ANTIINFLΆMMATORY HYDROXAMIC ACIDS AND N-HYDROXYUREAS

Background of the Invention

This invention relates to novel hydroxamic acid and N- hydroxyurea derivatives and their use. The compounds of the present invention inhibit the action of lipoxygenase enzyme and are useful in the treatment of inflammatory diseases or conditions in general, for example, allergies and cardiovascular diseases in mammals, including humans. This invention also relates to pharmaceutical compositions comprising such compounds, methods of producing such compounds and methods of using such compounds and compositions in the treatment of the aforementioned diseases and conditions.

Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of arachidonic acid metabolism is the release of esterified arachidonic acid and related unsaturated fatty acids from membrane phospholipids via the action of phospholipase. Free fatty acids are then metabolized either by cycloxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to

provide significant new therapy for both acute and chronic inflammatory conditions.

Recently, several review articles on lipoxygenase inhibitors have been reported. See, for example, H. Masamune and L. S. Melvin, Sr. , in Annual Reports in

Medicinal Chemistry- 24, 71-80 (Academic Press, 1989) and B. J. Fitzsimmons and J. Rokach in Leukotrienes and Lipoxyσenases. 427-502 (Elsevier, 1989) .

Furthermore, EP 279,263 A2, EP 196,184 A2, JP 63502179 and U.S. Patent No. 4,822,809 disclose lipoxygenase inhibitors.

The present inventors have worked to prepare compounds capable of inhibiting the action of lipoxygenase and, after extensive research, have succeeded in synthesizing a series of compounds as disclosed in detail herein.

Summary of the Invention

The present invention provides for the preparation and use of novel hydroxamic acids and N-hydroxyurea derivatives of the formula:

Formula I

where R ¹ is hydrogen, Cl to C4 alkyl, C2 to C4 alkenyl, alkylthioalkyl, alkoxyalkyl or -NR ² R ³ ;

R ² and R ³ are each independently hydrogen, Cl to C4 alkyl, hydroxyl, aryl or substituted aryl wherein the . substituent or substituents are selected from the group

consisting of halo, nitro, cyano, Cl to C12 alkyl, Cl to C12 alkoxy, Cl to C12 halosubstituted alkyl, Cl to C12 hydroxysubstituted alkyl, Cl to C12 alkoxycarbonyl, aminocarbonyl, Cl to C12 alkyla inocarbonyl, Cl to C12 dialkylaminocarbonyl and Cl to C12 alkylsulfonyl, with the proviso that R ² and R ³ are not both hydroxyl;

R ⁴ is hydrogen, a pharmaceutically acceptable cation, aroyl or Cl to C12 alkanoyl;

X is a chemical bond, oxygen, sulfur or NR ⁵ ; R ⁵ is hydrogen, Cl to C6 alkyl, C3 to C6 alkenyl, Cl to C6 alkanoyl, aryl, arylalkyl or aroyl; m is 0 or 1; n is 1 to 3;

A is Cl to C6 alkylene, C2 to C6 alkenylene or C2 to C6 alkylidene; each Y is independently hydrogen, halogen, hydroxy, cyano, Cl to C12 alkyl, halosubstituted alkyl, hydroxysubstituted alkyl, C2 to C12 alkenyl, Cl to C12 alkoxy, C3 to C12 alkenyloxy, C3 to C8 cycloalkyl, Cl to C8 thioalkyl, Cl to C12 alkoxycarbonyl, Cl to C12 arylalkoxycarbonyl, aminocarbonyl, Cl to C12 alkylaminocarbonyl, Cl to C12 dialkylaminocarbonyl, Cl to C12 arylalkyla ino, Cl to C12 arylalkyla inocarbonyl, alkoxyalkyl, aryl, aryloxy, aroyl, Cl to C12 arylalkyl, C2 to C12 arylalkenyl, Cl to C12 arylalkoxy or Cl to C12 arylthioalkoxy wherein said aryl, aryloxy, aroyl, arylalkyl, arylalkenyl, arylalkoxy and arylthioalkoxy may be optionally substituted with a substituent or substituents selected from the group consisting of halo, nitro, cyano, Cl to C12 alkyl, halosubstituted alkyl and .Cl to C12 alkoxy; and

Z is oxygen or sulfur.

The substituent(s) Y and the linking group A may be attached at any available position on either ring.

Detailed Description of the Invention

As used herein, the term "halo" means fluoro, chloro, bromo or iodo.

The term "aryl" as used herein means any substituted and unsubstituted carbocyclic and heterocyclic aromatic groups such as phenyl, naphthyl, pyridyl, furyl and pyrimidinyl. The substituents may be halo, nitro, cyano, Cl to 012 alkyl, Cl to 012 alkoxy, 03 to 012 alkenyloxy, Cl to C12 halosubstituted alkyl, Cl to 012 alkoxycarbonyl, aminocarbonyl, Cl to C12 alkylaminocarbonyl, Cl to C12 halosubstituted alkoxy, Cl to 012 dialkylaminocarbonyl and Cl to C12 alkylsulfonyl.

The term "σycloalkyl" as used herein means a cyclic group of 3 to 8 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "alkyl" means optionally a straight or branched chain.

The term "aroyl" as used herein means benzoyl, naphthoyl and their derivatives substituted with hydroxy, halo, nitro, cyano, Cl to C12 alkyl, alkoxy, hydroxysubstituted alkyl and halosubstituted alkyl.

The term "pharmaceutically acceptable cation" as used herein means non-toxic cations, including those of alkali and alkaline earth metals such as sodium, lithium, potassium, calcium and magnesium, and organic cations based on ammoniums and amines.

Some of the compounds of Formula I may form acid addition salts. The pharmaceutically acceptable acid addition salts are those formed from acids which form non- toxic acid addition salts, for example, the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or acid

phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate and formate salts.

This invention includes pharmaceutical compositions for treatment of inflammatory diseases, allergies and cardiovascular diseases in mammals which comprise a pharmaceutically acceptable carrier or diluent and a compound of Formula I or a pharmaceutically acceptable salt thereof.

This invention also includes pharmaceutical compositions for inhibiting the action of lipoxygenase enzyme in a mammal which comprise a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof.

This invention further includes processes for synthesizing the compounds of Formula I.

This invention still further includes methods of using the novel compounds and compositions in the treatment of conditions and diseases for which lipoxygenase activity has been implicated, for example, inflammatory conditions and diseases.

The compounds of Formula I may be prepared by a number of synthetic methods. In Formulae II, III, IV and V below, Q is

and X, Y, m and n are as defined previously. Although, in reaction Schemes 1 and 2 below, R ¹ is methyl and NH ₂ , respectively, and Z is oxygen, compounds of Formula I

wherein R ¹ and Z are as defined previously may be prepared in an analogous manner.

In one embodiment, compounds of Formula IV are prepared according to the reaction steps outlined in Scheme 1, below.

SCHEME 1

O H O λ c O H step 1 step 2 o- i-NH — ^► o- i ¹ ' ye ^Q - ⁽ *l- ^N

0 0

Formula II Formula III Formula IV

In step 1, the diacetyl compound (III) is prepared by standard methods known in the art. For example, the hydroxylamine (II) is reacted with acetyl chloride or acetic anhydride in a reaction-inert solvent in the presence of a suitable base. Preferred bases are triethylamine and pyridine. Suitable reaction-inert solvents include methylene chloride, chloroform, tetrahydrofuran, benzene and toluene. The reaction is usually carried out in a temperature range of from O'C to ambient temperature. Reaction times of from 30 minutes to a few hours are common. The product can be isolated and purified by conventional procedures, for example, recrystallization or chromatography.

Step 2 involves selective hydrolysis of the diacetyl compound (III) with an appropriate base. The bases suitably employed in this reaction include ammonia, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably in methanol, ethanol, isopropyl alcohol or water, though binary solvent systems such as alcohol-water, tetrahydrofuran-water and the like may be employed. Reaction temperatures are usually in the range of from -10 ^β C to ambient temperature and the reaction is

usually complete from within a few minutes to several hours. The product, having the structure shown in Formula IV, is isolated by standard methods and purification can be achieved by conventional means, for example recrystallization and chromatography.

