be human or belong to those species which have been shown to have the same pharmacology. In the study described below, the R-SAT assay was used on cells that were transiently transfected with human alpha2A (c10 gene), rat alpha2B (RNG gene), and human alpha2C (c4 gene) receptors. Rat alpha2B receptors have been shown to be pharmacologic to human alpha2B receptors (see, for example, Bylund et al., Pharmacol. Rev. 46, 127-129 (1994)).

Topical administration can be used especially in the treatment of glaucoma. Any topical formulation such as a solution, suspension, gel, ointment or ointment and the like can be administered to the eye in glaucoma or to the skin in other indications. The preparation of such topical formulations is well described in the pharmaceutical formulations exemplified, such as in Remington's Pharmaceutical Science, edition 17, Mack Publishing Company, Easton, Pennsylvania.

If the drug is to be administered systemically, it can be prepared as powders, pills, tablets and the like, as a syrup or elixir for oral administration. For intravenous, intraperitoneal, intrathecal or epidural administration, the compound is prepared as a solution or suspension that can be injected. In certain cases, it may be useful to prepare these compounds as suppositories or as sustained release depot preparations, including skin patches for placement on or under the skin, or by intramuscular injection.

The treatment of glaucoma or any other indication known or discovered to respond to treatment with adrenergic compounds is affected by the administration of a therapeutically effective dose of one or more compounds of the invention. A therapeutic concentration is a concentration that leads to an improvement in a certain condition or slows its expansion. In some cases, the drug may be instructed prophylactically to prevent the occurrence of a particular condition. The therapeutic concentration administered varies from case to case and, under certain conditions, depends on the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, it is best to determine the therapeutic dose administered empirically, in terms of time and space. However, it is contemplated that in the treatment of, eg, glaucoma, a composition comprising 0.001 to 5% by weight, preferably 0.01 to 3% by weight, will produce a therapeutically effective concentration. When administered systemically in an amount of 0.001 to 50 mg / kg, preferably 0.001 to 10 mg / kg of body weight per day, it will have a therapeutic effect in most cases.

Since compounds with alpha2B and alpha2B / 2C specific selective agonist activity lack substantial alpha2A side effects, treatment of the diseases or conditions with the compounds of this invention is particularly beneficial in people with cardiovascular problems.

The general structure of examples of specific alpha2B and alpha2C agonists or adrenergic compounds having the effect of selective alpha2B and alpha2B / 2C agonists that are used in the pharmaceutical compositions and therapeutic methods of the invention is shown by the general formula below.

According to one aspect of the invention, a compound having selective agonist activity at the alpha2B or alpha2B / 2C subtype (s) of adrenergic receptors is represented by the general formula:

Y

R IN H where the dotted lines represent preferred bonds, provided that the two double bonds do not share a common carbon atom; R is H or lower alkyl; X is S or C (H) R ¹ , wherein R ¹ is H or lower alkyl, but R ¹ is absent when the bond between X and the ring represented by a double; Y is O, N, S, (CR ¹ 2) _y , wherein y is an integer from 1 to 3, -CH = CH- or -Y ¹ CH ₂ - wherein Y ¹ is O, N, or S; x is an integer of 1 or 2, wherein x is 1 when R ² , R ³ , or R ^{4 is} bonded to an unsaturated carbon atom and x is 2 when R ² , R ³ or R ^{4 is} bonded to a saturated carbon atom;

R ² is H, lower alkyl, halogen, hydroxy and lower alkoxy, or, when attached to a saturated carbon atom, R ² is oxo; R ³ and R ⁴ are each H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together - (C (R ² ) x) ² -; -Y ¹ (C (R ² ) x) z '-; -Y ¹ (C (R ² ) x) y Y ¹ -; - (C (R ² ) x) -Y ¹ - (C (R ² ) x); (C (R ² ) x) -Y ¹ - (C (R ² ) x) - (C (R ² ) x) -; and -Y ¹ - (C (R ² ) x) -Y ¹ - (C (R ² ) x), wherein z is an integer from 3 to 5, z 'is an integer from 2 to 4, and x and y are the same as as defined above, and further, both ends of each of these divalent moieties of the molecule may attach to R ³ or R ⁴ to form a fused ring structure generally represented as

and the formed rings may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon in the ring has no more than 4 valences, nitrogen is no more than 3 valences, and O and S have no more than two valencies.

In another aspect of the invention, the above compound is represented by the formula

wherein X can be C (H) R ¹ and R ¹ is H.

In said compound of formula II, R ² can be H and

it may be a furanyl radical.

In these furanyl derivatives of formula II, R ³ and R ⁴ can both be (CH) ₄ , or R ³ can be H and R ^{4 is} t-butyl, or R ³ and R ⁴ can be H, or R ³ can be H and R ^{4 is} methyl or ethyl.

Alternatively, in the compound of formula I, R ¹ may be methyl and • ft · · »

»• ·

it may be a furanyl radical.

Alternatively, R ² in said compounds of formula II may be H and

it may be a thienyl radical.

In these thienyl derivatives of formula II, R ³ and R ⁴ can both be (CH 2) 4, or R ³ can be phenyl and R ⁴ H, or R ³ and R ⁴ can both be represented by (CH 2) 3 S, or R ³ and R ⁴ can be H, or R ³ and R ⁴ can both be reperesented with (CH) 4, or R ³ can be H and R ^{4 is} methyl, or R ³ can be bromine and R ⁴ H, or R ³ can be hydrogen and R ^{4 is} chlorine, or R ³ can be methyl and R ⁴ can be hydrogen.

Alternatively, in the compound of formula II, it may

represent a cyclohexyl radical.

In these cyclohexyl compounds of formula II, R ² can be hydrogen and R ³ and R ^{4 can} both be represented by (CH) ₄ , or R ² can be oxo and R ³ and R ^{4 can} both be (CH) ₄ , or R ² can be hydrogen or oxo and R ³ and R ⁴ may both be represented by (CH ₂ ) S, or R ² may be hydrogen and R ³ and R ⁴ may both be represented by (CH ₂ ) ₄ , thus forming octahydronaphthalene, or R ² may be oxo and R ³ and R ⁴ can both be ···· · · s!

represented by (CH 2) 4, or R ² may be oxo and R ³ and R ⁴ may both be represented by (CH) 2 C (CH 3) (CH), or R ² may be hydrogen and R ³ and R ⁴ may both be S (CH 2) 2, or R ² , R ³ and R ⁴ may be H, or R ² may be oxo and R ³ and R ⁴ may both be (CH) 2 C (OCH 3) CH, or R ³ and R ⁴ may both be represented by -Y ¹ -C (R ²⁾ x C ^(R2) xy ¹ -, wherein Y ¹ is N, forming a tetrahydroquinoxaline wherein R ² may be hydrogen or oxo.

Alternatively, in compounds of Formula II

may be a tetrahydroquinoline radical wherein R ³ and R ⁴ are both -Y ¹ -C (R ² ) x C (R ² ) x C (R ² ) X -, wherein Y ¹ is Ν. In such tetrahydroquinoline derivatives may be (R ²⁾ X is hydrogen or an oxo group, or may represent a tetrahydroisoquinoline radical wherein R ³ and R ⁴ are both -C (R ²⁾ Xy ¹ -C (R ²⁾ x C ^(R2) x wherein Y ¹ is N and (R ² ) _x may be hydrogen or oxo.

Alternatively, in compounds of Formula II

may represent a cyclopentyl radical.

In these cyclopentyl derivatives of formula II, R ² H and R ³ and R ^{4 may} both be represented by (CH) ₄ , or R ² may be oxo and R ³ and R ^{4 may} both be represented by (CH) 4, or R ² may be hydrogen and R ³ and R ^{4 are} both represented by (CH 2) ₃ .

··· «· · ···· · ·

Λ ’

In another aspect of the invention, Y is (CH ₂ ) 3 and X can be CH and R ^{2 is} oxo, or X can be CH 2 and R ² can be H. Alternatively, R ³ and R ⁴ can both be represented by (CH) 4, Y can be CH ₂ C (CR ¹ 2) ₂ , where R ¹ is hydrogen, or Y can be -CH ₂ C (Me) - and R ² can be hydrogen or oxo.

Finally, in the compounds of formula II

it may represent a phenyl radical.

In these phenyl derivatives of formula I, X can be CH ₂ , R can be H or CH ₃ , R ² , R ³ and R ⁴ can be H, or R ³ and R ⁴ can both be represented by O (CR ² ) ₂ O to form a 1,4-benzodioxane derivative, or alternatively X may be S and R ² , R ³ and R ⁴ may be H.

According to another aspect of the invention, said compound has the general formula

wherein Y is S or O.

In such a compound of formula III, XC (H) may be R ¹ , R, R ¹ , R ² , R ³ and R ⁴ may be H and Y may be O or S.

In another aspect of the invention said compound has the general formula

and R ³ and R ⁴ are both (CH) ₄ .

In these compounds of formula IV, Y ¹ may be O, R ^{2 is} oxo and X is CH or CH 2, or one of R ² is hydroxy and the other H, or R ² may be H.

In these compounds of formula IV, Y ¹ can be S, X can be CH ₂ and R ^{2 is} oxo, or R ² can be H and X can be CH and R ^{2 is} oxo.

In another aspect of the invention, a compound having selective activity at the 2B or 2B and 2C adrenergic receptor subtype (s) as compared to the 2A adrenergic receptor subtype is represented by the general formula

alternatively, W is a bicyclic radical selected from the group consisting of

8 9998 • 8 99 8 8 4 4 9 88 88 9 4 4 98 where R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected from the group consisting of H and lower alkyl, provided that at least one of R ⁵ and R ⁶ or R ⁶ and R ⁷ is OC (R ⁹ ) C (R ⁹ ) N (R) to form a condensed ring

XX wherein R ⁹ is H, lower alkyl or oxo; and

wherein R ¹⁰ is H, lower alkyl, phenyl or lower alkyl substituted phenyl, and Z is O or NH. Compounds wherein W is norbornyl are described and claimed in co-formulated application 09/003902, filed Jan. 7, 1998, which is hereby incorporated by reference in its entirety.

According to one aspect of the invention Z may be O and W may be

and R ¹⁰ may be selected from H, phenyl or o-methylphenyl, eg, R ¹⁰ may be o-methylphenyl.

In another aspect of the invention, W may be (R ⁹ ) x C (R ⁹ ) _x .c

wherein Z can be NR, R methyl or hydrogen, one of (R ⁹ ) _x can be H and R ⁵ can be H. Alternatively, W can be

wherein R can be H and R ^{8 is} methyl.

The invention is further illustrated by the following examples (including general synthetic schemes) which illustrate various aspects of the invention but do not limit the scope of the invention as defined in the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example A

Synthesis of 1-dimethylsulfamoyl-2- t -butyldimethylsilyl-5-imidazolecarboxaldehyde:

1) n-BuL 1, -78 ° C

SO ₂ NMe ₂

CISO ₂ NMe ₂

Et ₃ N, benzene

2) TBDMSCI

1) sec-BuLi, -20 ° C

2) DMF

About TBDMS OHC7 ~ N

SO ₂ NMe ₂

Method

Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N, N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to 320 mL benzene. The reaction mixture was stirred for 48 hours at room temperature and then filtered. The filtrate was concentrated under reduced pressure. Vacuum distillation of the crude product (-0.5 mmHg, 115-118 degrees Celsius) afforded 38.7 g (76%) of a clear and colorless oil. Upon cooling, the product solidifies as white crystals (2). 1- (Dimethylsulfamoyl) imidazole (2) (18.8 g, 0.11 mol) was added to 430 mL tetrahydrofuran (THF). The solution was cooled to -78 degrees Celsius. A solution of n-butyllithium (n-BuLi) in hexane (1.6 M, 70.9 mL, 0.11 mol) was added dropwise to the reaction vessel. After the addition was complete, the reaction mixture was stirred for 1 hour at -78 degrees Celsius. t-Butyldimethylsilyl chloride (17.8 g, 0.12 mol) in 50 mL of THF was added via cannula to the reaction. After the addition was complete, the reaction mixture was allowed to warm slowly to room temperature and then stirred for 24 hours. The reaction mixture was diluted with water and the organic layer was separated. The organic phase is washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (V (20% ethyl acetate / hexane) gave a pale yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3).

1-Dimethylsulfamoyl-2- t -butyldimethylsilylimidazole (3) (5.0 g, 17.3 mmol) was added to 100 mL of THF. The solution was cooled to -20 degrees Celsius. A solution of secondary butyllithium (s-BuLi) in hexane (1.3 M, 14.6 mL, 19 mmol) was added dropwise to the reaction vessel. After the addition was complete, the reaction mixture was stirred at -20 ° C for 1 hour. 8 ml of dimethylformamide (DMF) is added to the reaction and then stirred at room temperature for 3.5 hours. The reaction mixture was diluted with water and the organic layer was separated. The organic phase is washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (eluting with 20% ethyl acetate / hexane) gave a pale yellow oil. Upon cooling, the product solidifies to form yellow crystals of 1-dimethylsulfamoyl-2- t -butyldimethylsilyl-5-imidazolecarboxaldehyde.

Example B-1

Procedure for the preparation of 4 (S) - (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) -1H-imidazole hydrochloride:

40% HoSO ₄

90 ° C

O

Method

7-Methoxy-1-tetralone (1) (1.5 g, 8.5 mmol) and 1-dimethylsulfamoyl-2- t -butyldimethylsilyl-5-imidazolecarboxaldehyde (2) (2.7 g, 8.5 mmol) are added to 8.5 ml of a 40% sulfuric acid solution. The reaction mixture was then heated at 90 degrees Celsius for 24 hours. After cooling to room temperature, the reaction mixture was basified with an excess of concentrated ammonium chloride solution. The mixture was extracted twice with THF. The organic layers were combined and washed with brine. The organic layer was separated and dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to 0 ° C

4 4 4 4 5 6 7 8 9 10 11 12 11 12 13 14 15 16 17 18 19 20 2.7 g of a yellow solid (3) containing 3- (3H-imidazol-4 (5) ylmethylene) -7-methoxychroman-4-one. The crude product was resuspended in 100 mL of ethanol and palladium-carbon catalyst (10%, 0.27 g) was added. The mixture was shaken in a Parr hydrogenator at 40 psi hydrogen. After 19 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Column chromatography with 7% methanol in chloroform gave 1.05 g (46%) of a brownish solid containing 2- [3Himidazol-4 (S) -ylmethyl] -7-methoxy-3,4-dihydro-2H-naphthalene- 1-one (4) (B-1 a). (4) (0.5 g 1.95 mmol) was added to 20 mL methanol. Sodium borohydride (74 mg,

1.95 mmol). After stirring at room temperature for 2.5 hours, the reaction mixture was quenched with water. The reaction mixture was then extracted twice with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was separated and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 0.5 g of a white solid (5) containing 2- [3H-imidazol-4 (5) -ylmethyl] -7-methoxy-3,4-dihydro-2H- naphthalene-1-ol. The crude product was dissolved in 26 mL of dichloromethane. Triethylsilane (2.5 mL, 15.6 mmol) and trifluoroacetic acid (4.8 mL, 62.3 mmol) were added and the reaction mixture was stirred at room temperature for 22 hours. The reaction was then basified with 2 N NaOH and the organic layer was separated and washed with brine. The solution was dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography with 7% methanol in chloroform gave 0.39 g (83%) of a brownish oil (6). The product was dissolved in methanol and excess HCl in ether was added. The solution was concentrated under reduced pressure to give 0.3 g of a brownish solid. Column chromatography with 7% methanol in chloroform gave 0.25 g (46%) of 4 (S) - (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -1H-imidazole hydrochloride (B-1) as white crystals after recrystallization from a mixture of acetone and methanol.

• I • I *; ¹ H NMR (300 MHz, CD ₃ OD) 8.83 (s, 1H), 7.38 (s, 1H), 6.95 (d, 1H, J = 8.5Hz), 6.66 (d, 1H, J = 8.4Hz), 6.57 (s, 1H), 3.73 (s, 3H), 2.71 -2.81 (m, 5H), 2.43-2.52 (m, 1H), 1.90-2.14 (m,

2H), 1.40-1.51 (m, IH).

Following the procedure in Example B-1, various condensed ring compounds are reacted to give the imidazole derivatives listed below

Example B-2 (a-d)

4-Chromanone (2a) 3- (3H-imidazol-4 (5) -ylmethylene) chroman-4-one (2b) 3- (3H-imidazol-4 (5) ylmethyl) chroman-4-one (2c) 3 - (3H-imidazol-4 (5) ylmethyl) chroman-4-ol (2d) 4- (5) -chroman-3-ylmethyl-1H-imidazole

Example B-3 (a-b)

-tetralone (3a) 2- (3H-imidazol-4 (5) ylmethyl) -3,4-dihydro-2H-naphthalen-1-one (3b) 4 (5) - (1,2,3,4-tetrahydronaphthalene-2) -ylmethyl) -1 Himidazole

Example B-4 (a-b)

4-methyl-1-tetralone (4a) 4- (5) - (4-methyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) -1H-imidazole (4b) 2- (3H-imidazole-4) (S) -ylmethyl) -4-methyl-3,4-dihydro-2H-naphthalen-1-one

Example B-5 (a-b)

(5a) 3- (3H-imidazol-4 (5) -ylmethylene) thiochroman-4-one (5b) 3- (3H-imidazol-4 (5) -ylmethyl) thiochroman-4-one

Example B-6

The hydrochloride salt of the preceding compound was prepared according to Step 5 of the method of Example B-1 above.

