HU218963B - Retinoid-like compounds and pharmaceutical compns. contg. them - Google Patents

Abstract

The present invention relates to compounds of formula (I) or non-toxic pharmaceutically acceptable salts, physiologically hydrolysable esters or solvates thereof, wherein X-O-CO-, -NH-CO-, -CS-CO-, -CS-NH -, –CO – O–, –CO – NH–, –COS–, –SCO–, - SCH2–, –CH2– CH2–, –C? C–, –CH2 – NH–, –COCH2–, –NHCS -, -CH2S-, -CH2O-, -OCH2-, -NHCH2- or - CR5 = CR6-; R and Rk are hydrogen, halogen, alkyl, hydroxy, alkoxy or nitro; n is 0 or 1; R4 is (CH2) t-Y, alkyl or cycloalkyl; R1 is -COOZ or -CONHRy, alkyl, hydroxymethyl or formyl; R2 and R3 are hydrogen or alkyl; Ra and Rb are hydrogen or alkyl; but when n is 1, Ra and Rb together form a group of formula; Y is optionally substituted naphthyl or phenyl; Hydrogen or alkyl; R5, R6 and Ry are hydrogen or alkyl; and t is 0, 1, 2, 3, 4, 5, or 6. The invention also encompasses pharmaceutical compositions comprising a compound of formula (I) in admixture with one or more pharmaceutically acceptable carriers. ŕ

Description

The present invention also provides pharmaceutical compositions comprising a compound of formula (I) in admixture with one or more pharmaceutically acceptable carriers.

HU 218 963 B

The length of the description is 84 pages (including 4 pages)

EN 218 963 Β arotenoid and retino-benzoic acid derivatives of general formula (III),

The present invention relates to compounds having activity similar to that of retinoids. In particular, the compounds of the present invention are useful in the prevention and / or treatment of various skin disorders, such as acne, psoriasis and radiation damage. In addition, the compounds have anti-tumor and anti-gout activity.

Retinoic acid,

RETIC ACID and its natural and synthetic analogues (retinoids) have a variety of biological activities. They have an effect on cell growth and cell differentiation and are also used in the treatment of many cancers [Robert, A. B. and Spom, om. B., The Retinoids, Spom, Μ. B., Roberts, A. B., and Goodman, D. S., eds., 2, 209-286 (1984), Academic Press, New York; Lippman, S.M., Kessler, J.F., and Myskens, F.L., Cancer Treat. Rep., 71, 391 (1987); Lippman, S.M., Kessler, J.F., and Myskens, F.L., Cancer Treat. Rep., 71, 493 (1987); Hong, W. K. et al., N. Engl. J. Med., 323, 795 (1990); Huang, M. et al., Blood, 72, 567 (1988)]. Retinoids can also be used in the treatment of rheumatic diseases. See, e.g., J. W. Coffey et al., Retinoids as Potential Antirheumatic Agents, Chemistry and Biology of Synthetic Retinoids, 520-537, CRC Press Inc., Μ. I. Dawson and W. H. Okamura Ed. (1990)].

Some retinoids have already been used clinically in the treatment of dermatological diseases such as acne and psoriasis. For example, isotretinoin

ISOTRETINOIN is clinically used to treat severe acne orally while etretinate

ETRETINATE is particularly useful in the treatment of psoriasis (Orfanos, C.E., Ehlert, R., and Gollnick, H. Drugs, 34, 459-503 (1987)).

Other examples of retinoid compounds include Formula II

wherein Q is -NHCO-, -CONH-, -COCH = CH-, -CH = CHCO-, -COCH ₂ - and the like. (See, e.g., Loeliger, P., Bollag, W., and Mayer, H., Eur. J. Med. Chem., 15, 9-15 (1980); Kagechika, H. et al. (1988) J. Med. Chem. 31 (11): 2182-2192.

The present invention relates to a compound of formula (I)

or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, wherein X is -O-CO-, -NH-CO-, -CS-CO-,

-CS-NH-, -CO-O-, -CO-NH-, -COS-, -SCO-, -SCH ₂ -, -CH ₂ -CH ₂ -, -C = C-, -CH ₂ -NH -, -COCH ₂ -, -NHCS-, -CH ₂ S-, -CH ₂ O-, -OCH ₂ -, -NHCH ₂ - or -CR ⁵ = CR ⁶ -;

R ^m and R ^k are each independently hydrogen, halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, or nitro;

n is 0 or 1;

R ⁴ is - (CH ₂ ) -, -Y, -C 1-6 alkyl, or C 3-6 cycloalkyl;

R ¹ is -COOZ, C 1-6 -alkyl, hydroxymethyl, -CONHRy or formyl;

R ² and R ³ are each independently hydrogen or C 1-6 alkyl;

R ^a and R ^b are each independently hydrogen or C 1-6 alkyl; but if n is 1, R ^a and R ^b together are one

forms a group of the formula;

Y is naphthyl or phenyl, each of which may be 1-3, the same or different

It may be substituted by a different C 1 -C 6 alkyl group and / or halogen atom;

Z is hydrogen or C 1-6 alkyl;

^{R5, R6} and Ry are independently hydrogen or C1-6 alkyl; and t is 0, 1, 2, 3, 4, 5 or 6.

The invention also encompasses methods for the prevention and / or treatment of tumors, arthritis and non-malignant skin disorders comprising administering to a mammal a compound of formula (I). The present invention also provides pharmaceutical compositions comprising a compound of formula (I) in admixture with one or more pharmaceutically acceptable carriers.

Figures 1, 2 and 3 show dose-response curves for the L2987 lung line.

Figure 4 shows a dose-response curve for collagen-induced arthritis.