In another embodiment, compounds of Formula V are prepared as illustrated in reaction Scheme 2, below.

SCHEME 2 OH OH

Formula II Formula V

In this step the hydroxylamine (II) is treated with trimethylsilyl isocyanate in a reaction-inert solvent, usually at ambient through to reflux temperature. Suitable solvents which do not react with the reactants and/or products include, for example, tetrahydrofuran, dioxane, methylene chloride and benzene. An alternative procedure employs treatment of the hydroxylamine (II) with gaseous hydrogen chloride in a reaction-inert solvent such as benzene or toluene and then subsequent treatment with phosgene. Reaction temperatures are usually in the range of ambient temperature to the boiling point of the solvent. The intermediate carbamoyl chloride is not isolated but is subjected to (e.g. in situ) reaction with aqueous ammonia. The product thus obtained, having the structure shown in Formula V, is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The aforementioned hydroxylamine (II) is easily prepared by standard synthetic procedures from readily

available carbonyl compounds, e.g. ketones or aldehydes, or from alcohols or halogen compounds. For example, a suitable carbonyl compound is converted to its oxime and then reduced to the requisite hydroxylamine (II) with a suitable reducing agent (for example, see R. F. Borch, et al., J. Am. Chem. Soc.. 93, 2897 (1971)). Preferred reducing agents include sodium cyanoborohydride and borane complexes such as boron-pyridine, boron-triethylamine and boron- dimethylsulfide. Triethylsilane in trifluoroacetic acid may also be employed.

Alternatively, the hydroxylamine (II) can be prepared by treating the corresponding alcohol with N.O-bisftert- butyloxy-carbonyl)hydroxylamine under Mitsunobu-type reaction conditions followed by acid catalyzed hydrolysis of the N,0-protected intermediate product (See JP 1045344) . It is also noteworthy that the N,0-diacetyl compound (III) can be prepared employing N,0-diacetyl hydroxylamine in place of N,0-bis(tert-butyloxy-carbonyl)hydroxylamine, thus providing a convenient route to the product of Formula IV.

The aforementioned hydroxylamine (II) may also be prepared from a suitable halide compound by reaction with O-protected hydroxylamine and subsequent deprotection (see W. P. Jackson, et al., J. Med. Chem.. 31, 499 (1988)). Preferred O-protected hydroxylamines include o-tetrahydropyranyl-, O-trimethylsilyl- and O-benzylhydroxylamine.

The hydroxylamine of Formula II thus obtained by the above representative procedures is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The pharmaceutically acceptable salts of the novel compounds of the present invention are readily prepared by contacting said compounds with a stoichiometric amount of an appropriate mineral or organic acid in either aqueous

solution or in a suitable organic solvent. The salt may then be obtained by precipitation or by evaporation of the solvent.

The compounds of this invention inhibit the activity of the lipoxygenase enzyme. This inhibition has been demonstrated by an assay using rat peritoneal cavity resident cells which determines the effect of said compounds on the metabolism of arachidonic acid.

In this test some preferred compounds indicate low IC ₅₀ values, in the range of 0.1 to 30 μM, with respect to lipoxygenase inhibition. As used herein, IC ₅₀ refers to the concentration of the compound tested necessary to effect a 50% inhibition of lipoxygenase.

The ability of the compounds of the present invention to inhibit lipoxygenase enzyme makes them useful for controlling the symptoms induced by the endogenous metabolites arising from arachidonic acid in mammalian subjects. The compounds are therefore valuable in the prevention and treatment of such conditions and disease states in which the accumulation of arachidonic acid metabolites is a causative factor. Examples of such disease states include allergic bronchial asthma, skin disorders, rheumatoid arthritis, osteoarthritis and thrombosis.

Thus, the compounds of Formula I and their pharmaceutically acceptable salts are of particular use in the treatment or alleviation of inflammatory diseases, allergies, cardiovascular diseases in human subjects as well in the inhibition of the lipoxygenase enzyme.

For treatment of the various conditions described above, the compounds of Formula I and their pharmaceutically acceptable salts can be administered to a human subject either alone or, preferably, in combination with

pharmaceutically acceptable carriers or diluents in a pharmaceutical composition, according to standard pharmaceutical practice. A compound can be administered by a variety of conventional -routes of administration including orally, parenterally and by inhalation. When the compounds are administered orally, the dose range will be generally from about 0.1 to 20 mg/kg body weight of the subject to be treated, per day, preferably from about 0.1 to 1.0 mg/kg/day in single or divided doses. If parenteral administration is desired, then an effective dose will be generally from about 0.1 to 1.0 mg/kg body weight of the subject to be treated, per day. In some instances it may be necessary to use dosages outside these limits, since the dosage will necessarily vary according to the age, weight and response of the individual patient as well as the severity of the patient's symptoms and the potency of the particular compound being administered.

For oral administration, the compounds of Formula I and their pharmaceutically acceptable salts can be administered, for example, in the form of tablets, powders, lozenges, syrups or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. In addition, lubricating agents, such as magnesium stearate, are commonly added. In the case of capsules, useful diluents are lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile injectable solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solute should be controlled to make the preparation isotonic.

The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance spectra (NMR) were measured at 270 MHz unless otherwise indicated, for solutions in perdeuterodimethyl sulfoxide (DMS0-d ₆ ) and pea positions are expressed in parts per million (ppm) downfiel from tetramethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; , multiplet; br, broad.

EXAMPLES

Example 1 N-(Hydroxy)-N-(indan-1-yl)urea

1-Indanone (4.00 g, 30.3 mmol) and hydroxylamine hydrochloride (5.26 g, 75.7 mmol) were dissolved in a mixture of methanol (40 ml) and pyridine (10 ml) and stirre for 3 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the resultant residue was diluted with 1 N HC1 (100 ml) and extracted three times wit methylene chloride. The organic layer was dried over MgS0 ₄ and concentrated in vacuo to provide 4.13 g (93% yield) of the desired 1-indanone oxime as white needles.

The oxime (4.08 g, 27.7 mmol) prepared in the above step was dissolved in acetic acid (50 ml) and sodium cyanoborohydride (9.40 g, 63 mmol) was added portionwise over 1 hour. After reaction was complete, the reaction mixture was poured carefully into ice cold aqueous Na ₂ C0 ₃ such that the pH was adjusted to 9. The mixture was extracted with methylene chloride, dried over MgSO _A and concentrated in vacuo to afford 3.6 g of 1-indane hydroxylamine (87% yield) as a tan powder.

The hydroxylamine (1.26 g, 8.4 mmol) prepared in the above step was stirred for 1 hour with trimethylsilyl isocyanate (1.65 g, 16.8 mmol) in tetrahydrofuran. The reaction mixture was concentrated in vacuo and the residue

recrystallized from ethyl acetate to give 0.78 g (48% yield) of the product as a fine white powder.

m.p.: 158.7 - 159.4 ^β C

IR (KBr) : 3465, 3190, 1667, 1654, 1573, 759, 741 cm' ¹ NMR (CDC1 ₃ )$: 7.34-7.21 (m, 4H) , 5.92 (dd, J=5.8 and 8.1 Hz, 1H) , 5.3 (br., s, 2H) , 5.16 (s, 1H) , 3.07-3.02 (m, 1H) , 2.95-2.83 (m, 1H) , 2.46-2.35 (m, 1H) , 2.26-2.13 (m, 1H)

Example 2 N-Hvdroxy-N- (indan-1-yl )acetamide 1-Indane hydroxylamine (2.33 g, 15.6 mmol), prepared as in Example 1, and triethylamine (3.48 g, 34.3 mmol) were dissolved in methylene chloride (40 ml), cooled to 0 ^β C and acetyl chloride (2.33 ml, 32.8 mmol) was added. The mixture was stirred for thirty minutes and poured into 1 N HCl. The organic layer was separated, dried over MgS0 ₄ and concentrated in vacuo to afford 3.58 g (98% yield) of N-acetoxy-N-(indan-1-yl)acetamide.

