KR19990082311A - Histamine H₃ Receptor Ligand - Google Patents

Abstract

The compounds of formula (I) or (II) below and their pharmaceutically acceptable salts are ligands at the histamine H ₃ receptor:

Wherein R ¹ is C ₄ to C ₂₀ hydrocarbyl (wherein if R ¹ does not contain a -0-0- group, one or more hydrogen atoms may be replaced by halogen atoms, and up to three carbon atoms may be oxygen Can be replaced with nitrogen or sulfur atoms),

R ² is H or C ₁ -C ₃ alkyl,

m is 1-15,

n is 2 to 6,

Each X group independently represents (a), or one X group represents -N (R ⁴ )-,-0- or -S-, and the remaining X groups independently represent (a),

Wherein R ³ is H, C ₁ -C ₆ alkyl, -CO ₂ R ⁵ , -CONR ⁵ ₂ , -CR ⁵ ₂ OR ⁶ or -OR ⁵ (wherein R ⁵ and R ⁶ are H or C _1- C ₃ alkyl), R ⁴ is H or C ₁ -C ₆ alkyl,

Each Y group is independently -C (R ³ ) R ⁴ -or up to two Y groups are -N (R ⁴ )-, -0- or, -S-, and the remaining Y groups are independently -C (R ³ ) R ^4- , wherein R ³ is as described above, one R ⁴ group is imidazoyl, imidazoylalkyl, the remaining R ⁴ groups are H or C ₁ -C ₆ alkyl,

Z is> C (R ⁷ ) NR ² -or> N-, where R ⁷ is one of the groups listed for R ³ .

Description

Histamine H₃ Receptor Ligand

The present invention relates to compounds that bind to histamine H ₃ receptor and methods of preparing such compounds.

Histamine is well known as a mediator in the body's sensory hypersensitivity reactions such as allergic dermatitis, fever and asthma. Currently these diseases are generally treated by histamine's potent antagonists, the so-called "antihistamines".

In the 1940s, it was noted that the physiological effects of histamine, such as increased gastric acid secretion and cardiac irritation, were not hindered by the antihistamines that were acceptable at the time. This led to the claim that histamine receptors exist in at least two types, termed H ₁ receptors and H ₂ receptors. Subsequently, H ₂ antagonists (such as cimetidine, ranitidine and famotidine) have been identified and these have become important substances for the treatment of gastric ulcers.

In the early 1980s, histamine was also identified as a neurotransmitter in the central nervous system. Aran et al . Asserted the presence of a _third histamine receptor subtype (H ₃ ) located synapically on the histamine effector nerve endings ( Nature 302 , 832-883 (1983)). Aran et al. Hypothesized that the H ₃ receptor is involved in inhibiting the synthesis and release of histamine in the negative feedback mechanism. Later, the development of selective H ₃ agonists and antagonists confirmed the presence of H ₃ receptors (Aran et al ., Nature 327 , 117-123 (1987)). Subsequently, H ₃ receptors have been shown to regulate the release of other neurotransmitters in the central nervous system and peripheral organs, particularly the lungs and the GI tract. In addition, the H ₃ receptor has been reported to regulate the release of histamine from mast cells and enterochrome-like cells.

Efficient selective H ₃ ligands (agonists and antagonists) as a tool in studying the role of histamine as a neurotransmitter and as a tool in studying the role of histamine as a neurological hormone, endocrine and paracrine hormone Is required. In addition, H ₃ ligands are therapeutically useful for many applications, including as sedatives, sleep regulators, antispasmodics, modulators of hypopotalamo-hypophyseal secretion, anti-inhibitors and modulators of brain circulation. And therapeutic utility in the treatment of asthma and irritable bowel syndrome.

Many imidazole derivatives have been proposed in the patent literature as H ₃ ligands.

Representative patent documents are EP-A-0197840, EP-A-0214058, EP-A-0458661, EP-A-0494010, EP-A-0531219, WO91 / 17146, WO92 / 15567, WO93 / 01812, WO93 / 12093, WO93 / 12107, WO93 / 12108, WO93 / 14070, WO93 / 20061, WO94 / 17058, WO95 / 06037, WO95 / 11894, WO95 / 14007, US -A-4988689 and US-A-5217986.

The present invention provides a new class of H ₃ receptor ligands having sulfonamide groups or sulfamide groups at regular intervals from the imidazole ring.

According to the present invention there is provided a compound of the general formula and a pharmaceutically acceptable salt thereof:

Wherein R represents 0 to 2 substituents,

R ¹ is C ₄ to C ₂₀ hydrocarbyl (if R ₁ does not contain a -0-0- group, one or more hydrogen atoms may be replaced by halogen atoms, and up to four carbon atoms [especially 0 to 3 carbons) May be replaced with an oxygen atom, a nitrogen atom or a sulfur atom),

R ² is H or C _{1 to} C ₁₅ hydrocarbyl (if R ² does not contain a -0-0- group, one or more hydrogen atoms may be replaced by halogen atoms, and up to three carbon atoms may be oxygen atoms, nitrogen atoms Or sulfur atoms),

m is 1-15 (preferably 1-10, More preferably, 3-10, for example, 4-9),

n is 2 to 6,

Each X group independently Or one X group is -N (R ⁴ )-,-0- or -S- (unless the X group is adjacent to the -NR ² -group) and the remaining X groups are independently Wherein R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -CO ₂ R ⁵ , -CONR ⁵ ₂ , -CR ⁵ ₂ OR ⁶ or -OR ⁵ (where R ⁵ and R ⁶ are H or C ₁ -C ₃ alkyl), R ⁴ is H or C ₁ -C ₆ alkyl,

Each Y group is independently -C (R ³ ) R ⁴ -or up to two Y groups are -N (R ⁴ )-, -O- or -S-, and the remaining Y groups are independently -C (R ³ ) R ^4- , wherein R ³ is as defined above and one R ⁴ group is imidazoyl, imidazoylalkyl, substituted imidazoyl or substituted imidazoylalkyl, and the remaining R ⁴ groups are H Or C ₁ -C ₆ alkyl,

Z is> C (R ⁷ ) NR ² -or> N-, where R ⁷ is one of the groups listed for R ³ .

The present invention also encompasses inducible compounds ("pro-drugs") that degrade in vivo to produce compounds of formula (I) or (II).

In general (but not always), prodrugs are less potent at the target receptor compared to the resulting compacts they break down. In particular, prodrugs are useful when the desired compounds are difficult to administer or have inefficient chemical or physical properties. For example, the desired compounds may exhibit only insufficient solubility, may be insufficiently transported across the mucous epithelium, or may have undesirably short plasma half-lives. Additional discussion of prodrugs can be found in Stella, V.J. Et al., "Prodrugs" ( Drug Delivery Systems , pp. 112-176 (1985) and Drugs , 29 , pp. 455-473 (1985)).

Pharmaceutically active compounds of the invention in the form of prodrugs are compounds according to general formula (I) or (II) which generally have acid groups which are esterified or amidated. Such esterified acid groups include groups of the form -COOR ⁸ , wherein R ⁸ is C ₁ -C ₅ alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl or one of the following structural formulas.

Acid groups to be amidated include groups of the general formula —CONR ⁹ R ¹⁰ , wherein R ⁹ is H,

C ₁ -C ₅ alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, R ¹⁰ is one of the groups listed for —OH or R ⁹ .

Compounds of formula (I) or (II) having amino groups can be derived by aldehydes such as ketones or formaldehydes to produce Mannich bases. It is hydrolyzed at first reaction rate in aqueous solution.

Pharmaceutically acceptable salts of the acidic compounds of the present invention include salts with alkali and alkaline earth metals and salts with organic bases such as sodium, potassium, calcium and magnesium. Suitable organic bases include amines such as N -methyl-D-glucamine.

Pharmaceutically acceptable salts of the basic compounds of the present invention include salts derived from organic or inorganic acids. Suitable acids include hydrochloric acid, hydrobromic acid, trifluoroacetic acid, phosphoric acid, oxalic acid, maleic acid, succinic acid and citric acid.

The compounds of the present invention may exist in various enantiomeric, diastereomeric and tautomeric forms. The present invention includes not only mixed forms of enantiomers, diastereomers and tautomers, but also separate discrete enantiomeric forms, diastereomeric forms and tautomeric forms.

As used herein, the term "hydrocarbyl" refers to a monovalent group consisting of carbon and hydrogen. Thus, hydrocarbyl groups are alkyl, alkenyl and alkynyl groups (all of which are straight and branched chain forms), cycloalkyl groups (including polycycloalkyl groups), cycloalkenyl groups and aryl groups and combinations thereof, such as alkyl An aryl group, an alkenylaryl group, an alkynylaryl group, a cycloalkylaryl group, and a cycloalkenylaryl group are included.

The term "carbocyclic" group, as used herein, refers to one or more closed chains or rings consisting entirely of carbon atoms. Such groups include alicyclic groups (eg cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups and adamantyl groups), groups comprising alkyl moieties and cycloalkyl moieties (eg adamantanemethyl groups And aromatic groups (e.g., phenyl group, naphthyl group, indanyl group, fluorenyl group, (1,2,3,4) -tetrahydronaphthyl group, indenyl group and isoindenyl group).

The term "aryl" as used herein refers to an aromatic carbocyclic group containing the groups described above.

A "heterocyclic" group includes one or more closed chains or rings that contain at least one atom other than a carbon atom in the closed chain or ring. For example, benzimidazolyl, thienyl, furanyl, pyrroyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imida Zolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyridyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzo Furyl, indolyl, oxyindoleyl, isoindoleyl, indazolyl, indolinyl, 7-azaindoleyl, isoindazolyl, benzopyranyl, coumarinyl, isoquininyl, quinolyl, isoquinolyl, naphthyridinyl , Cinnaolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromenyl and carboryl.

Where substituted carbocyclic groups (eg substituted phenyl groups) or substituted heterocyclic groups are mentioned here, these substituents are preferably 1 to 3, C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy, C ₁ -C ₆ alkylthio, carboxy, C ₁ -C ₆ carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C ₁ -C ₆ alkylamino, di (C ₁ -C ₆ alkyl ) is selected from amino, aryl, C ₁ ~C ₆ alkyl, aryl, haloalkyl, sulfamoyl and cyano. If R is present, the R moiety can be one or two of the foregoing groups, preferably C ₁ -C ₃ alkyl or halo.

The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine.

Preferably R ² is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkylhydroxyalkyl, aryl C ₁ -C ₆ alkyl and Molar aryl C ₁ -C ₆ alkyl. For example, R ² can be H or C ₁ -C ₃ alkyl.

In some embodiments, -Xm- is a C ₁ -C ₈ alkylene group, for example a butylene group.

R ¹ includes alkyl-containing groups (such as phenyl, substituted phenyl, naphthyl and substituted naphthyl) and (cycloalkyl) alkyl groups (such as cyclohexylpropyl and adamantylpropyl).

Preferably, R ¹ is a group of the general formula:

Wherein p is 0 or 1, R ¹¹ is H or C ₁ -C ₃ alkyl and q is 0-4, R ¹² is carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocy Is a click group, R ¹³ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkylhydroxyalkyl, aryl C ₁ -C ₆ alkyl And substituted aryl C ₁ -C ₆ alkyl.

Preferably, R ¹³ is hydrogen.

In the compounds of the present invention, the imidazoylalkyl group contains 1 to 8 carbon atoms in the alkyl chain.

As measured by the two ileum based assays described below, the inventors have found that several conventional compounds exhibit significant inconsistencies in activity. Data analysis obtained by these specific functional groups and radioligand binding assays and other related biochemical assays suggests that activity mismatches may be at least partially related to the original residual efficacy in the compound structure. In practice, this means that certain compounds may act as agonists at least in some tissues.

Surprisingly, the inventors have found that when m is 3 or more, preferably 3 to 9, especially 4 to 8, the compounds disclosed herein do not show significant discrepancies in the two assays described above. Thus, these compounds may be considered to be typical antagonists of the action of natural hormones rather than having the potential to act as partial or total agonists. Thus, in one aspect, the present invention provides the use of these compounds as histamine antagonists and in the manufacture of a medicament for this purpose.

Compounds of the present invention which are sulfonamides can be prepared by reacting suitably protected derivatives of the compounds represented by the following general formula with sulfonyl chlorides of the general formula R ¹ SO ₂ Cl. Suitable protecting groups for the imidazole moiety include trityl and N, N-dimethylsulfamoyl groups. Other functional groups in the reactants may be protected by reagents well known to those skilled in the art.

The reaction with sulfonylchloride is carried out in a suitable non-aqueous solvent such as N, N-dimethylformamide or dried dichloromethane in the presence of a base such as triethylamine. Typically, this reaction is carried out at room temperature for several hours.

Compounds of the invention that are sulfamides can be prepared conventionally by the following steps a) to d):

a) reacting an appropriate alcohol of the general formula R ¹⁴ OH with chlorosulfonylisocyanate,

b) reacting the product of step a) with a suitably protected derivative of the compound represented by formula IV;

c) the step of reacting the product of a base and the step b), such as sodium hydride and then, is bonded to the carbon atom of R ¹ bromine atom is reacted with a compound represented by the general formula R ¹ -Br in and

d) acid treating the product of step c) to remove R ¹⁴ OCO- groups and other protecting groups,

In a preferred embodiment, the reagent of step c) has the general formula:

Wherein q, R ¹² and R ¹³ are as described above.

Particularly preferred alcohols for use in step a) are t-butanol and benzyl alcohol.

1 shows the synthesis of N- [5- (4 (5) -imidazoyl) pentyl] -N '-(4-chlorophenyl) -methyl-sulfamide by the above method.

In an alternative process, sulfamides according to the invention can be prepared by the following steps a) to d):

a) reacting an appropriate alcohol of the general formula R ¹⁴ OH with chlorosulfonylisocyanate,

b) reacting the product of step a) with a suitably protected derivative of the compound represented by the general formula R ¹ -H bonded to the nitrogen atom of hydrogen atom R ¹ ,

c) reacting the product of step b) with a suitably protected derivative of the compound represented by the following general formula;

And

d) acid treating the product of step c) to remove R ¹⁴ OCO- groups and other protecting groups.

In a preferred embodiment, the reagent used in step b) has the general formula:

Wherein q, R ¹² and R ¹³ are as described above. Figure 2 shows the synthesis of N- [4- (4 (5) -imidazoyl) butyl] -N'-cyclohexylmethylsulphamide by the above method.

Of course, pharmaceutically acceptable salts of the acidic or basic compounds of the present invention can be prepared by conventional methods, such as by reacting at least a stoichiometric amount of the desired salt-forming acid or salt-forming base with the free base or free acid. have.

The compounds of the present invention are expected to be capable of parenteral administration such as oral or intravenous administration, intramuscular administration, intraperitoneal administration, subcutaneous administration, rectal administration and topical administration.

For oral administration, the compounds of the invention are generally provided in the form of tablets or capsules or in aqueous solution or suspension.

Tablets for oral administration may include an active ingredient mixed with pharmaceutically acceptable excipients such as inert excipients, disintegrants, binders, lubricants, sweeteners, flavors, colorants and preservatives. Suitable inert excipients are sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate, and lactose, while suitable disintegrants are corn starch and alginic acid. The binder may include starch and gelatin, while the lubricant is generally magnesium stearate, stearic acid or talc. If desired, tablets may be coated with glycerin monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract.

Capsules for oral administration include hard gelatin capsules in which the active ingredient is combined with solid excipients and soft gelatin capsules in which the active ingredient is mixed with oils such as water or peanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous and intravenous administration, the compounds of the present invention are generally provided in sterile aqueous solutions or suspensions buffered to the appropriate pH and isotonicity. Suitable water soluble excipients include Ringer's solution and isotonic sodium chloride. Water-soluble excipients according to the present invention may include cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and suspending agents such as gum tragacanth and wetting agents such as lecithin. Suitable preservatives for water soluble suspensions include ethyl and n-propyl p-hydroxybenzoate.