4 (S) -thiochroman-3-ylmethyl-1H-imidazole thiochroman

Example B-7 (a-c)

indanone (7a) 2- (3H-imidazol-4 (5) -ylmethylene) indan-1-one (7b) 2- (3H-imidazol-4 (5) -ylmethyl) indan-1-one (7c) 4 (S) -indan-2-ylmethyl-1H-imidazole

Example B-8 (a-b)

7-Methyl-1-tetralone (8a) 2- (3H-imidazol-4 (5) -ylmethyl) -7-methyl-3,4-dihydro-2H-naphthalen-1-one (8b) 4 (5) - (7) methyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) -1H-imidazole

The hydrochloric acid salt of this compound was prepared according to the method described in Example B-6.

Example B9 (a-c)

4-keto-4,5,6,7-tetrahydrothianafthen (9a) 4 (5) - (4 ₁ 5 ₁ 6 _I 7-tetrahydrobenzo [b] thiophen-5-ylmethyl) -1H-imidazole

The hydrochloric acid salt of this compound was prepared according to the method described in Example B-6.

(9b) S-15H-imidazo-4H-ylmethyl-6-dihydro-5H-benzo [b] thiophen-4-one

The hydrochloric acid salt of this compound was prepared according to the method described in Example B-6.

(9c) 5- (octahydrobenzo [b] thiophen-5-ylmethyl-1H-imidazole) <RTIgt; ft </RTI> ftft

Example B-10

4,4-Dimethyl-1-tetralone 4- (5) - (4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-2- ylmethyl) -1H-imidazole

Example B-11 (a-b)

1 -Benzosuberon (11a) 4 (S) - (6,7,8,9-tetrahydro-5H-benzocyclohepten-6- ylmethyl) -1H-imidazole (11b) 6- (1H-imidazol-4 (S) -ylmethylene) -6,7,8,9- tetrahydrobenzocyclohepten-5-one

1 -Benzosuberon (11a) 4 (S) - (6,7,8,9-tetrahydro-5H-benzocyclohepten-6- ylmethyl) -1H-imidazole (11b) 6- (1H-imidazol-4 (S) -ylmethylene) -6,7,8,9- tetrahydrobenzocyclohepten-5-one Example C-1

Preparation of 4 (S) -thiophen-3-ylmethyl-1H-imidazole:

r «V

N

SO ₂ NMe ₂

1) n-BuLi

2) TBSCI

3) n-BuLi ^{4 &} sa 2

TBAF

CHO

//

N

EuSiH

CF, CO, H

CH ₂ Cl ₂

1ANHCl reflux

Method

1- (Dimethylsulfamoyl) imidazole (1) (2.0 g, 11.4 mmol) was stirred into 42 mL of anhydrous THF and cooled to -78 degrees Celsius. To solution (1) was added n-BuLi (6.6 mL, 10.6 mmol) dropwise. The resulting solution was stirred at -78 degrees Celsius for 30 minutes. To the reaction was added tert-butyldimethylsilyl chloride (TBSCI) (1.6 g, 10.6 mmol) in 8 mL of THF. The reaction mixture was warmed to room temperature and stirred overnight. The next day, the reaction was cooled to -20 degrees Celsius and 7.3 mL (11.6 mmol) of n-BuLi was added. After stirring at -20 degrees C for 45 min, 3-thiophenecarboxaldehyde (2) (1.0 mL, 11.6 mmol) was added to the reaction mixture. The reaction was then warmed to room temperature and stirred overnight. The next day, the reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over

• · • · '· ·· »· * ·· · • · • · • • · · • · ·· • · • • · • · · · • · • • · · · ·· ·· • ·

sodium sulfate and under reduced pressure to remove the solvent. By means of flash chromatography; 2: 5 ethyl acetate / hexane) afforded 3.0 g (7.5 mmol) of 2- (t-butyldimethylsilyl) -5- (hydroxythiophen-2-ylmethyl) imidazole-1-sulfonic acid dimethylamide (3). Compound (3) (1.5 g, 3.74 mmol) was stirred into 37 mL THF. To solution (3) was added dropwise a 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (4.1 mL, 4, After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate the next day, the organic layer was washed with water then brine, dried over sodium sulfate and the solvent was removed under reduced pressure. 0.94 g (0.33 mmol) of 5 (hydroxythiophen-2-ylmethyl) imidazole-1-sulfonic acid dimethylamide (4) is obtained (4) (0.5 g, 1.74 mmol) is stirred into 23 ml of water. ml of dichloromethane, 2.2 ml (13.9 mmol) of triethylsilane and 4.3 ml (55.7 mmol) of trifluoroacetic acid were added to the obtained solution, and they were stirred overnight at room temperature and then quenched with water and neutralized with solid acid. The organic phase is washed with water and then with brine, and the organic phase is dried over sodium sulfate and under reduced pressure. Flash chromatography using a 1: 1 mixture of ethyl acetate and hexane gives 0.42 g (1.55 mmol) of 5- (thiophen-2-ylmethyl) imidazole-1-sulfonic acid dimethylamide ( 5). (5) (0.42 g, 1.55 mmol) was stirred into 10 mL of 1.5 N HCl solution and the mixture was heated at reflux for 3 hours and then stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, neutralized with solid sodium bicarbonate, and then basified with 2 N NaOH. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. Flash chromatography using a 10: 1 mixture of chloroform and methanol affords 0.17 g (1.0 mmol) of 4 (S) -thiophen-3-ylmethyl-1H-imidazole (6) (C-1).

• φφ φφ ·· φφ • φφφφ φφφφ • φ φφφφ φφφφ • φφφφφ φ · φφφ Φφ φ φ φφφφ φφφφ φ φφ φφ φφ φφ ¹ Η NMR (300 MHz, CD ₃ OD) 7.52 (s, 1Η), 7, 25-7.27 (m, 1H), 6.96-7.01 (m, 2H), 6.77 (s,

1H), 3.98 (s, 2H).

Example C-2

The 2-carboxaldehyde isomer of 3-thiophenecarboxaldehyde is substituted according to the method of Example C-1 to give 4 (S) -thiophen-2-ylmethyl-1H-imidazole.

Example C-3

5-Methyl-2-thiophenecarboxaldehyde 3-thiophenecarboxaldehyde is substituted according to the method described in Example C-1 to give 4- (5) - (5-methylthiophen-2-ylmethyl) -1H-imidazole.

Example C-4

5-Chloro-2-thiophenecarboxaldehyde 3-thiophenecarboxaldehyde is substituted according to the method described in Example C-1 to give 4- (5) - (5-chlorothiophen-2-ylmethyl) -1Himidazole.

Example C-5

2-Furancarboxaldehyde is substituted according to the method of Example C-1 to give 4 (S) -furan-2-ylmethyl-1H-imidazole.

4 · · ♦ ·· 4 • 4 4 4 4 4 4 4 • · · · · · 4 9

Example C-6

3-Furancarboxaldehyde is substituted according to the method of Example C-1 to give 4 (S) -furan-3-ylmethyl-1H-imidazole.

Example C-7

5-Methyl-2-furancarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4 (S) - (5-methylfuran-2-ylmethyl) -1H-imidazole.

Example C-8

Benzaldehyde is substituted according to the method of Example C-1 to give 4 (S) -benzyl-1H-imidazole.

Example C-9

2-Thianaphthalecarboxaldehyde is substituted according to the method outlined in Example ΟΙ to give 4 (S) -benzo [b] thiophen-2-ylmethyl-1H-imidazole.

Example C-10

2-Benzofurancarboxaldehyde is substituted according to the method of Example

C-1 to give 4 (S) -benzofuran-2-ylmethyl-1H-imidazole.

* tt tt tt ttt ttt ttt tt ttt tttt ttttttttttttttt

Ttt 4 tt tttt

Example C-11

5-Ethyl-2-furancarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4 (S) - (5-ethyl-furan-2-ylmethyl) -1H-imidazole.

Example C-12

4-Bromo-2-thiophenecarboxaldehyde is substituted according to the method of Example C-1 to give 4- (5) - (4-bromothiophen-2-ylmethyl) -1H-imidazole.

Example C-13

4-Phenyl-2-thiophenecarboxaldehyde is substituted according to the method of Example C-1 to give 4- (5) - (4-phenylthiophen-2-ylmethyl) -1H-imidazole.

Example C-14

4-Methyl-2-thiophenecarboxaldehyde is substituted according to the method of Example C-1 to give 4- (5) - (4-methylthiophen-2-ylmethyl) -1H-imidazole hydrochloride.

Example D-1

Preparation of oxazolidin-2-ylidene- (3-phenylbicyclo [2.2.1] hept-2-yl) amine:

* β ·

99 99 88 88

8 8 9 9 «· · <

• 4 · 4

8998 88 89 9 9 9 89 fl • 9 9 9 8 9 9 8 i

98 88 98 98

CH ₃ NO ₂ / KOH / MeOH OH W'H ~~

HCl

C ₆ H _S 2 ^NO ₂ c ₂ ch ₂ ci

C _fi H

6 ⁿ 5

NO,

H ₂ / Pd-C

NH,

1) chloroisocyphate

2) NaHCO ₃ ? 6H _S

Λ7

HN ^

Method

As shown above, endo exo relative stereochemical compositions of the compound, namely beta-nitrostyrene, were prepared. Reaction of a methanol solution of benzaldehyde (10 g, 94.3 mmol) with nitromethane (51 mL, 943 mmol) in the presence of sodium hydroxide (3 N in methanol, pH = 8) gave the nitroalcohol in 60% yield. Dehydration of the alcohol was performed with methanesulfonyl chloride (3.56 g, 31.1 mmol) followed by triethylamine (6.3 g, 62.2 mmol) in dichloromethane (35 mL) to give the product in 97% yield. Kugelrohr distillation was used to purify the compound. The construction of the bicyclo [2.2.1] heptane skeleton takes place in one step. The Diels-Alder reaction was performed by heating nitrostyrene (4.5 g, 30.2 mmol) with cyclopentadiene (3.98 g, 60.4 mmol) in 1,2-dichloroethane (10 mL). The Diels-Alder reaction is approximately 3: 1 endo: exo. The ratio and relative stereochemical composition can be demonstrated by X-ray analysis. The reduction of both the nitro group and the olefin takes place in a hydrogen atmosphere in the presence of 10 wt% palladium on activated carbon. The isomers are readily separated at this stage by flash chromatography using methanol saturated with 5% ammonia in dichloromethane. The amine (0.7 g, 3.74 mmol) was first treated with chloroethyl isocyanate (0.38 mL, 4.49 mmol) to give chloroethyl urea, which was then heated in the presence of aqueous NaHCO ₃ to give oxazolidin-2-ylidene - (3-phenylbicyclo [2.2.1] hept-2-yl) amine (D-1) in 51% yield.

¹ H NMR (300 MHz, CDCl ₃ ) d 1.36-1.80 (m, 6H), 2.14 (d, 1H, J = 4.40 Hz), 2.37 (s, 1H), 2 65 (s, 1H), 3.71-3.78 (m, 2H), 3.95-3.98 (m, 1H), 4.19-4.25 (t, 2H, J = 17, 15 Hz, J = 8.36 Hz), 7.17-7.29 (m, 5H).

Example D-2

Oxazolidin-2-ylidene- (3-o-tolylbicyclo [2.2.1] hept-2-yl) amine was prepared by substituting omethyl-beta-nitrostyrene according to the method of Example D-1.

Example D-3

Bicyclo [2.2.1] hept-2-yl-oxazolidin-2-ylidenamine was prepared by substituting nitrothene according to the method of Example D-1.

Example E-1

Procedure for the preparation of imidazolidin-2-ylidene- (4-methyl-3,4-dihydro-2H-benzo (1,4) oxazin-6-yl) amine:

X, ν '•

Cl

THF / reflux / 24h

(1) HCHO / NaBH ₃ CN

2) AcOH reflux ·· · «

Pd-C / H ₂ THF / MeOH (1: 1)

r ~ \ hn ^ n with ₃ h

2 ^C oW ^3N

Method

To 2-amino-4-nitrophenol (1) (4.00 g, 25.95 mmol), triethylamine (15.20 mL, 109.0 mmol) and 4-dimethylaminopyridine (0.063 g, 0.52 mmol) in a mixture in anhydrous CH 2 Cl 2 (250 mL) at 0 ° C under argon was added chloroacetyl chloride (2.27 mL, 28.55 mmol) via syringe. After heating at reflux for 72 hours, the pure product was filtered off and washed with water. The original liquid is then washed with phosphoric acid (0.5 M), saturated sodium bicarbonate solution, water and brine, and dried over MgSO 4. This solution is adsorbed onto n, silica gel and purified by silica gel chromatography (flash). chromatography) with hexane / ethyl acetate (4: 6) to give another product. The combined solid products were dried under vacuum to give pure 6-nitro-4H-benzo [1,4] oxazin-3-one (2) (4.12 g) in 82% yield. To a slurry of (2) (1.49 g, 7.65 mmol) in anhydrous THF (40 mL) under an argon atmosphere in a two neck and round bottom flask equipped with a reflux condenser was added borane dimethyl sulfide complex (15.3 mL, 30 mL). , 62 mmol). The mixture was heated to reflux until the starting material could no longer be detected by thin layer chromatography (2 hours). The reaction mixture was cooled to room temperature and methanol was carefully added dropwise. The resulting mixture was then heated at reflux for a further 10 minutes. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography with hexane / ethyl acetate (8: 2) to give pure 6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine (3). ) (1.36 g) as an orange solid in 99% yield. To (3) (0.032 g, 0.178 mmol) and formalin (37% in H 2 O, 0.20 mL, 2.67 mmol) in anhydrous acetonitrile (1.5 mL) at room temperature was added sodium cyanoborohydride (0.034 g, 0.534). mmol). This solution was stirred for 30 minutes, then glacial acetic acid (0.032 mL, 0.534 mmol) was added. The resulting mixture was stirred for an additional 16 hours. The organics were separated in diethyl ether and washed sequentially with NaOH (2 N) and brine, dried over MgSO 4 and concentrated in vacuo. The resulting solids were purified by flash chromatography with hexane / ethyl acetate (7: 3) to give pure 4-methyl-6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine (4) ( 0.031 g) with 91% yield. To (4) (2.16 g, 11.12 mmol) and 10% palladium on activated carbon (0.216 g, 10% by weight) under argon was added methanol (MeOH) (30 mL) followed by THF (30 mL). . Hydrogen was bubbled through the resulting slurry until no residues (4) (2 hours) were detected by thin layer chromatography. Celite was added and the mixture was filtered through a celite pad followed by washing.

MeOH. The resulting solution was concentrated in vacuo to give pure 4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylamine (5) (1.86 g) as a pale purple oil with 100% yield which without further purification. To compound (5) (1.86 g, 11.34 mmol) and imidazoline-2-sulfonic acid (1.84 g, 12.24 mmol) in anhydrous acetonitrile (50 mL) under argon at 0 ° C. Add triethylamine (3.26 mL, 23.36 mmol). This solution was gradually warmed to room temperature and stirred for 16 hours. During this time, an additional amount of imidazoline-2-sulfonic acid (0.86 g, 5.55 mmol) was added and the resulting mixture was stirred for an additional 5 hours. The solution was concentrated in vacuo and the residues taken up in H 2 O. The organics were extracted with CH 2 Cl 2 and washed twice with NaOH and brine, dried over MgSO ₄ and concentrated in vacuo. The resulting foam was purified by flash chromatography with 20% methanol (saturated ammonia) in chloroform to give pure imidazolidin-2-ylidene- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-6). -ylamine (6) (E-1) (0.905 g) in 34% yield.

¹ H NMR (CDCl 3): 2.81 (s, 3H), 3.26 (t, J = 8.9 Hz, 2H), 3.60 (s, 4H), 4.26 (m, 2H), 4.60 (vbrs, 2H), 6.34 (dd, J = 8.2 Hz, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 6, 68 (d, J = 8.2Hz, 1H).