The acetamide (3.56 g, 15.3 mmol) was dissolved in a mixture of methanol (20 ml) and ammonia water (10 ml) at ambient temperature. After thirty minutes the mixture was concentrated in vacuo and the residue partitioned between water and methylene chloride. The organic phase was dried over MgS0 ₄ and concentrated in vacuo. The resultant residue was recrystallized from benzene to afford 2.06 g (70% yield) of the product as a fine white powder.

m.p. : 137.9 - 139.5 ^β C

IR (KBr): 3090, 2925, 1615 (br.), 757 cm" ¹ NMR (DMSO-d ₆ )6: 9.46 (s, 1H) , 7.22-7.12 (m, 4H) , 5.96 (br., t, J=8 Hz, 1H), 3.05-2.90 (m, 1H) , 2.85-2.70 (m, 1H) , 2.25-2.05 (m, 2H) , 2.06 (s, 3H)

Example 3 N-Hydroxy-N-[2-(2,3- dihydro-lH-inden-1-ylidene)ethyl1acetamide

Diethyl azodicarboxylate (3.94 g) in dry toluene (10 ml) was added to a stirred solution of 2-(2,3-dihydro-lH-

inden-1-ylidene) ethanol (2.41 g) , N,0-diacetylhydroxylamine (1.85 g) and triphenylphosphine (5.94 g) in dry toluene (60 ml) at -78*C under nitrogen atmosphere. The mixture was stirred at ambient temperature under nitrogen atmosphere for 30 minutes. The mixture was filtered and the residue was washed thoroughly with ethylacetate and hexane (1:1). The combined filtrate and washings were concentrated under reduced pressure. Chromatography on silica gel eluted with hexane-ethyl acetate (3:1) to give N-acetoxy-N-[2-(2,3- dihydro-lH-inden-1-ylidene) ethyl]acetamide (1.34 g) . The diacetate was dissolved in methanol (10 ml) , concentrated NH ₄ 0H was added, the mixture was stirred at ambient tempera¬ ture for 1 hour and concentrated under reduced pressure. The resulting pale yellow oil was extracted with ethyl acetate and washed with brine. The solution was dried over MgS0 ₄ and concentrated to give a pale yellow oil. Chromatography on silica gel eluted with hexane-ethyl acetate (1:1) followed by crystallization from isopropyl ether afforded the desired compound, a white solid (0.46 g) .

m.p.: 96.0 - 96.6°C

IR (KBr) v: 1650, 1610

NMR (270 MHz, CDCl ₃ )£: 8.30 and 6.40 (br. , s, 1H) , 7.44-7.51 (m, 1H) , 7.16-7.31 (m, 3H) , 6.08-6.18 (m, 1H) , 4.40 (d, 2H, J=6.2 Hz), 3.00-3.09 (m, 2H) , 2.78-2.87 (m, 2H) , 2.16 (s, 3H)

Example 4 N-Hydroxy-N-[l-(l-benzyl- 1.2.3.4-tetrahydroquinolin-6-y1)ethyl1urea

To a mixture of l-benzyl-l,2,3,4-tetrahydroquinolin-6- ylethan-1-ol (2.82 g, 10.6 mmol), BocNH-OBoc (2.48 g, 11.1 mmol) and triphenylphosphine (3.62 g, 13.8 mmol) in toluene (20 ml) was added diethyl azodicarboxylate (2.40 g, 13.8 mmol) at -78"C under nitrogen atmosphere. The mixture was stirred at -78 ^β C to ambient temperature for 30 minutes. The mixture was concentrated in vacuo to give a reddish brown oil (11.87 g) . Chromatography on silica gel eluted with hexane-ethyl acetate (15:1) to afford N,0-dibutoxycarbonyl-

N-[1-(1-benzyl-l,2,3,4-tetrahydroquinolin-6-yl)ethyl] hydroxylamine (2.57 g, 53.8% yield).

NMR (CDCl ₃ )fi: 7.17-7.35 (m, 5H) , 6.91-7.05 (m, 2H) , 6.43 (d, J=8.1 Hz, 1H) , 5.24 (q, J=6.8 Hz, 1H) , 4.45 (s, 2H) , 3.34 (t, J=5.5 Hz, 2H) ,

2.79 (t, J=5.9 Hz, 2H) , 1.92-2.05 (m, 2H) , 1.21-1.63 (m, 21H)

To a solution of N,0-dibutoxycarbonyl-N-[l-(l-benzyl- 1,2,3,4-tetrahydroquinolin-6-yl)ethyl]hydroxylamine (2.57 g, 5.70 mmol) in CH ₂ C1 ₂ (30 ml) was added trifluoroacetic acid (9 ml) at ambient temperature. The mixture was stirred at ambient temperature for 1 hour, concentrated in vacuo to afford a viscous oil which was extracted with ethyl acetate and washed with water and brine. The solution was dried over MgS0 ₄ and concentrated to give a yellow oil (1.38 g) . Without purification, the crude product was dissolved in tetrahydrofuran (5 ml) and treated with 90% trimethylsilyl isocyanate (1.1 ml, 7.33 mmol) for 1 hour at ambient temperature. Water (1 ml) was added to the mixture which was then concentrated in vacuo. The residue was dissolved in ethyl acetate and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo and crystallized from isopropyl ether-ethyl acetate to give a white solid. Recrystallization from ethyl acetate-isopropyl ether (4:1) afforded the title compound as a white solid (0.223 g, 12% yield) .

m.p.: 127.8 - 128.2'C (dec.) IR (KBr): 3500, 3460, 1645

NMR (DMSO)δ: 8.84 (s, 1H) , 7.18-7.37 (m, 5H) , 6.87 (s, 1H) , 6.84 (d, J=8.8 Hz, 1H) ,

6.36 (d, J=8.8 HZ, 1H) , 6.15 (s, 2H) , 5.11 (q, J=7.0 Hz, 1H) , 4.45 (s, 2H) , 3.20-3.56* (2H) , 2.70 (t, J=6.2 Hz, 2H) , 1.80-1.97 (m, 2H) , 1.30 (d, J=7.0 Hz, 3H) * This peak was hidden by H-.0 in DMSO-d ₆ .

By analogous methods, the following were prepared.

NMR:

(CDC1 ₃ ) : 8.45(br. s, IH), 7.26 - 7.16(m, AH), 4.85(br., IH). 3.40 (br., 2H),

3.17 - 3.08(m. 2H), 2.19(s. 3H)

5.01 (quint . , J=8Hz, IH) , 3.05-2.85 (m, 4H)

Example 7

N-Hydroxy-N- ( 2-phenyl-3 , 4-dihydro-2H-benzopyran-6-yl )methylacetamide

m.p. 119.5 -121.0 ^β C

IR: (KBr. cm ^*1 ) 3430 1611 1584 1490

NMR: (270MHz. CDC1 ₃ )

7.26-7.45 (m. 5H) 7.03 (br s.2H) 6.90 (d, IH. J= 8H2) 5.06 (dd. IH, J= 3.10Hz) 4.73 (s.2H) 2.93-3.06 (m, IH) 2.74-2.86 ( , IH) 2.03-2.30 (m. 2H) 2.20 (s.3H)

Example 8

N-Hydroxy-N-[2-(indan-l-yl)cthyl] acetamide

m. p. oil

IR: (film, cm ^"1 ) v 3160, 1610

^{N R:} (270mHz, CDCI ³ ) δ 8.30-8.55 (br s, IH), 7.10-7.28 (m.4H).3.73 (t, 2H. J=7.3 Hz). 3.13-3.27(m, IH), 2.79-3.03(m, 2H), 2.25-2.40(m, 2H), 2.10 (s, 3H),

1.90-1.63(m, 2H)

Ex ample 9

. . = z, . . r. s. . . . . . . . = z. . 3.08(dd. J = 11 and 16 Hz. IH). 2.80(dd. J = 4 and 16 Hz. IH). 2.04(s.3H)

Example 11 N-Hydroxy-N- ( 5-methoxyindan-l-yl lurea

m in.. p y>.. 159.3 - 159.7 ^β C

IR:

(KBr): 3460. 3200. 1654. 1570 cm -1

NMR:

(270 MHz. DMSO-d _δ ) δ : 8.89(s. IH). 7.05(d. J = 8 Hz, IH). 6.76(d. J = 2 Hz, IH). 6.71(dd. J = 2 and 8 Hz. IH). 6.35 (s. 2H), 5.59(t, J = 7 Hz, IH). 3.71(s. 3H). 2.9 - 2.86(m, IH). 2.74 - 2.7 l(m, IH). 2.2 - 2.0( . 2H).