The present invention relates to a compound of formula (I)

or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, wherein X is -O-CO-, -NH-CO-, -CS-CO-,

-CS-NH-, -CO-O-, -CO-NH-, -COS-, -SCO-, -SCH ₂ -, -CH ₂ -CH ₂ -, -C = C-, -CH ₂ -NH -, -COCH ₂ -, -NHCS-, -CH ₂ S-, -CH ₂ O-, -OCH ₂ -, -NHCH ₂ - or -CR ⁵ = CR ⁶ -;

R ^m and R ^k are each independently hydrogen, halogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, or nitro;

n is 0 or 1;

R ⁴ is - (CH ₂ ) -, -Y, -C 1-6 alkyl, or C 3-6 cycloalkyl;

R ¹ is -COOZ, C 1-6 -alkyl, hydroxymethyl, -CONHRy or formyl;

R ² and R ³ are each independently hydrogen or C 1-6 alkyl;

R ^a and R ^b are each independently hydrogen or C 1-6 alkyl; but if n is 1, Ra and R ^b together are one

forms a group of the formula;

Y is naphthyl or phenyl, each of which may be optionally substituted with 1 to 3, identical or different C 1 -C 6 alkyl and / or halogen atoms;

Z is hydrogen or C 1-6 alkyl;

R ^s, R ⁶ and R y are independently hydrogen or C1-6 alkyl; and t is 0, 1, 2, 3, 4, 5 or 6.

As used herein, the term "C 1-6 alkyl" refers to a straight or branched alkyl group containing up to 6 carbon atoms. Examples of such groups are methyl, ethyl, η-propyl, isopropyl, η-butyl, tert-butyl, n-pentyl, η-hexyl, 3-methylpentyl and the like. The term "C3-C6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. "Halogen" means fluorine, chlorine, bromine or iodine. Once defined in this specification, the symbols have the same meaning as long as no other definition is given to the symbol.

Some of the compounds of formula (I) may also be in the form of pharmaceutically acceptable metal or amine salts in which the cation does not substantially affect the toxicity or biological activity of the salt. These salts are also part of the invention. Suitable metal salts include sodium, potassium, calcium, barium, zinc and aluminum. Sodium and potassium salts are preferred. Examples of amines for forming stable salts include trialkylamines such as triethylamine, procaine, dibenzylamine, A-benzyl-p-phenethylamine, 1-ephenamine, N, N'-dibenzyl. ethylenediamine, dehydroabiethylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, and other pharmaceutically acceptable amines.

Where the compounds of formula (I) contain a carboxy group, the carboxy group may form physiologically hydrolyzable esters which may be used per se to hydrolyze the body as prodrugs to yield compounds of formula (I). Such derivatives are preferably administered orally, given that hydrolysis is in most cases effected by digestive enzymes. The ester may also be administered parenterally when the derivative is active on its own or when hydrolysis occurs in the blood. Physiologically hydrolyzable esters of the compounds of formula I include, for example, C 1-6 alkyl, benzyl, 4-methoxybenzyl, indanyl, phthalidyl, methoxymethyl, (1-6). C 1 -C 6 alkanoyloxy-C 1 -C 6 alkyl, such as acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C 1 -C 6 alkoxy-carbonyloxy- (C 1 -C 6) -alkyl; C1 -C4 alkyl) such as methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxol, -dioxolen-4-yl) methyl ester and other well known physiologically hydrolysable esters such as those used in the field of penicillins and cephalosporins. These esters may be prepared by methods well known in the art.

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The formulas and general formulas set forth herein are designed to best represent the structure of the compounds of the invention. However, certain tautomeric forms may exist in certain compounds of the invention in which certain hydrogen atoms may be displaced to another part of the molecule and consequently the chemical bonds of the molecules may be rearranged. Obviously, where tautomeric forms are possible, the formulas and the general formulas include all such forms.

The preparation of compounds of formula (I) may be carried out using conventional starting materials and methods. It is to be understood that the synthesis methods described below, as well as the specific preparation examples, are intended only to illustrate the invention and are not intended to limit its scope or scope. The compounds of the present invention may be prepared by other methods than those described herein.

Typically, a compound of formula (I) is synthesized in I to XXII. The reaction scheme may be prepared using one of the methods shown in Scheme I or one of the various variants of the methods described. I-XXII. Each step of the Schemes represents standard procedures that can be readily accomplished by one of ordinary skill in the art. The specific preparation conditions described below the Schemes also include the specific reaction conditions used in carrying out the steps of the Schemes; It is to be understood that the parameters given are illustrative only and are not intended to limit the scope or scope of the invention in any way.

The R ⁷ group in the Schemes represents a common carboxy protecting group. Preferably R ⁷ is C 1-6 alkyl or phenyl.

More preferably, R ⁷ is phenyl, methyl, ethyl or tert-butyl. Where ^R7 / tert-butyl group, the protecting group is removed by trifluoroacetic acid.

AIV. In step (a) of Scheme (a), a compound of formula (XVIII) is reacted with at least two equivalents of a compound of formula R ⁵ Li wherein R ⁵ is as defined above, preferably C 1-6 alkyl. [If a (XIX) the compound of formula is needed, in which R ⁵ represents a hydrogen atom, preferably a reducing agent that converts a carboxy group on the compound of formula (XVIII) into a formyl group. Reducing agents of this type are well known in the art.] Subsequently, the compound of formula XIX is subjected to a standard Homer-Wadsworth-Emmons reaction [see Org. React., 25, 73-253 (1977); Stec, Acc. It is reacted with [(diethoxyphosphoryl) methyl] benzene derivative anion, to give a compound (I ⁵⁾ of formula - Chem. Res, 411-417 (1983)] (XX) of the formula p.. Subsequent hydrolysis yields a compound of formula (I ⁶⁾ of formula. Compounds of formula I according to the invention (T ⁶⁾ may be prepared according to the procedures described IVa. Scheme alternatively. In Scheme V, R ⁸ is a (phenolic hydroxy) protecting group such as tert-butyldimethylsilyl which can be removed with tetrabutylammonium fluoride (TBAF).