Effective dosages of the compounds of the invention can be ascertained by conventional methods. The constant dosage level required for a particular patient depends on many factors, including the stringency of the condition being treated, the route of administration and the weight of the patient. However, the daily dose (whether administered in single or divided doses) is expected to be from 0.001 to 5000 mg / day, more generally from 1 to 1000 mg / day, most commonly from 10 to 200 mg / day.

Typical dosages expressed as dosages per unit weight are expected to be 0.01 μg / kg to 50 mg / kg, in particular 10 μg / kg to 10 mg / kg, for example 100 μg / kg to 2 mg / kg. .

The invention is further illustrated by the following examples.

Example 1

N- [2- (4 (5) -imidazoyl) ethyl] -2-naphthalenesulfonamide

Triethylamine (2.07 ml, 14.8 mmol) and 2-naphthalenesulfonylchloride (1.68 g, 7.41 mmol) were added to a histamine (824 mg, 7.41 mmol) suspension in dry N, N-dimethylformamide (10 ml). It was. The mixture was stirred for 48 h at room temperature, poured into water (50 ml) and extracted with ethyl acetate (3 × 20 ml). The combined organic extracts were washed with brine (3 × 20 ml), then the solvent was evaporated under reduced pressure and retained by flash column chromatography (silica, 1% NH ₃ aqueous solution (880) / 10% MeOH / CH ₂ Cl ₂ ). Water was purified. The resulting oil (R _f 0.17) was crystallized from tetrahydrofuran to give the title compound as a white solid (440 mg, 20%): ¹ H NMR (300 Hz, d ₆ -DMSO) 11.73 (1 H, s), 8.41 (1H, s), 8.13 (2H, m), 8.02 (1H, d), 7.80 (1H, dd), 7.67 (2H, m), 7.44 (1H, d), 6.74 (1H, S), 2.99 (2H, t), 2.58 (2H, t). Maleate salts were prepared by lyophilysis of eguimolar solutions of maleic acid with product in water / dioxane.

Found: C 54.67, H 4.69, N 10.07%;

C ₁₉ H ₁₉ N ₃ O ₆ S Theoretic: C 54.67, H 4.59, N 10.07%.

Example 2

N- [2- (4 (5) -imidazoyl) ethyl] -benzenesulfonamide

Step a. N- [2- (1-benzenesulfonyl-imidazoyl-4-yl) ethyl] -benzenesulfonamide.

To ethyl histamine (337 mg, 3.04 mmol) suspension in dry dichloromethane (60 ml) was added triethylamine (1.27 ml, 9.10 mmol) and benzenesulfonylchloride (775 μl, 6.08 mmol). The mixture was stirred at rt for 6 h, the solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate (50 ml). Triethylamine hydrochloride was filtered off and the filtrate was evaporated under reduced pressure. The residue was crystallized from ethyl acetate / hexanes to give the product as a white solid (1.04 g, 93%).

Step b. To a suspension of the product of step a (1.04 g, 2.82 mmol) in ethanol (115 ml) was added a solution of sodium carbonate (1.20 g, 11.3 mmol) in water (85 ml). The mixture was stirred for 24 hours and ethanol was removed at ambient temperature under reduced pressure. The aqueous mixture was extracted with chloroform (6 x 50 ml) and the combined extracts were washed with brine and then dried over anhydrous sodium sulfate. Filtration and evaporation under reduced pressure gave the title compound as a white solid (567 mg, 80%): ¹ H NMR (300 Hz, d ₆ -DMSO) 7.77 (2H, m), 7.60 (3H, m), 7.46 ( 1H, s), 6.74 (1H, s), 2.94 (2H, t), 2.57 (2H, t). Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane.

Found: C 45.65, H 4.74, N 10.95%;

C ₁₅ H ₁₇ N ₃ 0 ₆ S.1.0H ₂ O Theory: C 46.77, H 4.97, N 10.91%

Example 3

N- [2- (4 (5) -imidazoyl) ethyl] -1-naphthalenesulfonamide

Step a. N- [2- (1- (1-naphthalenesulfonyl) -4-imidazoyl) ethyl] -1-naphthalenesulfonamide

Triethylamine (1.48 ml, 10.6 mmol) and 1-naphthalenesulfonylchloride (2.01 g, 8.85 mmol) were added to a suspension of histamine (393 mg, 3.54 mmol) in dry dichloromethane (60 ml). The mixture was stirred at rt for 18 h, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). Triethylamine hydrochloride was removed by filtration and the filtrate was evaporated under reduced pressure. Flash column chromatography (silica, 70% ethyl acetate / hexanes) gave the product (R _f 0.35) as a colorless foam (1.32 g, 76%).

Step b. To a solution of the product of step a (1.18 g, 2.41 mmol) in ethanol (100 ml) was added a solution of sodium carbonate (1.02 g, 9.64 mmol) in water (35 ml). The mixture was stirred for 18 hours and the insolubles were removed by filtration. Ethanol was evaporated at ambient temperature under reduced pressure. The resulting precipitate was collected by filtration and then vacuum dried at 50 ° C. Flash column chromatography (silica, 1% NH ₃ aqueous solution (880) / 10% MeOH / CH ₂ Cl ₂ ) gave the title compound (R _f 0.29) as a white solid (366 mg, 50%): ¹ H NMR (300 Hz, d ₆ -DMSO) 11.70 (1H, br s), 8.64 (1H, dd), 8.21 (1H, d), 8.09 (2H, m), 8.03 (1H, t), 7.68 (3H, m) , 7.42 (1 H, d), 6.66 (1 H, s), 2.97 (2 H, m), 2.55 (2 H, m). Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane.

Found: C 53.42, H 4.73, N 9.69%;

C ₁₉ H ₁₉ N ₃ O ₆ S.6H ₂ 0 Theory: C 53.31, H 4.75, N 9.82%.

Example 4

N- [2- (4 (5) -imidazoyl) ethyl] -3-cyclohexylpropanesulfonamide

Step a. 3-cyclohexylpropanesulfonylchloride.

A mixture of 1-chloro-3-cyclohexylpropane (8.00 g, 50 mmol), thiourea (3.80 g, 50 mmol) and sodium iodide (100 mg) in ethanol (40 ml) was heated to reflux for 3 hours. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether. The product was collected by filtration, washed with diethyl ether and then air dried to give a white solid (6.64 g) which was suspended in water (50 ml) / dichloromethane (50 ml). By vigorously stirring for 30 minutes while maintaining the temperature below 20 ℃, bubbles of chlorine gas were generated through the mixture. The organic layer was separated and then washed with ice cold 10% aqueous sodium bisulfite solution (2 x 50 ml), saturated aqueous sodium bicarbonate solution (2 x 50 ml) and water (50 ml) and dried over magnesium sulfate. Filtration and evaporation gave the product as a colorless oil (3.60 g, 34%).

Step b. To a suspension of histamine (222 mg, 2.00 mmol) in dichloromethane (10 ml) was added a solution of triethylamine (278 μl, 2.00 mmol) and the product of step a (224 mg, 1.00 mmol) in dichloromethane (2 ml) over 5 minutes. Drops were added. The mixture was stirred for 18 hours and the solvent was evaporated under reduced pressure to give a white solid. Flash column chromatography (silica, 1% NH ₃ aqueous solution (880) / 10% MeOH / CH ₂ Cl ₂ ) gave the title compound (R _f 0.25) as a colorless oil (100 mg, 33%): ¹ H NMR (300 Hz, CDCl ₃ ) 8.80 (1 H, br s), 7.52 (1 H, dd), 6.83 (1 H, s), 5.80 (1 H, br s). 3.38 (2H, t), 2.93 (2H, t). 2.84 (2H, t), 1.78 (2H, m), 1.65 (5H, m), 1.25 (6H, m), 0.88 (2H, m).

Example 5

N- [2- (4 (5) -imidazoyl) ethyl]-(3- (1-adamantyl) propane) sulfonamide

3- (1-adamantyl) propanesulfonylchloride (700 mg, 2.50 mmol) prepared according to the method of step a of Example 4 was prepared by histamine (555 mg, 5.00 mmol) according to the method of step b of Example 4. Reacted with This resulted in the title compound as a colorless foam (340 mg, 39%): ¹ H NMR (300 Hz, CDCl ₃ ) 7.55 (1H, s), 6.86 (1H, s), 5.50 (1H, br s), 3.41 (2H, t), 2.93 (2H, t), 2.86 (2H, t), 1.94 (3H, s), 1.80-1.59 (8H, m), 1.46 (6H, s), 1.12 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Found: C 55.55, H 7.20, N 8.83%;

C ₂₂ H ₃₃ N ₃ O ₆ S.0.5H ₂ O Theoretic: C 55.44, H 7.19, N 8.82%.

Example 6

N- [5- (4 (5) -imidazoyl) pentyl] -2-naphthalenesulfonamide

Step a. N- [5- (1- (N ', N ¹ -dimethylsulfamoyl) -imidazol-4-yl) pentyl] -2-naphthalenesulfonamide.

Triethylamine (107 μl, 0.77 mmol) and 5- (5-aminopentyl) -1- (N, N-dimethylsulfamoyl) -imidazole ^{1 in} dry dichloromethane (2 ml), cooled on ice under an argon atmosphere. 166 mg, 0.64 mmol) was added 2-naphthalenesulfonylchloride (175 mg, 0.77 mmol). The solution was stirred at 0 ° C. for 45 minutes and then the solvent was evaporated. The residue was treated by flash column chromatography (silica; 0.5: 5: 95 ammonia (880) / methanol / dichloromethane) to give the product (R _f 0.76) as a colorless foam (224 mg, 79%).

Step b. The solution of the product of step a (224 mg, 0.50 mmol) in a mixture of ethanol (4 ml) and 1 M hydrochloric acid (4 ml) was heated to reflux for 6 hours and the solvent was removed in vacuo. The residue was treated with flash column chromatography (silica; 0.5: 5: 95-1: 10: 90 ammonia (880) / methanol / dichloromethane) to give the title compound (R _f 0.26; 1:10:90 ammonia (880). ) / Methanol / dichloromethane) was obtained as a colorless foam (138 mg, 81%):

¹ H NMR (300 Hz, d ₆ -DMSO) 11.74 (1H, br s), 8.41 (1H, d), 8.13 (2H, t), 8.02 (1H, d), 7.80 (1H, dd), 7.67 (3H , m), 7.44 (1H, s), 6.61 (1H, s), 2.79 (2H, dd), 2.37 (2H, t), 1.40 (4H, m), 1.22 (2H, dd)

Found: C 63.04, H 6.22, N 12.19%;

C ₁₈ H ₂₁ N ₃ O ₂ S Theoretical values: C 62.95, H 6.16, N 12.23%.

Example 7

N- [4- (4 (5) -imidazoyl) butyl] -2-naphthalenesulfonamide

Step a. 4- (4-chlorobutyl) -1- (triphenylmethyl) -imidazole.

5- (4-Chlorobutyl) -2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ (8.80) in a mixture of ethanol (100 ml) and 2M hydrochloric acid (100 ml) g, 23.2 mmol) was heated to reflux for 2 hours. Ethanol was evaporated and the aqueous solution was extracted with diethyl ether (2 x 50 ml). The aqueous layer was evaporated and the residue was dissolved in dry dichloromethane (100 ml). Triethylamine (6.50 ml, 46.6 mmol) and triphenylmethylchloride (7.10 g, 25.5 mmol) were added, the solution was stirred for 18 hours, then washed with water and dried over magnesium sulfate. Filtration and evaporation gave brown oil. The residue was treated by flash column chromatography (silica; 5% methanol / dichloromethane) to give the product as a yellow oil (7.20 g, 77%).

Step b. 4- (4-phthalimidobutyl) -1- (triphenylmethyl) -imidazole

Under argon atmosphere, potassium phthalimide (1.67 g, 9.00 mmol) was added to a solution of the product of step b (7.20 g, 18.0 mmol) in dry N, N-dimethylformamide (50 ml). The mixture was stirred, heated at 100 ° C. for 5 hours, then cooled to room temperature and poured into ice / water (150 ml). The resulting white precipitate was collected by filtration. The residue was dissolved in dichloromethane (100 ml), washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash column chromatography (silica; 5% methanol / dichloromethane) to separate the product into yellow oil (4.50 g, 98%).

Step C. 4- (4-Aminobutyl) -1- (triphenylmethyl) -imidazole.

To the suspension of the product of step b (3.00 g, 5.86 mmol) in ethanol (30 ml) was added hydrazine hydrate (1.5 ml, 25.8 mmol). The mixture was heated to reflux for 2 hours and then cooled to room temperature. The precipitate was removed by filtration. The filtrate was evaporated and the residue was triturated with chloroform. Filtration removed the solids again. The filtrate was evaporated and then trituration was repeated to give the product as a yellow oil (2.05 g, 92%).

Step d. N- [4- (1-triphenylmethyl) -imidazol-4-yl) butyl] -2-naphthalenesulfonamide.

To a solution of the product of step c (465 mg, 1.22 mmol) and triethylamine (185 μl, 1.33 mmol) in dry dichloromethane (15 ml) was added 2-naphthalenesulfonylchloride (227 mg, 1.22 mmol). The solution was stirred for 2 hours and then the solvent was evaporated. The residue was treated with flash column chromatography (silica; 5% methanol / dichloromethane) to give the product as a colorless foam (588 mg, 84%).

Step e. The solution of the product of step d (588 mg, 1.02 mmol) in trifluoroacetic acid (5 ml) was stirred for 18 hours and then the solvent was evaporated. The residue was treated by flash column chromatography (silica; 1: 10: 90 ammonia (880) / methanol / dichloromethane) to give the title compound (R _f 0.24) as a white solid (96 mg, 63%): ¹ H NMR (300 Hz, d ₆ -DMSO) 11.70 (1H, br s), 8.41 (1H, s), 8.13 (2H, t), 8.03 (1H, d), 7.80 (1H, dd), 7.67 (3H, m), 7.45 (1H, s), 6.62 (1H, s), 2.76 (2H, dd), 2.38 (2H.t), 1.48 (2H, m), 1.41 (2H, dd). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Found: C 56.55, H 5.31, N 9.31%; C ₂₁ H ₂₃ N ₃ O ₆ S. 0.5 H ₂ O Theoretic: C 56.62, H 5.20, N 9.43%.

Example 8

N- [6-4 (5) -imidazoyl) hexyl] -2-naphthalene sulfonamide

A subject compound was prepared according to the method of Example 6, and 5- (6-aminohexyl) -1- (N, N-dimethylsulfamoyl) -imidazole was used as the substrate in step a. The product in two steps was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.72 (1H, br s), 8.41 (1H, d), 8.13 (2H, dd), 8.03 (1H, d) , 7.80 (1H, dd), 7.67 (3H, m), 7.44 (1H, s), 6.62 (1H, s), 2.74 (2H, dd), 2.37 (2H, t), 1.42 (2H, m), 1.33 (2H, m), 1.17 (4H, m).

Found: C 60.99, H 6.59, N 11.17%; C ₁₉ H ₂₃ N ₃ O ₂ S. 0.9 H ₂ O Theoretic: C 61.07, H 6.69, N 11.24%.

Example 9

N- [5- (4 (5) -imidazoyl) pentyl]-(4-chlorophenyl) methanesulfonamide

Step a. N- [5- (1- (N ', N'-dimethylsulfamoyl) -imidazol-4-yl) pentyl]-(4-chlorophenyl) methanesulfonamide.