Example 12

N-Hydroxy-N- ( 3, -dihydro-2H-l-benzopyran-3-yl ) urea

m. p. 167.9 - 168.5 *C

IR:

(KBr): 3430. 3145, 1668 cm ^{* 1}

NMR:

(270 MHz, DMSO-d ₆ ) δ : 9.30(s. IH). 7.12-7.04(m. 2H). 6.84(dt. J = 1 and 8 Hz. IH). 6.76(d. J = 8 Hz. IH). 6.49(s. 2H). 4.41-4.37(m. IH). 4.17-4.11(m, IH). 3.87(t. J = 10 Hz. IH). - 3.05(dd. J = 11 and 16 Hz. IH). 2.68(dd. J = 4 and 16 Hz. IH)

Exam _p le 13 N- ( 1-Benzyl-l, 2, 3, 4-tetrahydroquinolin-6-yl )methyl-N-hydroxyacetamide

m. p. : 166-167 ^β C (dec)

IR: ( KBr. cm ^*1 ) 3125 2920 2850 1604 1510

NMR: (270MHz. CDCI ₃ )

8.30 (br s. IH) 7.23-7.35 (m. 5H) 6.91 (br $. 2H)

6.46 (d. IH. J= 8Hz) 4.64 (s, 2H)

4.47 (s. 2H)

3.37 (t. 2H. J= 6Hz) 2.81 (t. 2H. J= 6Hz) 2.17 (s. 3H) 2.01 (quin. 2H. J= 6Hz)

Example 14

N-Hydroxy- _N - (3, 4-dihydro-2H-l-benzopyran-2-yl )methylurea

m. p. 124.4 - 125.4 ^# C

IR:

(KBr): 3465. ^' 3200 ^' . 1663. 1631. 1583. 752 cm -1

NMR:

(270 MHz, DMSO-d ₆ ) 3 : 9.47(s. IH). 7.04(t. J = 8 Hz.2H). 6.78(dd. J = 1 and 8 Hz. IH). 6.72(d, J = 8 Hz. IH). 6.34(br. s.2H). 4.22(m. IH). 3.64(dd. J = 6 and 14 Hz. IH).

Example 15

N-Hydroxy-N- ( 3 , 4-dihydro-2H-l-benzopyran-2-yl )methylacetamide

m. p. 120.5 - 120.8 °C

Example 16

N-Hydroxy-N-(2-indan-l-yleihyl)urea

'NCONH, OH

^m - P- ^: 89.0-89.9 ^β C

IR: (KBr) v 34S0, 1635.

NMR: ₍₂ 70 MHz.CDCl ₃ ) δ 7.12-7.25 (m. 4H). 5.26 (br s. 2H). 3.55-3.76 (m.-2H), 3.07-3.21 (m. IH). 2.76-2.97 ( . 2H). 2.14-2.38 (m, 2H). 1.63-1.79 (m. 3H).

-21-

■Example 17

N-Hydroxy-N- (2-pheny 1-3, 4-dihydro-2H-benzopyran-6-yl)methylurea

O

Λ NH, yy OH

NMR: (270MHz. DMSO-d ₆ ) δ 9.25 (s. IH)

7.31-7.46 (m. 5H) 7.02 (br s. 2H) 6.76 (d. IH. J= 6Hz) 6.29 (br s. 2H) 5.10 (dd. IH, 3=2, 10Hz) 4.41 (s. 2H) 2.88-3.03 (m, IH) 2.63-2.76 (m. IH) 2.11-2.22 (m. IH) 1.91-2.07 ( . IH)

-22-

Exar.ole 18

N-Hydroxy-N- (6-methoxyindan-l-yl )urea

6.72(d. J = 2 Hz. IH). 6.42(s. 2H). 5.62(t. J = 7 Hz. IH). 3.71(s. 3H). 2.9 - 2.78(m. IH). 2.7 - 2.6(m. IH). 2.2 - 2.0(m. 2H).

ExamDle 19

N-Hydroxy-N- (6-methoxyindan-l-yl)acetamide

m. p. 153.2 - 154.2 ^β C

IR:

(KBr): 2850. 1610, 1586 cm ^*

NMR:

(270 MHz. DMSO-d ₆ ) δ : 9.45(s, IH), 7.13(d. J = 8 Hz. IH). 6.78(dd. J = 2 and 8 Hz. IH). 6.64(d. J = 2 Hz. IH). 5.90(t. 7 Hz. IH). 3.71(s, 3H), 2.95 - 2.82(m. IH). 2.76 - 2.64( . IH). 2.25 - 2.0(m, 2H). 2.06(s. 3H)

NMR: (270 MHz, D S0-d ₆ ) delta: 8.90(s,lH), 7.45-7.3(m,5H) , 7.06

(d, J=8Hz, IH), 6.85(d, J=2Hz, IH), 6.80 (dd, J=2 and 8Hz, IH),

6.36(s, 2H), 5.59(t, J=7Hz> IH), 5.06(s, 2H), 2.96-2.8(m, IH), 2.76-2.62(m, IH), 2.22-2.04(m, 2H)

6.27 (br s. 2H) 4.37 (s, 2H) 4.09 (i. 2H. J=5Hz) 2.70 (t. 2H. J=6Hz) 1.86-1.94 (m. 2H)

Example 23

N-Hydroxy-N- ( 6-methyl indan-1 -yl ) acetamide

m. p. 159.2 - 160.4 ^β C

IR:

(KBr): 2850. 1600. 1430 cm -1

NMR:

(270 MHz. DMSO-de) 3 : 9.44(s. IH). 7.1 l(d. J = 8 Hz. IH). 7.02(d. J = 8 Hz. IH). 6.92(s. IH). 5.93(t. J = 7 Hz. IH). 2.96 - 2.84(m. IH). 2.8 - 2.65(m. IH).

Example 24

N-(3,4-Dihydro-2H-benzopyran-6-yl)methyl-N-hydroxy acetamide

" ^■• P- ^' 115- 118°C

IR: ( KBr. cm ) 3435 1499 2935 1251 1619 1599

NMR: (270MHz, CDC1 ₃ ) δ 8.34 (br s, IH) 6.94-7.06 (m. 2H) 6.78 (d. IH. J= 8Hz) 4.70 (s.2H) 4.18 (t, 2H. J=5Hz) 2.78 (t.2H. J=6Hz)

2.18(s, 3H) 1.94-2.06(m,2H)

Example N-Hydroxy-N-(5-methylindan-1 -yl)urea

25

STRUCTURE:

m. p. 172.9-174.6°C

-1

IR: v (KBr): 3460, 1660, 1570, 1460 cm ^'

NMR: δ (DMSO-d ₆ ):

8.89 (s, 1H), 7.08-6.93 (m, 3H), 6.36 (s, 2H),

5.62 (t, J=7.7Hz, 1H), 2.95-2.80 (m, 1H), 2.77-2.62 (m, 1H),

2.26 (s, 3H), 2.23-1.98 (m. 2H)

Example N-Hydroxy-N-(5-chloroindan-1 -yl)urea

26

STRUCTURE:

m. p. 169.4-170.8°C

IR: v (KBr): 3480, 1655, 1530 cm ^"1 .

NMR: δ (DMSO-d ₆ ):

9.01 (S, 1H), 7.28-7.11 (m, 3H), 6.43 (s, 2H),

5.63 (t, J=7.5Hz, 1H), 2.97-2.85 (m, 1H), 2.82-2.59 (m, 1H),

2.28-2.04 (m, 2H).