AIII., IV., VI., VII., XI., XII. and XIII. The starting compounds of formula (XVIII) used in Scheme III can be prepared using conventional starting materials using conventional techniques. The synthesis of some of the compounds of formula (XVIII) is described in XIX-XXII. are shown in the following Schemes.

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I. REACTION SCHEME

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R ⁴ MgBr | (a)

pTsOH j (b)

hydrolysis)

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III. SCHEME

COOH

1) soci ₂

(the)

COOR ⁷

Hydrolysis (b)

CI ⁴ )

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Hydrolysis (c)

COOH

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Pd (OAc) ₂ , nBu ₄ NCl

(XL)

(XLI)

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V. REACTION SCHEME

CF.

OR (b)

R ^ ^ SnBu

Ph ^ As

Pd2dba3

(XXIII)

COOR

Hydrolysis jjd)

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VI. SCHEME

COOH

1) SOC1 ₂ or ClCOCOCl

R ^b / \ r2 r3

COOH

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VII. SCHEME

R <

1) ClCOCOCl

COOH

2) HS

COOH

COOH

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KOH

(XLIII)

(XLIVj (XLVI)

R ⁴ MgBr

(XLV) (XLVII)

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VIII. REACTION SCHEME (cont'd)

1) p-TsOH

2) Hydrolysis

1) p-TsOH

2) Hydrolysis

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IX. REACTION SCHEME

(XLVIII) (XII)

HC == C-Si-

Pd (OAc) ₂ ,

PPh3 cs = c-si—

(L)

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IX. REACTION SCHEME (cont'd)

R ⁴ MgBr

Ψ

COOR ⁷ p-TsOH

Ψ

COOR ⁷

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1) p ₂ s ₅

2) Hydrolysis Ψ

(I ¹ )

1) p ₂ s ₅

2) Hydrolysis

COOH

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XI. SCHEME

(XVIII) ^C00H «ΙΪ j

1) cicococi ^ = 1 ==== ^ 1 ^

2) H ₃ CO-NHHCl R ² R ³

OCH-

(I ²⁰ )

hydrolysis

(I ² Í)

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XII. SCHEME

(LVI)

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XIII. SCHEME

CBr ₄ / PPh ₃ l

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XIII. REACTION DRAFT (continued)

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XIV. REACTION SCHEME

OH

COOCHg

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XV. SCHEME

(VI) ο

II

(LXI)

R SnBug

PhgAs

Pdgdbag

Ψ

R ⁴

(LXII)

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XV. REACTION DRAFT (continued)

R ⁴

53Κ

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1. NaOH

2. (COC1) ₂

3. 4-NH ₂ -Ph-COOR ⁷ pyridine

4. Hydrolysis

Ψ

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XVI. REACTION SCHEME (cont'd)

COOH

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XVII. SCHEME

2. R ₄ SnBu ₃

Pdgdba ^, Ph ^ As

(LXX)

FeCl ₃ / Fe

Ψ

R ⁴

nh ₂ (LXXI)

1. p-ClOCPhCOOR ⁷ pyridine _v 2. Hydrolysis

COOH

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XVIII. SCHEME

Pd (0Ac) 2

Bu ₄ NC1

NaHCO> 3

(I ³³ )

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XIX. SCHEME

oso ₂ cf ₃

p-TsOH

hydrolysis

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XX. SCHEME

COOR ⁷

1. TMSC1, DBU ^

2. Pd (OAc) 2

(XXX)

(XXXI)

COOR ⁷

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(XXXVI)

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XXII. SCHEME

(XXX)

1. R ⁴ MgBr ->

2. p-TsOH

al (

Hydrolysis ->

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The following Specific Preparation Examples are intended to illustrate the synthesis of representative compounds of the invention and are not intended to limit the scope or scope of the invention. The disclosed methods may be modified in order to obtain compounds within the scope of the invention but not specifically described. Slightly different variations of the process for preparing the same compounds will be apparent to those skilled in the art.

Unless otherwise noted, all temperatures are given in degrees Celsius (° C). Nuclear Magnetic Resonance Spectrum (NMR) data represent the chemical shift (δ) in ppm (paris per million) per tetramethylsilane (TMS) internal standard. The relative area values (integrals) for the different chemical shifts of the H-NMR spectra are proportional to the number of hydrogen atoms in a single functional group in the molecule. To denote the multiplicity of signals with a given chemical shift, the following abbreviations are used: broad singlet = bs; broad doublet = bd; broad triplet = bt; broad quartet = bq; s = singlet; m = multiplet; d = doublet; q = quartet; t = triplet; doublet doublet = dd; triplet doublet = dt; quartet doublet = dq. The NMR spectra were obtained using the following solvents: DMSO-c ^: (DMSO-), _D2 O (deuterated water); CDC1 ₃ (deuterochloroform) and other conventional deuterated solvents. In the infrared spectra (IR), only the absorption wavelengths (cm ^-1 ) suitable for identifying the functional groups are given.

Celite is a registered trademark of Johns-Manville Products Corporation diatomaceous earth product.