Tri (5- (5-aminopentyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ (412 mg, 1.58 mmol) and tree in dry dichloromethane (5 ml), cooled under argon atmosphere. To a solution of ethylamine (264 μl, 1.90 mmol) was added dropwise a solution of (4-chlorophenyl) methanesulfonyl chloride (533 mg, 2.37 mmol) in dry dichloromethane (5 ml). The resulting solution was stirred for 18 hours, warmed to room temperature and the solvent was evaporated. Treat the residue with flash column chromatography (silica; 0.5: 5: 95 ammonia (880) / methanol / dichloromethane) to give the product (R _f 0.66; 1: 10: 90 ammonia (880) / methanol / dichloromethane) Was obtained as a colorless oil (307 mg, 43%).

Step b. The solution of the product of step a (275 mg, 0.61 mmol) in a mixture of ethanol (4 ml) and 1 M hydrochloric acid (4 ml) was heated to reflux for 18 hours, and then the solvent was removed in vacuo.

Treat the residue with flash column chromatography (silica; 1: 10: 90 ammonia (880) / methanol / dichloromethane) to give the product (R _f 0.34; 1: 10: 90 ammonia (880) / methanol / dichloromethane) Was obtained as a white crystalline solid (181 mg, 87%): ¹ H NMR (300 Hz, d ₆ -DMSO) 11.75 (1H, br s), 7.46 (1H, s), 7.43 (2H, dd), 7.37 (2H, d), 7.04 (1H, t), 6.68 (1H, s), 4.31 (2H, s), 2.87 (2H, dd), 2.45 (2H, t), 1.50 (2H, m), 1.40 ( 2H, m), 1.27 (2H, m).

Found: C 52.88, H 6.13, N 12.28%; C ₁₅ H ₂₀ ClN ₃ O ₂ S Theory: C 52.70, H 5.90, N 12.29%.

Example 10

N- [4- (4 (5) -imidazoyl) butyl]-(4-chlorophenyl) methanesulfonamide

The subject compound was prepared according to the method of Example 9, and 4- (4-aminobutyl) -1- (triphenylmethyl) -imidazole (Example 7 step c) was used as the substrate in step a. Two stages of the product were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.47 (1 H, s), 7.43 (2H, dd), 7.37 (2H, d), 7.05 (1 H, t), 6.69 (1H, s), 4.31 (2H, s), 2.89 (2H, dd), 2.46 (2H, t), 1.55 (2H, m), 1.45 (2H, m).

Maleate salts were prepared by liophysis of equimolar solutions of maleic acid and product in water / dioxane.

Found: C 48.68, H 5.14, N 9.32%; C ₁₈ H ₂₂ ClN ₃ O ₆ S Theory: C 48.70, H 5.00, N 9.47%.

Example 11

N- [6- (4 (5) -imidazoyl) hexyl]-(4-chlorophenyl) methanesulfonamide

A subject compound was prepared according to the method of Example 9, and 5- (6-aminohexyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was used as a substrate in step a.

Two steps of the product were obtained as a white crystalline solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.71 (1H, br s), 7.46 (1H, s), 7.43 (2H, ddd), 7.37 (2H, ddd), 7.05 (1H, t), 6.68 (1H, s), 4.31 (2H, s), 2.86 (2H, dd), 2.46 (2H.t), 1.52 (2H, m), 1.37 (2H, m ), 1.27 (4H, m).

Found: C 51.51, H 6.28, N 15.05%; C ₁₆ H ₂₂ ClN ₃ O ₂ S requires: C 51.81, H 6.25, N 15.11%.

Example 12

N- [5- (4 (5) -imidazoyl) pentyl] -N '-(4-chlorophenyl) methyl-sulfamide

Step a. N- [5- (1- (N ", N" -dimethylsulfamoyl) -imidazol-4-yl) pentyl] -N'-tert-butoxycarbonyl-sulfamide.

To a solution of chloro sulfonylisocyanate (211 μl, 2.42 mmol) in dry dichloromethane (3 ml), cooled on ice under an argon atmosphere, to dry t-butanol (346 μl, 3.63 mmol) in dry dichloromethane (3 ml). The solution was added dropwise. The solution is warmed to room temperature, stirred for 10 minutes, and then under argon 5- (5-aminopentyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ (484 mg, in dry dichloromethane (6 ml) 1.86 mmol) and triethylamine (388 μl, 2.79 mmol) were added dropwise to an ice cooled solution. The mixture was stirred for 18 hours, warmed to room temperature and the solvent was evaporated. Treat the residue with flash column chromatography (silica; 0.5: 5: 95 ammonia (880) / methanol / dichloromethane) to give the product (R _f 0.29; 1:10:90 ammonia (880) / methanol / dichloromethane) Was obtained as a colorless oil (400 mg, 49%).

Step b. N '-(4-chlorophenyl) methyl-N- [5- (1- (N ", N" -dimethylsulfamoyl) -imidazol-4-yl) pentyl] -N'-tert-butoxycarbonyl Sulfamide.

To a solution of 4-chlorobenzylbromide (183 mg, 0.89 mmol) and the product of step a (390 mg, 0.89 mmol) in dry N, N-dimethylformamide (3 ml), cooled to -15 ° C. under argon atmosphere. Sodium hydride (36 mg, 0.89 mmol, 60% dispersion in oil) was added. The mixture was stirred for 18 hours and then slowly warmed up to ambient temperature. Water (15 ml) was added and the mixture was extracted with ethyl acetate (4 × 10 ml). The combined organics were washed four times with water, then dried over sodium sulfate and evaporated. The residue was treated with flash column chromatography (silica; 0.2: 2: 98 ammonia (880 / methanol / dichloromethane) to give the product (R _f 0.29; 1:10:90 ammonia (880) / methanol / dichloromethane). Obtained as a colorless oil (378 mg, 75%).

Step c. The suspension (374 mg, 0.66 mmol) of the product of step b in a mixture of ethanol (5 ml) and 1 M hydrochloric acid (5 ml) was heated to reflux for 18 hours and the solvent was removed in vacuo. The residue was treated with flash column chromatography (silica; 1: 10: 90 ammonia (880) / methanol / dichloromethane) to give the product (R _f 0.24) as a white solid (132 mg, 56%): ¹ H NMR (300 Hz, d ₆ -DMSO) 7.46 (1H, s), 7.43 (5H, m), 6.87 (1H, t), 6.68 (1H, s), 4.03 (2H, d), 2.78 (2H, dd), 2.45 (2H, t), 1.58 (2H, m), 1.47 (2H. M), 1.27 (2H, m). Found: C 50.33, H 5.88, N 15.55%; C ₁₅ H ₂₁ ClN ₄ O ₂ S requires: C 50.48, H 5.93, N 15.70%.

Example 13

N- [4- (4 (5) -imidazoyl) butyl] -N '-(4-chlorophenyl) methyl-sulfamide

A subject compound was prepared according to the method of Example 12, and 4- (4-aminobutyl) -1- (triphenylmethyl) -imidazole (Example 7 step c) was used as the substrate of step a.

Three steps of product were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.68 (1 H, br s), 7.47 (1 H, d), 7.36 (4 H, m), 6.86 (1 H, t) , 6.68 (1H, s), 3.98 (2H, d), 2.79 (2H, dd), 2.45 (2H, t), 1.53 (2H, m), 1.43 (2H, m).

Found: C 49.08, H 5.61, N 16.23%;

C ₁₄ H ₁₉ ClN ₄ O ₂ S Theory: C 49.05, H 5.59, N 16.34%.

Example 14

N- [3- (4 (5) -imidazoyl) propyl] -N '-(4-chlorophenyl) methyl-sulfamide

Step a. 4- (3-phthalimidopropyl) -1- (triphenylmethyl) -imidazole.

Under argon atmosphere, phthalimide was added to a solution of 3- [1- (triphenylmethyl) imidazol-4-yl] propan-1-ol ³ (2.24 g, 6.07 mmol) in dry tetrahydrofuran (10 ml). 1.16 g, 7.89 mmol) and triphenylphosphine (2.07 g, 7.89 mmol) were added. The suspension was cooled with ice and then dropwise added a solution of diethylazodicarboxylate (1.24 ml, 7.89 mmol) in dry tetrahydrofuran (10 ml). The mixture was warmed to room temperature and then stirred for 2 hours. Diethyl ether (20 ml) was added. The precipitate was collected by filtration and dried in vacuo to yield a white solid (2.08 g, 68%).

Step b. 4- (3-aminopropyl) -1- (triphenylmethyl) -imidazole

To the suspension of the product of step a (4.09 g, 8.22 mmol) in ethanol (82 ml) was added hydrazine hydrate (2.32 ml, 41.1 mmol). The mixture was heated to reflux for 3 hours and then cooled to room temperature. The precipitate was removed by filtration. The filtrate was evaporated and the residue was triturated with chloroform. Filtration removed the solids again. The filtrate was evaporated and the softening process was repeated to give quantitative yield of yellow oil as a product.

Step c. N- [3- (1-triphenylmethyl) -imidazol-4-yl) propyl] -N'-tert-butoxycarbonyl-N '-(4-chlorophenyl) methyl-sulfamide.

The product of step b was converted to the product according to the method of steps a and b of Example 12.

Step d. The solution of the product of step c (308 mg, 0.46 mmol) in trifluoroacetic acid (3 ml) was stirred for 18 hours and then the solvent was evaporated. The residue was treated with flash column chromatography (silica; 1: 10: 90 ammonia (880) / methanol / dichloromethane) to give the title compound (R _f 0.18) as a white solid (96 mg, 63%): ¹ H NMR (300 Hz, d ₆ -DMSO) 11.77 (1H, br s), 7.37 (4H, m), 6.99 (1H, t), 6.72 (1H, s), 3.98 (2H, d), 2.81 (2H, dd ), 2.48 (2H, m), 1.72 (2H, m).

Found: C 47.30, H 5.26, N 16.95%;

C ₁₃ H ₁₇ ClN ₄ O ₂ S requires: C 47.49, H 5.21, N 17.04%.

Example 15

N- [6- (4 (5) -imidazoyl) hexyl] -N '-(4-chlorophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, and 5- (6-aminohexyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was used as a substrate in step a. Three steps of product were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.46 (1 H, d), 7.35 (5 H, m), 6.86 (1 H, t), 6.67 (1 H, s), 3.98 (2H, d), 2.75 (2H, dd), 2.45 (2H, t), 1.52 (2H, m), 1.38 (2H, m), 1.25 (4H, m).

Measured value: C 51.51, H 6.28, N 15.05%

C ₁₆ H ₂₃ ClN ₄ O ₂ S requires: C 51.81, H 6.25, N 15.11%.

Example 16

N- [2- (4 (5) -imidazoyl) ethyl] -3,4-dichlorobenzenesulfonamide

A subject compound was prepared according to the method of Example 2, using histamine and 3,4-dichlorobenzenesulfonylchloride (basically prepared according to step a of Example 4) as substrates in step a.

The product in two steps was obtained as a white crystalline solid. ¹ H NMR (300 Hz, d ₆ -DMSO) 11.80 (1 H, br s), 7.94 (1 H, d), 7.90 (1 H, m), 7.87 (1 H, m), 7.72 (1 H, dd), 7.47 ( 1H, s), 6.76 (1H, s), 3.00 (2H, t), 2.59 (2H, t).

Example 17

N- [2- (4 (5) -imidazoyl) ethyl] -2-phenylethanesulfonamide

Step a. 4- (2-phthalimidoethyl) -1- (triphenylmethyl) -imidazole.

Under argon atmosphere, a suspension of 4 (5)-(2-phthalimidoethyl) -imidazole ² (838 mg, 3,48 mmol) in dry dichloromethane (10 ml) was charged with triethylamine (728 μl, 5.22 mmol). Triphenylmethylchloride (1.16 g, 4.18 mmol) was added. The residue was treated with flash column chromatography (silica; 0.2: 2: 98-1: 10: 90 ammonia (880) / methanol / dichloromethane) to give the product as a foam (1.20 g, 71%).

Step b. 4- (2-aminoethyl) -1- (triphenylmethyl) -imidazole

To the suspension of the product of step a (1.20 g, 2.48 mmol) in ethanol (25 ml) was added hydrazine hydrate (702 ml, 12.4 mmol). The mixture was heated to reflux for 90 minutes and cooled to room temperature. The precipitate was removed by filtration. The filtrate was evaporated and the residue was triturated with chloroform. Filtration removed the solids again. The filtrate was evaporated and the softening process was repeated to give the product as a yellow oil (818 mg, 93%).

Step c. N- [2- (1- (triphenylmethyl) imidazoyl-4-yl) ethyl] -2-phenylethanesulfonamide.

To a solution of triethylamine (154 μl, 1.10 mmol) in dry dichloromethane (5 mL) and the product of step b (353 mg, 1.00 mmol), 2-phenylethanesulfonylchloride (basically in dry dichloromethane (2 mL)) A solution (205 mg, 1.00 mmol) prepared according to Example a step a) was added. The solution was stirred for 30 minutes, then washed with water and dried over magnesium sulfate. Filtration and evaporation gave the product (R _f 0.68; 1: 10: 90 ammonia (880) / methanol / dichloromethane) as a white solid (450 mg, 86%).

Step d. The solution of the product of step c (440 mg, 0.84 mmol) in trifluoroacetic acid (4 ml) was stirred for 18 hours and then the solvent was evaporated. The residue was treated by flash column chromatography (silica; 1: 10: 90 ammonia (880) / methanol / dichloromethane) to give the title compound (R _f 0.25) as an oil (61 mg, 26%): ¹ H NMR (300 Hz, CDCl ₃ ) 7.83 (1H, s), 7.20 (5H, m), 6.93 (1H, s), 3.39 (2H, m), 3.27 (2H, m), 3.08 (2H, m), 2.88 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Found: C 51.35, H 5.41, N 10.62%: C ₁₇ H ₂₁ N ₃ O ₆ S Theoretical value: C 51.64, H 5.35, N 10.63%.

Example 18

N- [2- (4 (5) -imidazoyl) ethyl] -3-phenylpropanesulfonamide

The subject compound was prepared according to the method of Example 17, and 3-phenylpropanesulfonylchloride (basically prepared according to step a of Example 4) was used as a substrate in step c. Four steps of product (R _f 0.26; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as colorless oil: ¹ H NMR (300 Hz, CDCl ₃ ) 9.80 (1 H, br s), 7.50 ( 1H, S), 7.42 (2H, t), 7.20 (1H, m), 7.13 (2H, m), 6.80 (1H, s), 3.30 (2H, t), 2.95 (2H, t), 2.79 (2H , t), 2.70 (2H, t), 2.07 (2H, quint.). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 52.69, H 5.71, N 10.23%; C ₁₈ H ₂₃ N ₃ O ₆ S Theoretical values: C 52.80, H 5.66, N 10.27%.

Example 19

N- [2- (4 (5) -imidazoyl) ethyl] -2-naphthylmethanesulfonamide.

The subject compound was prepared according to the method of Example 17, and 2-naphthyl methane sulfonyl chloride (basically prepared according to step a of Example 4) was used as the substrate in step c.

Four steps of product (R _f 0.27; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.75 (1 H, br s), 7.89 (4H, m), 7.51 (4H, m), 7.17 (1H, t), 6.79 (1H, s), 4.46 (2H, s), 3.17 (2H, dd), 2.66 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 54.30, H 5.09, N 9.55%: C ₂₀ H ₂₁ N ₃ O ₆ S. 0.5 H ₂ O Theoretic: C 54.33, H 5.03, N 9.53%.

Example 20

(E) -N- [2- (4 (5) -imidazoyl) ethyl] -2-phenylethenesulfonamide.

The subject compound was prepared according to the method of Example 17, and trans-β-styrene sulfonyl chloride was used as the substrate in step c. Four steps of product (R _f 0.13; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained in a colorless form: ¹ H NMR (300 Hz, CDCl ₃ ) 7.56 (1H, d), 7.42 ( 6H, m), 6.84 (1H, s), 6.73 (1H, d), 3.36 (2H, t), 2.86 (2H, t). Found: C 54.41, H 5.49, N 14.69%; C ₁₃ H ₁₅ N ₃ O ₂ S.0.5 H ₂ O Theory: C 54.53, H 5.63, N 14.67%.