-28-

Example N-Hydroxy-N- {5-(2-quinolylmethoxy)indan- l -yl }urea

29

STRUCTURE:

mp: 182.8-184.1°C

-1

IR (KBr) cm : 3480, 3200, 1650, 1570, 1490, 1430, 1330, 1280, 1140, 920

8.92(s. IH), 8.40(d, J=8.43Hz, IH). 8.00(t. J=8.43Hz.2H), 7.78(m. IH). 7.62(m, 2H), 7.07(d. J=8.43Hz, IH). 6:87(m, 2H). 6.35(s.2H), 5.59(m. IH), 5.33(s, 2H). 2.85(m. IH). 2.69(m, IH). 2.13(m.2H)

Examplθ N-Hydroxy-N-[4-{(3,4-dihydro-2H-benzopyran)6-yl}3-buten-2-yl ]acetamide 31

STRUCTURE

mp 90-93°C

IR: v (Nujol): 1610, 1590, 1490, 1240, 1170, 1060, 1005, 970, 820 cm ^"1

NMR: δ (CDCI ₃ -DMSO-d ₆ ): 8.95(s, IH), 7.10(d, J=8.4Hz, IH) , 7.05(s, IH), 6.70(d, J=8.4Hz, IH), 6.42 (d, J=15.7Hz, IH), 6.12 (d d, J=6.6, 15.7Hz,lH),

5.29 (m, IH), 4.16 (t. J=5.1Hz. 2H),2.75 (t, J=6.2Hz, 2H), 2.14 (s, 3H), 1.99 (m, 2H),

1.37 (br d. 3H)

-30-

Example N-Hydroxy-N-(5-phenoxyindan-1-yl)acetamide

33

STRUCTURE

mp 111.0 - 111.5 ^# C

IR: v (KBr): -1

3450.3150.2700, 1605.1590. 1485, 1250.780, 695 cm

NMR: δ (DMSO-de): 9.48 (s, 1H), 7.38 (t, J - 8 Hz, 2H), 7.14 (t, J » 8 Hz, 2H),

6.98 (dd, J =.8 and 2 Hz.2H).6.85 (s, 1H), 6.83 (d. J = 8 Hz, 1H), 5.94 (t, J = 7 Hz, 1H), 3.0 - 2.9 (m.1H), 2.85 - 2.7 (m, 1H), 2.3 - 2.05 (m.2H), 2.05 (s.3H)

E 1 ,2,3,4-tetrahydroquinolin-

STRUCTURE:

m. p.

180.7-181.0°C/dec.

IR: v (KBr): ₃₄₅₀₎ 1670, 1610

NMR: δ(DMSO):

9.01 (s, IH), 7.32-7.43 (m, 5H), 7.15 (s, IH), 6.84-6.90 (m, IH),

6.75-6.81 (m, IH), 6.26 (s, 2H), 5.20 (q, J= 7.0 Hz, IH), 3.71 (t, J= 6.2 Hz, 2H),

2.79 (t, J= 6.6 Hz, 2H), 1.86-1.99 (m, 2H), 1.34(d, J= 7.0 Hz, 3H)

c _« -. _m« iβ N-Hydroxy-N-{ l-(l -benzoyl-l,2,3,4-tetrahydroquinolin-

Exampie 7-yl)ethyl } urea

36

STRUCTURE:

m. p.

161.4-161.7°C/dec.

IR: v (KBr): 3500, 1652, 1610

NMR: δ (DMSO):

8.85 (s, IH), 7.26-7.43 (m, 5H), 7.08 (d, J= 8.1 Hz, IH),

6.93 (dd, J= 7.7 Hz, 1.5 Hz, IH), 6.69 (s, IH), 6.16 (s, 2H),

4.94 (q, J= 7.0 Hz, IH), 3.64-3.86 (m, 2H), 2.78 (t, J= 6.6 Hz, 2H), 1.88-2.01 (m, 2H), 0.91 (d, J= 7.0 Hz, 3H)

Exam _D le N-Hydroxy-N-(l-allyl- 1 ,2,3, 4-tetrahydroquinolin-

" 6-yl)methylurea

37

STRUCTURE:

m. p.

114.3-114.6°C/dec.

IR: v (KBr): 3440, 1665, 1640, 1610

NMR: δ (DMSO):

9.14 (s, IH), 6.85 (d, J= 8.4 Hz, IH), 6.81 (s, IH), 6.45 (d, J= 8.4 Hz, IH), 6.21 (s, 2H), 5.73-5.89 (m, IH), 5.08-5.19 (m, 2H), 4.30 (s, 2H), 3.79-3.88 (m, 2H), 3.21 (t, J= 5.7 Hz, 2H), 2.66 (t, J= 6.2 Hz, 2H), 1.80-1.91 (m, 2H)

Example N-Hydroxy-N- { l -(2-phenylethyl)- 1 ,2,3 , 4-tetrahydroquinolin- 41 6-yl} methylurea

STRUCTURE: O A NH, _N 1 J OH

m. p. :

132.4-132.8°C/dec.

IR: v (KBr): 3480, 1641

NMR: δ (DMSO):

9.26(s, IH), 7.14-7.33 (m, 5H), 6.91 (d, J= 8.4 Hz, IH), 6.80 (s, IH), 6.56 (d, J= 8.4 Hz. IH), 6.20 (s, 2H), 4.31 (s, 2H), 3.34-3.45 (m, 2H), 3.14 (t, J= 5.3 Hz, 2H), 2.69-2.80 (m, 2H), 2.60 (t, J= 6.2 Hz, 2H), 1.66-1.83 (m, 2H)

Exa { l -(3 -methoxybenzyl)- 1 ,2,3, 4-tetrahydroquinol in- txammopliee N ₆ _.- _y H _l y} d _m r _e o _t x _h y _y - _l N - _u rea

STRUCTURE:

m. p. 120.7-121.0°C/dec.

IR: v (KBr): 3500, 1640

NMR: δ (DMSO):

9.13 (s, IH), 7.16-7.24 (m, IH), 6.72-6.83 (m, 5H), 6.34 (d, J= 8.4 Hz, IH), 6.17 (s, 2H), 4.40 (s. 2H), 4.27 (s. 2H), 3.68 (s, 3H), 3.17-3.46 ⁺ (2H). 2.68 (t, J= 6.2 Hz. 2H), 1.80-1.95 (m, 2H) ^♦ This peak was hidden by H ₂ 0 in DMSO-dβ

Example N-Hydroxy-N- { l -(3-uifluoromethylbenzyl)-l ,2,3,4 ^H teirahydroquinol in-6-yl } methylurea

STRUCTURE:

m. p. :

133.7-133.8°C/dec.

IR: v (KBr): 3500, 1618

NMR: δ (DMSO):

9.16 (s, IH), 7.50-7.63 (m, 4H), 6.85 (s, IH). 6.80 (d, J= 8.4 Hz, IH), 6.37 (d, J= 8.4 Hz, IH), 6.21 (s, 2H), 4.56 (s, 2H). 4.30 (s. 2H). 3.27-3.46 ⁺ (2H), 2.73 (t, J= 6.2 Hz, 2H). 1.86-1.99 (m, 2H) ^♦ This peak was hidden by H ₂ O in DMSO-dβ

-37-

Example ^N - ^H y ^dro - ^N - U -(3-chlorobenzyl)- 1.2.3, 4-tetrahydroquinolin-

47 6-yl) methylurea

STRUCTURE: A NH,

• 1 /4H ₂ 0

m. p. :

119.7-121.6 ^β C/dec.

IR: v (KBr): 3480. 1638

NMR: δ (DMSO):

9.15 (s. IH). 7.35 (t, J= 7.3 Hz, IH), 7.25-7.32 (m, 2H), 7.20 (d, J= 7.3 Hz, IH). 6.84 (s. IH). 6.81 (d. J= 8.4 Hz, IH), 6.35 (d, J= 8.4 Hz, IH), 6.21 (s, 2H), 4.47 (s. 2H). 4.30 (s, 2H), 3.26-3.45 ^# (2H), 2.72 (t, J= 6.2 Hz, 2H), 1.85-1.93 (m, 2H) ^♦ This peak was hidden by H ₂ 0 in DMSO-d ₆

Example N-Hydroxy-N- { l -(3-fluorobenzyl)- 1 ,2,3.4-tetrahydroquinolin-

49 6-yl ) melhyIurea

STRUCTURE:

m. p. 123.5-123.9°C/dec.