Abbreviations commonly used in the art are used herein, for example:

MS = mass spectrometry HRMS = high resolution mass spectrometry DCI = desorption (or direct) chemical ionization Hex = hexane (s) tBu = tert-butyl group h = hour min = min

Ph = phenyl

THF = tetrahydrofuran

Tf ₂ O = trifluoromethanesulfonic anhydride SEMC1 = 2- (trimethylsilyl) ethoxymethyl chloride

Example 1

5,5-Dimethyl-dihydrofuran-2-one (IV)

To a solution of 50.0 g (0.345 mol) of ethyl levulinate in 200 ml of anhydrous diethyl ether and 200 ml of anhydrous benzene was added dropwise over 30 minutes at 0 ° C 121.0 ml (0.365 mol) of 3.0 M methyl ether in diethyl ether. -magnesium bromide. The diethyl ether was removed by slow distillation and the resulting benzene solution was refluxed for 2 hours. To the mixture was added 500 ml of 20% aqueous phosphoric acid and 500 ml of ethyl acetate at 0 ° C. The organic layer was then separated, washed once with 300 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residual oil was purified by distillation (boiling point: 43 DEG C., 0.35 mm Hg). This gave 26.0 g (66%) of the title 2-furanone.

1 H-NMR (CDCl ₃ ): δ 2.62 (t, J = 8.5 Hz, 2H), 2.05 (t, J = 8.5 Hz, 2H), 1.42 (s, 6H).

Example 2

4.4- Dimethyl-1-tetralone (V)

To a solution of 59.36 g (0.446 mmol) of anhydrous aluminum chloride in 94.0 ml of anhydrous benzene was added 17.0 g (0.149 mmol) of 5,5-dimethyl-dihydrofuran-2-one at 45 ° C over 45 minutes. The reaction mixture was then slowly heated to 90-100 ° C. After 3 hours, the reaction was quenched by the addition of ice water, 1M hydrochloric acid and ethyl acetate at 0 ° C. The organic phase was separated and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (3:97, v / v). The yield of 4,4-dimethyl-1-tetralone was 18.70 g (72%).

1 H-NMR (CDCl ₃ ): δ 8.01 (m, 1H), 7.50 (m, 1H),

7.41 (m, 1H), 7.28 (m, 1H), 2.72 (t, J = 7.0 Hz, 2H), 2.02 (t, J = 7.0 Hz, 2H), 1.39 (s, 6H).

MS (DCI) m / e: 174 (MH +).

Elemental Analysis for: C ₁₂ H ₁₄ O Calculated: C, 81.77; H, 9.14;

Found: C, 81.70; H, 9.12.

Example 3

4.4- Dimethyl-7-nitro-1-tetralone (VI)

The title compound was prepared according to Heck and Winstein, J. Org. Chem., 37 (6), 825 (1972)].

1 H-NMR (CDCl ₃ ): δ 8.84 (d, J = 2.5 Hz, 1H), 8.36 (dd, J = 7.0 Hz, J = 2.5 Hz, 1H), δ, 62 (d, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 3H), 2.08 (t, J = 7.0 Hz, 3H),

1.45 (s, 6H).

MS (DCI) m / e: 220 (MH +).

Example 4

7-Amino-4,4-dimethyl-1-tetralone (VII)

The title compound was prepared according to Heck and Winstein, J. Org. Chem., 37 (6), 825 (1972)].

1 H-NMR (CDCl ₃ ): δ 7.28 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 8) , 5 Hz, J = 2.5 Hz, 1H), 3.73 (bs, 2H), 2.70 (t, J = 7.0 Hz, 2H), 1.97 (t, J = 7.0) Hz, 2H), 1.37 (s, 6H).

MS (DCI) m / e: 190 (MH +).

Example 5

Methyl 4 - {[(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthyl) amino] carbonyl} benzoate (IXa)

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A solution of monomethyl terephthalate (Villa) (2.86 g, 15.89 mmol) in sulfonyl chloride (50 mL) containing 2 drops of N-dimethylformamide was stirred at room temperature. The mixture became homogeneous within 30 minutes. The reaction mixture was then concentrated. The residue was dissolved in 30 ml of anhydrous pyridine and 3.00 g (15.9 mmol) of 7-amino-4,4-dimethyl-1-tetralone was added. The reaction mixture was stirred at room temperature for 16 hours and then 1M hydrochloric acid was added. The resulting mixture was extracted with ethyl acetate and washed with 1M hydrochloric acid (4 x 200 mL) and saturated aqueous sodium bicarbonate (2 x 200 mL). The organic phase was then separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. This gave the title compound (5.07 g, 91%).

1 H-NMR (CDCl 3): δ 8.27 (dd, J = 8.7 Hz, J = 2.5 Hz, 1H), 8.19 (bs, 1H), 8.14 (d, J = 8 , 4 Hz, 2H),

7.95 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 2.5 Hz, 1H),

7.46 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H), 2.70 (t, J = 7.0 Hz, 3H), 2.00 (t, J = 7 , 0 Hz, 3H), 1.38 (s, 6H).

MS (DCI) m / e: 352 (MH ⁺ ),

Example 6

Methyl-N- [2- (trimethylsilyl) ethoxymethyl] -4 - {[(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthyl) amino] karbonilj- benzoate (Xa)

Methyl 4 - {[(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthyl) amino] carbonyl} benzoate (5.07 g, 14.4 mmol) in anhydrous 75 ml To a solution of N-dimethylformamide at 0 ° C was added 477 mg (15.9 mmol) of 80% sodium hydride. When the evolution of hydrogen was complete, 3.61 g (21.7 mmol) of 2- (trimethylsilyl) ethoxymethyl chloride was added slowly. The reaction mixture was stirred at room temperature for 16 hours, then diluted with 100 ml of 10% w / w aqueous sodium bicarbonate solution and then extracted with diethyl ether. The organic phase was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (20:80, v / v). This gave the title compound (4.24 g, 61%).

1 H-NMR (CDCl ₃ ): δ 7.90 (d, J = 7.5 Hz, 2H),

7.82 (s, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.25 (m, 2H),

5.22 (bs, 2H), 3.93 (s, 3H), 3.67 (t, J = 8.0 Hz, 2H),

2.69 (t, J = 7.0 Hz, 2H), 1.98 (t, J = 7.0 Hz, 2H), 1.33 (s, 6H), 0.96 (t, J = 8) , 0 Hz, 2H), 0.00 (s, 9H).