Example 21

N- [2- (4 (5) -imidazoyl) ethyl] -phenylmethanesulfonamide

A subject compound was prepared according to the method of Example 9, and phenylmethanesulfonylchloride was used as the substrate in step c.

Four steps of product (R _f 0.27; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.50 (1 H, s), 7.31 (5H, m), 7.20 (1H, t), 6.80 (1H, s), 4.27 (2H, s), 3.13 (2H, m), 2.63 (2H, t). Found: C 54.39, H 5.73, N 15.60%; C ₁₂ H ₁₅ N ₃ O ₂ S Theoretical values: C 54.32, H 5.70, N 15.84%.

Example 22

N- [2- (4 (5) -imidazoyl) ethyl] -8-quinolinesulfonamide

A subject compound was prepared according to the method of Example 17, and 8-quinolinesulfonylchloride was used as a substrate in step c. Four steps of product (R _f 0.34; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a colorless crystalline solid: ¹ H NMR (300 Hz, CDCl ₃ ) 8.82 (1H, dd), 8.42 (1H, dd), 8.25 (1H, dd), 8.05 (1H, d), 7.64 (1H, dd), 7.51 (1H, dd), 7.38 (1H, d), 6.66 (1H, d), 3.17 (2H, t), 2.74 (2H, t). Found: C 55.33, H 4.81, N 18.47%; C ₁₄ H ₁₄ N ₄ O ₂ S Theoretical values: C 55.61, H 4.67, N 18.53%.

Example 23

N- [2- (4 (5) -imidazoyl) ethyl] -2-cyclohexylethanesulfonamide

A subject compound was prepared according to the method of Example 17, and 2-cyclohexylethanesulfonylchloride (basically prepared according to step a of Example 4) was used as a substrate in step c.

Four steps of product (R _f 0.27; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.80 (1 H, br s), 7.51 (1H, s), 7.05 (1H, t), 6.81 (1H, s), 3.13 (2H, dd), 2.90 (2H, m), 2.65 (2H t), 1.62 (5H, m), 1.47 ( 2H, m), 1.16 (4H, m), 0.86 (2H, m). Found: C 54.68, H 8.20, N 14.71%; C ₁₃ H ₂₃ N ₃ O ₂ S requires: C 54.70, H 8.12, N 14.72%.

Example 24

N- [2- (4 (5) -imidazoyl) ethyl]-[3,4-dichlorophenyl] methanesulfonamide

A subject compound was prepared according to the method of Example 9, and (3,4-dichlorophenyl) methanesulfonylchloride (basically prepared according to step a of Example 4) was used as a substrate in step a.

Four steps of product (R _f 0.31; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.85 (1 H, br s), 7.60 (3H, m), 7.32 (1H, dd), 7.23 (1H, t), 6.82 (1H, s), 4.36 (2H, s), 3.16 (2H dd), 2.65 (2H, t). Found: C 42.79, H 3.98, N 12.49%; C ₁₂ H ₁₃ Cl ₂ N ₃ O ₂ S requires: C 43.12, H 3.92, N 12.57%.

Example 25

N- [2- (4 (5) -imidazoyl) ethyl]-(4-chlorophenyl) methanesulfonamide

The subject compound was prepared according to the method of Example 9, and (4-chlorophenyl) methanesulfonylchloride (basically prepared according to step a of Example 4) was used as a substrate in step a.

Four steps of product (R _f 0.19; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.54 (1H, d), 7.43 (2H, d), 7.34 (2H, d), 7.16 (1H, t), 6.82 (1H, s), 4.31 (2H, s), 3.14 (2H, dd), 2.65 (2H, t). Found: C 48.01, H 4.80, N 14.14%; C ₁₂ H ₁₄ ClN ₃ O ₂ S requires: C 48.08, H 4.71, N 14.02%.

Example 26

N- [3- (4 (5) -imidazoyl) propyl]-(4-chlorophenyl) methanesulfonamide

Step a. N- [3- (1- (triphenylmethyl) imidazoyl-4-yl) propyl]-(4-chlorophenyl) methanesulfonamide.

Example 9 According to the method of step a, 4- (3-aminopropyl) -1- (triphenylmethyl) -imidazole (step b of Example 14) in the presence of triethylamine (270 μl, 1.94 mmol) (593 mg, 1.61 mmol) and (4-chlorophenyl) methanesulfonylchloride (basically prepared according to step a of Example 4) (545 mg, 2.42 mmol) were reacted. The resulting product was separated into a colorless foam (489 mg, 62%).

Step b. The product of step a was deprotected according to the method of Example 17 step d, and the subject compound (R _f 0.17: 1: 10: 90 ammonia (880) / methanol / dichloromethane) was isolated in quantitative yield as a white solid. ¹ H NMR (300 Hz, d ₆ -DMSO) 11.77 (1 H, br s), 7.50 (1 H, s), 7.43 (2 H, d), 7.37 (2 H, d), 7.14 (1 H, t), 6.72 ( 1 H, s), 4.32 (2H, s), 2.92 (2H, dd), 2.46 (2H, t), 1.70 (2H, m). Found: C 49.54, H 5.38, N 13.12%; C ₁₃ H ₁₆ ClN ₃ O ₂ S requires: C 49.76, H 5.14, N 13.39%.

Example 27

N- [3- (4 (5) -imidazoyl) propyl] -benzenesulfonamide

A subject compound was prepared according to the method of Example 26, and benzenesulfonylchloride was used as the substrate in step a.

Four steps of product (R _f 0.16; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, CDCl ₃ ) 7.86 (2H, d), 7.54 (4H m), 6.76 (1H, s), 3.04 (2H, t), 2.67 (2H, t), 1.81 (2H quint.). FAB M / S: [M ⁺ + H] 266; Exact mass: 266.0936; C ₁₂ H ₁₆ N ₃ O ₂ S requires: 266.0963.

Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane.

Example 28

N- [3- (4 (5) -imidazoyl) propyl] -2-naphthalenesulfonamide

A subject compound was prepared according to the method of Example 26, and 2-naphthalenesulfonylchloride was used as the substrate in step a.

Four steps of product (R _f 0.17; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 8.40 (1H, s), 8.10 (2H, t), 8.02 (1H, d), 7.74 (4H, m), 7.44 (1H, s), 6.62 (1H s), 2.78 (2H, dd), 2.43 (2H, t), 1.62 (2H , quint.). Found: C 60.69, H 5.51, N 13.18%; C ₁₆ H ₁₇ N ₃ O ₂ S Theoretical values: C 60.93, H 5.43, N 13.32%.

Example 29

N- [7- (4 (5) -imidazoyl) heptyl] -2-naphthalene sulfonamide

Step a. 2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) -imidazole.

A solution of 1- (N, N-dimethylsulfamoyl) -imidazole ¹ (4.48 g, 25.6 mmol) in dry tetrahydrofuran (100 ml) was cooled to -78 ° C under argon atmosphere. n-butyllithium (1.5 M in hexane) (18.0 ml, 27.0 mmol) was added over 30 minutes, and the solution was further stirred for 30 minutes. To the resulting brown solution, a solution of tert-butyldimethylsilylchloride in dry tetrahydrofuran (20 ml) was added over 15 minutes. The solution was warmed to room temperature and then stirred for 24 hours. Saturated ammonium chloride solution (100 ml) and diethyl ether (100 ml) were added and the ether extracts were washed with brine and then dried over magnesium sulfate. Filtrate and evaporation of the filtrate gave an oily residue, which was purified by flash column chromatography (silica; ethyl acetate) to give the product as a brown solid (6.97 g, 94%).

Step b. 5- (7-bromoheptyl) -2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) imidazole.

The solution of product of step a (2.50 g, 8.64 mmol) in dry tetrahydrofuran (30 ml) was cooled to -78 ° C under argon atmosphere. n-butyllithium (1.5 M in hexane) (8.50 ml, 12.7 mmol) was added over 15 minutes and the solution was stirred for 30 minutes. A solution of 1,7-dibromoheptane (4.60 g, 17.3 mmol) in dry tetrahydrofuran (6 ml) was added over 10 minutes. The solution was stirred for 30 minutes, warmed to room temperature and then stirred for 18 hours. Saturated ammonium chloride solution (50 ml) and ethyl acetate (50 ml) were added, and the organic extracts were washed with brine and then dried over sodium sulfate. The filtrate was filtered and evaporated and then purified by flash column chromatography (silica; 20% ethyl acetate / hexanes) to give the product (R _f 0.55) as a white solid (2.48 g, 62%).

Step c. 1- (N, N-dimethylsulfamoyl) -5- (1-phthalimidoheptyl) -imidazole.

Under argon atmosphere, potassium phthalimide (1.67 g, 9.00 mmol) was added to the solution of the product of step b (2.10 g, 4.50 mmol) in dry N, N-dimethylformamide (10 ml). The mixture was stirred and heated to 100 ° C. for 18 hours and then cooled to room temperature.

Water (75 ml) was added and the mixture was extracted with dichloromethane (3 × 40 ml). The combined extracts were evaporated and the residue was dissolved in ethyl acetate (75 ml) and the solution washed five times with brine. After evaporation of the solvent, the residue was purified by flash column chromatography (silica; ethyl acetate) to separate the product as a yellow oil (1.75 g, 93%).

Step d. 5- (7-aminoheptyl) -1- (N, N-dimethylsulfamoyl) -imidazole.

The product of step c was deprotected according to the method of Example 17 step b.

Step e. A subject compound was prepared according to the method of Example 6, and 5- (7-aminoheptyl) -1- (N, N-dimethylsulfamoyl) -imidazole was used as the substrate in step a.

Two steps of product (R _f 0.38; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 8.41 (1H, s), 8.13 (2H, dd), 8.02 (1H, dd), 7.80 (1H, dd), 7.67 (3H, m), 7.45 (1H, d), 6.64 (1H, s), 2.75 (2H, dd), 2.38 ( 2H, t), 1.43 (2H, m), 1.32 (2H, m) 1.13 (6H, m).

Example 30

N- [8- (4 (5) -imidazoyl) octyl] -2-naphthalenesulfonamide.

A subject compound was prepared according to the method of Example 6, and 5- (8-aminooctyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was used as a substrate in step a.

Two steps of product (R _f 0.39; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.72 (1H, br s), 8.40 (1H, d), 8.13 (2H, dd), 8.02 (1H, dd), 7.80 (1H, dd), 7.65 (3H m), 7.45 (1H, d), 6.65 (1H, d), 2.75 ( 2H, dd), 2.41 (2H, t), 1.45 (2H, quint.), 1.32 (2H, quint.), 1.12 (8H, m).

Example 31

N- [10- (4 (5) -imidazoyl) decyl] -2-naphthalenesulfonamide.

A subject compound was prepared according to the method of Example 6, and 5- (10-aminodecyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was used as a substrate in step a.

Two steps of product (R _f 0.33; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 8.40 (1H, d), 8.12 (2H, dd), 8.02 (1H, dd), 7.80 (1H, dd), 7.66 (3H, m), 7.46 (1H, d), 6.66 (1H, s), 2.75 (2H, dd), 2.44 ( 2H, t), 1.47 (2H, m), 1.31 (2H, m), 1.10 (12H, m).

Example 32

N- [7- (4 (5) -imidazoyl) heptyl]-(4-chlorophenyl) methanesulfonamide.

A subject compound was prepared according to the method of Example 9, and 5- (7-aminoheptyl) -1- (N, N-dimethylsulfamoyl) -imidazole (step d of Example 29) was prepared as a substrate in step a. Used.

Two stages of product (R _f 0.30; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 7.56 (1H, s), 7.42 (2H, d), 7.37 (2H, d), 7.04 (1H, t), 6.72 (1H, s), 4.30 (2H, s), 2.85 (2H, dd), 2.48 (2H, m), 1.53 (2H, m), 1.37 (2H, m), 1.24 (6H, m).

Example 33

N- [8- (4 (5) -imidazoyl) octyl]-(4-chlorophenyl) methanesulfonamide

Step a. 5- (8-bromooctyl) -2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) imidazole.

A solution of 2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) imidazole (step a) of Example 29 (2.62 g, 9.05 mmol) in dry tetrahydrofuran (30 ml) was prepared. Cooled to -78 ° C under argon atmosphere. n-butyllithium (1.5 M in hexane) (7.25 ml, 10.9 mmol) was added over 15 minutes, then the solution was stirred for 30 more minutes. A solution of 1,8-dibromooctane (2.55 ml, 13.6 mmol) in dry tetrahydrofuran was added over 10 minutes. The solution was stirred for 2 hours, warmed to room temperature and then stirred for 18 hours. Saturated ammonium chloride solution (30 ml) and diethyl ether (30 ml) were added and the ether extract was washed with brine and then dried over sodium sulfate. The filtrate was filtered and evaporated and then purified by flash column chromatography (silica; 20% ethyl acetate / hexanes) to give the product (R _f 0.43) as a white solid (2.36 g, 54%).

Step b. 2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) -5- (8-phthalimidooctyl) imidazole (A) and 1- (N, N-dimethylsulfamoyl)- 5- (8-phthalimidooctyl) -imidazole (B).

Under argon atmosphere potassium phthalimide (1.84 g, 9.95 mmol) was added to a solution of the product of step a (2.39 g, 4.97 mmol) in dry dimethylformamide (16 ml). The mixture was stirred and heated at 100 ° C. for 18 hours and then cooled to room temperature. Water (80 ml) was added, then the mixture was extracted with dichloromethane (3 x 40 ml). The combined extracts were evaporated and the residue was dissolved in ethyl acetate (80 ml), then the solution was washed four times with brine. The solvent was evaporated and the residue was purified by flash column chromatography (silica; ethyl acetate) to separate compound (A) (R _f 0.72) into brown oil (639 mg, 23%). (R _f 0.27) was separated off as an oily solid (1.56 g, 73%).

Step c. 5- (8-aminooctyl) -2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) imidazole

Compound A of step b was deprotected according to the method of Example 17 step b.

Step d. A subject compound was prepared according to the method of Example 9, wherein 5- (8-aminooctyl) -2- (tert-butyldimethylsilyl) -1- (N, N- Dimethylsulfamoyl) -imidazole was used. Product (R _f 0.42; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid; ¹ H NMR (300 Hz, d ₆ -DMSO) 7.47 (1H, d), 7.43 (2H, d), 7.36 (2H, d), 7.03 (1H, t), 6.68 (1H, s), 4.30 (2H, s), 2.85 (2H, dd), 2.46 (2H, t), 1.53 (2H, m), 1.37 (2H, m) 1.23 (8H, m). Found: C 55.99, H 7.04, N 10.67%; C ₁₈ H ₂₆ ClN ₃ O ₂ S Theoretic: C 56.31, H 6.83, N 10.94%

Example 34

N- [10- (4 (5) -imidazoyl) decyl]-(4-chlorophenyl) methanesulfonamide.

A subject compound was prepared according to the method of Example 9, and 5- (10-aminodecyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was used as a substrate in step a.

Two steps of product (R _f 0.37; 1: 10: 90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.46 (1H, d), 7.43 (2H, dd), 7.37 (2H, d), 7.04 (1H, t), 6.67 (1H, s), 4.31 (2H, s), 2.85 (2H, dd), 2.45 (2H, t), 1.53 ( 2H, m), 1.37 (2H, m), 1.21 (12H, m).

Example 35

N- [2- (4 (5) -imidazoyl) ethyl] -N'-phenylmethyl-sulfamide

Example 12 4- (2-aminoethyl) -1- (triphenylmethyl) -imidazole (step b of Example 17) was N-2- [1- (triphenylmethyl) imide according to the method of step a. Dazol-4-yl] ethyl-N'-tert-butoxycarbonyl-sulfamide. Subsequently, alkylation with benzylbromide was basically carried out according to step b of Example 12, whereby N- [2- (1- (triphenylmethyl) imidazol-4-yl) ethyl] -N'-tert- Butoxycarbonyl-N'-phenylmethylsulfamide was produced.