IR: v (KBr): 3420, 1662, 1615

NMR: δ (DMSO):

9.15 (s, IH). 7.32-7.42 (m, IH), 6.99-7.12 (m, 3H). 6.84 (s, IH), 6.80 (d, J= 8.4 Hz, IH), 6.35 (d, J= 8.4 Hz, IH), 6.20 (s, 2H), 4.47 (s, 2H), 4.29 (s, 2H), 3.24-3.53 ⁺ (2H), 2.72 (t, J= 6.2 Hz, 2H). 1.86-1.98 (m. 2H) ^♦ This peak was hidden by H ₂ 0 in DMSO-dβ

Example N-Hydroxy-N- { l-(3-allyloxybenzyl)- 1 ,2, 3,4-tetrahydroquinolin- ₅₂ 6-yl } methylurea

STRUCTURE:

m. p. :

120.8-121.5°C/dec.

IR: v (KBr): 3490, 1630

NMR: δ (DMSO):

9.13 (s, IH), 7.18-7.26 (m, IH), 6.76-6.85 (m, 5H), 6.37 (d, J= 8.1 Hz, IH),

6.20 (s, 2H), 6.01 (ddt, J= 17.2 Hz, 10.2 Hz, 5.1 Hz, IH),

5.36 (dtt, J= 17.2 Hz. 1.8 Hz. 1.8 Hz. IH). 5.23 (dtt, J= 10.2 Hz, 1.8 Hz, 1.8 Hz, IH),

4.52 (ddd, J= 5.1 Hz, 1.5 Hz, 1.5 Hz, 2H), 4.42 (s, 2H), 4.29 (s, 2H),

3.24-3.41*(2H), 2.71 (t, J= 6.4 Hz, 2H), 1.85-1.97 (m, 2H)

^♦ This peak was hidden by H ₂ 0 in DMSO-dβ

Example N-Hydroxy-N- { l-(3-metboxyphenylethyl)- 53 l ,2,3,4-tetrahydroquinolin-6-yl } methyIurea

STRUCTURE:

m. p. 126.0-126.7°C/dec.

IR: v (KBr): 3500, 3450, 3200, 1670, 1640, 1615

NMR: δ (DMSO):

9.13 (s, IH), 7.25 (t, J= 7.7 Hz, IH), 6.77-6.91 (m, 5H), 6.57 (d, J= 9.2 Hz, IH), 6.20 (s, 2H), 5.03 (q, J= 6.5 Hz, IH). 4.30 (s. 2H). 3.77 (s, 3H). 3.25-3.44*(2H), 2.67-2.71 (m, 2H), 1.68-1.91 (m, 2H), 1.48 (d, J= 6.5 Hz, 3H) ^♦ This peak was hidden by H ₂ 0 in DMSO-d _δ

Example N-Hydroxy-N- { 1 -(3 -phenylpropyl)- 1 ,2,3, 4-tetrahydroquinolin- 55 6-yl } methylurea

STRUCTURE:

m. p.

113.1- 113.8°C/dec.

IR: v (KBr): 3500, 1635

NMR: δ (DMSO):

9.13 (s, IH), 7.14-7.33 (m, 5H), 6.83 (dd, J= 8.2 Hz, 1.9 Hz, IH),

6.78 (d, J= 1.9 Hz, IH), 6.39 (d, J= 8.2 Hz, IH), 6.20 (s, 2H), 4.29 (s, 2H),

3.15-3.28 (m, 4H), 2.56-2.69 (m, 4H), 1.71-1.90 (m, 4H)

Example N-Hydroxy-N-(l ,2,3 ,4-tetrahydroquinolin-6-yl)methylurea

57

STRUCTURE:

m. p. : 121.0- 121.6°C/dec.

IR: v (KBr): 3490, 3390, 1640

NMR: δ (DMSO):

9.11 (s, IH), 6.73-6.79 (m, 2H), 6.34 (d, J= 8.8 Hz, IH), 6.19 (s, 2H), 5.51 (s, IH), 4.27 (s, 2H), 3.09-3.18 (m, 2H), 2.62 (t, J= 6.2 Hz, 2H), 1.70-1.82 (m, 2H)

-43-

N-Hydroxy-N- { l-(3-methoxymethylbenzyl)-l , 2, 3, 4-

Example tetrahydroquinolin-6-yl } methylurea

60

STRUCTURE:

m. p. 94.9-95.2°C/dec.

IR: v (KBr): 3420, 1645

NMR: δ (DMSO):

9.13 (s, IH), 7.29 (t, J= 7.5 Hz, IH), 7.12-7.22 (m, 3H), 6.83 (d, J= 1.9 Hz, IH), 6.79 (dd. J= 8.4 Hz. 1.9 Hz. IH), 6.38 (d, J= 8.4 Hz, IH), 6.20 (s, 2H), 4.45 (s, 2H), 4.38 (s, 2H), 4.29 (s, 2H). 3.28-3.39^(2H). 3.27 (s, 3H). 2.71 (t, J=6.4 Hz, 2H), 1.85-1.96 (m, 2H) ^♦ This peak was hidden by H ₂ O in DMSO-dβ

Example N-(l-Phenyl-l ,2,3,4-tetrahydroquinolin-6-yl)methyl- ₆₃ N-hydroxyurea

STRUCTURE:

m. p. :

89-90 °C

IR: v (KBr): 3440, 1646, 1595, 1566, 1498.1490 cm ^"1

NMR:δ(CDCI ₃ ): 7.06-7.38 (m, 5H), 7.04 (br s, IH), 6.91 (dd, IH, J= 8, 2Hz),

6.68 (d. IH, J= 8Hz), 5.92 (br s, IH), 5.20 (br s, 2H), 4.56 (s, 2H) 3.61 (t.2H. J= 6Hz), 2.84 (t, 2H. J= 6Hz), 2.04 (quin.2H. J= 6Hz)

Example N-Hydroxy-N-(3-allyloxy-l -phenyl- 1 ,2,3, 4-tetrahydroquinolin- 65 6-yl)methylurea

STRUCTURE:

m. p.

(amorphous solid)

IR: v (KBr): 3500, 1650

NMR: δ (DMSO):

9.23 (s, IH), 7.34 (t, J= 7.3 Hz, 2H), 7.19 (d, J= 7.3 Hz, 2H),

7.06 (t, J= 7.0 Hz, IH), 6.99 (s, IH), 6.84 (d, J= 8.4 Hz, IH),

6.61 (d, J= 8.4 Hz, IH), 6.26 (s, 2H), 5.84 (ddt, J= 15.4 Hz, 10.3 Hz. 5.1 Hz. IH),

5.19 (dtt, J= 15.4 Hz, 1.5 Hz, 1.5 Hz, IH), 5.08 (d, J= 10.3 Hz, IH), 4.36 (s, 2H),

3.87-4.07 (m, 3H), 3.71 (dd, J= 13 Hz, 4 Hz, IH), 3.52 (dd, J= 13 Hz, 6 Hz, IH),

3.05 (dd, J= 15 Hz, 4 Hz, IH), 2.76 (dd, J= 15 Hz, 6 Hz, IH)

Example N-Hydroxy-N- { l-(3-difluoromethoxybenzyl)-8-fluoro-l , 2, 3,4-tetra- ₇₃ hydroquinolin-6-yl } methylurea

STRUCTURE:

m. p. 109-110°C

IR: v (KBr): _{3495) 1645j 1625) m5} cm .-l

NMR: δ (DMSO): 9.31 ( _s , IH), 7.40 (dd, IH, J=7.9, 7.9Hz), 7.22-7.26 (m, IH), 7.22 (t, IH, J=74.2Hz), 7.17 (br. IH), 7.05-7.09 (m, IH), 6.77-6.85 (m, 2H), 6.33 (s, 2H), 4.38 (s, 2H), 4.28 (s, 2H), 2.98-3.02 (2H), 2.70 (t, 2H, J=6.2Hz), 1.77 (br, 2H)

-51-

Example N-Hydroxy-N- { l -(3-methoxybenzyl)-7-fluoro-l ,2,3,4-tetrahydro- 81 quinolin-6-yl } methylurea

STRUCTURE: O

A NH, OH

^m - P- ^: 150-151°C

IR:v (KBr): 3490, 3200, 1645, 1520, 1280 cm ^"1

NMR: δ(DMSO):

9.20 (s, IH), 7.21-7.27 (m, IH), 6.88 (d, IH, J=8.8Hz), 6.79-6.81 (m, 3H), 6.26 (s, 2H), 6.15 (d, IH, J=13.6Hz), 4.44 (s, 2H), 4.35 (s, 2H), 3.72 (s, 3H), 3.29-3.37 (2H), 2.65-2.69 (m, 2H), 1.87-1.92 (m, 2H).