MS (DCI) m / e: 428 (MH ⁺ ).

Example 7

Methyl-N- [2- (trimethylsilyl) ethoxymethyl] -4 - {[(5,5-dimethyl-8-ethyl-8-hydroxy-5,6,7,8-tetrahydro-2-naphthyl) amino ] carbonyl} benzoate (Xla)

To a solution of (Xa) (1.07 g, 2.22 mmol) in dry tetrahydrofuran (15 mL) at -78 ° C was added a solution of ethyl magnesium bromide (3.06 mL, 3.15 mmol) in diethyl ether. After 10 minutes, the reaction mixture was allowed to warm to room temperature, stirred at room temperature for 3 hours, then diluted with 100 mL of ethyl acetate and washed with 100 mL of water. The organic phase was evaporated and the residue was chromatographed on silica gel eluting with 20:80 ethyl acetate / hexane. This gave the title compound (103 mg, 9%).

1 H-NMR (CDCl ₃ ): δ 7.87 (m, 2H), 7.40 (m, 2H), 7.20 (m, 1H), 7.10 (m, 2H), 5.40 ( m, 1H), 5.20 (m, 1H),

3.90 (s, 3H), 3.75 (m, 2H), 2.00 (m, 1H),

1.78-1.42 (m, 5H), 1.27 (s, 3H), 1.25 (s, 3H), 1.05 (t, J = 8.0 Hz, 3H), 0.95 (m, 2H), 0.00 (s, 9H).

MS (DCI) m / e: 494 (MH + - H ₂ O).

Example 8

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-ethyl-2-naphthyl) -

To a solution of compound (Xla) (169 mg, 0.33 mmol) in toluene (10 mL) (some crystals) was added p-toluenesulfonic acid monohydrate (p-TsOH). The reaction mixture was heated at 75 ° C for 5 minutes and then concentrated in vacuo. The rest

It was chromatographed on silica gel, eluting with 15:85 ethyl acetate / hexane (v / v). This gave 34 mg (28%) of the title compound.

1 H-NMR (CDCl ₃ ): δ 8.20 (d, J = 8.5 Hz, 2H),

7.95 (d, J = 8.5 Hz, 2H), 7.50 (m, 2H), 7.35 (d, J = 7.0 Hz, 1H), 5.80 (t, J = 4 , 4 Hz, 1H), 3.95 (s, 3H),

2.50 (q, J = 7.0 Hz, 2H), 2.20 (d, J = 4.4 Hz, 2H), 1.25 (s, 6H), 1.10 (t, J = 7 , 0 Hz, 3H).

Example 9

4 - {[(5,6-Dihydro-5,5-dimethyl-8-ethyl-2-naphthyl) amino] carbonyl} benzoic acid (I ² a)

COOH

To a stirred solution of (Ia) mg (0.094 mmol) of Compound (Ia) in 5 mL of a 1: 1 mixture of ethanol / tetrahydrofuran was added 0.1 mL (1.0 mmol) of 10 M aqueous sodium hydroxide at room temperature. After 72 hours, an excess of 1M hydrochloric acid (20 mL) was added. The precipitate was collected by vacuum filtration, washed with 1M hydrochloric acid and water and air dried. This afforded the title compound (21 mg, 64%).

1 H-NMR (DMSO-d 6): δ 10.32 (s, 1H), 8.05 (s, 4H), 7.67 (m, 2H), 7.27 (d, J = 9.0 Hz) , 1H), 5.78 (t, J = 4.4 Hz, 1H), 2.41 (q, J = 7.0 Hz, 2H), 2.13 (d, J = 4.4 Hz, 2H) ), 1.18 (s, 6H), 1.12 (t, J = 7.0 Hz, 3H).

³ C NMR (DMSO-d6: δ 166.79, 164.63, 164.55, 140.30, 138.64, 136.99, 136.75, 133.50, 133.26, 129.26 , 127.84, 123.94, 122.48, 119.13, 115.43, 38.06, 32.86, 28.23, 25,13, 13.22.

MS (DCI) m / e: 350 (MH +).

IR (KBr): 2962, 1700, 1652, 1532.

Elemental Analysis for: C ₂₂ H ₂₃ O ₃ NH ₂ O: Calculated: C, 72.80; H, 6.80; N, 3.86;

Found: C, 72.49; H, 6.56; N, 3.74.

Example 10

Methyl N- [2- (trimethylsilyl) ethoxymethyl] -4 - {[(5,5,8-trimethyl-8-hydroxy-5,6,7,8-tetrahydro-2-naphthyl) -amino] -carbonyl} benzoate (Xlb)

To a solution of (Xa) (438 mg, 0.91 mmol) in dry tetrahydrofuran (10 mL) was added a solution of ethyl magnesium bromide (3.0 M, 0.43 mL, 1.30 mmol) in diethyl ether at -78 ° C. After 10 minutes, the reaction mixture was allowed to warm from -78 ° C to room temperature, stirred at room temperature for 3 hours, then diluted with 100 mL of ethyl acetate and washed with 100 mL of water. The organic phase was evaporated and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (20:80, v / v). This gave 90 mg (20%) of the title compound.

1 H-NMR (CDCl ₃ ): δ 7.97 (m, 2H), 7.40 (m, 2H),

7.25 (m, 2H), 7.10 (m, 1H), 5.25 (m, 2H), 3.90 (s, 3H),

3.70 (m, 2H), 1.90 (t, J = 7.0 Hz, 2H), 1.75 (t, J = 7.0 Hz, 2H), 1.30 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H), 1.00 (t, J = 8.0 Hz, 3H), 0.00 (s, 9H).

MS (DCI) m / e: 480 (MH + - H ₂ O).