The final deprotection step was carried out according to the method of Example 17 step b, wherein the main compound (R _f 0.21; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was separated into a colorless oil. : ¹ H NMR (300 Hz, d ₆ -DMSO) 7.50 (1H, s), 7.30 (6H, m), 6.95 (1H, t), 6.78 (1H, s), 3.96 (2H, s), 3.03 (2H dd), 2.65 (2H, t).

Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Found: C 48.05, H 5.10, N 13.87%;

C ₁₆ H ₂₀ N ₄ O ₆ S Theoretical value: C 48.48, H 5.09, N 14.13%.

Example 36

N- [3- (4 (5) -imidazoyl) propyl] -N'-phenylmethyl-sulfamide.

A subject compound was prepared according to the method of Example 35, and 4- (3-aminopropyl) -1- (triphenylmethyl) -imidazole (step b of Example 14) was used as an initial substrate, and a white solid ( R _f 0.10; 1:10:90 ammonia (880) / methanol / dichloromethane): ¹ H NMR (300 Hz, d ₆ -DMSO) 11.75 (1H, br s), 7.49 (1H, s), 7.30 (5H, m), 7.25 (1H, m), 6.96 (1H, t), 6.71 (1H, s), 3.98 (2H, s), 2.82 (2H, m), 2.48 (2H, m), 1.72 ( 2H, m).

Found: C 53.03, H 6.19, N 18.89%;

C ₁₃ H ₁₈ N ₄ O ₂ S Theoretical values: C 53.04, H 6.16, N 19.03%.

Example 37

N- [2- (4 (5) -imidazoyl) ethyl] -N '-(4-chlorophenyl) methyl-sulfamide.

The subject compound was prepared according to the method of Example 35, and 4-chlorobenzylbromide was used in the alkylation step, and was separated into a white solid (R _f 0.20; 1:10:90 ammonia (880) / methanol / dichloromethane). ¹ H NMR (300 Hz, d ₆ -DMSO) 11.75 (1 H, br s), 7.51 (1 H, s), 7.36 (5 H, m), 6.99 (1 H, t), 6.75 (1 H, s), 3.96 ( 2H, s), 3.01 (2H, doublet), 2.65 (2H, t).

Measured value: C 45.47, H 4.83, N 17.93%:

C ₁₂ H ₁₅ ClN ₄ O ₂ S Theory: C 45.79, H 4.80, N 17.80%.

Example 38

N- [7- (4 (5) -imidazoyl) heptyl] -N '-(4-chlorophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, and 5- (7-aminoheptyl) -1- (N, N-dimethylsulfamoyl) -imidazole (step d of Example 29) was prepared as a substrate in step a. Used. Three steps of product (R _f 0.28; 1:10:90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.45 (1 H, s), 7.36 (5H, m), 6.84 (1H, t), 6.67 (1H, s), 3.98 (2H, s), 2.79 (2H, dd), 2.46 (2H, t), 1.53 (2H, m), 1.37 ( 2H, m), 1.23 (6H, m).

Found: C 53.17, H 6.62, N 14.53%;

C ₁₇ H ₂₅ ClN ₄ O ₂ S Theory: C 53.05, H 6.55, N 14.56%.

Example 39

N- [8- (4 (5) -imidazoyl) octyl] -N '-(4-chlorophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, and 5- (8-aminooctyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was used as the substrate in step a. Three steps of product (R _f 0.30; 1:10:90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.45 (1 H, s), 7.36 (5H, m), 6.82 (1H, t), 6.67 (1H, s), 3.98 (2H, d), 2.74 (2H, dd), 2.45 (2H, t), 1.55 (2H, m), 1.37 ( 2H, m), 1.23 (8H, m).

Example 40

N- [10- (4 (5) -imidazoyl) decyl] -N '-(4-chlorophenyl) methyl-sulfamide.

5- (10-aminodecyl) -2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) -imidazole was prepared according to the methods of steps a, b and c of Example 33. In step a, 1,10-dibromodecan was used as the alkylation reagent. The amine was converted to the subject compound according to the method of Example 12. The product (R _f 0.41; 1:10:90 ammonia (880) / methanol / dichloromethane) was isolated as white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.45 (1H, s), 7.35 (5H, m), 6.82 (1H, t), 6.66 (1H, s), 3.98 (2H, d), 2.74 (2H, dd), 2.45 (2H, t), 1.53 (2H, m), 1.37 (2H, m ), 1.21 (12H, m).

Found: C 55.97, H 7.55, N 12.88%;

C ₂₀ H ₃₁ ClN ₄ 0 ₂ S requires: C 56.26, H 7.32, N 13.12%.

Example 41

N- [4- (4 (5) -imidazoyl) butyl) -N '-(3,4-dichlorophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, using 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole as substrate in step a, and as substrate in step b. 3,4-dichlorobenzylbromide was used. The product (R _f 0.26; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, CDCl ₃ ) 7.51 (1H, d), 7.42 (2H, m) , 7.19 (1H, dd), 6.76 (1H, d), 4.17 (2H, s), 3.06 (2H, t), 2.62 (2H, t), 1.68 (2H, quint.), 1.59 (2H, quint. ). Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane.

Example 42

N- [4- (4 (5) -imidazoyl) butyl] -N '-(3-chlorophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, using 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a, and substrate in step b. 3-chlorobenzylbromide was used. The product (R _f 0.26; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.73 (1H, br s), 7.47 (1H , d), 7.35 (5H, m), 6.88 (1H, t), 6.69 (1H, s), 4.00 (2H, d), 2.79 (2H, dd), 2.45 (2H, t), 1.55 (2H, m), 1.42 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 43

N- [4- (4 (5) -imidazoyl) butyl] -N '-(2-chlorophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, using 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a, and substrate in step b. 2-chlorobenzylbromide was used. The product (R _f 0.26; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.75 (1H, br s), 7.53 (1H , d), 7.47 (1H, s), 7.35 (4H, m), 6.95 (1H, t), 6.68 (1H, s), 4.09 (2H, d), 2.83 (2H, dd), 2.45 (2H, t), 1.55 (2H, m), 1.46 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 44

N- [4- (4 (5) -imidazoyl) butyl] -N '-(4- iodophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, using 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a, and substrate in step b. 4-iodobenzylbromide was used. The product (R _f 0.24; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.75 (1H, br s), 7.67 (2H , d), 7.49 (1H, s), 7.33 (1H, t), 7.14 (2H, d), 6.85 (1H, t), 6.70 (1H, s), 3.94 (2H, d), 2.79 (2H, dd), 2.46 (2H, t), 1.55 (2H, m), 1.46 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 45

N- [4- (4 (5) -imidazoyl) butyl] -N '-(4-bromophenyl) methyl-sulfamide.

Step a. N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N ¹ -tert-butoxycarbonyl-sulfamide.

Example 12 5- (4-Aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was converted to the product according to the method of step a.

Step b. N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N '-(4-bromophenyl) methyl-N'-tert-butoxycarbonyl Sulfamide (A).

Example 12 The product of step a (500 mg, 1.27 mmol) was reacted with 4-bromobenzylbromide according to the method of step b. The crude mixture was purified by flash column chromatography (silica; 50% ethyl acetate / dichloromethane) to yield crude (A) (R _f 0.37) and N, N as yellow oil (267 mg, 35%). '-Di-[(4-bromophenyl) methyl] -N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N'-tert-part Toxylcarbonyl-sulfamide (B) (Rf 0.56) (220 mg, 23%) was obtained.

Step c. Example 12 The product (A) of step b was deprotected according to the method of step c to yield the subject compound (R _f 0.28; 1:10:90 ammonia (880) / methanol / dichloromethane) as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 7.50 (3H, m), 7.35 (1H, t), 7.28 (2H, d), 6.87 (1H, t), 6.71 (1H, s), 3.96 (2H, d ), 2.78 (2H, dd), 2.46 (2H, t), 1.55 (2H, m), 1.42 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Found: C 40.66, H 4.90, N 10.67%;

C ₁₈ H ₂₃ BrN ₄ O ₆ S.1.5H ₂ O Theoretic: C 40.76, H 4.94, N 10.56%.

Example 46

N- [4- (4 (5) -imidazoyl) butyl] -N '-(4-fluorophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, with 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a and 4 as substrate in step b. Fluorobenzylbromide was used. The product (R _f 0.26; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.67 (1H, br s), 7.46 (1H , s), 7.35 (3H, m), 7.14 (2H, m), 6.85 (1H, t), 6.68 (1H, s), 3.97 (2H, d), 2.79 (2H, dd), 2.46 (2H, m), 1.54 (2H, m), 1.45 (2H, m). Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane.

Found: C 44.92, H 5.61, N 11.42%;

C ₁₈ H ₂₃ FN ₄ O ₆ S.2.0H ₂ O Theory: C 45.18, H 5.69, N 11.71%.

Example 47

N- [4- (4 (5) -imidazoyl) butyl] -N '-(4-trifluoromethyl) phenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, with 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a and 4 as substrate in step b. -(Trifluoromethyl) benzylbromide was used. Three steps of product (R _f 0.26; 1:10:90 ammonia (880) / methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.70 (1 H, br s), 7.68 (2H, d), 7.54 (2H, d), 7.44 (2H, m), 6.90 (1H, t), 6.68 (1H, s), 4.09 (2H, d), 2.80 (2H, dd), 2.45 (2H, t), 1.55 (2H, m), 1.45 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Found: C 43.17, H 4.99, N 10.88%;

C ₁₉ H ₂₃ F ₃ N ₄ O ₆ S.2.0H ₂ O Theory: C 43.18, H 5.15, N 10.60%.

Example 48

N- [4- (4 (5) -imidazoyl) butyl] -N '-(4-methoxyphenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, with 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a and 4 as substrate in step b. -Methoxybenzylbromide was used. The product (R _f 0.26; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.70 (1H, br s), 7.47 (1H , s), 7.22 (2H, d), 7.18 (1H, t), 6.87 (2H, d), 6.79 (1H, t), 6.68 (1H, s), 3.90 (2H, d), 3.72 (3H, s), 2.79 (2H, dd), 2.45 (2H, d), 1.55 (2H, m), 1.44 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 50.19, H 5.80, N 12.36%; C ₁₉ H ₂₆ N ₄ O ₇ S Theoretical: C 50.21, H 5.77, N 12.33%.

Example 49

N- [4- (4 (5) -imidazoyl) butyl] -N '-(4-biphenyl) methyl-sulfamide.

5- (4-aminobutyl) -2- (tert- during the preparation of 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ according to a method analogous to Example 33 Butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) -imidazole was isolated as a byproduct. This was converted to the subject compound by the method of Example 12, using (4-chloromethyl) biphenyl as substrate in step b. Step b was further modified by heating the reaction mixture at 50 ° C. for 2 hours prior to work up. The product (R _f 0.28; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.75 (1H, br s), 7.63 (4H , m), 7.42 (5H, m), 7.33 (2H, m), 6.86 (1H, t), 6.69 (1H, s), 4.03 (2H, d), 2.82 (2H, dd), 2.46 (2H, t), 1.54 (2H, m), 1.45 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 54.71, H 5.87, N 10.80%; C ₂₄ H ₂₈ N ₄ 0 ₆ S.1.5H ₂ 0 Theory: C 54.63, H 5.92, N 10.61%.

Example 50

N- [4- (4 (5) -imidazoyl) butyl] -N'-2-naphthylmethyl-sulfamide.

A subject compound was prepared according to the method of Example 12, and 5- (4-aminobutyl) -2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) -imide as substrate in step a Dozol (Example 49) was used, in step b, 2-bromomethyl-naphthalene as the substrate. The product (R _f 0.24; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.70 (1H, br s), 7.85 (4H , m), 7.48 (4H, m), 7.40 (1H, t), 6.88 (1H, t), 6.71 and 6.58 (1H, 2 x br s), 4.16 (2H, d), 2.83 (2H, dd) , 2.43 (2H, m), 1.53 (2H, m), 1.45 (2H, m). Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane. Found: C 55.49, H 5.66, N 11.59%; C ₂₂ H ₂₆ N ₄ 0 ₆ S Theoretical values: C 55.68, H 5.52, N 11.81%.

Example 51

N- [4- (4 (5) -imidazoyl) butyl] -N'-cyclohexylmethyl-sulfamide.

Step a. (Z) -4- [4- (1,3-dioxolan-2-yl) but-2-enyl] -1- (triphenylmethyl) -imidazole.

Suspension of [2- (1,3-dioxolan-2-yl) ethyl] triphenylphosphonium bromide (48.54 g, 109 mmol) in dry tetrahydrofuran (500 ml) was cooled to -20 ° C under argon atmosphere. . n-butyllithium (1.6 M in hexane) (68.3 ml, 109 mmol) was added dropwise, and the solution was stirred for 1 hour.

A solution of [1- (triphenylmethyl) imidazol-4-yl] carboaldehyde ⁴ (36.80 g, 109 mmol) in dry tetrahydrofuran (500 ml) was slowly added dropwise, and then the reaction mixture was stirred at room temperature. Stir for hours. The reaction mixture was concentrated in vacuo, water was added, and the mixture was filtered through a pad of celite. The filtrate was extracted with dichloromethane (2 x 500 ml), then the combined extracts were dried over magnesium sulfate. Yellow oil was obtained by filtration and evaporation. Flash column chromatography (silica; 10-20% ethyl acetate / hexanes) separated the product into yellow oil (19.73 g, 42%).

Step b. 4- [4- (1,3-dioxolan--2-yl) butyl] -1- [triphenylmethyl) -imidazole.

The solution of the product of step a in ethanol was hydrogenated in the presence of palladium on charcoal at 10% of the catalytic amount for 18 hours at atmospheric pressure and atmospheric temperature. The product was separated into colorless oil in quantitative yield.

Step c. 4- [1- (triphenylmethyl) imidazol-4-yl] butan-1-al.

The suspension of the product of step b (19.8 g, 46.6 mmol) in a mixture of acetone (300 ml) and 2M hydrochloric acid (50 ml) was stirred at room temperature for 20 hours. The mixture was neutralized with sodium hydrogen carbonate, filtered and the filtrate was extracted with dichloromethane (3 x 100 ml). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give the product as a colorless oil (16.1 g, 91%).

Step d. 4- [1- (triphenylmethyl) imidazol-4-yl] butan-1-ol.

The solution of product of step c (16.1 g, 42.4 mmol) in ethanol (300 ml) was cooled to 0 ° C. under argon atmosphere. Sodium borohydride (1.57 g, 42.4 mmol) was added and the mixture was stirred for 4 hours and then quenched carefully with saturated ammonium chloride. The mixture was extracted with dichloromethane (3 x 100 ml). The combined extracts were dried over magnesium sulfate, filtered and evaporated to afford a white solid which was dissolved in 5% methanol / dichloromethane and then treated with diethyl ether to precipitate. The product was isolated as a colorless crystalline solid (9.34 g, 58%).

Step e. N-tert-butoxycarbonyl-N'-cyclohexylmethyl-sulfamide.

Example 12 The cyclohexylmethylamine was converted to the product using the method of step a.

Step f. N-tert-butoxycarbonyl-N- [4- [1- (triphenylmethyl) imidazol-4-yl] butyl] -N'-cyclohexylmethyl-sulfamide.

Dry tetrahydro in a solution of the product of step d (764 mg, 2.00 mmol), the product of step e (642 mg, 2.20 mmol) and triphenylphosphine (576 mg, 2.20 mmol) in dry tetrahydrofuran (20 ml) under argon atmosphere. A solution of diethylazodicarboxylate (383 mg, 2.20 mmol) in furan (5 ml) was added over 10 minutes. The mixture was stirred for 2 hours, the solvent was evaporated and the residue was purified by flash column chromatography (silica; 30% ethyl acetate / dichloromethane). The product was separated into a colorless foam (800 mg, 60%).