Example N-Hy droxy-N- { l -(thiophen-2-yl)methy 1- 1.2.3, 4-tetrahydro- ₈ 4 quinolin-6-yl ) methylurea

STRUCTURE:

m. p. : 135-136°C (dec.)

IR: v (KBr): 3470, 1625, 1515 cm ^'1

NMR: δ (DMSO): _{9Λ6 S) 1H} ), 7.35 (dd, IH. J=4.8. 1.5Hz). 7.01 (br, IH), 6.96 (dd, IH. J=4.8, 3.7Hz), 6.82-6.87 (m, 2H). 6.64. (d, IH, J=8.4Hz), 6.21 (s. 2H), 4.62 (s. 2H), 4.30 (s. 2H). 3.28-3.32 (2H), 2.66 (t, 2H, J=6.7Hz), 1.85-1.90 (br, 2H).

Example N-Hydroxy-N-(7-phenoxyindan-1 -yl)urea

89

STRUCTURE:

mp 157.6 - 158.8 ^β C

IR: v (KBr): 3500.3350, 3190, 1645, 1585, 1465. 1250.765, 695 cm -1

NMR: δ (DMSO-d ₆ ): 8.87 (s.1H), 7.35 (dt, J = 8 and 2 Hz, 2H).7.17 (t, J = 8 Hz, 1H), 7.1 (t, J = 8 Hz, 1H).7.01 (dd, J = 8 and 2 Hz, 2H).6.98 (t, J = 7 Hz, 1H), 6.53 (d, J = 8 Hz.1H), 6.14 (s, 2H), 5.82 (dd, J = 8 and 2 Hz, 1H), 3.1 - 2.95 (m, 1H), 2.85 - 2.7 (m, 1H), 2.3 - 2.15 (m, 1H), 2.08 - 1.96 (m, 1H)

Example N-Hydroxy-N-[4-{(3,4-dihydro-2H-benzopyran)6-yl)3-buten-2-yl ] 91 urea

STRUCTURE:

m. p. : 138-140°C

IR:v (nujol) 3440, 1640, 1250, 1060, 970.815 cm -1

NMR: δ

(DMSO-d ₆ ); 9.67 (s, IH).7.76 (m.2H), 7.34 (d, J=8.8Hz, IH).7.02 (d, J=15.1Hz, IH), 6.99 (s.2H).6.78 (d d. J=6.6Hz, IH), 5.45 (m. IH), 4.79 (t. J=6.2Hz.2H), 3.40 (t. J=6.2Hz, 2H), 2.57 ( , 2H), 1.88 (d. J=7.0Hz.3H)

Example N-Hydroxy-N- {5-(3-methoxyphenoxy)indan- l-yl } urea 92

STRUCTURE:

m. p. : 143.1-144.6°C

IR: v (KBr): 3450, 3300, 3200, 2900, 1660, 1580, 1360, 1340, 1250, 870 cm ^{" 1}

NMR: δ (DMSO-de):

8.97(s, IH), 7.26(t, J=8.43Hz, IH), 7.14(d, J=8.43Hz, IH), 6.83(br.s, IH), 6.82(d, J=6.60Hz, IH), 6.68(d, 9.16Hz. IH) 6.52(m, 2H), 6.40(br.s, 2H), 5.64(t, J=7.33Hz, IH), 3.73(s, 3H), 2.87(m, IH), 2.74(m, IH), 2.16(m, 2H)

Example N-Hydroxy-N- { 5-(3-fluorophenoxy)indan-l-yl } urea

93

STRUCTURE:

m. p. : 150.2- 153.2°C

IR: v (KBr): 3450, 3000-3400, 1680, 1610, 1580, 1480, 1260, 1140, 960 cm ^{" 1}

NMR: δ (DMSO-d ₆ ):

8.99(s, IH), 7.39(m, IH), 7.18(d, J=8.06Hz, IH), 6.87(m, 5H), 6.41(br.s, 2H), 5.65(t, J=7.33Hz, IH), 2.87(m, IH), 2.74(m. IH), 2.17(m, 2H)

Example N-Hydroxy-N- (5 -(4-phenylphenoxy)indan- l-yl} urea

94

STRUCTURE:

m. p. : 167.9- 169.2°C

IR: v (KBr): 3500, 3300, 2900, 1630, 1550, 1490, 1250, 1010, 980, 690 cm ^{* 1}

NMR: δ (DMSO-d ₆ ):

9.00(s, IH), 7.65(m, 4H), 7.45(m, 2H), 7.34(m, IH).

7.18(d, J=8.42Hz, IH), 7.05(m, 2H), 6.87(m, 2H), 6.42(br.s, 2H),

5.66(t, J=7.36Hz. IH), 2.91(m, IH), 2.76(m,lH), 2.17(m, 2H)

Example N-Hydroxy-N- { 5- (3 , 4-dimethylenedioxyphenoxy)ind an- l -yl ) urea

95

STRUCTURE:

m. p. : 173.2-174.0°C

-1

IR: v (KBr): 3450, 3200, 2900. 1650, 1570, 1480, 1240, 1040, 920 cm

NMR:δ(DMSO-d ₆ ):

8.95(s, IH), 7.1l(m, IH), 6.89(d, J=8.42Hz, IH), 6.76(m.2H). 6.68(d, J=2.56Hz, IH), 6.45(dd, J=2.20, 8.06Hz, IH), 6.38(br.s, 2H), 6.03(br.s, 2H), 5.62(t, J=6.96Hz, IH), 2.87(m, IH), 2.72(m, IH), 2.13(m, 2H)

Example N-Hydroxy-N-{5-(4-fiuorophenoxy)indan- l-yl }urea 96

STRUCTURE:

m. p. : 175.2-176.6°C

- 1

IR: v (KBr): 3460, 3250, 2950, 1650, 1580, 1500, 1430, 1320, 1200 cm

NMR: δ (DMSO-de):

8.97(s, IH), 7.18(m, 3H), 7.02(m, 2H). 6.79(m, 2H), 6.39(br.s, 2H). 5.63(t, J=7.32Hz. IH). 2.87(m. IH), 2.72(m, IH), 2.15(m, 2H)

Example N-Hydroxy-N- {5-(3-fluoro-4-methoxyphenoxy)indan- l-yl } urea

97

STRUCTURE:

m. p. : 166.3- 167.5°C

IR:v (KBr): 3200-3500, 2950, 1660, 1510, 1490, 1440, 1260, 1150, 970 cm ^*1

NMR: δ (DMSO-de):

8.97(s, IH), 7.14(m, 2H), 6.97(dd, J=2.57, 12.09Hz, IH), 6.79(m, 3H), 6.39(br.s, 2H), 5.62(t, J=7.33Hz, IH), 3.81(s, 3H), 2.86(m, IH), 2.73(m, IH), 2.14(m, 2H)

Example N-Hy droxy-N- {5-(3-trifluoromethylphenoxy)indan- l-yl ) urea

98

STRUCTURE:

m. p. : 164.0-165.1°C

IR: v (KBr): 3450, 3300, 2900, 1650, 1630, 1320, 800 cm - l

NMR: δ (DMSO-de):

9.00 (s, IH), 7.60(1. J=7.70Hz, IH), 7.46(d, J=7.70Hz, IH ), 7.23(m, 3H), 6.90(m, 2H), 6.42(s, 2H), 5.66(t, J=7.33Hz, IH), 2.89(m, IH,), 2.76(m, IH). 2.18(m. 2H)

Example N-Hydroxy-N- {5-(3-methylphenoxy)indan- l-yl } urea

99

STRUCTURE:

m. p. : 163.9-165.4°C

IR: v (KBr): 3450, 3000-3400, 2850, 1660. 1570. 1480, 1260, 1150, 950 cm ^'1

NMR: δ (DMSO-de):