Examples F and G

Preparation of 6- (imidazolidin-2-ylideneamino) -5-methyl-4H-benzo [1,4] oxazin-3-one (F) and imidazolidin-2-yliden-5-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) amine (G):

· «>’ Tt • ·

νη ₂

ΌΗ

2)

C, -Cl ^CI

Pd-C (10%) / hr ₂

THF-MeOH 1: 1

'6

EfcN (2.5 e-Uy.) CH ₃ CN / ref. 80h

Γ ~ \

NyNH

SO3H (3.6 elcv

Method

To 2-amino-3-methylphenol (1) (14.72 g, 0.12 mol), triethylamine (35.0 mL, 0.251 mol) and dimethylaminopyridine (0.29 g, 2.39 mmol) in anhydrous CH ₂ CI ₂ (100 mL) at 0 degrees Celsius in an argon atmosphere is added dropwise via a syringe via a syringe. · ·· · ·. Chloroacetyl chloride (10.0 mL, 0.126 mol). After the addition was complete, the resulting solution was heated to reflux for 24 hours. The organics were washed successively with phosphoric acid (0.5 M), saturated sodium bicarbonate solution, water and brine, and then dried over MgSO 4. The resulting solution was concentrated and separated in THF to which ether was added. The resulting crystals were filtered to give pure 5-methyl-4Hbenzo [1,4] oxazin-3-one (2) (12.30 g) in 63% yield. To (2) (14.64 g, 89.72 mmol) dissolved in concentrated H2SO4 (65 mL) at -10 degrees Celsius was added 70% HNO3 (8.08 g, 89.72 mmol) in concentrated H2SO4 ( 25 ml) with rapid mechanical stirring at a rate at which the internal temperature remains below -5 degrees Celsius. Immediately after the addition was complete, the mixture was poured onto crushed ice (500 mL) and the resulting solid products were filtered and slurried in cold water (300 mL) to form a slurry, adding sufficient NaOH to adjust the pH to 7. The yellow obtained the powder was dissolved in THF, allowed to adsorb onto silica gel and purified by flash chromatography with 60% hexane and ethyl acetate to give the nitro product as a mixture of two regioisomers, ie the desired 6-substituted aromatic containing 6-nitro-5-methyl-4H -benzo [1,4] oxazin-3-one (3) (55%) and an 8-substituted by-product containing 8-nitro-5-methyl-4H-benzo [1,4] oxazin-3-one (4) (22%). These isomers are difficult to isolate at this point and therefore proceed as a mixture to the next step. To a mixture of compounds (3) (1.93 g, 9.27 mmol) and (4) (0.48 g, 2.32 mmol) dissolved in a solution of MeOH (300 mL) and THF (300 mL) under argon atmosphere. 10% palladium on charcoal (1.20 g) was added. The resulting solution is then exposed to H ₂ at atmospheric pressure. After 16 hours, the catalyst was filtered off and the resulting solution was concentrated in vacuo and purified by flash chromatography with 50% hexane and ethyl acetate to give 6-amino-5-methyl-4H-benzo [1,4] oxazine-3 -one (5) (0.96 g) in 46% yield and 8 amino-5-methyl-4H-benzo [1,4] oxazin-3-one (6) (0.17 g) in 8% yield. (5) (1.20 g, 6.74 ·. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «

• imidazoline-2-sulfonic acid (2.02 g, m.p. 13.48 mmol) and triethylamine (2.35 mL, 16.85 mmol) were heated under reflux in anhydrous acetonitrile (50 mL) under argon for 48 hours. Additional amounts of imidazoline-2-sulfonic acid (1.01 g, 6.74 mmol) and triethylamine (1.41 mL, 10.12 mmol) were then added and the resulting mixture was stirred for an additional 24 hours. The solution was concentrated in vacuo and the residue was dissolved in CHCl 3 / iso -propyl alcohol (3: 1) solution and then washed with NaOH (1N) and brine, dried over MgSO 4 and concentrated in vacuo. The resulting foam was purified by flash chromatography on silica gel using 20% methanol saturated with ammonia in chloroform to give 6- (imidazolidin-2-ylideneamino) -5-methyl-4H-benzo [1,4] oxazin-3-one (7). (0.42 g) as a 27% yield foam along with 55% recycled starting material. The hydrochloric acid salt is recrystallized from a mixture of ethanol and diethyl ether (ΕίΟΗΖΕί ₂ Ο) to give fine white needles.

'NMR (DMSO): 2.10 (s, 3H); 3.59 (s. 4H); 4.53 (s, 2 H); 6.83 (d, J = 8.6Hz, 1H); 6.90 (d,

J = 8.6 Hz, 1H); 8.07 (brs, 2H); 1015 (brs, 1H); 10.42 (s, 1 H).

Compound (6) (0.222 g, 1.35 mmol), imidazoline-2-sulfonic acid (0.223 g, 1.49 mmol) and triethylamine (0.415 mL, 2.98 mmol) were heated at 95 degrees Celsius for 2 hours. Anhydrous acetonitrile (10 mL) in a sealed tube. An additional amount of imidazoline-2-sulfonic acid (0.112 g, 0.75 mmol) was then added and the reaction allowed to proceed for a further 16 hours.

The solution was concentrated in vacuo and the residue was dissolved in CHCl 3 / isopropanol (3: 1) and then washed with NaOH (2 N) and brine, dried (MgSO 4) and concentrated in vacuo. The resulting oil was recrystallized from CHCl 3 to give pure 6- (imidazolidin-2-ylideneamino) -5-methyl-4H-benzo [1,4] oxazin-3-one (8) (F) (0.048 g) as a white powder of 15 % yield together with 35% recycled starting material. To the porridge of

0 (:

(8) (0.08g, 0.321 mmol) in anhydrous THF (50 mL) under argon in a 3-neck round bottom flask equipped with a reflux condenser was added borane-dimethylsulfide complex (0.48 mL, 0.936 mmol). The mixture was heated to reflux until the starting material was no longer detectable by thin layer chromatography (3 hours). The reaction mixture was cooled to room temperature and carefully quenched by dropwise addition of methanol. The crude reaction mixture is concentrated in vacuo and purified by flash chromatography on silica gel using 20% methanol saturated with ammonia / chloroform to give imidazolidin-2-ylidene- (5-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) amine (9) (G) (0.03 g) as the HCl salt in 37% yield.

1 H NMR (CDCl ₃ ): 2.07 (s, 3H); 3.46 (t, J = 4.3Hz, 2H); 3.55 (s, 4H); 4.24 (t, J = 4.3Hz, 2H);

5.60 to 5.95 (vbrs, 2H); 6.44 (d, J = 8.0Hz, 1H); 6.57 (d, J = 8.0Hz, 1H).

Example H

Preparation of 4 (S) -phenylsulfanyl-1H-imidazole:

SO ₂ NMe ₂ +

If

SO ₂ NMe ₂

TBAF

SO ₂ NMe ₂

S. ν HCl

Procedure 1- (N, N-Climethylsulfamoyl) imidazole (1.5 g, 8.6 mmol) was dissolved in 28 mL THF. The solution was cooled to -78 degrees Celsius and n-Buli (5.4 mL, 5.6 mmol) was added dropwise via cannula. After stirring at -78 degrees C for 1 h, TBSCl (1.3 g, 8.65 mmol) in 10 mL of THF was added. Remove the bath and allow the reaction mixture to warm to room temperature. The reaction mixture was then stirred overnight. The reaction mixture was cooled to -20 degrees Celsius and n-Buli (5.4 mL, 8.6 mmol) was added. After 45 min, phenyl disulfide (1.9 g, 8.6 mmol) in 8 mL of THF was added. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic solvent layer was separated and washed with water and then brine. The organic layer was collected and washed with water and then brine. The solution was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography gave 2.5 g (7.0 mmol) of 2- (t-butyldimethylsilyl) -5-phenylsulfanyl-imidazole-1-sulfonic acid dimethylamide (1) as a yellow solid. oily substances. Compound (1) (2.8 g, 7.0 mmol) was dissolved in THF and the solution was cooled to 0 degrees Celsius. TBAF (7.0 mL, 7.0 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature overnight. The next day the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine. The solution was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (50% EtOAc / hexane) yielded 474 mg of 5-phenylsulfanilimidazole-1-sulfonic acid dimethylamide (2) and 290 mg of 5-phenylsulfanyl-1 H -imidazole (3) (H). 478 mg of compound (2) was added to 2N HCl and the solution was refluxed for 2 hours. The reaction mixture was basified with 2 N NaOH and extracted with ethyl acetate. The organic solvent layer was washed with water followed by brine. The solution is dried over sodium sulphate and the solvent is removed under t t t t t t t t t t t t t t t pod pod pod tt tttt tt tttt tttt reduced pressure. Flash chromatography (EtOAc) gave compound (3) as a white crystalline solid. Mixing gave a total amount of 360 mg (2.0 mmol) of compound (3).

¹ H NMR (300 MHz, CD ₃ OD): 7.91 (s, 1H), 7.37 (s, 1H), 7.19-7.23 (m, 2H), 7.07-7.11 (m,

3H).

Example I

Preparation of 4 (S) - (1,2,3,4-tetrahydronaphthalen-2-ylmethyl) -4,5-dihydro-1H-imidazole methanesulfonate:

O

BH _{3 -} Me ₂ S

HIM'

1) Ex

THF / 20 ° C

2) ₁₂ / benzene.

THF / CuI -78 ° C to 25 ° C

24h / 70 ° C

NaN ₃ / acetone-F 2 O

Method

To 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1) (4.93 g, 27.42 mmol) in anhydrous THF (250 mL) at 20 degrees Celsius under argon was added via cannula 3.26 mL (32.90 mmol) of borane-dimethylsulfide (BH 3 -Me ₂ S). After stirring for 16 hours, MeOH (4 mL) was added and the mixture was heated to 55 degrees Celsius until gas evolution no longer occurred. The mixture is concentrated to an oil, dissolved in Et ₂ O and then washed with 2 M hydrochloric acid • '♦ · · · tt tttt tt ·· · ¹ · TT' » 'tt' ti .tttt ♦ tt tt · tttttt.» - tt tt «.

• ···· · tt »· tt 'tt-tt' - - tt · tt · tttttt · tttttt ·« · '·.' . The reaction mixture was dried over MgSO 4 and concentrated again. The resulting oil was purified under high vacuum (Kugelrohr distillation) at 150 degrees Celsius to give pure alcohol (1,2,3,4-tetrahydronaphthalen-2-yl) methanol (2) (4.09 g) in 93% yield. To triphenylphosphine (10.179 g, 38.809 mmol) and imidazole (2.64 g, 38.809 mmol) in anhydrous benzene (75 mL) was added iodine (8.06 g, 33.865 mmol) in benzene (75 mL) with rapid stirring followed by compound (2) in benzene (50 mL). After 3 hours, the solids are filtered off and the filtrate is reduced to 50 ml in vacuo. Hexane (200 mL) was then added. The resulting solids were filtered off, and the filtrate was subsequently washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel with hexane to give pure 2-iodomethyl-1,2,3,4-tetrahydronaphthalene (3) (6.239 g) in 90% yield. To compound (3) (10.02 g, 36.85 mmol) and CuI (1.41 g, 7.37 mmol) in anhydrous THF (50 mL) at -78 degrees Celsius under argon was slowly added vinylmagnesium bromide ( 1M in THF, 73.70 mL, 73.70 mmol) slowly so as not to stain. This solution was allowed to warm to 0 degrees Celsius and stirred for 6 hours. The resulting mixture was recooled to -40 degrees Celsius and quenched cautiously with 2 M phosphoric acid (35 mL). This solution was diluted with 100 mL of water and extracted with hexanes. The organic fractions were then washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel with hexane to give 2-allyl-1,2,3,4-tetrahydronaphthalene (4) (5.618 g) in 88% yield. Compound (4) (5.615 g, 32.645 mmol) and meta-chloroperbenzoic acid (m-CPBA) (14.08 g, 81.613 mmol) were stirred in anhydrous methylene chloride (50 mL) for 16 h. The solids were filtered off and KF (5.11 g, 88.142 mmol) was added, and the mixture was stirred for an additional hour.

The solids were filtered off and the reaction concentrated in vacuo. The resulting oily substance · "" · * 88 88 » '· 8' 8]» '·''* 8 · 8 ·' · '8 8 »·»; 8 / »' · ^'•! '' · '''' - <- '- - · · · · ···. Purify by flash chromatography on silica gel with 5% ethyl acetate in hexane to give 2- (1,2,3,4-tetrahydronaphthalen-2-ylmethyl) oxirane (5) (5.41 g). ) with 88% yield. To compound (5) (1.626 g, 8.649 mmol) in a solution of acetone (20 mL) and water (5 mL) was added sodium azide (1.97 g, 30.271 mmol). This solution was heated to 85 degrees Celsius and stirred for 48 hours. The solution was concentrated in vacuo and the residue was dissolved in CHCl ₃ and then washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel with 30% ethyl acetate in hexane to give pure 1-azido-3 (1,2,3,4-tetrahydronaphthalen-2-yl) propan-2-ol (6). (1.722 g) with 88% yield. A mixture of compound (6) (1.88 g, 8.140 mmol), triphenylphosphine (2.67 g, 10.173 mmol), phthalimide (1.50 g, 10.173 mmol), diethyl azodicarboxylate (DEAD) (1.77 g, 10.173 mmol) The mixture was stirred for 4 hours in anhydrous THF (50 mL). This solution was concentrated in vacuo, dissolved in a solution of hexane (25 mL) and ether (25 mL) and stirred for 16 hours. The solids were filtered off and the filtrate was concentrated in vacuo. The resulting oil is purified by flash chromatography on silica gel with 20% ethyl acetate in hexane to give 2- [1-azidomethyl-2- (1,2,3,4-tetrahydronaphthalen-2-yl) ethyl] isoindole-1, 3-dione (7) (2.487 g) contaminated with a small amount of impurities that were not removed by further purification. A mixture of compound (7) (3.93 g, 10.917 mmol) and hydrazine (0.680 mL, 21.833 mmol) was refluxed in ethanol (60 mL) for 16 h. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 5% MeOH in CH ₂ Cl ₂ to give 1azidomethyl-2- (1,2,3,4-tetrahydronaphthalen-2-yl) ethylamine (8) (2.057 g) with 88% yield.

A mixture of (8) (2.056 g, 8.940 mmol) and 10% palladium on charcoal (0.260 g) was stirred in MeOH (30 mL) under hydrogen at 1 atm for 16 hours. The solids were filtered off and the filtrate was concentrated in vacuo. The residue is purified by flash chromatography on silica gel with 10% MeOH saturated with ammonia in CH 2 Cl 2 to give 3- (1,2,3,4-tetrahydronaphthalen-2-yl) propane-1,2-dione (9) (1,557) g) with 85% yield. A mixture of compound (9) (0.590 g, 2.892 mmol) and methanesulfonic acid (0.980 mL, 14.460 mmol) was heated in triethyl orthoformate (10 mL) at 105 ° C for 3 h. The reaction mixture was concentrated in vacuo and the solids were filtered off. Subsequent recrystallization of these solids from a mixture of MeOH and ether affords pure 4 (S) - (1,2,3,4-tetrahydronaphthalen-2-ylmethyl) 4,5-dihydro-1H-imidazole methanesulfonate (I) (0.435 g). 48% yield.

¹ H NMR (CDCl 3): 1.37-1.56 (m, 1H), 1.56-1.70 (m, 1H), 1.80-2.02 (m, 2H), 2.32-1.5 2.55 (m, 2H); 2.72 to 2.95 (m, 3H); 3.48 to 3.59 (m, 1H); 3.93 to 4.08 (m, 1H); 31 to 4.47 (m, 1H), 7.00 to 7.20 (m, 4H), 8.46 (s, 1H), 10.04 (s, 1H), 10.35 (brs, 1H) .

Example J-1

Preparation of 4 (S) -cyclohexylmethyl-1H-imidazole:

rt SAtbs SO ₂ NMe ₂ 1 1) n-BuLi SO ₂ NMe _{2 Λ} ² TBAF oaz ™ 3 ^2, cc SO? NMe? H cn \ N reflux N 4 5

Method

2-Tert-Butyldimethylsilyl-1-dimethylsulfamoylimidazole (1) (4.1 g, 14.2 mmol) was dissolved in 47 mL of anhydrous THF and cooled to -20 degrees Celsius. n-BuLi (8.9 ml,

4 ',' 4 '4

Φ 4> Φ · ΦΦ '· I Φ · ···· 4 * 4 4 · «<4' 4 · · 44 44 Φ 4 4 '4 4 4« · · 4 4 4' · 4 '· ··

14.2 mmol) is added dropwise to solution (1). The resulting solution was stirred at -20 degrees Celsius for 45 min. Cyclohexylmethyl iodide (2) (3.14 g, 14 mmol) was then added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature and stirred overnight. The next day the reaction was quenched with saturated ammonium chloride solution and diluted with water. The mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and washed with water followed by brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (4: 1 ethyl acetate / hexane) afforded 2.26 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsulfamoylimidazole (3). Compound (3) (2.26 g, 5.6 mmol) was dissolved in 56 mL THF and cooled to 0 ° C. A 1M solution of TBAF (5.6 mL, 5.6 mmol) was added dropwise to solution (3). The reaction mixture was warmed to room temperature and stirred overnight. The next day the reaction was quenched with water and then extracted with ethyl acetate. The organic layer was washed with water followed by brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (1: 1 ethyl acetate / hexane) gave 1.2 g (4.42 mmol) of 5-cyclohexylmethyl-1-dimethylsulfamoylimidazole (4). Compound (4) (1.2 g, 4.42 mmol) was dissolved in 25 mL of 1.5 N HCl solution and refluxed for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the mixture was adjusted to 13 with 2 N NaOH and then extracted with chloroform (4 x 100 mL). The organic layers were combined and washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. Flash chromatography (9: 1 chloroform / methanol) yielded 700 mg (4.27 mmol) of 4 (S) -cyclohexylmethyl-1H-imidazole (5) (J-1).

¹ H NMR (CDCl ₃ ): 0.92-1.0 (m, 2H), 1.16-1.26 (m, 3H), 1.57-1.73 (m, 6H), 2.48 (d,

J = 6.9 Hz, 2H), 6.77 (s, 1H), 7.56 (s, 1H).