Step g. In a mixture of ethanol (15 ml) and 2 M hydrochloric acid (5 ml), the solution of step f (800 mg, 1.20 mmol) was heated to reflux for 2 hours. The solvent was evaporated and purified by flash column chromatography (silica; 1:10:90 ammonia (880) / methanol / dichloromethane). The subject compound (R _f 0.28) was isolated as white solid (184 mg, 49%). Maleate salts were prepared by lyophysis of equimolar solutions of maleic acid with product in water / dioxane: ¹ H NMR (300 Hz, d ₆ -DMSO) 8.87 (1H, s), 7.36 (1H, s) , 6.70 (1H, t), 6.02 (1H, s), 2.80 (2H, dd), 2.61 (4H, m), 1.63 (7H, m), 1.44 (3H, m), 1.13 (3H, m), 0.83 (2H, m).

Example 52

N- [4- (4 (5) -imidazoyl) butyl] -N'-adamant-1-ylmethyl-sulfamide.

A subject compound was prepared according to the method of Example 51, and 1-adamant-1-ylmethylamine was used as substrate in step e. The product (R _f 0.32; 1:10:90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO) 11.66 (1H, br s), 7.45 (1H , s), 6.70 (1H, br, s), 6.66 (1H, t), 6.57 (1H, t), 2.78 (2H, m), 2.48 (4H, m), 1.91 (3H, s), 1.56 ( 8H, m), 1.44 (8H, m). Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane.

Example 53

N- [3- (4 (5) -imidazoyl) propyl] -2- (4-chlorophenyl) ethanesulfonamide.

Step a. N- [3- (1- (triphenylmethyl) imidazoyl-4-yl) propyl] -2- (4-chlorophenyl) ethanesulfonamide.

Example 9 4- (3-aminopropyl) -1- (triphenylmethyl) -imidazole (Example 14 step b) (500 mg, in the presence of triethylamine (155 μl, 1.94 mmol) according to the method of step a 1.01 mmol) and 2- (4-chlorophenyl) ethanesulfonylchloride (basically prepared according to step a of Example 4) (266 mg, 1.01 mmol) were reacted together. The product was separated into a colorless foam (494 mg, 86%).

Step b. Example 17 The product of step a (494 mg, 0.87 mmol) was deprotected according to the method of step d, and then the subject compound was separated into a white solid (154 mg, 54%). : ¹ H NMR (300 Hz, d ₄ -MeOH) 7.66 (1H, s), 7.38 (2H, d), 7.63 (2H, d), 6.90 (1H, s), 3.37 (2H, m), 3.14 (4H , m), 2.74 (2H, t), 1.94 (2H, quint.).

Found: C 51.25, H 5.61, N 12.72%;

C ₁₄ H ₁₈ ClN ₃ O ₂ S Theory: C 51.29, H 5.53, N 12.82%.

Example 54

N- [5- (4 (5) -imidazoyl) pentyl] -2- (4-chlorophenyl) ethanesulfonamide.

Step a. N- [5- (2- (tert-butyldimethylsilyl) -1- (N ', N'-dimethylsulfamoyl) imidazol-4-yl) pentyl] -2- (4-chlorophenyl) ethanesulfonamide .

According to a method analogous to Example 33, 5- (5-aminopentyl) -2- (tert during the preparation of 5- (5-aminopentyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ -Butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) -imidazole was isolated as a byproduct. This was reacted with 2- (4-chlorophenyl) ethanesulfonyl chloride (basically prepared according to step a of example 4) according to the method of example 9 step a. The product was obtained as a yellow oil.

Step b. Example 12 After the product of step a (494 mg, 0.87 mmol) was deprotected according to the method of step c, the subject compound was separated into a white solid (227 mg, 92%): ¹ H NMR (300 Hz, d ₄ -MeOH). ) 7.58 (1H, s), 7.34 (2H, d), 7.29 (2H, d), 6.80 (1H, s), 3.31 (2H, m), 3.09 (4H, m), 2.63 (2H, m), 1.70 (2H, m), 1.60 (2H, m), 1.44 (2H, m).

Found: C 54.04, H 6.27, N 11.55%; C ₁₆ H ₂₂ ClN ₃ O ₂ S Theoretic: C 54.00, H 6.23, N 11.83%.

Example 55

N- [4- (4 (5) -imidazoyl) butyl] -2- (4-chlorophenyl) ethanesulfonamide.

A subject compound was prepared according to the method of Example 54, and 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was used as the amine component in step a. The product was obtained as a white solid: ¹ H NMR (300 Hz, CDCl ₃ ) 7.56 (1H, s), 7.30 (2H, dd), 7.16 (2H, d), 6.78 (1H, s), 4.55 (1H, br s), 3.25 (2H, m), 3.09 (4H, m), 2.64 (2H, t), 1.72 (2H, quint.), 1.58 (2H, quint.).

Found: C 52.52, H 5.92, N 12.11%;

C ₁₅ N ₂₀ ClN ₃ O ₂ S Theory: C 51.70, H 5.90, N 12.29%.

Example 56

N- [3- (4 (5) -imidazoyl) propyl] -N'-2- (4-chlorophenyl) ethyl-sulfamide.

Step a. N-tert-butoxycarbonyl-N'-2- (4-chlorophenyl) ethyl-sulfamide.

Basically, 2- (4-chlorophenyl) ethylamine was converted to the product by the method of Example 12 step a.

Step b. N-tert-butoxycarbonyl-N- [3- [1- (triphenylmethyl) imidazol-4-yl] propyl] -N'-2- (4-chlorophenyl) ethyl-sulfamide.

Example 51 Under the conditions of step f, the product of step a was reacted with 3- [1- (triphenylmethyl) imidazol-4-yl] propan-1-ol ³ . The product was separated into white foam.

Step c. Example 12 After the product of step b was deprotected according to the method of step c, the subject compound was separated into a white solid: ¹ H NMR (300 Hz, d ₄ -MeOH), 7.58 (1H, s), 7.28 (4H , m), 6.82 (1H, s), 3.20 (2H, t), 2.86 (4H, m), 2.64 (2H, t), 1.83 (2H, quint.). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 46.87, H 5.14, N 12.36%; C ₁₈ H ₂₃ ClN ₄ O ₆ S Theory: C 47.11, H 5.05, N 12.21%.

Example 57

N- [4- (4 (5) -imidazoyl) butyl] -N'-2- (4-chlorophenyl) ethyl-sulfamide.

A subject compound was prepared according to the method of Example 56, and 4- [1- (triphenylmethyl) imidazol-4-yl] butan-1-ol (Example 51 step d) was used in step b. The product was obtained as a colorless oil: ¹ H NMR (300 Hz, d ₄ -MeOH), 7.53 (1H, s), 7.24 (4H, m), 6.75 (1H, s), 3.15 (2H, t), 2.83 ( 4H, m), 2.57 (2H, t), 1.57 (4H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 48.28, H 5.44, N 11.62%; C ₁₉ H ₂₅ ClN ₄ O ₆ S Theory: C 48.25, H 5.33, N 11.85%.

Example 58

N- [6- (4 (5) -imidazoyl) hexyl] -N '-(4-bromophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, comprising 5- (6-aminohexyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a and 4 as substrate in step b. Bromobenzyl bromide was used. The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 7.52 (3H, m), 7.37 (1H, t), 7.31 (2H, d), 6.86 (1H, t), 6.70 ( 1H, s), 3.99 (2H, d), 2.77 (2H, dd), 2.48 (2H, t), 1.55 (2H, m), 1.41 (2H, m), 1.28 (4H, m). Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane. Found: C 44.92, H 5.17, N 10.58%; C ₂₀ H ₂₇ BrN ₄ O ₆ S Theoretical value: C 45.20, H 5.12, N 10.54%.

Example 59

N- [6- (4 (5) -imidazoyl) hexyl] -N '-(4-fluorophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, comprising 5- (6-aminohexyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a and 4 as substrate in step b. Fluorobenzylbromide was used. The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 11.50 (1H, br s), 7.48 (1H, s), 7.35 (3H, m), 7.16 (2H, m), 6.86 (1H, t), 6.70 (1H, s), 4.00 (2H, d), 2.78 (2H, dd), 2.48 (2H, t), 1.55 (2H, m), 1.42 (2H, m), 1.28 ( 4H, m). Maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane.

Found: C 51.25, H 5.79, N 11.72%; C ₂₀ H ₂₇ FN ₄ O ₆ S Theoretic: C 51.05, H 5.78, N 11.91%.

Example 60

N- [6- (4 (5) -imidazoyl) hexyl] -N '-(4-trifluoromethyl) phenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, comprising 5- (6-aminohexyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a and 4 as substrate in step b. -(Trifluoromethyl) benzylbromide was used. The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 11.70 (1H, br s), 7.70 (2H, d), 7.58 (2H, d), 7.49 (1H, s), 7.47 (1H, s), 6.91 (1H, t), 6.70 (1H, s), 4.12 (2H, d), 2.78 (2H, dd), 2.48 (2H, t), 1.54 (2H, m), 1.41 ( 2H, m), 1.27 (4H, m). Maleate salts were prepared by liophysis of equimolar solutions of product in water / dioxane and maleic acid.

Example 61

N- [6- (4 (5) -imidazoyl) hexyl] -N '-(4- iodophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, comprising 5- (6-aminohexyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ as substrate in step a and 4 as substrate in step b. Iodobenzyl bromide was used. The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 11.75 (1H, br s), 7.67 (2H, d), 7.45 (1H, s), 7.33 (1H, t), 7.14 (2H, d), 6.82 (1H, t), 6.67 (1H, s), 3.94 (2H, d), 2.74 (2H, dd), 2.46 (2H, t), 1.52 (2H, m), 1.37 ( 2H, m), 1.25 (4H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 41.62, H 4.75, N 9.59%; C ₂₀ H ₂₇ IN ₄ O ₆ S Theoretical value: C 41.53, H 4.71, N 9.69%.

Example 62

N- [6- (4 (5) -imidazoyl) hexyl] -N '-(4-biphenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 49, and 5- (6-aminohexyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was used. The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 11.75 (1H, br s), 7.62 (4H, m), 7.42 (5H, m), 7.33 (2H, m), 6.83 (1H, t), 6.66 (1H, s), 4.03 (2H, d), 2.78 (2H, dd), 2.44 (2H, t), 1.51 (2H, m), 1.38 (2H, m), 1.26 ( 4H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 63

N- [5- (4 (5) -imidazoyl) pentyl] -N '-(4-trifluoromethyl) phenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, and 5- (5-aminopentyl) -2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) imidazole as a substrate in step a. (Example 54 Step a) was used in step b as 4- (trifluoromethyl) benzylbromide as substrate. The product was obtained as a white crystalline solid: ¹ H NMR (300 Hz, d ₄ -MeOH), 7.62 (2H, d), 7.56 (3H, m), 6.75 (1H, s), 4.40 (2H, s), 2.92 (2H, t), 2.57 (2H, t), 1.63 (2H, quint.), 1.55 (2H, quint.), 1.38 (2H, m).

Example 64

N- [5- (4 (5) -imidazoyl) pentyl] -N '-(4-bromophenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 12, and 5- (5-aminopentyl) -2- (tert-butyldimethylsilyl) -1- (N, N-dimethylsulfamoyl) imidazole as a substrate in step a. (Example 54 Step a) was used, in step b, 4-bromobenzylbromide as the substrate. The product was obtained as a white crystalline solid: ¹ H NMR (300 Hz, d ₄ -MeOH), 7.53 (1H, s), 7.47 (2H, d), 7.28 (2H, d), 6.75 (1H, s), 4.08 (2H, s), 2.90 (2H, t), 2.57 (2H, t), 1.63 (2H, quint.), 1.50 (2H, quint.), 1.38 (2H, m).

Example 65

N- [5- (4 (5) -imidazoyl) pentyl] -N '-(4-fluorophenyl) methyl-sulfamide

A subject compound was prepared according to the method of Example 12, and 5- (5-aminopentyl) -1- (N, N-dimethylsulfamoyl) -imidazole as a substrate in step a.^Oneof, In step b, fluorobenzylbromide was used as the substrate. The product was obtained as a white solid:^OneH NMR (300 Hz, d₄-MeOH), 7.54 (1H, s), 7.37 (2H, dd), 7.04 (2H, t), 6.75 (1H, s), 4.09 (2H, s), 2.90 (2H, t), 2.50 (2H, t), 1.64 (2H, quint.), 1.52 (2H, quint.), 1.37 (2H, m).

Example 66

N- [5- (4 (5) -imidazoyl) pentyl] -N '-(4- iodophenyl) methyl-sulfamide

A subject compound was prepared according to the method of Example 12, and 5- (5-aminopentyl) -1- (N, N-dimethylsulfamoyl) -imidazole as a substrate in step a.^Oneof, In step b 4-iodobenzylbromide was used as substrate. The product was obtained as a white solid:^OneH NMR (300 Hz, d₄-MeOH), 7.67 (2H, d), 7.54 (1H, s), 7.16 (2H, d), 6.76 (1H, s), 4.06 (2H, s), 2.89 (2H, t), 2.58 (2H, t), 1.63 (2H, quint.), 1.50 (2H, quint.), 1.36 (2H, m).

Example 67

N, N'-di-[(4-bromophenyl) methyl] -N- [4- (4 (5) -imidazoyl) butyl] -sulfamide.

N, N'-di-[(4-bromophenyl) methyl] -N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N'- Tert-butoxycarbonyl-sulphamide (Example 45 step b, product (B)) was deprotected according to the method of Example 12 step c, and the main compound (R _f 0.45; 1: 10: 90 ammonia (880) ) / Methanol / dichloromethane) were obtained as a white solid: ¹ H NMR (300 Hz, CDCl ₃ ), 7.43 (5H, m), 7.16 (4H, d), 6.68 (1H, s), 4.27 (2H, s ), 4.12 (2H, s), 3.13 (2H, t), 2.53 (2H, m), 1.53 (4H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 44.62, H 4.29, N 8.35%. C ₂₅ H ₂₈ Br ₂ N ₄ O ₆ S requires C 44.66, H 4.20, N 8.33%.

Example 68

N '-(4-chlorophenyl) methyl-N, N'-dimethyl-N- [4- (4 (5) -imidazoyl) butyl] -sulfamide.

Step a. N, N'-dimethyl-N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N'-tert-butoxycarbonyl-sulfamide.

N- [4- (1- (N ", N" dimethylsulfamoyl) imidazol-4-yl) butyl] -N'-tert-butoxycarbonyl- in dry N, N-dimethylformamide (4 ml) A solution of sulfamide (Example 45 step a) (686 mg, 1.67 mmol) and iodine methane (218 μl, 3.50 mmol) was cooled to 0 ° C. under argon.

Sodium hydride (147 mg, 3.67 mmol) was added and the reaction mixture was stirred and then warmed to room temperature overnight. The reaction was quenched with brine and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed three times with water, dried over magnesium sulfate, filtered and evaporated to give a yellow oil. Flash column chromatography (silica: 0.5: 5: 95 ammonia (880) / methanol / dichloromethane) gave the product as a colorless oil (356 mg, 48%).

Step b. N, N'-dimethyl-N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -sulfamide.

The solution of the product of step a (352 mg, 0.80 mmol) in trifluoroacetic acid (1 ml) was stirred for 30 minutes and the acid component was evaporated. The residue was dissolved in dichloromethane, neutralized with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (3 × 10 ml). The combined extracts were dried over magnesium sulfate, then filtered and evaporated to give quantitative yield of the product as colorless oil (271 mg).

Step c. N '-(4-chlorophenyl) methyl-N, N'-dimethyl-N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -sulfamide.

Example 12 The product of step b (315 mg, 0.93 mmol) was alkylated with 4-chlorobenzylbromide according to the method of step b.