Example 11

Methyl 4 - {[(5,6-dihydro-5,5,8-trimethyl-2-naphthyl) amino] carbonyl} benzoate (Pb)

(Pb)

To a solution of (Xlb) (218 mg, 0.44 mmol) in toluene (10 mL) was added p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol). The reaction mixture was heated at 75 ° C for 15 minutes and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (20:80, v / v). This afforded the title compound (28 mg, 18%).

1 H-NMR (CDCl 3): δ 8.20 (d, J = 9.0 Hz, 2H),

7.95 (d, J = 9.0 Hz, 2H), 7.90 (bs, 1H), 7.50 (m, 2H),

7.35 (d, J = 8.5 Hz, 1H), 5.80 (m, 1H), 3.95 (s, 3H),

2.25 (m, 2H), 2.10 (d, J = 1.4 Hz, 3H), 1.30 (s, 6H).

MS (DCI) m / e: 350 (MH +).

Example 12

4 - {[(5,6-Dihydro-5,5,8-trimethyl-2-naphthyl) -amino] carbonyl] -benzoic acid (Pb)

mg (0, 097 mmol) of compound (Pb) in 5 ml of a 1: 1 mixture of ethanol / tetrahydrofuran

To a stirred stirred solution of HU 218 963 was added 0.1 mL (1.0 mmol) of 10 M aqueous sodium hydroxide solution at room temperature. After 72 hours, an excess of 1M hydrochloric acid (20 mL) was added. The precipitate was collected by vacuum filtration, washed with 1M hydrochloric acid and water and air dried. This gave the title compound (14 mg, 43%).

1 H-NMR (DMSO-d ₆ ): δ 10.32 (s, 1H), 8.04 (s, 4H), 7.66 (dd, J = 8.3 Hz, J = 2.1 Hz, 1H )

7.62 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 5.80 (m, 1H), 2.14 (m, 2H), 2.01 (d, J = 1.4 Hz, 3H),

1.18 (s, 6H).

"C NMR _(DMSO-d6): δ 166,79,164,64, 139.95, 136.96, 134.15, 130.84, 129.27, 127.85, 124.41, 123,84,119, 30,115,72,38,25, 32,96,28,42,19,18.

MS (DCI) m / e: 336 (MH +).

IR (KBr): 3422, 2962, 1700, 1652, 1532.

Elemental analysis for C ₂ jH ₂₁ O ₃ N.1,5 H ₂ O:

Found: C, 69.60; H, 6.68; N, 3.86; Found: C, 69.53; H, 6.97; N, 3.76.

Example 13

Methyl-N- [2- (trimethylsilyl) ethoxymethyl] -4 - {[(5,5-dimethyl-8-phenyl-8-hydroxy-5,6,7,8-tetrahydro-2-naphthyl ) amino] carbonyl} benzoate (XIc)

CH ₂ OCH ₂ CH ₂ Si (CH ₃ ) ₃

(XIc)

To a solution of (Xa) (595 mg, 1.24 mmol) in anhydrous tetrahydrofuran was added 0.59 mL (1.76 mmol) of 3.0M phenylmagnesium bromide in diethyl ether at -78 ° C. After 10 minutes, the reaction mixture was allowed to warm from -78 ° C to room temperature, stirred at room temperature for 3 hours, then diluted with 100 mL of ethyl acetate and washed with 100 mL of water. The organic phase was evaporated and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (20:80, v / v). This gave the title compound (449 mg, 67%).

1 H-NMR (CDCl ₃ ): δ 7.85 (d, 2H), 7.20-6.80 (m, 10H), 5.20 (m, 2H), 3.95 (s, 3H), 3 , 65 (m, 2H), 2.20-2.00 (m, 2H), 1.85 (m, 1H), 1.50 (m, 1H), 1.40 (s, 3H), 1, 30 (s, 3H), 0.95 (m, 2H), 0.00 (s, 9H).

MS (DCI) m / e: 542 (MH + - H ₂ O).

Example 14

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) amino] carbonyl} benzoate (Pc)

(I'c)

449 mg (0.83 mmol) of the monohydrate form of compound (XIc) were dissolved in toluene (10 mL) and p-toluenesulfonic acid (190 mg, 1.0 mmol) was added. The reaction mixture was heated at 75 ° C for 30 minutes, then diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The organic phase was concentrated in vacuo. The residue was chromatographed on silica gel eluting with 15:85 ethyl acetate / hexane. This afforded the title compound (162 mg, 48%).

1 H-NMR (CDCl ₃ ): δ 8.15 (d, J = 8.5 Hz, 2H),

7.90 (d, J = 8.5 Hz, 2H), 7.90 (m, 1H), 7.65 (m, 1H),

7.40 (m, 5H), 6.90 (m, 1H), 6.05 (t, J = 4.6 Hz, 1H),

3.95 (s, 3H), 2.40 (d, J = 4.6 Hz, 2H), 1.40 (s, 6H).

MS (DCI) m / e: 412 (MH +).

Example 75

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) -amine]

To a stirred solution of (c) (mg) (0.21 mmol) in 5 mL of a 1: 1 mixture of ethanol / tetrahydrofuran was added 0.21 mL (2.1 mmol) of 10 M aqueous sodium hydroxide at room temperature. After 72 hours, an excess of 1M hydrochloric acid (20 mL) was added. The precipitate was collected by vacuum filtration, washed with 1M hydrochloric acid and water and dried. This gave the title compound (74 mg, 89%).

1 H-NMR (DMSO-d 6): δ 10.29 (s, 1H), 7.98 (m, 4H), 7.76 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H ), 7.35 (m, 7H), 5.97 (t, J = 4.6 Hz, 1H), 2.89 (d, J = 4.6 Hz, 2H), 1.27 (s, 6H) ).