4'4 '• 4 ·· | · ·' · · »9 · * 4 .4 · 4 4 '

4 4 43 · 4 · 4 4 4

4 4 4 4 4

Example J-2 (S) -2-iodomethyl-1,2,3,4-tetrahydronaphthalene is substituted according to the method of Example J-1 to give (S) -4 (5) - (1,2,3,4) (tetrahydro-naphthalen-2-ylmethyl) -1H-imidazole. (S) -2-Iodomethyl-1,2,3,4-tetrahydronaphthalene was prepared from (S) -1,2,3,4-tetrahydro-2-naphthoic acid. (S) -1,2,3,4-tetrahydronaphthoic acid is prepared by melting 1,2,3,4-tetrahydronaphthoic acid (J. Med. Chem. 1983, 26, 328-334).

Example J-3 (R) -2-iodomethyl-1,2,3,4-tetrahydronaphthalene is substituted according to the method outlined in Example J-1 to give (R) -4 (5) - (1,2,3,4) (tetrahydro-naphthalen-2-ylmethyl) -1H-imidazole. (R) 2-Iodomethyl-1,2,3,4-tetrahydronaphthalene was prepared from (R) -1,2,3,4-tetrahydro-2-naphthoic acid. (R) -1,2,3,4-tetrahydro-naphthoic acid is prepared by melting 1,2,3,4-tetrahydro-naphthoic acid (J. Med. Chem. 1983, 26, 328-334).

Example K-1

Preparation of 4 (S) - (4,5,6,7-tetrahydrobenzo [b] thiophen-2-ylmethyl) -1H-imidazole:

• · • · ' »· ·· ·· ·· «· • * * «Ί • · • • •. » • Φ • • • • • • · • · • · • • ·· · • • » • · ··

1) n-BuLi

2)

OHC [| γ-TBDMS SO ₂ NMe ₂

TBDMS

SO ₂ NMe ₂

Method

4,5,6,7-tetrahydrobenzo [b] thiophene (1) (2.1 g, 15 mmol) was dissolved in 75 mL of anhydrous THF and cooled to -78 ° C. n-Buli (6.0 mL, 15 mmol) was added dropwise to solution (1). The resulting solution was stirred at -78 ° C for 60 min. 1-Dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde (2) (4.8 g, 15 mmol) in 25 mL of THF was added to the reaction. The reaction mixture was warmed to room temperature and stirred for 2 hours before quenching with water and diluting with ethyl acetate. The organic layer was washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. By flash chromatography (1: 3 ethyl acetate / hexane) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «9 9« «9 9 · · 9

9 9 9 9 9

9 9 9 9 9.9 99 · * yielding 5.2 g (11 mmol) of 2- (tert-butyldimethyisilyl) -5- [hydroxy (4,5,6,7-tetrahydrobenzo [b] thiophen-2) dimethylamide] -yl) methyl] imidazole-1-sulfonic acid (3). Compound (3) (5.2 g, 11.3 mmol) was dissolved in 57 mL of THF. A 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF (11.3 mL, 11.3 mmol) was added dropwise to solution (3). The reaction mixture was stirred for 1 hour 15 min before quenching with water and then extracting with ethyl acetate. The organic layer was washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. Recrystallization from hexane / ethyl acetate gave 5- [hydroxy- (4,5,6,7-tetrahydro-benzo (b) thiophen-2-yl) -methyl] -imidazole-1-sulfonic acid dimethylamide (4) (2.1 g, 6.2 mmol) Compound (4) (2.0 g, 5.9 mmol) was dissolved in 78 mL of dichloromethane, 7.5 mL (46.9 mmol) of triethylsilane and 14 mL of methylene chloride were added. The reaction mixture was stirred overnight at room temperature, then quenched with water and neutralized with 2 N NaOH, the organic layer was washed with water followed by brine. Flash chromatography with ethyl acetate / hexane 1: 1 gave 0.75 g (2.3 mmol) of 5- (4,5,6,7-tetrahydrobenzoic acid) dimethylamide. [b] thiophen-2-ylmethyl) imidazole-1-sulfonic acid (5).

Compound (5) (0.42 g, 1.55 mmol) was dissolved in 15 mL of 1.5 N HCl solution and heated at reflux for 2 hours then stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and neutralized with 2 N NaOH. The organic layer was washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The crude product was dissolved in methanol and excess HCl in ether was added. The solvent was removed under reduced pressure to give 0.6 g (2.3 mmol) of 4 (S) - (4,5,6,7-tetrahydro-benzo [b] thiophen-2-ylmethyl) -imidazole (6) (K-1).

φ ' »· φ φφ φφ φφ • Φ φ φφφ» φφφφ φφ φ φφφφ φφφφ φ φφφφ φ ♦ φ φ ' φφφ · φ φ φ φ φφφφ φφφφ φφφ φ φφ φφ φφ φφ ¹ Η NMR (CD ₃ OD): 8 80 (s, 1Η), 7.34 (s, 1,), 6.57 (s, 1Η), 4.18 (s, 2Η), 2.65-2.69 (m, 2H), 2 51 to 2.55 (m, 2H); 1.74 to 1.83 (m, 4H).

Example K-2

2- (Tert-butyl) furan is substituted according to the method of Example K-1 to give 4- (5) - (5-tert-butylfuran-2-ylmethyl) -1H-imidazole.

Example K-3

5,6-Dihydro-4H-thieno [2,3-b] thiopyran is substituted according to the method described in Example K-1 to give 4 (S) - (5,6-dihydro-4H-thieno [2,3-b] thiopyran-2) -ylmethyl) -1H-imidazole.

Example L

Preparation of 4 (S) - (1-furan-2-ethyl-ethyl) -1H-imidazole:

• * 99 99 • 9 99 • 9 · • 9 ' • 9 9 9 9 9 9 · • • 9 • 9 9 9 9 « 9 9 9 9 • 9 9 9 • « 999 9 9 « 99 99 99

AND

SO ₂ NMe ₂

1) n-BuLi

TBAF

Et ₃ SiH

CF ₃ CO ₂ H

Crf ₂ Cl ₂

MeMgCI

1.5NHCl reflux

Method

2- (Tert-Butyldimethylsilyl) -1- (dimethylsulfamoyl) imidazole (1) (3.3 g, 11.4 mmol) was dissolved in 38 mL of anhydrous THF and cooled to -78 ° C. n-Buli (7.2 mL, 11.4 mmol) was added dropwise to solution (1). The resulting solution was stirred at -78 ° C for 30 min. 2-Furfural (2) (0.94 mL, 11.4 mmol) was added to the reaction. The reaction mixture is warmed to room temperature and ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft Ftftft ftft ftft ftft ftft ·· stir overnight. The next day, the reaction was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The organic layer was washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. Flash chromatography (4: 1 ethyl acetate / hexane) afforded 4.4 g (11.4 mmol) of 2- (t-butyldimethylsilyl) -5- (furan-2-ylhydroxymethyl) imidazole-1-sulfonic acid dimethylamide ( 3). Compound (3) (4.4 g, 11.4 mmol) was dissolved in 110 mL of THF and cooled to 0 ° C. A 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF (11.4 mL, 11.4 mmol) was added dropwise to solution (3). The reaction mixture was stirred at room temperature overnight. The next day the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. 3.9 g of crude 5- (furan-2-ylhydroxymethyl) imidazole-1-sulfonic acid dimethylamide (4) are obtained. Compound (4) (1.0 g, 3.7 mmol) was dissolved in 37 mL of dichloromethane, and 1.6 g (18.5 mmol) of manganese dioxide was added. The reaction mixture was stirred overnight at room temperature and then filtered through Celite. The solvent was removed from the eluent under reduced pressure.

Flash chromatography using ethyl acetate / hexane (1: 1) afforded 0.69 g (2.6 mmol) of 5- (furan-2-ylcarbonyl) imidazole-1-sulfonic acid dimethylamide (5). Compound (5) (0.69 g, 2.6 mmol) was dissolved in 26 mL of THF.

The solution was cooled to -78 ° C. Add 1.7 mL (5.1 mmol) of a 3 M methylmagnesium chloride solution. After stirring at -78 ° C for 1.5 h, the reaction mixture was warmed to room temperature and stirred for an additional hour. The reaction mixture was quenched with water and then extracted with ethyl acetate.

The organic layer was washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether / hexane gave 0.39 g (1.4 mmol) of 5- (1-furan-2-yl-1-hydroxy-ethyl) -imidazole-1-sulfonic acid dimethylamide (6). An additional 0.19 g of compound (6) was obtained. Compound • 9 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 (6) (0.58 g, 2.0 mmol) is dissolved in 27 ml of dichloromethane and 2.6 ml (16.3 ml) is added to the solution. mmol) of triethylsilane and 5.5 ml (71.4 mmol) of trifluoroacetic acid. The reaction mixture was stirred overnight at room temperature and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer was washed with water followed by brine.

The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. Flash chromatography (ethyl acetate / hexane 2: 1) yielded 0.53 g (2.0 mmol) of 5- (1-furan-2-ethyl-ethyl) -imidazole-1-sulfonic acid dimethylamide (7). Compound (7) (0.34 g, 1.3 mmol) was dissolved in 10 mL of 1.5 N HCl solution and heated at reflux for 30 min and then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and then basified with 2 N NaOH. The organic layer was washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. Flash chromatography (10: 1 chloroform / methanol) gave 0.1 g (0.62 mmol) of 4- (5) - (1-furan-2-ylethyl) -1H-imidazole (8) (L). .

¹ H NMR (300 MHz, CDCl ₃ ) 7.56 (m, 1H), 7.33-7.34 (m, 1H), 6.81 (m, 1H), 6.29-6.31 (m ,

1H), 6.06-6.07 (m, 1H), 4.22 (q, J = 7.2Hz, 1H), 1.63 (d, J = 7.2Hz, 3H).

Example M

Preparation of 4 (S) - (2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) -4-methyl-1H-imidazole:

SO ₂ NMe ₂

1) n-BuLi

2) TBDMSCI

θ ^Η SO ₂ NMe ₂

θ ^Η SO ₂ NMe ₂ N> -TBS

TBAF

Et, SiH

CF, CO ₂ H

CH ₂ Cl ₂

1.5 N HCl reflux

Method

4-Methyl-1- (dimethylsulfamoyl) imidazole (1) (2.0 g, 10.6 mmol) was dissolved in 42 ml of anhydrous THF and cooled to -78 ^Q C. n-BuLi (6.6 mL, 10 6 mmol) is added dropwise to solution (1). The resulting solution was stirred at -78 ° C for 30 min. To the reaction was added tert-butyldimethylsilyl chloride (TBSCI) (1.6 g, 10.6 mmol) in 10 mL of THF. The reaction mixture was warmed to room temperature and stirred overnight. The following day, the reaction mixture was cooled to -20 ° C and n-Buli (7.3 mL, 11.6 mmol) was added. After stirring at -20 ° C for 30 min, 1,4-benzodioxane-6-carboxaldehyde (2) (1.92 g, 11.7 mmol) in 10 mL of THF was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with water followed by brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (1: 2 ethyl acetate / hexane) yielded 2.9 g (8.4 mmol) of 2- (t-butyldimethylsilyl) -5 - [(2,3-dihydrobenzo [1,4] dioxine-] dimethylamide; 6-yl) hydroxymethyl] -4-methylimidazole-1-sulfonic acid (3). Compound (3) (1.0 g, 2.14 mmol) was dissolved in 21 mL of THF. A 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF (2.35 mL, 2.35 mmol) was added dropwise to solution (3). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layer was washed with water followed by brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography using ethyl acetate as eluant gave 0.75 g (2.12 mmol) of 5 - [(2,3-dihydrobenzo [1,4] dioxin-6-yl) hydroxymethyl] -4-methylimidazole-1 dimethylamide. - sulfone (4). Compound (4) (0.75 g, 2.12 mmol) was dissolved in 28 mL of dichloromethane, 2.7 mL (17.0 mmol) of triethylsilane and 5.2 mL (67.8 mmol) of trifluoroacetic acid were added. . The reaction was stirred overnight at room temperature and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer was washed with water followed by brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography using a 3: 1 mixture of ethyl acetate and hexane gave 0.63 g (1.87 mmol) of 5- (2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) dimethylamide. 4-methylimidazole-1-sulfonic acid (5). Compound (5) (0.63 g, 1.87 mmol) was dissolved in 10 mL of 1.5 N HCl and heated to reflux. The reaction mixture was diluted with ethyl acetate and neutralized with solid sodium bicarbonate. The organic layer was washed with water followed by brine. The organic phase is dried over sodium sulphate and the solvent is dried over sodium sulphate and the solvent is evaporated. * ·· is removed under reduced pressure. Crystallization from ether / hexane gave 0.33 g (1.43 mmol) of 4- (5) - (2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) -4-methyl-1H-imidazole (6). (M).

¹ H NMR (300 MHz, acetone-d ⁶ ) 7.37 (s, 1H), 6.66-6.67 (m, 3H), 4.18 (s, 4H), 3.73 (s, 1H) )

2.13 (s, 3H).

Example N

Preparation of 2- (3H-imidazol-4 (S) -ylmethyl) -3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (N-1), 4 (5) - (2) , 3,4,4a, 5,6,7,8-octahydronaphthalen-2-ylmethyl) -1H-imidazole (N-2) and 4 (5) - (1,2,3,4,5,6, 7,8-octahydronaphthalen-2-ylmethyl) -1H-imidazole (N-3):

O

1) NaOH / EtOH reflux

2) 40% H ₂ SO ₄ reflux

N

H

H ₂ NNH ₂

NaOH, reflux diethylene glycol

Method

1-Decalon (10.0 g, 66 mmol) and 4 (S) -imidazolecarboxaldehyde (6.3 g, 66 mmol) were added to 100 mL ethanol. To the solution was added NaOH (5.2 g, 130 mmol) in 20 mL of water. The reaction mixture was heated to reflux for 5 days. The reaction mixture was cooled. The reaction mixture was cooled. Tttttttttttttttttttt to room temperature and basified with aqueous HCl solution. The solution was extracted with THF / ethyl acetate. The organic layers were combined and washed with brine. The organic phase is dried over magnesium sulphate and the solvent is removed under reduced pressure to give the crude product. The crude product was refluxed in 40% H 2 SO 4 for 1 day. The reaction mixture was cooled to room temperature and basified with saturated K 2 CO 3 solution. The solution was extracted with THF / ethyl acetate. The organic layers were combined and washed with brine. The organic phase is dried over magnesium sulphate and the solvent is removed under reduced pressure. Purification by flash chromatography (15: 1 CH ₃ Cl / 1 H / OH) afforded N-1 (4.9 g, 32% yield).

¹ H NMR: 7.55 (s, 1H), 6.77 (s, 1H), 3.08-3.14 (m, 2H), 1.52-2.46 (m, 13H).

N-1 hydrochloride free base (3.0 g, 11 mmol) was prepared with NaOH and then added to diethylene glycol (100 mL). To the solution was added hydrazine hydrate (3.2 mL, 100 mmol) and the reaction mixture was allowed to stir overnight at room temperature. NaOH (3.1 g, 77 mmol) was added and the solution was heated to reflux for 5 days. The reaction mixture was cooled to room temperature and diluted with water. The solution was extracted with THF / ethyl acetate. The organic layers were combined and washed with brine. The organic phase is dried over magnesium sulphate and the solvent is removed under reduced pressure. Purification by flash chromatography (8: 1 CH 2 Cl / MeOH) gave N-2 (0.64 g, 27% yield).

¹ H NMR: 7.58 (s, 1H), 6.76 (s, 1H), 5.24 (d, J = 4.3 Hz, 1H), 0.91-2.58 (m, 16H) .

Compound N-2 (1.0 g, 4.6 mmol) was added to 10 mL of concentrated HCl. The solution was stirred at room temperature for 30 min and then neutralized with K 2 CO 3. The solution was extracted with THF / ethyl acetate. The organic layers were combined and washed with brine. Dry the organic phase over magnesium sulfate and remove the solvent by ⁵³

I • 4 • 4 • 4 4

4 4 4 ··· · 4 · β

4444 ··· ·· 4 4 · · 4 4

4 4 4 4 4 · · ·

4 4 4 4 44 44 44 reduced pressure. Purification by flash chromatography (15: 1 CH 2 Cl / MeOH) gave N-3.

¹ H NMR: 7.54 (s, 1H), 6.74 (s, 1H), 2.45-2.52 (m, 3H), 1.46-1.97 (m, 14H).

Example O

Preparation of 4 (S) -octahydropentalen-2-ylmethyl) -1H-imidazole hydrochloride:

pcc, ch ₂ or ₂ rcflux

H '0

Method

A. Following synthesis by the procedure of White and Whitesell, Synthesis, p. 602-3 (1975), ether (10 mL) was placed in a flask, dried over a flame and cooled to 0 ° C, which was then kept under an argon atmosphere. Then, n-butyl lithium (35 mL of a 2.5 M solution in hexane, 2.2 equivalents) was added, followed by slow addition of diisopropylamine (14 mL, 2.5 mL). * '· «* ♦» fc · ···· · · • · · · · f · f f f f f f f f f f f And the mixture was allowed to stir at 0 ° C for 30 minutes. To the thus prepared lithium diisopropylamide solution was added cyclooctenoxide (5.0 g, 1.0 equivalents). The mixture was stirred at room temperature for 1 day and then refluxed under argon for 2 days. The reaction is stopped by addition of NH 4 Cl. The solution was extracted with THF / EtOAc. The organic extracts were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 1-hydroxy-octahydropentalene as a tan oil. The compound was used in the next step without further purification.