Flash column chromatography (silica; 0.5: 5: 95 ammonia (880) / methanol / dichloromethane) afforded the product as a pale yellow oil (325 mg, 75%).

Step d. Example 12 The product of step c (325 mg, 0.70 mmol) was deprotected according to the method of step c, and the subject compound was obtained as a white solid (81 mg 32%): ¹ H NMR (300 Hz, CDCl ₃ ). , 7.55 (1H, d), 7.33 (2H, dd), 7.26 (2H, dd), 6.78 (1H, s), 4.26 (2H, s), 3.24 (2H, t), 2.81 (3H, s), 2.65 (5H, m), 1.68 (4H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Found C 49.04, H 5.73, N 11.39%; C ₂₀ H ₂₇ ClN ₄ O ₆ S requires C 49.33, H 5.59. N 11.51%.

Example 69

N '-(4-chlorophenyl) methyl-N- [4- (4 (5) -imidazoyl) butyl] -N-methylsulfamide.

Step a. N '-(4-chlorophenyl) methyl-N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N'-tert-butoxycarbonyl- Sulfamide.

Example 12 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ was converted to the product according to a similar method to steps a and b.

Step b. N '-(4-chlorophenyl) methyl-N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N-methyl-N'-tert-part Oxycarbonyl-sulfamide.

Example 68 The product of step a (310 mg, 0.58 mmol) was methylated according to the method of step a. The product was obtained as pale yellow oil (309 mg, 97%).

Step c. Example 12 The product of step b (325 mg, 0.70 mmol) was deprotected according to the method of step c, and the subject compound was obtained as a white solid (80 mg, 42%). : ¹ H NMR (300 Hz, CDCl ₃ ), 7.50 (1H, s), 7.32 (4H, m), 6.77 (1H, s), 4.17 (2H, s), 3.18 (2H, t), 2.77 (3H, s), 2.64 (2H, t), 1.66 (4H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found C 48.33, H 5.41, N 11.56%; C ₁₉ H ₂₅ ClN ₄ O ₆ S requires C 48.25, H 5.33. N 11.85%.

Example 70

N '-(4-chlorophenyl) methyl-N- [4- (4 (5) -imidazoyl) butyl] -N'-methyl-sulfamide.

Step a. N '-(4-chlorophenyl) methyl-N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -sulfamide.

Example 6 N '-(4-chlorophenyl) methyl-N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N according to the method of step b The tert-butoxycarbonyl group of '-tert-butoxycarbonyl-sulfamide (Example 10) (414 mg, 0.77 mmol) was removed. The product was obtained as a white solid (290 mg, 86%).

Step b. N '-(4-chlorophenyl) methyl-N- [4- (1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) butyl] -N'-methyl-sulfamide.

Using iodomethane (43 μl, 0.69 mmol) and sodium hydride (28 mg, 0.70 mmol), the product of step a (290 mg, 0.66 mmol) was methylated according to the method of Example 68 step a. The product was obtained as a colorless oil (49 mg, 17%).

Step c. Example 12 The product of step b (49 mg, 0.11 mmol) was deprotected according to the method of step c, and the subject compound was obtained as a colorless oil (22 mg, 58%). ¹ H NMR (300 Hz, CDCl ₃ ), 7.56 (1H, s), 7.32 (2H, dd), 7.26 (2H, dd), 6.76 (1H, s), 4.26 (2H, s), 3.09 (2H, t ), 2.68 (3H, s), 2.64 (2H, t), 1.71 (2H, m), 1.61 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 48.36, H 5.52, N 11.61%; C ₁₉ H ₂₅ ClN ₄ O ₆ S requires C 48.25, H 5.33. N 11.85%.

Example 71

(R)-(+)-N- [2- (4 (5) -imidazoyl) -1-methyl-ethyl] -2-naphthalenesulfonamide.

A subject compound was prepared according to the method of Example 3 using (R) -α-methyl-histamine as the amine component. The product (R _f 0.18; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was obtained as a white foam: ¹ H NMR (300 Hz, CDCl ₃ ), 8.42 (1H, br s), 7.93 (3H, m), 7.80 (1H, m), 7.57 (2H, m), 7.52 (1H, s), 6.72 (1H, s), 3.61 (1H, m), 2.72 (1H, dd), 1.57 (1H, dd) ), 1.11 (3H, d);

[α] _D = + 41.80 ° (C = 0.91, 1: 9 methanol / dichloromethane). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane. Found: C 55.36, H 5.08, N 9.40%; C ₂₀ H ₂₁ N ₃ O ₆ S Theoretical values: C 55.67, H 4.90, N 9.37%.

Example 72

N- [2- (4 (5) -imidazoyl) -trans-cyclopropyl] -2-naphthalenesulfonamide.

Step a. 2- (1-triphenylmethyl) imidazoyl-4-yl) -trans-cyclopropylamine.

[2- (1- (triphenylmethyl) imidazoyl-4-yl) -trans-cyclopropyl] according to the Burger synthesis method of the corresponding ethyl ester using R-(+)-2-naphthylethanol ⁵ -Carbamic acid 1R- (2-naphthyl) -ethylester was prepared. It was dissolved in 1: 1 methanol / tetrahydrofuran and hydrogenated under an atmospheric pressure and atmospheric temperature for 18 hours in the presence of a palladium catalyst on a 10% charcoal catalyst. The reaction mixture was filtered and evaporated to afford amine product.

Step b. Example 6 According to the method of step a, N- [2- (1-triphenylmethyl) imidazoyl-4-yl] -trans-cyclopropyl by reaction between the product of step a and 2-naphthalene sulfonyl chloride ] -2-naphthalene sulfonamide was prepared.

Step c. Example 17 The product of step b was deprotected according to the method of step d and the subject compound (R _f 0.26; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was separated into a white foam: ¹ H NMR (300 Hz, CDCl ₃ ), 8.44 (1H, s), 7.92 (3H, m), 7.84 (1H, dd), 7.62 (2H, m), 7.47 (1H, s), 6.72 (1H, s), 2.48 (1H, m), 2.15 (1H, m), 1.27 (1H, m), 1.21 (1H, m).

Example 73

3- (4 (5) -imidazoyl) -2S- (2-naphthalene) sulfonamino-propionic acid methyl ester.

Step a. 3- (1- (triphenylmethyl) imidazoyl-4-yl) -2S- (2-naphthalene) sulfonamino-propionic acid methyl ester.

Under argon atmosphere, 2-naphthalenesulfonylchloride (238 mg) in a solution of triethylamine (304 μl, 2.20 mmol) and triphenylmethylhistidinemethylester hydrochloride (488 mg, 1.00 mmol) in dry dichloromethane (20 ml). , 1.05 mmol) was added. The solution was stirred for 1 h, washed with water (2 x 20 ml), dried over magnesium sulfate, filtered and evaporated.

The residue was recrystallized from 1: 2 ethyl acetate / hexanes to give the product as a white solid (438 mg, 73%).

Step b. According to the method of step d of example 17, the product of step a (550 mg, 0.91 mmol) was deprotected and the subject compound (R _f 0.32; 1: 10: 90 ammonia (880) / methanol / dichloromethane) Isolated as a white solid (114 mg, 35%): ¹ H NMR (300 Hz, d ₆ -DMSO), 11.75 (1 H, br s), 8.45 (1 H, d), 8.28 (1 H, d), 8.09 (1 H) , dd), 8.02 (2H, t), 7.68 (3H, m), 7.39 (1H, d), 6.72 (1H, s), 4.08 (1H, dd), 3.21 (3H, s), 2.76 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 74

N- [1S-hydroxymethyl-2- (4 (5) -imidazoyl) ethyl] -2-naphthalenesulfonamide.

Step a. N- [1S-hydroxymethyl-2- (1- (triphenylmethyl) imidazoyl-4-yl) ethyl] -2-naphthalenesulfonamide.

In a solution of the product of Example 73 step a (438 mg, 0.73 mmol) in methanol (6 ml) and tetrahydrofuran (12 ml), sodium borohydride (378 mg, 10.0 mmol) and lithium chloride (420 mg, 10.0). mmol) was added in small portions over several hours with stirring. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afford the product as a white foam (305 mg, 73%).

Step b. Example 17 The product of step a (300 mg, 0.52 mmol) was deprotected according to the method of step d, and the main compound (R _f 0.32; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was white solid. (56 mg, 33%): ¹ H NMR (300 Hz, d ₆ -DMSO), 8.34 (1H, s), 8.09 (1H, d), 8.00 (2H, m), 7.67 (3H, m) 7.41 (1H, d), 6.69 (1H, s), 3.25 (3H, m), 2.64 (1H, dd), 2.46 (1H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 75

3- (4 (5) -imidazoyl) -2S- (2-naphthalene) sulfoneamino-propionic acid

Step a. 3- (1-Triphenylmethyl) imidazoyl-4-yl) -2S- (2-naphthalene) sulfoneamino-propionic acid.

Under argon atmosphere, 2-naphthalene sulfonyl chloride (238 mg, 1.05 mmol) in a solution of triphenylmethylhistidine (398 mg, 1.00 mmol) and triethylamine (304 μl, 2.20 mmol) in dry dichloromethane (20 ml). Was added. The solution was stirred for 1 hour and then water (20 ml) was added. Dilute acetic acid was added until pH5. The mixture was shaken. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afford the product as a pale yellow solid (486 mg, 83%).

Step b. The solution of the product of step a (486 mg, 0.83 mmol) in trifluoro acetic acid (5 ml) was stirred for 18 hours and then the solvent was evaporated.

The residue was triturated with diethyl ether and the white solid obtained was recrystallized with propan-2-ol / diethyl ether. Trifluoroacetic acid salt of the main compound (R _f 0.07; 20% methanol / dichloromethane) was isolated as a white solid (115 mg, 30%): ¹ H NMR (300 Hz, d ₆ -DMSO), 8.30 (1 H, d), 8.00 (4H, m), 7.68 (3H, m), 6.98 (1H, s), 4.06 (1H, dd), 2.93 (1H, dd), 2.81 (2H, dd). Found: C 47.08, H 3.59, N 9.20%; C ₁₈ H ₁₆ F ₃ N ₃ O ₆ S Theoretical value: C 47.06, H 3.51, N 9.15%.

Example 76

N- [5- (4 (5) -imidazoyl) pentyl] -N '-(2-hydroxyethyl) -sulfamide.

Step a. N- [5- (2- (tert-butyldimethylsilyl) -1- (N ", N" -dimethylsulfamoyl) imidazol-4-yl) pentyl] -N '-(2-hydroxyethyl)- Sulfamide.

Example 12 According to the method of step a, 5- (5-aminopentyl) -2- (tert-butyldimethylsilyl)-(N, N-dimethylsulfamoyl) imidazole (Example 54 step a) and 2- Bromoethanol was reacted with chlorosulfonylisocyanate.

The solution of the final compound in ethanol was treated with 2M NaOH (2 equiv) solution, heated to reflux for 2 minutes, and then the solvent was evaporated. Water was added to the residue, then the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated.

The residue was purified by flash column chromatography (silica; 2-4% methanol / dichloromethane) and the product was separated into colorless oil.

Step b. Example 12 The product of step b was deprotected according to the method of step c. The main compound (R _f 0.35; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was obtained as a colorless oil: ¹ H NMR (300 Hz, d ₆ -DMSO), 11.70 (1H, br s), 7.46 (1H, s), 7.10 (1H, t), 6.87 (1H, t), 6.68 (1H, s), 3.60 (2H, t), 3.12 (2H, dd), 2.79 (2H, dd), 2.46 ( 2H, t), 1.61 (2H, quint.), 1.46 (2H, quint.), 1.37 (2H, quint.).

Example 77

N- [4- (4 (5) -imidazoyl) butyl]-(4-bromophenyl) methanesulfonamide.

A subject compound was prepared according to the method of Example 9, and 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ and (4-bromophenyl) were used as substrates in step a. Methanesulfonylchloride (basically prepared according to example 4 step a) was used. The product in two steps was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 7.56 (1H, s), 7.47 (2H, d), 7.30 (2H, d), 7.04 (1H, t) , 6.69 (1H, s), 4.28 (2H, s), 2.87 (2H, dd), 2.46 (2H, m), 1.53 (2H, quint.), 1.41 (2H, quint.). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 78

N- [4- (4 (5) -imidazoyl) butyl]-(4-trifluoromethylphenyl) methane sulfonamide.

A subject compound was prepared according to the method of Example 9, and 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ and (4-trifluoromethylphenyl) were used as substrates in step a. Methanesulfonylchloride (basically prepared according to example 4 step a) was used. The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₄ -MeOH), 7.67 (2H, d), 7.60 (2H, d), 7.55 (1H, s), 6.76 (1H, s), 4.39 ( 2H, s), 3.00 (2H, t), 2.57 (2H, t), 1.64 (2H, quint.), 1.48 (2H, quint.). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 79

N- [4- (4 (5) -imidazoyl) butyl]-(4-fluoromethylphenyl) methanesulfonamide.

A subject compound was prepared according to the method of Example 9, and 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ and (4-fluoromethylphenyl) were used as substrates in step a. Methanesulfonylchloride (basically prepared according to example 4 step a) was used. The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 7.47 (1H, s), 7.39 (2H, dd), 7.18 (2H, t), 7.01 (1H, t), 6.69 ( 1H, s), 4.28 (2H, s), 2.86 (2H, dd), 2.48 (2H, m), 1.52 (2H, quint.), 1.42 (2H, quint.). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 80

N- [4- (4 (5) -imidazoyl) butyl] -N '-(1R-phenylethyl) sulfamide.

A subject compound was prepared according to the method of Example 51, and in step e, (R)-(+)-α-methylbenzylamine was used as the substrate. The product (R _f 0.24; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 11.80 (1 H, br s), 7.47 ( 1H, s), 7.28 (5H, m), 7.21 (1H, dd), 6.66 (1H, s), 6.65 (1H, t), 4.29 (1H, m), 2.65 (2H, m), 2.40 (2H , t), 1.47 (2H, m), 1.41 (3H, d), 1.36 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 81

N- [4- (4 (5) -imidazoyl) butyl] -N '-(1S-phenylethyl) -sulfamide.

A subject compound was prepared according to the method of Example 51, and (S)-(+)-α-methylbenzylamine was used as the substrate in step e. The product (R _f 0.24; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 11.80 (1 H, br s), 7.47 ( 1H, s), 7.28 (5H, m), 7.21 (1H, dd), 6.66 (1H, s), 6.65 (1H, t), 4.29 (1H, m), 2.65 (2H, m), 2.40 (2H , t), 1.47 (2H, m), 1.41 (3H, d), 1.36 (2H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 82

N- [5- (4 (5) -imidazoyl) pentyl] -N '-(4-biphenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 49 using 5- (5-aminopentyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ . The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₄ -MeOH), 7.60 (4H, m), 7.52 (1H, s), 7.43 (4H, m), 7.32 (1H, dd), 6.72 ( 1H, s), 4.16 (2H, s), 2.91 (2H, t), 2.55 (2H, t), 1.59 (2H, quint.), 1.51 (2H, quint.), 1.38 (2H, quint.).

Example 83

N- [5- (4 (5) -imidazoyl) butyl] -N '-(1,1-diphenyl) methyl-sulfamide.

A subject compound was prepared according to the method of Example 51, and C, C-diphenylmethylamine was used as the substrate of step e. The product (R _f 0.28; 1: 10: 90 ammonia (880) / methanol / dichloromethane) was obtained as a white solid: ¹ H NMR (300 Hz, d ₆ -DMSO), 11.70 (1H, br s), 8.03 ( 1H, d), 7.46 (1H, s), 7.27 (10H, m), 6.76 (1H, t), 6.63 (1H, s), 5.42 (1H, d), 2.52 (2H, t), 2.32 (4H , t), 1.36 (2H, quint.), 1.19 (2H, quint.) maleate salts were prepared by liophysis of equimolar solutions of maleic acid with product in water / dioxane.