8.97(s. IH), 7.24(t. J=7.70Hz, IH), 7.14(d, J=8.79Hz, IH), 6.93(d, J=7.32Hz, IH), 6.78(m, 4H), 6.40(br.s, 2H), 5.64(t, J=8.06Hz, IH ), 2.88(m, IH), 2.73(m, IH), 2.28(s, 3H); 2.14(m, 2H)

Example N-Hydroxy-N- {5-(4-methoxyphenoxy)indan- l-yl } urea 100

STRUCTURE:

^m - P- ^: 159.0-160.2°C

IR: v (KBr): 3450, 3300, 2800-3000, 1670, 1650, 1580, 1500, 1240, 1030, 920, 910 cm ^"1

NMR: δ (DMSO-de):

8.94(s, IH). 7.10(d, J=7.70Hz. IH), 6.95(m, 4H), 6.71(m, 2H). 6.38(br.s, 2H), 5.61(t, J=6.96Hz. IH). 3.74(s, 3H), 2.86(m. IH), 2.71(m, IH), 2.13(m, 2H)

Example N-Hydroxy-N- {5-(3-Ωuoro-4-methylphenoxy)indan- l-yl} urea 101

STRUCTURE:

m. p. : 156.1 -157.5°C

IR: v (KBr): 3450, 3200, 2950, 1660, 1580, 1450, 1280, 1150, 1100, 960, 910 cm ^"1

NMR: δ (DMSO-de):

8.97(s, IH), 7.26(t, J=8.79Hz, IH), 7.15(d. J=8.79Hz, IH), 6.77(m, 4H), 6.40(br.s, 2H), 5.64(t, J=6.96Hz, IH), 2.87(m, IH), 2.74(m, IH), 2.16(m, 2H)

Example N-Hydroxy-N- {5-(3,4-difluorophenoxy)indan- l-yl) urea

102

STRUCTURE:

m. p. : 167.9-169.1°C

IR: v (KBr): 3450, 3250, 1660, 1520, 1490, 1420, 1250, 1150, 960, 940 cm ^{' l}

NMR: δ (DMSO-de):

8.99(s, IH), 7.43(m, IH). 7.14(m, 2H). 6.83(m, 3H). 6.41(br.s, 2H). 5.64(t, 7.33Hz, IH), 2.88(m. IH), 2.75(m, IH), 2.16(m, 2H),

Example N-Hydroxy-N- {5-(5-trifluoromethyl-2-pyridyIoxy)indan- l-yl } urea 104

STRUCTURE:

m. p- : 155.0- 156.3°C

IR:v(KBr): 3450, 3200, 2900, 1670, 1610, 1580, 1490. 1420. 1390, 1130, 1080, 940 cm ^*1

NMR: δ (DMSO-de):

9.05(s, IH), 8.55(m, IH), 8.20(dd, J=2.56, 8.06Hz, IH),

7.20(d, J=8.43Hz, 2H), 6.98(m, 2H). 6.43(br.s, 2H),

5.67(t, J=7.33Hz, IH), 2.90(m, IH), 2.76(m, IH), 2.14(m, 2H)

Example N-Hy droxy-N-{5-(3-chloro-2-pyridyloxy)indan- l -yl } urea

105

STRUCTURE:

m. p. : 169.3-170.4°C

IR:v (KBr):3450. 3350, 2900, 1630, 1580, 1420. 1250, 1130, 1040, 940 cm ^"1

NMR: δ (DMSO-de):

9.50(s, IH), 8.05(m, 2H), 7.16(m, 2H), 6.94(m, 2H), 6.42(br.s, 2H). 5.67(t, J=7.32Hz, IH), 2.89(m. IH), 2.77(m, IH), 2.17(m, 2H)

Example N-Hydroxy-N-{5-(4-chlorophenoxy)indan-1 -yl)urea

106

STRUCTURE:

m. p. 178.2-179.0 C

IR:v(KBr): 3470, 3270, 1660, 1580, 1485, 1420, 1250 cm ^"1 ,

NMR: δ (DMSO-de):

8.98 (S. 1H), 7.37-7.45 (m, 2H), 7.17 (d, J=7.7Hz, 1H), 7.03-6.95 (m, 2H), 6.88-6.82 (m, 2H), 6.41 (s, 2H), 5.65 (t, J=7.5Hz, 1H). 2.96-2.85 (m, 1H), 2.80-2.66 (m, 1H), 2.24-2.07 (m, 2H).

Example N-Hydroxy-N-{5-(2-pyridyloxy)indan-1 -yljurea

107

STRUCTURE:

m. p. 161.6-162.8 C

-1

IR: v (KBr): 3490, 3200, 1665, 1470. 1430 cm .

NMR: δ (DMSO-de):

8.17 (s, 1H), 7.30-7.25 (m, 1H), 7.01-6.92 (m, 1H), 6.33-6.20 (m, 2H), 6.16-5.99 (m, 3H), 5.56 (s, 2H), 4.81 (t, J=7.5Hz, 1H), 2.15-2.01 (m, 1H), 1.96-1.83 (m, 1H), 1.44-1.20 (m, 2H).

Example N-Hydroxy-N-{5-(3-phenylpropyloxy)indan-1 -yl}urea

109

STRUCTURE:

m. p. : 1 60.5-162.0 C

IR:v (Nujol): 3460, 3200, 1670, 1244, 1039 cm ^*1 .

NMR: δ(DMSO-d ₆ ):

8.90 (s, 1H), 7.32-7.15 (m, 5H), 7.04 (d, J=8.0Hz, 1H), 6.75-6.70 (m, 2H), 6.35 (s, 2H), 5.59 (t, J=7.5Hz, 1H), 3.92 (t, J=6.5Hz, 2H), 2.89-2.83 (m, 1H), 2.76-2.67 (m, 3H), 2.21-1.94 (m, 4H).

Example N-Hydroxy-N- {5-(2-thiazoIyloxy)indan- l -yl } urea

110

STRUCTURE:

m. p. : 138.1 - 139.9°C

IR: v (KBr): 3450. 3000-3400, 2950, 1670, 1570, 1440. 1240, 1160, 940 cm ^*1

NMR: δ (DMSO-de):

9.40(s, IH), 7.27(d. J=3.66Hz, IH), 7.15(m.4H), 6.44(br.s, 2H), 5.67(t. J=7.69Hz.- IH ). 2.91(m. IH). 2.79(m, IH), 2.18(m, 2H).

Example N-H droxy-N- { 5-(4-tetrahydropyranyloxy)indan- l-yl } urea

111

STRUCTURE:

m. p. : 152.4- 153.9°C

IR: v (KBr): 3450, 3200. 2950, 2850, 1670, 1580, 1490, 1450, 1240, 1 140, 1150, 1090, 1070. 990, 860, 810 cm ^{" 1}

NMR: δ (DMSO-de):

8.89(s, IH), 7.39(d, J=8.06Hz, IH), 6.80(br.s, IH),

6.74(d, J=8.43Hz, IH), 6.35(br.s, 2H), 5.58(t, J=6.96Hz, IH),

4.50(m, IH), 3.83(m, 2H), 3.43(m. 2H),

2.87(m, IH), 2.70(m, IH), 2.1 l(m, 2H), 1.94(m, 2H),

1.55(m, 2H)

Example N-Hydroxy-N- { 5-(3,4-dimethoxyphenoxy)indan- l -yl } urea 113

STRUCTURE:

mp: 148.1-149.3°C

IR (KBr) cm : 3450, 3200, 2850, 1670, 1580, 1520, 1470, 1450, 1230, 1150, 1110, 1020, 960

NMR (DMSO-de) δ: 8.94(s, IH), 7.11(d, J=8.06Hz. IH), 6.93(d, J=8.79Hz, IH) 6.74(m, 3H), 6.94(dd, J=2.92, 8.79Hz, IH), 6.38(br.s, 2H), 5.62(t, J=6.96Hz, IH),

3.73(s, 3H), 3.72(s, 3H), 2.84(m, IH), 2.71(m, IH), 2.14(m, 2H)