13 C NMR (DMSO-d 6): δ 166.70, 164.58, 140.46, 140.33, 138.81, 138.62, 136.78, 133.78, 133.39, 133.10, 129, 16, 128.42, 128.35, 127.89, 127.18, 126.83, 124.04, 119.84, 118.03, 38.41, 32.99, 28.04.

MS (DCI) m / e: 398 (MH +).

IR (KBr): 3056, 2958, 1700, 1652, 1532.

Elemental analysis for C ₂₆ H ₂₃ O ₃ N.1.54 H ₂ O:

Found: C, 73.45; H, 5.81; N, 3.29; Found: C, 73.05; H, 5.53; N, 3.22.

HU 218,963 Β

Example 16

7- [Diazo- (tetrafluoroborate)] - 4,4-dimethyl-1-tetralone (XIII)

A mixture of 27.86 ml of tetrafluoroboric acid and 27.86 ml of water was added at 0 ° C to 15.10 g (79.89 mmol) of 7-amino-4,4-dimethylltetralone. The resulting mixture was then added slowly

A cold solution of sodium nitrate (13.75 g, 199 mmol) in water (27.86 mL) was maintained while maintaining the temperature at about 10 ° C. The mixture was cooled to 0 ° C, filtered, washed with 200 ml of a 5% w / w solution of tetrafluoroboric acid and dried under vacuum. 20.5 g (89%) of the title compound were obtained.

1 H-NMR (DMSO-d ₆ ): δ 9.15 (d, J = 2.5 Hz, 1H),

8.75 (dd, J = 8.5 Hz, J = 2.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 2.87 (t, J = 7.0 Hz, 2H), 2.07 (t, J = 7.0 Hz, 2H),

1.43 (s, 6H).

MS (DCI) m / e: 193 (MH + - N ₂ BF ₄ ).

Example 17

4.4- Dimethyl-7-hydroxy-1-tetralone (XIV)

Compound XIII (1.19 g, 4.13 mmol) was added to a boiling solution of sulfuric acid (3.0 mL) and water (30 mL). The reaction mixture was refluxed for 1 hour, then cooled and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (20:80, v / v). This afforded the title compound (690 mg, 88%).

1 H-NMR (CDCl 3): δ 7.48 (d, J = 2.5 Hz, 1H),

7.33 (d, J = 8.5 Hz, 1H), 7.05 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 2.75 (t, J = 7.0 Hz, 2H), 2.00 (t, J = 7.0 Hz, 2H), 1.38 (s, 6H).

Example 18

4.4- Dimethyl-7- (trifluoromethanesulfonate) -1-tetralone (XV)

To a solution of (XIV) (690 mg, 3.63 mmol) in anhydrous pyridine (10 mL) was added trifluoromethanesulfonic anhydride (0.74 mL, 4.42 mmol) at 0 ° C. The reaction mixture was then allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo. 1.17 g (100%) of the title compound were obtained.

1 H-NMR (CDCl ₃ ): δ 7.88 (d, J = 2.8 Hz, 1H),

7.52 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 8.7 Hz, J = 2.8 Hz, 1H), 2.76 (t, J = 7.0) Hz, 2H), 2.04 (t, J = 7.0 Hz, 2H),

1.40 (s, 6H).

MS (DCI) m / e: 323 (MH +).

Example 19

Methyl 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (XVIa)

To a solution of (XV) (1.15 g, 3.57 mmol) in methanol (10.8 mL) and dimethyl sulfoxide (10.8 mL) was added triethylamine (1.09 mL, 7.82 mmol), 24 mg (0.11). mmol) palladium (II) acetate and 44 mg (0.11 mmol) 1,3-bis (diphenylphosphino) propane. The reaction mixture was then saturated with carbon monoxide at room temperature and then heated at 70 ° C for 3 hours under a carbon monoxide balloon. The mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic phase was concentrated in vacuo and the residue was chromatographed on silica gel eluting with 15:85 ethyl acetate / hexane. This gave the title compound (692 mg, 93%).

1 H-NMR (CDCl 3): δ 8.66 (d, J = 2.0 Hz, 1H), 8.18 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 7, 52 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 2.76 (t, J = 7.0 Hz, 2H), 2.04 (t, J = 7.0Hz) , 2H), 1.41 (s, 6H).

MS (DCI) m / e: 233 (MH ⁺ ).

Example 20

Methyl 5,5-dimethyl-8-phenyl-8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (XVIIa)

To a solution of XVIa (167 mg, 0.72 mmol) in dry tetrahydrofuran (5 mL) at -78 ° C was added a solution of phenylmagnesium bromide (3.05 mL, 1.08 mmol) in diethyl ether. The reaction mixture was allowed to warm from -78 ° C to room temperature over 2 hours and then concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90 v / v). This afforded the title compound (152 mg, 68%).

1 H-NMR (CDCl 3): δ 7.95 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), δ, 50 (d, J = 8.3 Hz, 1H),

7.25 (m, 5H), 3.82 (s, 3H), 2.20 (m, 2H), 1.85 (m, 1H),

1.60 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H).

MS (DCI) m / e: 311 (MH ⁺ ).

Example 21

5,5-Dimethyl-5,6-dihydro-8-phenyl-2-naphthalenecarboxylic acid (XVIIIa)

HU 218,963 Β

Example 23

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl

To a solution of (XVIIa) (150 mg, 0.484 mmol) in toluene (7 mL) was added a few milligrams (2-4 mg) of ptoluenesulfonic acid. The reaction mixture was heated at 70 ° C for 5 minutes, then cooled and concentrated in vacuo. The residue was dissolved in ethanol (7 mL), and then aqueous sodium hydroxide (0.74 mL, 7.5 mmol) was added at room temperature. After 16 hours, excess 1M hydrochloric acid (30 mL) was added and the precipitate was collected by vacuum filtration. This gave the title compound (135 mg, 99%).