B. The thus obtained alcohol (5.0 g, 1 equivalent) was dissolved in dichloromethane (200 mL) and pyridinium chlorochromate (13 g, 1.5 equivalents) was added and the mixture was stirred at room temperature for 1 day. The solution was then filtered through a short column of SiO ₂ using diethyl ether as eluent. The resulting solution was concentrated in vacuo to give a pale green-yellow oil which was used in the next step without further purification.

C. Oktahydro-pentalen-1-one (5.0 g, 1.0 equivalent) from the previous step was added to 4 (S) -imidazolecarboxaldehyde (3.8 g, 1.0 equivalent) and 40% H2SO4 (20 mL) The mixture was kept at 90 ° C for 3 days. The reaction was then quenched by addition of ammonium hydroxide and extracted with tetrahydrofuran / ethyl acetate. The organic extracts are combined, washed with brine and dried over magnesium sulfate. The resulting aqueous layer was neutralized with HCl / NH 4 Cl. The aqueous layer was re-extracted as above and the combined organic fractions were concentrated in vacuo to give an orange solid.

D. Dissolve this orange solid in ethanol to which palladium on charcoal (0.5 g) was added. The reaction flask was placed under 40 psi of hydrogen for 1 day. The reaction solution was filtered through Celite along with additional ethanol used as eluent. The solution was concentrated in vacuo to give a tan oil. Purification by column chromatography using a 17: 1 chloroform / methanol mixture gives the ketone product in an incomplete pure state.

Υ '· - - - - - - - ♦; · ·; ························································

Ε. The ketone functionality was then removed by adding the product from the previous step (8.2 g, 1.0 equivalents) to diethylene glycol (80 mL) and hydrazine hydrate (13.0 g, 1.0 equivalents). Potassium hydroxide (11.0 g, 5.0 equivalents) was added and the solution was heated at reflux for 1 day. The reaction solution was cooled to room temperature and washed with water. The solution was extracted with THF / EtOAc and the combined fractions were washed with brine. over magnesium sulfate and concentrated in vacuo to give a yellow oil The monohydrochloride salt was prepared by dissolving the oil in anhydrous ethanol saturated with HCl and heating.

Example P

Preparation of 7- (3H-imidazol-4 (5) -ylmethyl) -6,7-dihydro-5H-isoquinolin-8-one (P1) and 7- (3H-imidazol-4 (5) -ylmethyl) -5 (6 ₎ 7,8-tetrahydroisoquinoline (P-2):

1) H ₂ , Pd / C

2) K ^ · _f

P-l

P-2

Method

A. Dissolve 3,4-lutidine (21.4 g, 1 equivalent) in 200 ml of water at 20 ° C and add potassium permanganate in 6.32 g portions twice daily for a total of 63.2 g, 2 equivalents). After 5 days, the solution is stored in the freezer, then thawed, and allowed to thaw. · '♦.

• 9 4 9 9 9 9 9

9 9 9 9 4 9 4

4 4 '4 »4 4 4 <41 4 4 is filtered through Celite. The resulting colorless solution was concentrated at 90 ° C in a rotary evaporator until a white solid was obtained. This solid was recrystallized from 5N HCl to give 9.56 g of white crystals. NMR showed a mixture of two regioisomers, the desired isomer being the major product.

B. The crystals were refluxed in anhydrous ethanol saturated with gaseous HCl under an argon atmosphere for 6 hours. Then the ethanol is removed from the solution by rotary evaporation and the residue is dissolved in 100 ml of water and the pH is adjusted to between 7 and 8 with solid sodium bicarbonate. The aqueous phase is extracted with diethyl ether (3x) and the combined organic fractions are washed with brine. over magnesium sulfate and then filtered and concentrated to give a colorless oil (3.56 g, 10.8% yield).

C. Diisopropylamine (2.84 g, 1.3 equivalents) was added via cannula to n-BuLi (11.21 mL, 1.3 equivalents) in 100 mL of anhydrous THF under argon atmosphere at -78 ° C to prepare lithium diisopropylamide in situ. To this solution was added via cannula the product from previous step B (3.56 g, 1 equivalent) in 20 mL tetrahydrofuran, and the mixture was stirred at -78 ° C for 20 min. At this point, methyl acrylate (4.85 ml,

2.5 equivalents) in 20 mL of tetrahydrofuran. The solution was stirred for an additional 2 hours and then quenched by the addition of 40 mL of 10% potassium acetate. The solution was allowed to warm to 20 ° C and then concentrated on a rotary evaporator. The aqueous residue was extracted three times with chloroform. The combined fractions were washed with brine and dried over magnesium sulfate, filtered and concentrated to a black solid which was stored under high vacuum. Chromatography on silica gel with hexane / ethyl acetate (7/3 6/4) gave 2.41 g (58.2%) of the desired product which was used in the next step without further purification.

D. The material from Step C (0.48 g, 1 equivalent) was dissolved in 1 mL of 6 M HCl and heated at 105 ° C for 16 hours, then the solution was concentrated to a solid by rotary evaporation at 80 ° C.

• 9 9 9 9 9 9 9 9 4 · '44 4 4 4 4 44 4 · 4 ·

4444 44 44 4

4,444 4,444

444 * 9 9 44 ·· ··

The residue was dissolved in 2 mL of water and neutralized with solid sodium bicarbonate. The neutralized solution was extracted with chloroform (3x) and the combined fractions were washed with brine, dried over magnesium sulfate and concentrated to give a colorless oil (0.456 g, 93.4%).

E. Isoquinolone (1.91 g, 1 equivalent) obtained in Step D above was heated for 30 hours with 4 (S) -imidazolecarboxaldehyde (1.25 g, 1 equivalent) at 110 ° C in 15 mL of 40% sulfuric acid. The reaction mixture was stored under argon at 0 ° C for several days. The solution was then diluted with 20 mL of water and basified to pH 8.9 with NH 4 OH. The solids were collected by filtration and dried under high vacuum. The product as a yellow solid (2.81 g, 96.1%) contains a mixture of both positional isomers in an exo double bond.

F. Dissolve the product of Step E in 150 mL of methanol and add Pd / C (0.412 g, 0.15 equivalent weight) to this solution. The methanol solution is then saturated with H ₂ by repeated evacuation and refilling with hydrogen. The solution was then stirred for 20 hours under a H ₂ pressure of 1 atmosphere until no starting unsaturated material remained by TLC. The solution was then filtered through Celite and concentrated to an oil. Chromatography on silica gel using dichloromethane and methanol (9/1) gave pure product (1.853 g, 65.04%) as a white foam. This was dissolved in methanol to which fumaric acid (0.4817 g, 1.5 equivalents) was added and the mixture was heated to dissolve the solids. The solution was cooled slowly to give off-white crystals (0.826 g, 74%) which represented Compound P-1. Compound P-2 is obtained by hydrazine reduction in the same manner as described in Step E above

Example O.

í>

Example Q

Preparation of (Z) -6- (3H-imidazol-4 (5) -ylmethylene) -7,8-dihydro-6H-quinolin-5-one (Q-1), (E) -6- (3H-imidazole -4 (5) -ylmethylene) -7,8-dihydro-6H-quinolin-5-one (Q-2), 6- (3H-imidazol-4 (5) -ylmethyl) -7,8-dihydro-6H-quinoline -5-one (Q-3), 6- (3H-imidazol-4 (5) ylmethyl) -5,6,7,8-tetrahydroquinolinedihydrochloride (Q-4), and 6- (3H-imidazol-4 (5)) -ylmethyl) octahydroquinolin-5-one (Q-5):

NaN ₃ . CH ₃ CN, CU

N, »· ♦: · 9. · · _{+ + +} • •>>>>>

Η, Ο. Na ₂ S ₂ O ₃ DMF, NaN ₃

CH 3 Cl 2, Ph 3 P, rt

40% H ₂ SO ₄ , 90 ° C

N,

N = PPh ₃

1) hydrazine. diethyien glycol

2) KOH

3) Ha

Λ / fcroUin

Pd / C ΐα HoutuVlo tsowietru

Li / _NH3

H ₂ . Pd / C MeOH mp. tt ttt ttt ttt ttt ttt ttttt tt ttt ttt ttt ttt ttt tttt

Method

A. The reactive azido reagent of the first step was prepared in situ by adding iodo monochloride (67.6 g, 1.15 equivalents) in 50 mL acetonitrile dropwise to a stirred slurry of sodium azide (58.84 g, 2.5 equivalents) at 350 ml of anhydrous acetonitrile at -10 ° C under argon. Addition is complete within 30 minutes, the mixture is stirred for an additional 30 minutes, and cyclohexenone (34.81 g, 1.0 equivalents) is added via syringe, and then stirred for an additional 20 hours at 20 ° C. The mixture was then poured into 1 liter of water and extracted with three 200 ml portions of diethyl ether. The combined fractions were washed with 5% sodium thiosulfate and then brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo at 20 ° C. The residue was dissolved in 11 DMSO at 0 ° C and a second portion of NaN 3 was added and the mixture was stirred while warming to ambient temperature. The mixture was then diluted with 2.5 L of ice water and extracted ten times with dichloromethane (10 x 250 mL). The combined fractions were concentrated by rotary evaporation to a volume of I1, and this concentrate was extracted three times with 250 mL of water followed by brine, then dried over magnesium sulfate and concentrated to a dark oil (39.5 g) and stored at -40 ° C. Noc: 2 ° C. The oil is purified by chromatography on silica gel using 9/1 to 8/2 hexane: ethyl acetate. Two isomers were obtained, the first having an azido group alpha on the ketone function in an amount of 13.22 g with a 26.6% yield. The beta-isomer was obtained in an amount of 15.825 g with a 32.0% yield.

B. Triphenylphosphine was dissolved in 20 mL of dichloromethane and placed under argon at 20 ° C. The beta-isomer obtained above was added via cannula to the stirred solution and kept at 20 ° C for 2 hours. As the reaction proceeds, nitrogen is released from the solution and after 2 hours no residual starting material can be detected by TLC. The solution is concentrated and passed through a silica gel column with dichloromethane as the liquid phase, which is then exchanged with a mixture.

Dichloromethane: methanol 95/5 as eluent. The amidophosphonate intermediate was obtained in an amount of 2.139 g with a 65.1% yield.

C. The amidophosphonate was dissolved in 100 mL of anhydrous o-xylene and then 10% Pd / C was added with stirring. Freshly distilled acrolein is added to the mixture via syringe and the mixture is refluxed for 4 hours. The remaining acrolein is then added and heating under finger condenser for an additional 44 hours under argon. After this time, any remaining intermediates can be detected by TLC, so an additional 0.5 g of Pd / C is added and the mixture is refluxed for an additional 8 hours. The mixture was cooled to room temperature, filtered and concentrated on a rotary evaporator to eliminate excess acrolein until about 100 mL of the o-xylene solution remained. The solution was cooled by adding ice and extracted three times with 1N HCl. The combined aqueous fractions were extracted 3x with Et 2 O. The aqueous phase is then cooled to 0 ° C and the pH is adjusted to about 10 with concentrated NaOH. The aqueous fraction is then extracted 5 times with 100 ml portions of chloroform. The combined chloroform fractions were washed with water and then brine and dried over magnesium sulfate, filtered and finally concentrated to give 3.51 g (84.4% yield) of 7,8-dihydro-6H-quinolin-5-one as an oil.

D. Condensation of 4 (S) -imidazolecarboxaldehyde with the quinolinone described in Step E of Example P yields both Q-1 and Q-2.

E. The exo double bond is then reduced with palladium on charcoal as described in Step E of Example P above to give two products which, after separation by chromatography, yields Q-3 and A.

F. The keto group is removed by the same hydrazine reduction as described above

Step E of Example O to form Q-4.

Φ φ φ φ · · • • • •

ΦΦΦ φ φ · · · · · · φ φ · · · φ φ φ φ φ

G. The completely reduced chimoline ring Q-5 product was obtained by standard reduction of Compound A with lithium / ammonia. (Li, 10 equivalents in NH ₃ at -78 ° C for 10 min, quench with NH ₄ OH, gradually warming with evaporation of NH ₃ ).

Example R-1

Preparation of (E) -6- (3H-imidazol-4 (S) -ylmethylene) -7,8-dihydro-6H-quinoxalin-5one:

Method:

A. A mixture of 5,6,7,8-tetrahydroquinoxaline (23.75 g, 1 equivalent), benzaldehyde (19.81 mL, 1.1 equivalents) and acetic anhydride (33.4 mL, 2.0 equivalents) was added. Stir 15 hours at 150 ° C under argon. After this time, most of the desired product with small starting material residues can be detected by TLC. The starting materials were removed by vacuum distillation using a Vigreux column at 170 ° C. The residue in the vessel is then subjected to Kugelrohr distillation at a temperature of from 170 to 220 ° C. The first fraction is slightly contaminated with starting materials (4.71 g). The second fraction was pure (18.93 g). Application of high vacuum to • · · φφ φ φ φ φ φ φ φ φ φ φ φ φ • • způsob způsob φ φ φ φ φ φ • • φ φ φ · · * * * způsob způsob způsob crystallization. The combined fractions yielded 20.11 g of the substance in 51% yield.

B. The product from Step A above was dissolved in 100 mL of methanol and warmed gently, then cooled to -35 to -40 ° C and ozone was bubbled through the solution. After a few minutes the starting material crystallizes out of solution. The solution was warmed and an additional 200 mL of methanol was added and the reaction repeated. After 30 minutes, the solution becomes pale blue.

Nitrogen was bubbled into the solution for 30 minutes, then methyl sulfide (3.5 mL) was injected, then the solution was stirred for an additional 30 minutes at -35 ° C and allowed to warm to ambient temperature with stirring. After 48 hours at 20 ° C, the mixture was distilled with water vapor to remove solvents to give a 8.4g residue as a tan oil. The residue was dissolved in diethyl ether and extracted 3 times with 25 ml portions of 1 N HCl. The combined aqueous fractions were washed 3 times with diethyl ether. The aqueous solution was gradually basified with concentrated NaOH to pH 8. The free amine was then extracted from the aqueous phase with chloroform (3x). The combined chloroform extracts were washed twice with brine, dried over MgSO 4 and concentrated to a yellow oil (3.01 g). After 1 hour of high vacuum storage, 2.97 g remained. This amount was recrystallized from diethyl ether to give 2.35 g of a bright yellow solid. Yield 67.5%.

C. 7,8-Dihydroquinoxalin-5-one and 4 (S) -imidazolecarboxaldehyde (Aldrich Chemicals) were resuspended in 75 mL of anhydrous tetrahydrofuran at 20 ° C under argon followed by addition of piperidine followed by acetic acid. The mixture was stirred at 20 ° C for 16 hours.

After 20 hours, no traces of quinoxalone remain detectable by TLC. The solids were collected by filtration and washed with a small amount of tetrahydrofuran followed by chloroform. The solid was dried under high vacuum to give 6.58 g of compound R-1. Yield 90.3%.

4 • 4

• 4 4 4

4 4 »4 4 4

49 · «

4 4 4

4 4 4

4 · 4

4 4 V

44

Examples R-2 and R-3

In a similar manner to compound R-1, 5,6,7,8-tetrahydroisoquinoline (5.42 g, 1 equivalent, Aldrich) was mixed with benzaldehyde (5.182 g, 1.2 equivalents) and acetic anhydride (6.309 g, 2 1.0 g), which was distilled under vacuum and used without further purification in a subsequent step. Yield (impure): 8.28 g.

The crude product (7.96 g) from the previous step was subjected to ozonolysis as described in Step B above. The final chromatography step yielded 5.18 g of a pale oil. Yield 97.8% assuming pure starting materials. The resulting 7,8-dihydro-6H-isoquinolin-5-one (1.692 g, 1 equivalent) is condensed with 4 (S) -imidazolecarboxaldehyde as described above in Step C to give 2.23 g of an unsaturated compound analogous to R-1 according to the preceding scheme yield 92.8%. This product is reacted with palladium on activated carbon as described in Step F of Example P, reducing the exo double bond to give 6- (3H-imidazol-4 (S) -ylmethyl) -7,8-dihydro-6H- isoquinolin-5-one (R2) with 52% yield.

The above ketone was reduced with hydrazine and converted to the fumarate salt according to the procedure in Example P, Step F. Reduction yield: 62%. Yield of the fumarate salt after recrystallization: 30.4% of 6- (3H-imidazol-4 (S) -ylmethyl) -5,6,7,8-tetrahydroisoquinoline (R-3).

Example S

The method of measuring alpha-agonist selectivity involves the determination of RSAT (Receptor

Selection and Amplification Technology, as described in Messier et al. (1995) High throughput assays of cloned adrenergic, muscarinic, neurokinin and neurotrophin receptors in living mammalian cells, Pharmacol.Toxicol. 76: 308-11 and which has been adapted for use with alpha2-receptors. The assay measures receptors mediated loss of contact inhibition resulting in selective proliferation of receptor-containing cells in a mixed population of confluent cells. The increase in cell number is determined by a suitable transfected marker gene, such as beta-galactosidase, whose activity can be easily measured in a 96-well plate. G protein activating receptors, such as G _q , enhance the response. Alpha2 receptors that normally bind to Gj activate the RSAT response when expressed together with a hybrid G _q protein having a G 1 receptor recognition domain termed G _q / j ₅ ² . See, Conklin et al. (1993) Substitution of three amino acids shifts the receptor specificity of G _q and gj. "(Substitution of three amino acids switches receptor specificity of G _q and That of gj) Nature 363: 274-6.