Example 84

N- [4- (4 (5) -imidazoyl) butyl]-(4-biphenyl) methane sulfonamide.

A subject compound was prepared according to the method of Example 9, and 5- (4-aminobutyl) -1- (N, N-dimethylsulfamoyl) -imidazole ¹ and (4-biphenyl) methane as substrates of step a Sulfonylchloride (basically prepared according to step a of example 4) was used. The product was obtained as a white solid: ¹ H NMR (300 Hz, d ₄ -MeOH), 7.63 (4H, m), 7.56 (1H, s), 7.48 (4H, m), 7.32 (1H, m), 6.76 ( 1H, s), 4.34 (2H, s), 3.00 (2H, t), 2.58 (1H, t), 1.65 (2H, quint.), 1.52 (2H, quint). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

Example 85

N- [4- (4 (5) -imidazoyl) butyl] -N-methyl-2- (4-chlorophenyl) ethanesulfonamide.

N- [4- (1- (N ', N'-dimethylsulfamoyl) imidazol-4-yl) butyl] -2- (4-chlorophenyl) ethanesulfonamide as an intermediate in the synthesis of Example 55 Was methylated with iodomethane as in step a of Example 68.

The deprotection reaction according to step b of Example 9 gave the subject compound as colorless oil: ¹ H NMR (300 Hz, d ₄ -MeOH), 7.55 (1H, d), 7.27 (4H, m), 6.78 (1H) , s), 3.26 (2H, m), 3.21 (2H, t), 3.06 (2H, m), 2.83 (3H, s), 2.63 (2H, t), 1.64 (4H, m). Maleate salts were prepared by liophysis of an equimolar solution of maleic acid with a product in water / dioxane.

references

1. R.C. Vollinga, W.M.P.B. Mange, R. Leurs, H. Timmerman J. Med. Chem.

1995, 38, 266.

2. J.C. Emmett, F.H. Holloway, J.L. Turner J.C.S. Perkin I 1979 1341.

H. Stark, K. Purand, A Huls, X. Ligneau, M. Garbarg, J.-C.

Schwartz, W. Schunack J. Med. Chem. 1996, 39, 1220.

4. J.L. Kelley, C. A. Miller, E.W. McLean J. Med. Chem. 1977, 20, 721.

5. A. Burger, M. Bernabe, P.W. Collins J. Med. Chem. 1970, 13. 33.

H ₃ receptor bioassay

The biological activity of the compounds according to the examples was determined using the ileal fibromyalgia, long muscle plexus assay described by Patton and Abuja ( J. Physiol. 194, 13-33 (1968)). Male Dunkin-Hartley guinea pigs (250-400 g) were used. Briefly, 20 cm of the terminal of the ileum was separated and 50 cm of the ileum adjacent to the cecum was removed. The ileal segments (3 cm) were washed by using a Pasteur pipette (size: 13.8 cm long, 0.65 cm diameter) by slowly passing Krebs-Henselate buffer containing 3 μM mepyramine into the ileum. To avoid unnecessary damage to the tissue, Krebs-Henselate buffer was passed through ileal segments horizontally placed in a Petri dish. Thus, the ileum did not swell excessively, and the buffer solution flowed easily. Passing each ileal segment across the Pasteur pipette and then stroking to a slight stroke away from the mesenteric attachment, the moistened cotton was used to chop the myofibular and coccyx nasal muscle layers. The tissues were suspended in 20 ml organ baths containing Krebs-Henselate buffer at 37 ± 1 ° C., followed by a gas of 95% CO ₂ /5% O ₂ . The tissues were tied to two parallel stainless wires located between two platinum electrodes (0.76 cm long, 0.06 cm diameter). All measurements were recorded the same size (glass FTO3 transducer). As described by Coasters & Watts (1968), tissues were stimulated with electrical pulses at an initial load tension of 1 g followed by a frequency of 0.1 Hz and a pulse duration of 0.5 msec. Initially the tissues were stimulated with ultra-high voltage (1.3 times maximum voltage) for 30 minutes, then washed and re-stimulated. A "sighter dose" of R- (α) -methylhistamine (0.3 μM), a selective histamine H ₃ -receptor antagonist (Aran et al. 1987) was administered. As soon as the reaction appeared, the "test dose" was removed from the tissue by "wash" (six washes over 60 minutes), during which time electrical stimulation was stopped. These tissues were then restimulated and then stabilized prior to addition of the drug to be placed on randomized blocks based on the trachea. Following the incubation period, a single cumulative E / [A] curve was obtained. The experimental E / [A] curve data is expressed as percent inhibition of the peak height of the electrically-stimulated concentration. Shield's method (Arunlatcshama & Schild, 1949) was used to calculate the affinity value of the antagonist from the degree of right shift of the R- (α) -methylhistamine E / [A] curve.

Histamine H ₃ Radioligand binding assay

Preparation of the Membrane

Male Dunkin Hitley guinea pigs (200-300 g) were used. The small intestine was quickly removed (˜5 cm from the ileum and 5 cm from the stomach) and then immersed in ice cold 20 mM Hepes-NaOH buffer (pH 7.4, 21 ± 3 ° C.). The tissue was cut into 10 cm segments, immersed in ice-cold 20 mM Hepes-NaOH buffer, and then placed in a beaker containing fresh buffer at 4 ° C. A 10 cm ileum segment was mounted on a glass pipette, and the long root plexus was removed from the circular muscle using a damp cotton ball. Immediately, the myomas muscles were immersed in an ice-cold viaspan solution (-100 ml for 3 guinea pig tissues) and stored in the refrigerator for 24 hours.

Pre-soaked tissue was weighed and chopped with scissors. This tissue was then homogenized in viaspan solution using Polytron (Kinematica AG; PT-DA 3020 / 2TS, 3 × 1-2 s). 50 ml of 500 mM Tris HCl (pH 6.9, 21 ± 3 ° C.) was added to the tissue and then the mixture was centrifuged at 39,800 × g at 4 ° C. for 12 minutes. Discard the supernatant and 100 ml ice-cold 20 mM Hepes-NaOH buffer (pH7.4, 21 ± 3 ° C) using a teflon-in-glass homogenizer (set 10; 3x) Re-homogenization at. The centrifuge was recentrifuged to 39,800 × g, and then the pellet was resuspended in 20 mM Hepes-NaOH buffer (pH7.4, 21 ± 3 ° C) using polytron (Brinkman, PT10, 3 × 1s). The concentration of the tissue was adjusted to 50 mg / ml.

Constant temperature condition

165 g of guinea pig ileal longitudinal plexus (400 μl) was added at a final volume of 500 μl containing 20 mM Hepes-NaOH buffer containing [ ³ H] -R-α-methyl histamine (50 μl; 3 nM). Incubated at 21 ± 3 ° C. for min. 50 [mu] L of buffer and 50 [mu] L of 10 [mu] M thioperamide were used to determine the [ ³ H] -R- [alpha] -methyl histamine of total and nonspecific binding. The assay was terminated using a Brandel cell harvester, quickly filtered through Whatman GF / B filters and pre-soaked (2 hours) in 0.1% polyethyleneimine. Wash the filter using ice-cold 50 mM Tris-HCl (pH6.9, 21 ± 3 ° C) (3 x 3 ml), transfer to a scintillation vial, add 5 ml of liquid scintillation cocktail and after 4 hours Beckman liquid scintillation counter Bound radioactivity was measured by the calculation method.

Data analysis

Data is analyzed using the general formula for the competing curve with GraphPad Prism and Variable Hill Slope (n _H ).

Where X is the log concentration of the competing compound,

Y is the bond obtained at each concentration of X,

pIC ₅₀ is the concentration of the competitor required to compete for half of the specific binding.

IC ₅₀ is converted to K ₁ using the Cheng Prusoff equation:

K ₁ = IC ₅₀ / (1+ (L / K _D ))

Where IC ₅₀ is the concentration of the competitor required to compete for half of the specific binding,

L is the concentration of radioligand used,

K _D is the equilibrium dissociation constant of the radioligand measured by saturation experiment.

The results obtained by the two analyzes are as follows.

Example pK _B pK ₁

(Functional Analysis) (Combination Analysis)

1 6.70 7.77

2 5.62

3 6.27

4 6.40

6 6.96 7.50

7 6.81 7.42

8 7.11 7.49

9 7.33 7.94

10 8.62 8.53

11 8.01 7.95

12 8.20 8.23

13 8.68 8.56

Example pK _B pK ₁

(Functional Analysis) (Combination Analysis)

14 7.04 7.28

15 8.77 8.36

16 6.77

17 6.35

18 6.79

19 〈5.0 5.95

20 <5.50 7.26

21 〈5.0 5.54

23 5.87 7.55

26 6.29

27 5.11

28 5.39

29 6.88 7.40

30 6.62 6.97

31 5.79 7.07

32 7.36 7.44

33 6.64 7.27

34 7.23

Example pK _B pK ₁

(Functional Analysis) (Combination Analysis)

35 5.59

36 6.16

37 5.71

38 8.37 8.15

39 7.37 7.80

40 6.02

41 8.41 8.37

42 7.86 7.79

43 6.42 7.25

44 8.49 8.68

45 8.91 8.71

46 7.70 7.84

47 8.48 8.57

48 7.06 7.58

49 8.32 8.12

50 7.73 7.78

51 7.01 7.10

52 6.70

Example pK _B pK ₁

(Functional Analysis) (Combination Analysis)

53 6.74 7.25

54 7.80 8.00

55 8.22 8.11

56 6.35 6.86

57 7.96 7.84

58 8.98 8.36

59 8.43 8.08

60 7.84 8.34

61 8.62 8.46

62 8.13 8.24

63 8.39 8.18

64 8.41 8.30

65 7.32 7.98

66 8.06 8.11

67 6.22 6.85

68 7.77 7.95

69 8.92 8.73

70 7.80 7.95

Example pK _B pK ₁

(Functional Analysis) (Combination Analysis)

71 p [A] ₅₀ = 6.11 8.44

72 6.02

73 4.99α-20%

77 8.51

78 8.45

79 8.13

80 6.76

81 6.84

82 7.56

84 8.10

85 8.05

A typical variable in functional analysis is ± 0.15 log units. Typical variables in binding assays are ± 0.12 log units. This means that if the discrepancy between the two analyzes is greater than about 0.5 log units, the average of these differences is important.

Claims (22)

Compounds of the general formula or pharmaceutically acceptable salts thereof Wherein R represents 0 to 2 substituents, R ¹ is C ₄ to C ₂₀ hydrocarbyl (wherein if R ¹ does not contain a -0-0- group, one or more hydrogen atoms may be replaced by halogen atoms, and up to four carbon atoms may be oxygen atoms, nitrogen May be replaced with an atom or a sulfur atom), R²H or C_One-C₁₅Hydrocarbyl (where R²end If it does not contain a -0-0- group, one or more hydrogen atoms can be replaced by halogen atoms, and up to three carbon atoms can be replaced by oxygen atoms, nitrogen atoms or sulfur atoms.), m is 1-15, n is 2 to 6, Each X group independently Or one X group is -N (R ⁴ )-, -0- or -S-, unless the X group is adjacent to the -NR ² -group, and the remaining X groups are independently Wherein R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -CO ₂ R ⁵ , -CONR ⁵ ₂ , -CR ⁵ ₂ OR ⁶ or -OR ⁵ (where R ⁵ and R ⁶ are H or C ₁ -C ₃ alkyl), R ⁴ is H or C ₁ -C ₆ alkyl, Each Y group is independently -C (R ³ ) R ⁴ -or up to two Y groups are -N (R ⁴ )-, -0- or -S-, and the remaining Y groups are independently -C ( R ³ ) R ^4- , wherein R ³ is as described above and one R ⁴ group is imidazoyl, imidazoylalkyl, substituted imidazoyl or substituted imidazoylalkyl, and the remaining R ⁴ Groups are H or C ₁ -C ₆ alkyl, Z is> C (R ⁷ ) NR ² -or> N-, where R ⁷ is one of the groups listed for R ³ . A compound according to claim 1 having the following general formula: Wherein -X _m -is bonded to the 4- or 5- position of the imidazole ring. The compound according to claim 1 or 2, having the following general formula: Where m is at least 3. 4. A compound according to claim 2 or 3, wherein -X _m -is C ₃ -C ₉ alkylene. The compound of claim 1, wherein R ² is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkylhydroxy. Alkyl, aryl C ₁ -C ₆ alkyl or substituted aryl C ₁ -C ₆ alkyl. The compound of claim 5, wherein R ² is hydrogen or C ₁ -C ₃ alkyl. The compound according to any one of claims 1 to 6, wherein R ¹ is a group of the general formula: Wherein p is 0 or 1, R ¹¹ is H or C ₁ -C ₃ alkyl, q is 0-4, R ¹² is carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocy Is a click group, R ¹³ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkylhydroxyalkyl, aryl C ₁ -C ₆ alkyl And substituted aryl C ₁ -C ₆ alkyl. 8. A compound according to claim 7, wherein R ¹³ is H. The compound of any one of claims 1-8, wherein R ¹ is an aryl group or a substituted aryl group. 10. The compound of claim 9, wherein the aryl group is phenyl or substituted phenyl. 10. The compound of claim 9, wherein the aryl group is naphthyl or substituted naphthyl. A compound according to claim 1 having the following general formula: Where m is 3 to 10, R ² and R ¹¹ are independently H or methyl, p is 0 or 1, q is 0 to 3, and R ¹² is 2-naphthyl, phenyl, 4-chlorophenyl , 3,4-dichlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-iodophenyl, 4-bromophenyl, 4-fluorophenyl, 4- (trifluoromethyl) phenyl, 4-methoxy Phenyl, 4-biphenyl, cyclohexyl and adamantyl, and R ¹³ is independently selected from H, methyl and phenyl. The compound of any one of claims 1-8, wherein R ¹ is a (cycloalkyl) alkyl group. The compound of claim 13, wherein the (cycloalkyl) alkyl group is cyclohexylpropyl or adamantylpropyl. 15. The compound of any one of claims 1-14, wherein m is 3-9. The compound according to any one of claims 1 to 15, which is degraded in vivo. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable excipient or carrier. A process for preparing a compound according to claim 1 comprising reacting a sulfonylchloride of formula R ¹ SO ₂ Cl with an appropriately protected derivative of the general formula: Wherein R, R ¹ , R ² , X, Y, Z, m and n are as defined in any one of claims 1 to 15. Method for producing a sulfamide compound according to claim 1, comprising the following steps a) to d): a) reacting chlorosulfonyl isocyanate with an appropriate alcohol, b) reacting the product of step a) with a suitably protected derivative having the general formula c) step b) step of the product and allowed to react with a base such as sodium hydride and then, is bonded to the carbon atom of R ¹ bromine atom is reacted with a compound represented by the general formula R ¹ -Br in which, d) acid treating the product of step c), Wherein R, R ¹ , X, Y, Z, m, n and R ² are as defined in any one of claims 1 to 15. The process according to claim 19, wherein the compound of general formula R ¹ -Br used in step c) has the following general formula: Wherein q, R ¹² and R ¹³ are as defined in claim 7. Method for producing a sulfamide compound according to claim 1, comprising the following steps a) to d): a) reacting chlorosulfonyl isocyanate with an appropriate alcohol, b) step a) step of the product and is bonded to the nitrogen atom of the hydrogen atoms R ¹ reacting a suitably protected derivative of a compound of the general formula R ¹ -H in which, c) reacting the product of step b) with a suitably protected derivative of a compound having the general formula And d) acid treating the product of step c), Wherein R, R ¹ , X and m are as defined in any one of claims 1 to 15. The process of claim 21, wherein the compound of formula R ¹ -H used in step b) has the general formula: Wherein q, R ¹² and R ¹³ are as defined in claim 7.