NIH-3T3 cells are plated at a density of 2 x 10 ⁶ cells per 15 cm dish and stored in Dulbecco's modified Eagle's medium supplemented with 10% calf serum. After one day, cells are cotransfected by calcium phosphate precipitation with mammalian expression plasmids encoding β-SV-beta-galactosidase (5-10 mg), receptor (1-2 mg) and G protein (1-2 mg). 40 mg of salmon sperm DNA may also be present in the transfection mixture. The next day we add fresh medium and 1-2 days later the cells are harvested and frozen in 50 aliquots for assay. Thaw cells and add 100 ml to 100 ml aliquots containing different concentrations of drug in 96 well plates (all run in 3 replicates). Incubation is continued at 37 degrees Celsius for 72 to 96 hours. After washing with phosphate buffered saline, beta-galactosidase activity is determined by the addition of 200 ml of a chromogenic substrate (including 3.5 mM o-nitrophenyl-beta-D-galacto67). Pyranoside and 0.5% nonidet P-40 in physiological saline containing phosphate buffer) and incubated overnight at 30 degrees Celsius. Enzyme activity is determined spectrophotometrically at 420 nm. Absorbance is a measure of cell-dependent enzyme activity and reflects receptor-mediated cell proliferation. The EC 50 value and the maximal effect of each drug on all alpha ₂ receptors are determined. Efficacy or intrinsic activity is calculated as the ratio of the maximal effect of the drug to the maximum effect of the standard full agonist for each receptor subtype. Brimonidine, also called UK14 304-18, is used as a standard agonist for alpha 1 and alpha _{2 C} receptors. Oxymetazoline is a standard agonist used for the alpha ₂ B receptor.

Tab. 1 below shows intrinsic activity values on alpha2-adrenoreceptor subtypes as determined by RSAT assays for the compounds of Examples B-R above and for some adrenergic compounds that do not have selective agonist activity on the alpha2B or alpha2B / alpha2C subtype (s). On the alpha 2A subtype, the compounds of these Examples are inactive or exhibit low potency (less than or equal to 0.4). They are more potent on the alpha2B and alpha2C subtypes than on the alpha2A subtype. Therefore, unlike ophthalmic alpha2 adrenoreceptor compounds such as clonidine and brimonidine, the compounds of Examples B to R may selectively activate alpha2 adrenoreceptor subtypes other than the alpha2A subtype.

B)

Tab. 1: Intrinsic activity relative to brimonidine / oxymetazoline

Example Structure / compound Brimonidine Alfa2A Oxvmelazoline Alfa2B Brimonidine. Alfa2C oxymetazoline 0.63 i, .O 0 _f 58 clonidine 0.78 0 _f 75 0.55 brimonidini ¥ 0.93 ¥ 4- (5) - (3-methylthiophene-2- ylmethyl) -1H- imidazole 0.43 ¥ 0.5 D-3 v> HN-V bicyclo [2.2.1] hept-2-yl oxazolidin-2-yl amide 0 ° i ⁴ 0

phil · • 4 ··

Example Structure / compound Brimonidine. Oxvmetazoline>. Brimonidine 1 Alfa2A Alfa2B A! Fa2C

P-l HN ^ / oxazolidin-2-ylidene. - (3-phenyl bicyclo [2.2.1] hept-2-yl) amine 0 0.47 0 F ςχ / ϊΧ 6- (imidazolidin-2-ylidene amino) -5-methyl-4H-benzophenyl] -4-oxazin-3-one. 0.9 0.2 G HCI r -NH ^ Ν Ν'γ ^ ^H ΝΗ of imidazolidin-2-ylidene - (5-methyl-3,4-dihydro-2H-benzo [l, 4] oxazin-8-yl) -amine:;, UCI ffSl θ / ¹ 0.87 0.33 JJ. ~ CA0 4 (S) -cyclohexylmethyl-1H- θ, ι 0.83 0

· · · · · · · · · · · · ·

Example Structure / compound Brimonidim Alfa2A OxYmelazolim Alfa2B Brimonidir A / fa2C imidazole · E-1 ςτ.00 Η 1 imidazolidin-2-ylidene - (4-methyl-3,4-dihydro-2H-benzo (1,4) oxazin-6-yl) amine 0.33 O _f 83 0 (35 M <Tjo ^of I - and 4 (5) - (2,3-dihydro- benzo [1,4] dioxin-6-ylmethyl) -4-methyl-lH-imidazole tp 0 ₍ 97 0 (27 C-2 ^N = FA 4 (S) -thiophen-2-ylmethyl-1H-imidazole 0.23 IN ° 1 ⁵ C-1 ( ^N ) - (4) (5) -thiophen-3-ylmethyl-1H-imidazole 0 O _ř 83 0

Example Structure / compound Brimonidine · Alfa2A Oxvmetazoline Alfa2B Brimonidine Alfa2C C-9 / = ^N > / after 4 (5) -benzo [b] thiophen-2-ylmethyl-1H-imidazole OjO6 0.88 0.43 C-3 4 (S) - (5-methylthiophen-2-ylmethyl) -1H-imidazole ° ₍₁ 0.88 0.43 C-8 / = t ΓΊ 4 (S) -benzyl-1H-imidazole ° _f 0.9 0.4 H / = Π 4 (S) -phenylsulfanes 1-1Himidazole 0.2 0.93 0 15 C-5 / = ^N. o 4 (S) -furan-2-ylmethyl-1H-imidazole · 0 • V 0.4

Ύ it ···· *

Example Structure / compound Bnmonidin Alfa2A Oxymetazolin · Alfa2B Brimonidine Alfa2C B-3b 0 in 0 4- (5) - (1,2,3,4-Tetrahydronaphthalen-2 'ylmethyl) -1H-imidazole L2 0 0.8 0 (S) -4 (5) - (1,2,3,4-Tetrahydronaphthalen-2-ylmethyl) -1H-imidazole · - L3 / = ^Ν ' θ, · ¹ 1 0.15 1 (R) -4 (S) - (1,2,3,4-Tetrahydronaphthalen-2-ylmethyl) -1H-imidazole L / = ^N > r \ 0.23 0.9 0.57 4 (S) - (1-furan-2-ylethyl) -1H-imidazole. C-6 0.2 0.67 IN 4 (S) -Furan-3-ylmethyl-1H-imidazole

b

7 ´ '· · · * • In 9 Φ «* · · · · · ·

Example Structure / compound Brimonidine . AIfa2A, Oxvmetazolini Alfa2B Brimonidine Alfa2C C-4 4- (5) - (5-chlorothiophen-2-ylmethyl) -1H-imidazole 0.05 0) 82 ° l ⁵ D-2 HN-V oxazoidin-2-yliden - (3-o-tolyl bicyclo (2.2.1) hept-2-yl) amine 0.25 0.75 0 C-10 / = t ΐτζ ~) 4- (5) -benzofuran-2-ylmethyl-1H-imidazole 0.05 0.48 ° /> C-7 -ΟΰΛ 4 (S) - (5-methylfuran-2-ylmethyl) -1H-imidazole 0 _} 08 0.73 O, ²

Example Structure / compound Brimonidin- Alfa2A Oxvmeiazoline; Alfa2B Brimonidine Alfa2C B-3a / = ^N X fYY θί ¹ 0.8 and 0.07 and O 2- (3H-imidazole-4 (5)) ylmethyl) -3,4-dihydro-2H- naphthalen-l-oru and CH ₃ SO ₃ H 0 IN T 4 (5) - (1,2,3,4-tetrahydronaphthalen-2-ylmethyl) ^{-4,5-dihydro-1} H -imidazo methane <5> IT | foha '| B-2a / = ^Ν Χ (.η 0 0 ^ 63 0 _? 15 Dec O 3- (3H-Imidazol-4 (5) ylmethylene) chroman-4-one B-2b A / x / = ^N x ( 0 0 (77 0 O 3- (3H-imidazole-4 (5)) ylmethyl) chroman-4-one 1

• · · · · · · · · · · · · · · ·

Example Structure / compound Brimonidine Alfa2A Oxvmetazoline. Álfa2B Brimonidine Alfa2C B-2d _N 0 0 _f 6 0 4 (S) -chroman-3-ylmethyl-1H- imidazole B-2c ^M = ^N V (Y 2 OH) 0 0 _f 65 0 3- (3H-Imidazol-4 (5) ylmethyl) chroman-4-ol - B-9a H 0 _{ 08 0.46 0 4 (5) - (4,5,6,7-) tetrahydrobenzo [b] thiophen-5-ylmethyl) -1H-imidazole B-4a / = ^r ; (TI 0 0 ^ 75 θί ¹ 4 (5) - (4-Methyl-1,2,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -1H-imidazole · 1

Example Structure / compound Brimonidim Alfa2A Oxymeiazobn Alfa2B Brimonidine Alfa2C B-4b / = ^N , fjPj Op 0/7 0.6 O 2- (3H-imidazole-4 (5)) (4-methyl-3,4- dihydro-2H-naphthalen-1-or. B-11b 0 0.3 0 6- (1H-imidazol-4 (5) ylmethylene.) - 6,7,8,9-tetrahydro-benzocyclohepten-5-one: B-6 HCl N 0 0 _? 35 0 4 (S) -thiochrom-3-ylmethyl-1H-imidazole HC1 B-5b / = ^N \ ( 0 0 _ř 5 0.2 l O 3- (3H-imidazol-4 (5) - ylmethyl) thiochroman-4-one

i »Á

Example Structure / compound Brimonjóin. Alfa2A Oxvmelazolir ' Alfa2B Brimonidine '. Alfa2C B-5a / = ^N V (.η 0 0.5 0. ^ 37 O 3- (3H-imidazol-4 (5) ylmethylene) thiochroman-4- he B-7a / = ⁿ at yO 0 IN 0 O 2- (3H-Imidazol-4 (5) ylmethylene)} indan-1-one B-Ila OCTQ 0.4 IN 0 4- (5) - (6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylmethyl) - 1 H-imidazole B-7b. r {) 0 0/3. O O 2- (3H-Imidazol-4 (5) ylmethyl) indan-1-one

4 4 • 4 44 44 44 ·· 4 4 ' 4 ' • 4 4 ' • 4 4 4 4 4 4 4 • 4 '4 4 4 4 4 4 4 4 4 ' 4 4 4 4 4 4 44 · 4 4'4 '4 4 4 4 4 «

Example Structure / compound Brimonióin Alfa2A Oxvmeiazoline. 'Alfa2B Brimonidin ' Alfa2C B-l HCl 0.15 0.45 0.3 4- (5) - (7-methoxy-1,2,3,4 [etrahydronaphthalen-2-ylmethyl) -1H-2-ol; H-imidazole ·, B-la 0.15 0.6 0 O 2- (3H-imidazole-4 (5)) ylmethyl) -7-methoxy-3,4- dihydro-2H-naphthalen-1-one B-9b HCl / = * {ΓΊό 0 0.68 0 _? 15 Dec O 5- (3H-imidazol-4 (5) ylmethyl) -6,7-dihydro-5Hbenzo [b] thiophen-4-one; Učt Cfi B-7c 0 0.9 0 4- (S) -indan-2-ylmethyl-1H-imidazole

· Tttt tttt

Example Structure / compound Brimonidine Alfa2A Oxvmetazolini Alfa2B Brimonidi »» Alfa2C B-JO / = N pour 4- (5) - (4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -1H-imidazole * 0 ¥ 0 B-8b HCl -4 (5) - (7-methyl-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -1H-2-ol; H-imidazole. KCÍ 0 0.6 0.2 B-8a / = ^N \ O ΠΠ 2- (3H-imidazol-4 (5) ylmethyl) -7-methyl-1-3,4--dihydro-2H-naphthalen-1-one 0 0.4 0 K-l (= ⁿ in nT) 4 (5) - (4,5,6,7-tetrahydrobenzo [b] thiophen-2-ylmethyl) -1H-imidazole 0 0.53 0

4.1. · 44 4 «44 • · · <4 4 4

445 44 ««

Example Structure / compound Brimonidine. Alfa2A Oxvmetazoline Alfa2B Brimonidine. Alfa2C C-12 ^Β 'ν-Λ Γ-ΝΗ 0.2 1.3 o, ³ 4- (5) - (4-bromothiophen-2-ylmethyl) -1H-imidazole C-13 ^Ph M— \ r-NH OM? 0 0.5 0 4 (5) - (4-phenylthiophen-2-ylmethyl) -1H-imidazole · K-3 / = ^N IRCF> 4 (5) - (5,6-dihydro-4H-thieno [2,3-b] thiopyran-2yimethyl) -1H-imidazole · 0 0.37 0 K-2 1-1 / r-NH n 0 o, ⁷ 0 4 (S) - (5-tert-Butylfuran-2-ylmethyl) -1H-imidazole C-1 1 --- _r NH AU ' 0.2 ° i ⁵ 0 4 (S) - (5-ethyl-furan-2-ylmethyl) -1H-imidazole

• φ

Brimonidine. Alfa2A

2 φ ► 2

Example

Structure / compound

Oxvmetazoline

Brimonidine

Alfa2C

C-14 í5 HCl 0.27 ° r ⁷ IN 4 (S) - (4-methylthiophen-2-ylmethyl) -1H-imidazole, N-I O Ha 0.24 0.75 0.26 2- (3H-imidazole-4 (5)) ylmethyl) -3,4,5,6,7,8- Hexahydro-2H-naphthalene-1- or ,, Hq 0 = 3 O θ) ¹ 0.9 and 0.23 1 6- (3 H -imidazole-4 (5) - ylmethyl) -7,8-dihydro-6H- quinolin-5-one 0 = 2 0.1 0.87 0.13

4 · • 4 ·· ·· · • 4 4 4 • 4 • • • 4 4 • • 4 · 4 • • 4 • 4 • 4 4 4 · • • 4 • »* · 4 4 4 • · * » • 4

Example Structure / compound Brimonidine Alfa2A Oxvmetazolin ·· . Alfa2B Brimonidine · Alfa2C (E) -6- (3H-imidazol-4 (5) ylmethylene) -7,8-dihydro-6H- quinolin-5-one From w H (Z) -6- (3H-imidazol-4 (5) ylmethylene) -7,8-dihydro-6Hquinolin-5-one. 0 0.75 0.2 N-2 _H 0UOO 0 ° r ⁵ 005 4 (5) - (2,3,4,4a, 5,6,7,8-octahydronaphthalen-2-ylmethyl) -1H-imidazole QdL 2HC1 _n 0.8 ^o .> 6- (3H-imidazol-4 (5) ylmethyl) -5,6,7,8-tetrahydroquinoline dihydrochloride

A Φ ΦΦ V V V

Φ Φ Φ · · Φ Φ Φ Φ Φ Φ · · · · · · · · · · · · · · · β β β · · β · β β · · β · ΦΦ · ΦΦ ΦΦ

Example Structure / compound Brimonidine Alfa2A Oxymelazoline Álfa2B Brimonidine. Alfa2C 0 ^hci si 0 0 (67 0 (1 4 (S) -octahydro-pentalen-2-ylmethyl-1H-imidazole. hydrochloride B-9c H HCl 0 0.3 0 5- (octahydro benzo [b] thiophen-5-ylmethyl) -1H-imidazole. hydrochloride R-3 (HO ₂ C-CH). ₅ 0 0 _f 6 ¥ 6- (3H-imidazol-4 (5) ylmethyl) -5,6,7,8-tetrahydroisotphhinoliil fumarate R-2 2 HCl o 0 0.6 0.4 6- (3H-imidazol-4 (5) ylmethyl) -7,8-dihydro-6H-isoquinolin-5-ol dihydrochloride.

<> ’4 4 4 4 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Example Structure / compound Brimonidine Alfa2A • «ati Oxyme ^ plin Alfa2B > · · · »- BrŇnonidin Alfa2C R-1 ýjjQĎ O ° z ³ 0.8 0.4 (E) -6- (3H-Imidazol-4 (5) ylmethyl) -7,8-dihydro-6H-quinoxalin-5-one; Ed _H 0 - QCn / _J = qAo W / 0 0.4 0 7- (3H-imidazol-4 (5) ylmethyl) -6,7-dihydro-5H-iodolin-8-one, fumarate? P-2 C 0 _0; 4 0 7- (3H-imidazol-4 (5) ylmethyl) -5,6,7,8-tetrahydro- isocM nolur, fumarate N-3 H0UOO 0 0.75 0 [HQzCU, J \ CQ ^ 4 (5) - (1,2,3,4,5,6,7,8-octahydronaphthalen-2-ylmethyl) -1H-imidazole, fumarat - From O 0 1.0 0 • 6- (3H-Imidazol-4 (S) -ylmethyl) -octahydrocyclolin-5-one

Example T

Intraocular pressure (IOP) - decreasing and sedative side effects.

Intraocular pressure (IOP) measurements were performed on female Cynomolgus monkeys weighing 3-4 kg in full consciousness, with constant elevated IOP induced in the right eye by photocoagulation of the trabecular portion of the retina using an argon laser. The animals could be used for experiments for approximately 2 months after surgery. During the experiments, monkeys consisted of specially designed chairs (Primate Products, San Francisco) and were fed with orange juice and fruit as needed. IOP was measured using a Digilab Model 30R Pneumatonometer (Alcon, Texas).

ml of anesthetics (proparacaine) was administered topically to each monkey prior to IOP measurements to minimize discomfort caused by tonometry. Two control measurements were taken prior to drug dripping and periodic measurements were then performed for 6 hours after drug administration. Test compounds were administered to only one eye as one 50 microliter drop; an equal volume of saline was dropped into the other eye.

Many alpha2B or alpha2B / 2C selective compounds of the Examples were tested in monkeys. Surprisingly, as also shown in Tab. 2, all of these structurally different compounds reduced IOP in the test eye.

At the same time, the damping effect (sedation) was measured and evaluated according to the following scale: 0 = standby, typical sound signals, movements, etc .; 1 = quiet, fewer movements; 2 = slight calming, occasionally audible signals, animal responds to stimulation; 3 = calm, no beeps, occasional response to pacing; 4 = animal sleeping.

The compounds of the invention also did not induce attenuation. This contrasts with the action of clonidine and brimonidine, which induced sedation.

• · · · ···

Tab. 2. Effects of alpha ₂ -adrenoceptor agonists on IOP and attenuation in Cynomolgus monkeys observed consciously after eye application, in which the intraocular pressure was unilaterally increased by argon laser photocoagulation. The measurements were taken periodically for 6 hours. The sedative effect was evaluated subjectively during IOP experiments according to the following scale: 0 = standby, typical sound signals, movements, etc .; 1 = quiet, fewer movements; 2 = slight attenuation, occasional audible signals, animal responds to stimulation; 3 = attenuation, no audible signals, intermittent response to pacing; 4 = animal sleeping. The number of animals in the group was 6-9.

• · • ···

Tab- 2 Maximum powes from pre-treatment levels \%) Compounds Batch (%) Hypertensive eye Attenuation (0-4) 7 ± 2 0-1 Clonidine; 0.1 and 25 ± 4 1 0.3 41 ± 5 2 Brimonidine · ' θ, ¹ 25 ± 3 1 0.3 40 ± 4 2 J-l 1 26 ± 5 0 3 33 ± 3 0 E-1 ° l ³ 25 ± 4 0 1 27 ± 3 0 NO. 1 1 25 ± 4 0 3 29 ± 4 0 D-1 1 25.6 ± 3.9 f 0 M 1 22 _f 5 ą 5 4 0 C-2 1 29.6 ± 5.5 1 f 0

• ·

C-9 IN 1 13 _ø 7 ± 4 _f 5 25.1 ± 4.9 0 0 C-3 0.3 20.6 ± 4.8 0 1 25.0 ± 6.4 0 C-8 1 31 2 ± 3 _f 3 0 B-3b <V 25.9 ± 3.5 0 in 31.2 ± 4.3 0 C-4 ³ ° F 17.7 ± 4.0 0 1 29.3 ± 4.9 0 C-7 1 32.3 ± 5.7 0 J-2 0.03 12.4 ± 3.7 0 IN 27.3 ± 3.1 0 J-3 o, 03 16.4 ± 4.7 0 26.5 ± 3.8 1 i 0 B-2d 0.1 1 22.0 ± 4.6 0 0.3 17.0 ± 4.2 0 1 18.1 ± 5.2 0

·· ·· ·· ·· · · · · · ·

B-9a 0,03 O, ¹ 0.3 t 1 17 _f 6 ± 1.7 26.7 ± 6.1 24.8 ± 3.3 26.8 ± 5.4 0 0 0 0 B-6 °, ³ 13.8 ± 2.4 0 1 22.1 ± 6.3 0 B-9b 0.1 18.7 ± 5.5 0 Op 26.9 ± 6.1 0

Example U

Measurement of cardiovascular side effects

Cardiovascular measurements were performed in another group of monkeys using an automated sphygmomanometer model BP 100S (Nippon Colin., Japan). Intravenous (IV) administration of some of the compounds of this invention at doses 10 to 30 times higher than those used for clonidine and brimonidine did not reduce the working heart rate or lower blood pressure. Interestingly, 4 (S) -3-methylthiophen-2-ylmethyl) -1 Himidazole, which exhibited intrinsic activity of 0.43 on the alpha2A subtype, had a weak effect on heart rate. Clonidine and brimonidine had a higher effect on heart rate. See Tab. 3 below.

Tab. 3. Effects of alpha ₂ -adrenoceptor agonists on cardiovascular variables in Cynomolgus monkeys following IV administration of conscious execution. The measurements were taken periodically for 6 hours. The number of animals in the group was 6 to 10.

J ..Ai ...

99

9 9 • «· '

Tab ^ 3 Dose (gg / kg) Maximum decrease from pre-treatment levels (%) Compounds Average arterial blood pressure Heart rate 7 ± 4 8 + 3 Clonidine 17 29 + 7 32 + 4 50 35 ± 5 50 + 5 Brimonidine 17 36 + 3 52 ± 3 50 37 + 5 54 + 3 J-l 17 7 + 5.3 13 + 4 50 4 + 2 6 + 2 167 7 + 5 3 ± 3 500 13 + 3 7 + 4 E-1 17 7 ± 4 11 + 4 50 7 + 2 14 + 5 167 9 + 4 11 + 5 C-1 50 12.8 ± 12 tons 12 ± 4 500 +5 + 8 * +11 ± 9 M 500 0.8 + 2 .3 5 _{ 5 + 1.9 C-2 500 6.6 + 1.7 ——

C-9

9.4 + 3.0 + 9.4 ± 1 _f 8 * 16 ± 3.2

3.0 5.0 + 2 _f 3 17 1.0 + 4.1 50 0.1 + 3.8 500 6.0 ± 2.2

C-3 500 - 2,3 +2,7 --r- -7-- 10.6 ± 3.4 C-8 500 5.5 + 2.7 -/-F- 16.6 ± 1.9 C-5 500 3.9 + 2.8 1) 7.1 ± 3.9 B-3b 50 2.4 + 4.3 l ¹ 10.0 ± 2.8 C-4 500 í i 5.3 + 2.9 -and-.- 1 l 10 _f 9 ± 3 6

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

C-7 500 3.0 + 3.9 6.1 + 3 7 J-2 500 í ¹ +0,6 ± 3,1 * t i- 6.4 ± 3.3 J-3 500 +10 ± 2 ^ 1 -f-f— - +10.6 ± 6.0 * B-2b 500 5 _f 7 + 14 6.4 ± 3.6 B-2d 500 +8.9 ± 3.4 * i / +15.5 ± 3.4 * B-9a 500 i i + 10.8 ± 3.2 * ι 1 +23.8 ± 4.4 * B-9b 500 ¹ / 2.8 ± 1.8 f ( +20.2 ± 3.4 * 4 (5) - methylthiophen -2-ylmethyl) - IH-imidazok 50 167 9 ± 3 8 ± 6 I I 23 ± 4 32 ± 8 * vivusP ř tafrcřl Wvetl

Example V

Studies of the above Examples T and U show that the therapeutic effect of alpha2 agonists can be separated from the sedative and cardiovascular side effects. This separation can be achieved for compounds having a property of preferential activity on the alpha2B and alpha2B / alpha2C subtypes as compared to the alpha2A subtype.

Alpha2 adrenergic agonists known in the art that activate all three alpha2 receptors induce attenuation, hypotension and bradycardia, preventing or severely limiting their use for the specific treatment of diseases and disorders in which they act positively. These diseases and disorders include muscular spasticity including hyperactive frequent urination, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases including optic nerve neuropathy, spinal ischemia and stroke, memory and consciousness disorders, attention deficit, psychosis including manic conditions , anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion. See, eg, Hieble et al., Therapeutic Applications of Alpha-Adrenoceptor Interacting Agents, in Alpha-Adrenoceptors: Molecular Biology, Biochemistry and Pharmacology ”, in Alpha-Adrenoceptors: molecular biology, biochemistry and pharmacology” ). Prog. Basic Clin. Pharmacol. (Basel, Karger) 8, 180220 (1991). For example, clonidine has been found to be clinically effective in relieving pain in postoperative neurogenic and cancer-related pain. However, as reported by Maze and Tranquilli, Maze MB and Tranquilli W. ”Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia”, Anesthesiology 74, 581-605 (1991) ), the full clinical promise of this and other alpha2 agonists requires the development of compounds that do not have a sedative effect, do not lower blood pressure or cause bradycardia.

• .44 4 4 4 4 4 4 4 4 4 4 4 4 44444 44 444 '44 4

4 4 4 4 4 9 4 4 5

4 4 4 4

The above-mentioned diseases and disorders can be treated by altivating the alpha2B or alpha2B / 2C receptor subtype (s). Therefore, the alpha2 compounds described above, which do not show a sedative effect and a cardiovascular effect, are useful and advantageous for the treatment of these conditions.

The improvement of neuronal degeneration in glaucomatous neuropathy is another example of the novel utility of the compounds of the invention. Recent studies have shown that clonidine and other alpha2 agonists have a neuroprotective effect on retinal cells in a number of neuronal degenerations observed in the rat model. These models include light-induced photoreceptor degeneration in white rats, as described by Wen et al., Alpha2 adrenergic agonists induce expression of basic fibroblast growth factor in photoreceptors in vivo and improve light damage. expression in photoreceptors in vivo and ameliorate light damage) J. Neurosci. 16, 5986-5992, and a calibrated rat optic nerve injury resulting in a secondary loss of retinal ganglion cells as described by Yoles et al. ”(Injury-induced secondary degeneration of rat optic nerve can be attenuated by alpha2-adrenoceptor agonists AGN 191103 and brimonidine), Invest. Ophthalmol. You know. Sci. 37, 540, S114. In contrast to the compounds of the invention, however, the doses used in these studies - 0.1 to more than 1 mg / kg by intraperitoneal or intramuscular injection also had a sedative effect and a cardiovascular effect. Induction of basic fibroblast growth factor (bFGF) expression is considered to be a sensitive indicator of alpha2 receptor retinal activation (Wen et al., Supra) and measurement of induction of bFGF following topical administration of alpha2 agonists in the rat eye indicates that approximately A 1% dose is required to induce a 2-3 fold level of bFGF that corresponds to neuroprotection

AND.

• 4 4 4 4 4 4 44 444 4 4 5

4 4 '4' 4 · · '· · ·

4'4 4 4 4'4 44 4'4 4 4 mediated by an alpha2 agonist (see Wen et al., Supra, and Lai et al., Neuroprotective effect of ocular hypotensive agent brimonidine) in Proceedings of the 20th Congress of the European Society of Opththalmology (Bologna, Monduzzi Editore), 439-444). These topical doses of common alpha2 agonists, such as clonidine, induce systemic side effects such as sedation and hypotension, which prevent their use as ocular neuroprotective agents. Further, co-pending application 08 / 496,292, filed Jun. 28, 1995, describes and claims the use of certain non-selective alpha2-adrenergic agents for the treatment of neural damage, and its contents are incorporated herein by reference in their entirety.

The compounds of the invention do not have a sedative or cardiovascular effect after topical administration of at least 3% of the doses to monkeys. Such neuroprotective concentrations of these agents can be achieved in humans without causing side effects. In fact, as shown below, the compound of Example B-9 (b) has been shown to have a neuroprotective effect in the calibrated optic nerve injury model of rats according to Yoles et al. (see above). See also Tab. 4, below.

Tab. 4. Retinal ganglion cell numbers 2 weeks after injury (cells / microscope field) Control (vehicle i.p.) Example B-9 (b) (0.5 mg / kg i.p.)

33 + 8 73 + 12 n = 8 n = 5

This level of neuroprotection is comparable to the effect seen in previous studies with the standard alpha2-adrenoceptor agonist, brimonidine, and the neuroprotective agent MK801.

··

t.

• 9 9 «« »« »· · · · · * · * · * * 9 9 9 9 9 9 »'···« ·· · ·· ♦ · ·' * ··

Example W

Pain relief, including neuropathic pain, is another example of a disorder where the compounds of the invention are useful and advantageous because pain is relieved without undesirable side effects. Clonidine, an agonist that activates all three alpha2 receptors, is clinically used to treat chronic pain, but its usefulness for this indication is limited as it exhibits sedative and cardiovascular side effects. Compounds of the invention were compared to clonidine and brimonidine in a rodent neuropathic pain model known to be predictive of clinical activity. (See, e.g., Kim, S. and Chung, J. Experimental model for peripheral neuropathy induced by segmental spinal nerve ligation in rats. Pain 50, p. 355- 363 (1992) After ligation of the two spinal nerves, the animals develop a sensitivity to normally non-painful stimuli such as touch.The ability of the alpha2 compounds to reverse this sensitivity, called allodynia, was tested 30 minutes after dosing of the substance administered intrathecally or intraperitoneally. Substances of the invention, such as N-1, are capable of attenuating allodynia without having a sedative effect, even at very high doses, in contrast to clonidine and brimonidine, which have a sedative effect only slightly higher than their anti-allodynic doses. See Tables 5 and 6, below.

• · · · 9 9 9 9

9 9 * 9 9 9 9 9 9 9 9 9 9 9 9

9 9 99 ·· · '*' ··

Tab. Anti-allodynic and sedative effects of alpha2-adrenoceptor agonists in rats 30 minutes after intrathecal administration (N = 6).

Compound Dose (microgram) Reversal of tactile allodynia (%) Attenuation (%)

Clonidine 0.1 20 * ND 1 96 * 15 Dec 10 ND 60 * N-1 3 13 ND 30 64 * 0 300 ND 0

* p <0.05 compared to control (saline) • ND means not determined

Tab. 6. Anti-allodynic and sedative effect of alpha2-adrenoceptor agonists in rats 30 minutes after intraperitoneal administration (N = 6).

Compound Dose (mg / kg) Reversal of touch allodynia (%) Attenuation (%)

Brimonidine 3 0 ND 30 37 * 24 300 ND 67 * N-1 3 3 ND 30 41 * ND 10 000 ND 0 * p <0.05 compared with control (saline)

• ND means not determined

The results of these Examples show that the common side effects of alpha2-adrenoceptor drugs are mediated by the alpha2A-subtype, and that their ocular antihypertensive and other therapeutic effects may be mediated by a subtype other than the alpha2A-subtype. Thus, alpha2-adrenoceptor agents belonging to different groups according to their structure, which share a common low functional activity on the alpha2A-subtype, reduce IOP and induce other therapeutic effects without exhibiting dose-limiting side effects.

While a particular embodiment of the present invention is described, it will be understood that the present invention is not limited to this embodiment, as many obvious modifications can be made, and the invention will be readily apparent to those skilled in the art.

8 8 9 8 88 8 8 8 8 • ·············

9 9 8 8 8 9 8 · φ

The authors include in the present invention any modification that fits the scope of the appended claims.

After describing the invention, we formulate the following claims.

Industrial applicability

The invention relates to a method of treating animals of mammalian species, including humans, with a pharmaceutical composition comprising, as an active ingredient, one or more compounds having the effect of specific or selective alpha2B or alpha2B / 2C agonists, used to treat many diseases or conditions against which alpha adrenergic compounds are useful , including but not limited to glaucoma, intraocular pressure reduction, chronic pain, diarrhea and nasal congestion. Further, the compounds of the invention are useful for the treatment of muscle spasticity including hyperactive frequent urination, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases including optic nerve neuropathy, spinal cord ischemia and stroke, memory and consciousness disorders, attention disorders, psychoses including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion.

The present invention also encompasses pharmaceutical compositions used in the above-described method of treatment and particularly relates to a method of treating diseases and conditions in which adrenergic compounds are useful, but their use is limited due to known side effects.

Claims (93)

PATENT CLAIMS kooo -γγ A compound having selective agonist activity at the alpha2B or alpha2B / alpha2C adrenergic receptor subtype (s) as compared to the adrenergic receptor 2A subtype represented by the general formula Although the dotted lines indicate preferred double bonds; R is H or lower alkyl; X is S or C (H) R ¹ , wherein R ¹ is H or lower alkyl or R ¹ is absent when X is S or when the bond between X and the ring represented is a double bond; Y is O, N, S, (CR ¹ x) _y wherein y is an integer from 1 to 3, -CH = CH- or -Y ¹ CH ₂ -, wherein Y ¹ is O, N, or S; x is an integer having a value of 1 or 2, wherein x is 1 if R ² , R ³ or R ⁴ are bonded to an unsaturated carbon atom and x is 2 if R ² , R ³ or R ⁴ are bonded to a saturated carbon atom; R ² is H, lower alkyl, halogen, hydroxy or lower alkoxy, or, when attached to a saturated carbon atom, ^R2 may be oxo; R ³ and R ⁴ are each H, lower alkyl, hydroxy, lower alkoxy, or phenyl, or, taken together, are 100 φ · »». - (C (R ² ) x) ² -; -Y ¹ (C (R ² ) x) z '; -Y ¹ (C (R ² ) x) y Y ¹ -; - (C (R ² ) x) -Y ¹ - (C (R ² ) x) -; - (C (R ² ) x) -Y ¹ - (C (R ² ) x) (C (R ² ) x) - and -Y ¹ - (C (R ² ) x) -Y ¹ - (C ( R ² ) x) - wherein z is an integer from 3 to 5, z 'is an integer from 2 to 4 and χ and y are as defined above, and further each of the ends of all these divalent moieties of the molecule may join to R ³ or R ⁴ to form a fused cyclic structure and the ring thus formed may be fully unsaturated, partially unsaturated or fully saturated, provided that the ring carbon atom has no more than 4 valences, the nitrogen atom more than 3 valences and O and S do not more than 2 valencies, including pharmaceutically acceptable salts of said compound. The compound of claim 1 wherein said compound is represented by the general formula A compound according to claim 2 wherein X is C (H) R ¹ . A compound according to claim 3 wherein R ¹ is H. 101 4 4 44 44 4 4 44 44 · 4 4 4 4 4 '4 4 9 4 4 4 4 4 44 4 4 4 4 4 4 • 4 4 4 '4 4 4 4 • 44 4 44 '9 4 44 44 A compound according to claim 4 wherein R ² is H and represents a furanyl radical. A compound according to claim 5 wherein R ³ and R ⁴ are (CH) 4. A compound according to claim 5 wherein R ³ is H and R ⁴ is t-butyl. A compound according to claim 5 wherein R ³ and R ⁴ are H. The compound of claim 5 wherein R ³ is H and R ⁴ is methyl or ethyl. The compound of claim 4 wherein R ² is H and represents a thienyl radical A compound according to claim 10 wherein R ³ and R ⁴ represent (ChhH A compound according to claim 10 wherein R ³ is phenyl and R ⁴ is H. A compound according to claim 10 wherein R ³ and R ⁴ represent (ChfefeS. 102 A compound according to claim 10 wherein R ³ and R ⁴ are H. A compound according to claim 10 wherein R ³ and R ⁴ represent (CH) ₄ . A compound according to claim 10 wherein R ³ is H and R ⁴ is methyl. A compound according to claim 10 wherein R ³ is bromo and R ⁴ is H. The compound of claim 4 wherein it represents a cyclohexyl radical. A compound according to claim 18 wherein R ² is H and R ³ and R ⁴ represent (CH) 4. A compound according to claim 18 wherein R ² is H and R ³ and R ⁴ represent (CH) 2 S. A compound according to claim 18 wherein R ² is H and R ³ and R ⁴ represent (CH 2) 4. A compound according to claim 18 wherein R ² is dimethyl and R ³ and R ⁴ represent (CH) 4. A compound according to claim 18 wherein Y is -CH ₂ CH (CH 3) -, R ² is hydrogen or oxo and R ³ and R ⁴ represent (CH) 4. 103 9 · 99 9 9 « 9 99 99 9 9 * « 9 9 9 9 · 9 9 A compound according to claim 18 wherein R ² is oxo and R ³ and R ⁴ represent S (CH) 225. A compound according to claim 18 wherein Y is -CH 2 C (CH 3) 2 -, R ² is hydrogen or oxo and R ³ and R ⁴ represent (CH) ₄ . A compound according to claim 18 wherein R ² is oxo and R ³ and R ⁴ are (CH) ₄ . A compound according to claim 18 wherein R ² is oxo and R ³ and R ⁴ represent (CH) ₂ C (OCH ₃ ) CH. The compound of claim 4 wherein Y represents a cyclopentyl radical. A compound according to claim 28 wherein R ² is H and R ³ and R ⁴ represent (CH) ₄ . A compound according to claim 28 wherein R ² is hydrogen and R ³ and R ⁴ represent (CH ₂ ) 3 · The compound of claim 4 wherein 104 v / y 4 ♦ 4 * 4 * 44 44 • 4 4 • • 4 4 4 4 4 4 4 4 4 • • 4 * · 4 4 4 4 4 • 4 4 • · 4 4 44 · • ·· 4 4 44 4 » represents a benzyl radical. A compound according to claim 31 wherein R ² , R ³ and R ⁴ are H. The compound of claim 1, wherein said chemical has the general formula The compound of claim 33 wherein X is C (H) R ¹ and R, R ¹ , R ² , R ³ and R ⁴ are H. The compound of claim 34 wherein Y is O. The compound of claim 35 wherein Y is S. The compound of claim 1 wherein said chemical has the general formula 105 © · · € · · · · 9 · · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 99 phil • * ··· * · A compound according to claim 37 wherein R ³ and R ⁴ represent (CH) 4. The compound of claim 38 wherein Y ¹ is O. The compound of claim 39 wherein R ¹ is oxo. The compound of claim 40 wherein X is CH. The compound of claim 40 wherein X is CH 2. The compound of claim 39 wherein one of R ² is hydroxy and the other is H. The compound of claim 39 wherein R ² is H. The compound of claim 38 wherein Y ¹ is S. The compound of claim 45 wherein X is CH 2. The compound of claim 46 wherein R ² is oxo. A compound according to claim 46 wherein R ² is H. The compound of claim 45 wherein X is CH and R ² is oxo. A compound according to claim 3 wherein Y is (CH ₂ ) 3 · 106; · · · · R. A compound according to claim 50 wherein X is CH and R ² is oxo. The compound of claim 50 wherein X is CH ₂ and R ² is H. A compound according to claim 2 wherein X is S and is phenyl. A compound according to claim 3 wherein R ¹ is methyl and is furanyl. The compound of claim 4 wherein Y is CH ₂ (CR ¹ 2) ₂ wherein R ¹ is hydrogen or methyl. A compound according to claim 55 wherein R ² is H. A compound according to claim 55 wherein R ² is an oxo group. 107 iii · '· A compound according to claim 3 wherein R is CH 3 represents a phenyl radical and R ³ and R ⁴ represent O (CR ₂ ) 2 O · A compound according to claim 2 wherein X is CH, Y represents a cyclopentyl radical and R 2 is an oxo group. 60. A compound represented by the formula A compound according to claim 1 represented by the general formula 108 where Y is (R ¹ X) 2, R ³ + R ⁴ is (C (R ² ) _X ) 4 and X is attached to one of the two ring positions, as shown by a wavy line, with the remaining position occupied by hydrogen, assuming that two double bonds cannot occupy the same ring atom. The compound of claim 61, wherein said compound is represented by the general formula wherein (R ² ) _X is hydrogen or oxo. The compound of claim 61, wherein the structure is A compound according to claim 62 wherein the structure is A compound according to claim 2 wherein R is hydrogen, R ³ + R ⁴ are - (C (R ² ) X) -N- (C (R ² ) X) - (C (R ² ) _X ) - and X is CHR ¹ as represented by the general formula 109 ft · N. // NH The -CHR 1 group CHR ¹ is attached at one of the two ring positions, as shown by the wavy line, with the remaining position occupied by hydrogen, and provided that the two double bonds cannot occupy the same ring atom. A compound according to claim 65 wherein said compound has the general formula and (R ² ) _x is hydrogen or oxo. A compound according to claim 65 wherein said compound has the general formula and (R 2) _X is hydrogen or oxo. A compound according to claim 1 wherein R ³ + R ⁴ are selected from the group consisting of -Y ¹ - (C (R ² ) x) (C (R ² ) x) -Y ¹ - and -Y ¹ (C (R ²⁾ ) x) - (C (R ² ) x) - (C (R ² ) x) - and Y ¹ is N or O or S as represented by the general formula 110 f wherein X and X 'are selected from the group consisting of N, O and C and at least one of X and X' is N. A compound according to claim 68 wherein said compound is represented by the general formula wherein (R ² ) x is hydrogen or oxo. The compound of claim 68, wherein said compound is represented by the formula wherein (R ² ) x is hydrogen or oxo. 71. A compound having selective agonist activity at the adrenergic alpha2B or alpha2B / 2C receptor or on the subtype (s) of the adrenergic alpha2B and alpha2C receptors as compared to the adrenergic alpha2A receptor subtype represented by the formula And pharmaceutically acceptable salts thereof. 72. A method of administering a pharmaceutical composition to a mammalian host, including a human, comprising using a pharmaceutical composition comprising an effective dose of the active compound to treat or prevent glaucoma without sedative or cardiovascular side effects, said compound having adrenergic activity and being selective an alpha2B adrenoceptor subtype agonist or alpha2B / alpha2C adrenoreceptor adrenoceptor subtype (s), which it prefers to adrenoceptor alpha2A subtype. 73. The method of claim 72, wherein the active compound has an activity comparable to a standard full agonist that is at least 0.3 higher on the alpha2B or alpha2C adrenoceptor subtypes compared to the alpha2A adrenoceptor subtype, and its efficacy on the alpha2A adrenoceptor subtype is less than or equal to 0.4. 74. The method of claim 72, wherein the active compound is at least ten times more potent for the adrenoceptor subtype alpha2B or alpha2C than for the adrenoceptor alpha 2A receptor. 112 75. The method of claim 74 wherein about 0.001 to 5% by weight of the active compound is administered topically, once or twice daily to the host mammal. 76. The method of claim 75 wherein about 0.01 to 3% by weight of the active compound is administered to the host mammal topically, once or twice daily. 77. The method of claim 72, wherein said compound has no activity on the adrenoreceptor subtype alpha 2A. 78. The method of claim 72, wherein said compound has no activity on the adrenoreceptor subtypes alpha 2A and alpha 2C. 79. A method of administering a pharmaceutical composition to a mammalian host, including a human, comprising using a pharmaceutical composition comprising an effective dose of the active compound to treat elevated intraocular pressure without sedative or cardiovascular side effects, wherein the compound has adrenergic activity and is a selective adrenoceptor agonist. (adrenoceptor) subtype (s) alpha 2B or alpha 2B / alpha 2C, which prefers adrenoceptor receptor subtype alpha 2A. 80. The method of claim 79, wherein the active compound has activity comparable to a standard full agonist that is at least 0.3 greater on the alpha 2B or 2C adrenoceptor subtypes than on the adrenoceptor subtype. 113 ·· subtype alpha 2A, and its activity on the adrenoceptor subtype alpha 2A is less than or equal to 0.4. 81. The method of claim 80 wherein 0.001 to 5% by weight of the active compound is administered to the host mammal locally once or twice daily. 82. The method of claim 81, wherein 0.01 to 3.0% by weight of the active compound is administered to the host mammal locally once or twice daily. 83. The method of claim 79, wherein said compound has no activity on alpha2A adrenoreceptor subtypes. 84. The method of claim 79, wherein said compound has no activity on the adrenoreceptor subtypes alpha2A and alpha2C. 85. A method of treating a mammalian organism which reduces intraocular pressure without cardiovascular and sedative side effects by selectively agonizing the alpha2B adrenoceptor subtype or alpha2B / alpha2C adrenoceptor subtype (s), which prefers adrenoceptor alpha A subtype. 86. A method of selectively agonizing an alpha2B adrenoceptor subtype or alpha2B / alpha2C adrenoceptor subtypes without agonizing the adrenoceptor alpha2A subtype, comprising administering a therapeutically effective 114 amounts of selective alpha2B or alpha2B / alpha1C2 receptor subtype agonist (s). 87. An alpha adrenergic agonist, which selectively activates the alpha2B or alpha2B / alpha2C receptor subtype (s), which it prefers to the alpha2A receptor subtype. 88. The method of claims 72, 79, 85 or 91, wherein the active compound is selected from the group consisting of compounds of the general formula wherein the dotted lines represent preferred double bonds; R is H or lower alkyl; X is S or C (H) R ¹ , wherein R ¹ is H or lower alkyl or R ¹ is absent if X is S or when the bond between X and the ring represented is a double bond; Y is O, N, S, (CR ¹ x) _y , wherein y is an integer from 1 to 3, -CH = CH- or Y ¹ CH ₂ - wherein Y ¹ is O, N or S; x is 1 or 2, wherein x is 1 when R ² , R ³ or R ⁴ are bonded to an unsaturated carbon atom and x is 2 if R ² , R ³ or R ⁴ are bonded to a saturated carbon atom; R ² is H, lower alkyl, halogen, hydroxy or lower alkoxy, or, when R ^{2 is} attached to a saturated carbon atom, may be an oxo group; R ³ and R ⁴ are 115 • both Η, lower alkyl, hydroxy, lower alkoxy or phenyl, or, together are - (C (R ² ) x) -; Y ¹ (C (R ² ) x) z '-; -Y ¹ (C (R ² ) x) y Y ¹ ; -C (R ² ) x) -Y ¹ - (C (R ² ) x) -; - (C (R ² ) x) -Y ¹ - (C (R ² ) x) - (C (R ² ) x) - aY ¹ (C (R ² ) x) -Y ¹ - (C (R ²⁾ x) -, wherein z is an integer from 3 to 5, z 'is an integer from 2 to 4 axes are as defined above, and further both ends of all these divalent portions of the molecule may be attached to either R ³ or to R ^4a forms a fused ring structure and the ring thus formed may be fully unsaturated, partially saturated or fully saturated, provided that the carbon in the ring has no more than 4 valences, nitrogen is no more than 3 valences and O and S have no more than 2 valencies ; or wherein W is a bicyclic radical selected from the group consisting of 116 4 · 4 44 4 · ·· 4 4 <4 4 4 4 · · 4 4 4 · · 444 4 44 4 444 44 · 444 44 4 wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected from the group consisting of H and lower alkyl, provided that at least one of R ⁵ and R ⁶ or R ⁶ and R ⁷ is OC (R ⁹ ) C (R ⁹ ) N (R) and forms a fused ring with wherein R ⁹ is H, lower alkyl or oxo and wherein R ¹⁰ is H, lower alkyl, phenyl or lower alkyl substituted phenyl and Z is O or NH. 89. A method of administering a pharmaceutical composition comprising an effective dose of an active compound having adrenergic activity to a mammalian host, including a human, to treat or prevent glaucoma, wherein the active compound has the biological property of being a selective receptor (s) receptor subtype agonist (s). alpha2B or alpha2B / alpha2C subtypes, which prefer to alpha2A receptor subtype, and said selectivity is measured by determining that cells that naturally express individual alpha2 subtypes or have one of the subtypes introduced are used, wherein the receptors are human or of a species has been shown to have the same pharmacological properties, and in this assay, the potency of the active compound relative to a standard compound measured at the alpha2B or alpha 2C receptor subtype is determined to be at least 0.3 greater than the active compound to standard The compound measured on the alpha2A receptor subtype, and its activity on the alpha2A receptor subtype is less than or equal to 0.4, and / or the active compound is at least 10 fold more potent on the alpha2B or alpha2C receptor subtypes than on the alpha2A receptor subtype. 90. The method of claim 89 wherein 0.001 to 5% by weight of the active compound is administered locally to the host mammal per day. 91. A method of administering a pharmaceutical composition comprising an effective dose of an active compound to a mammalian host, including a human, to treat or prevent muscle spasticity including hyperactive frequent urination, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases including optic nerve neuropathy , spinal cord ischemia and stroke, memory and consciousness disorders, attention deficit disorder, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion without sedative or cardiovascular side effects, characterized in that: said compound has adrenergic activity and is a selective agonist of the adrenoceptor (s) receptor subtype (s) alpha2B or alpha2B / alpha2C, which it prefers over the adrenoceptor receptor subtype em alfa2A. 92. A method of administering a pharmaceutical composition comprising an effective dose of an active compound having adrenergic activity to a mammalian host, including a human, for the treatment of muscle spasticity including hyperactive frequent urination, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases 118 • φ φ Φ Φ φ φ φ φ>>:::: nerv nerv φ · · · · · · · φ φ φ φ φ nerv nerv nerv φ φ φ spinal cord ischemia and stroke, memory and consciousness disorders, attention deficit disorder, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion without sedative or cardiovascular side effects characterized by active the compound has the biological property of being a selective alpha2B or alpha2B / alpha2C receptor subtype agonist that it prefers to the alpha2A receptor subtype, and said selectivity is measured by determining that cells that naturally express individual alpha2 subtypes are used or have one of the subtypes introduced, wherein the receptors are human or of a species that has been shown to have the same pharmacological properties, and in this assay, the potency of the active compound relative to a standard compound measured at the alpha2B or alpha 2C receptor subtype is determined to be at least 0.3 greater than the active compound. , and its activity on the alpha2A receptor subtype is less than or equal to 0.4, and / or the active compound is at least 10 times more potent on the alpha2B or alpha2C receptor subtypes than on the alpha2A receptor subtype. 93. A method of administering a pharmaceutical composition comprising an effective dose of an active compound having adrenergic activity to a mammalian host, including a human, for treating muscular spasticity including hyperactive frequent urination, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases including optic nerve neuropathy , spinal cord ischemia and stroke, memory and consciousness disorders, attention deficit disorder, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion without sedative or cardiovascular side effects characterized by: 119 99 ·· ·· 9 '9 9 9 9 9 9: 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 The compound has the biological property of being a selective alpha2B or alpha2B / alpha2C receptor subtype agonist that prefers alpha2A receptor subtype, and said selectivity is measured by RSAT assays where activation The alpha2A and alpha2C receptor subtype of the test compound is compared to brimonidine, and activation of the alpha2B receptor subtype is compared to oxymetazoline, and wherein the respective alpha2A, alpha2B and alpha2C receptor subtypes are expressed in NIH-3T3 cells, and in this assay the activity of the active compound on the alpha2 receptor subtype. based on the activity of brimonidine or the activity of the active compound on the alpha2B receptor subtype relative to the effect of oxymetazoline is determined to be at least 0.3 higher than the activity of the active compound on the alpha2A receptor subtype relative to brimonidine, and its activity on the alpha2A receptor subtype is less or equal to 0.4 and / or the active compound is at least 10 fold more potent on the alpha2B or alpha2C receptor subtypes than on the alpha2A receptor subtype. 94. The method of claim 74, wherein the active compound is at least 100 times more potent on the adrenoceptor subtype alpha2B or alpha2C than on the adrenoceptor subtype alpha2A.