1 H-NMR (DMSO-d ₆ ): δ 7.95 (dd, J = 2.0 Hz, J = 8.5 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.38 (m, 5H), 6.05 (t, J = 4.6 Hz, 1H),

2.40 (d, J = 4.6 Hz, 2H), 1.40 (s, 6H).

MS (DCI) m / e: 279 (MH +).

Example 22

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} benzoate (Pa)

A solution of XVIIIa (135 mg, 0.485 mmol) in sulfonyl chloride (50 mL) containing 2 drops of N-dimethylformamide was stirred at room temperature. The mixture became homogeneous within 60 minutes. The reaction mixture was then concentrated in vacuo. The residue was dissolved in 5 ml of anhydrous pyridine to which was previously added 81 mg (0.534 mmol) of methyl 4-aminobenzoate (Aldrich). After stirring for 16 hours at room temperature, the reaction mixture was diluted with 1M hydrochloric acid, extracted with ethyl acetate, and washed with 1M hydrochloric acid (3 x 100 mL) and saturated aqueous sodium bicarbonate (2 x 100 mL). The organic phase was then separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. This gave the title compound (68 mg, 34%).

1 H-NMR (CDCl 3): δ 8.05 (d, J = 7.0 Hz, 2H),

7.75 (m, 2H), 7.65 (d, J = 7.0 Hz, 2H), 7.50 (m, 1H),

7.40 (m, 5H), 6.08 (t, J = 4.6 Hz, 1H), 3.90 (s, 3H),

2.45 (d, J = 4.6 Hz, 2H), 1.40 (s, 6H).

MS (DCI) m / e: 412 (MH +).

in 5 ml of ethanol, stirred solution of mg (0.165 mmol) of (I ³ a) compound at room temperature was added 0.165 mL (1.65 mmol) of 10 M aqueous sodium hydroxide solution. After 72 hours, an excess of 1M hydrochloric acid (30 mL) was added. The precipitate was collected by vacuum filtration, washed with 1M hydrochloric acid and water and air dried. This gave the title compound (45 mg, 69%).

1 H-NMR (DMSO-d 6): δ 10.42 (s, 1H), 7.83 (m, 5H), 7.52 (d, J = 8.0 Hz, 1H), 7.38 (m, 6H), 6.05 (t, J = 4.6 Hz, 1H), 2.33 (d, J = 4.6 Hz, 2H), 1.30 (s, 6H).

3 C NMR (DMSO-d 6): δ 166.91, 166.00, 148.26, 143.25,143,14,139,86,138,29,133,36,132,48, 130,17, 128.55,128,31,127,41,127,31,126, 84,125,40,125,00, 123.95,119,38,119.30, 37.99, 33,52,27,75.

MS (DCI) m / e: 398 (MH +).

IR (KBr): 2958, 1688, 1596, 1522.

Elemental analysis for C ₂₆ H ₂₃ O ₃ N.0,5 H ₂ O:

Found: C, 76.83; H, 5.95; N, 3.45; Found: C, 76.47; H, 6.00; N, 3.22.

Example 24

Methyl 5,5-dimethyl-8-ethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (XVIIb)

Preparation of the title compound in an analogous manner to the procedure for the preparation of the 8-phenyl derivative (XVIIa) afforded 130 mg (24%) of XVIa (490 mg, 2.11 mmol).

Example 25

5,5-Dimethyl-5,6-dihydro-8-ethyl-2-naphthalenecarboxylic acid (XVIIIb)

HU 218,963 Β

MS (DCI) m / e: 350 (MH +).

IR (KBr): 2964,1690,1596,1524.

Elemental analysis for C ₂₂ H ₂₃ O ₃ N.0.75 H ₂ O:

Found: C, 72.81; H, 6.80; N, 3.86;

Found: C, 72.84; H, 6.61; N, 3.86.

Example 28

Methyl 8-hydroxy-5,5,8-trimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate (XVIIc)

Preparation of the title compound in an analogous manner to the procedure described for the preparation of the (XVIIIa) 8-phenyl derivative afforded 130 mg (0.49 mmol) of XVIIb (113 mg, 100%).

1 H-NMR (DMSO-d ₆ ): δ 7.98 (d, J = 2.0 Hz, 1H),

7.95 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 5.83 (t, J = 4.6 Hz, 1H), 2.55 (q, J = 7.5 Hz, 2H),

2.15 (d, J = 4.6 Hz, 2H), 1.27 (s, 6H), 1.18 (t, J = 7.5 Hz, 3H).

Example 26

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-ethyl-2-naphthyl) carbonyl] amino} benzoate (Pb)

The preparation of the title compound was carried out analogously as described in (I ³ b) of 8-phenyl derivative in the preparation procedure, to yield 163 mg (92%) of the desired compound using the compound (113 mg, 0.491 mmol) (XVIIIB).

1 H-NMR (CDCl ₃ ): δ 8.08 (d, J = 8.5 Hz, 2H),

7.95 (bs, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 8 , 0 Hz, J = 2.0 Hz, 1H),

7.40 (d, J = 8.0 Hz, 1H), 5.88 (t, J = 4.6 Hz, 1H), 3.90 (s, 3H), 2.55 (q, J = 7 , 5 Hz, 2H), 2.25 (d, J = 4.6 Hz, 2H),

1.30 (s, 6H), 1.18 (t, J = 7.5 Hz, 3H).

MS (DCI) m / e: 364 (MH ⁺ ).

Example 27

4 - {[(5,6-Dihydro-5,5-dimethyl-8-ethyl-2-naphthalenyl) carbonyl] amino} benzoic acid (I ⁴ b)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation procedure, to yield 128 mg (92%) of the desired compound using the compound (163 mg, 0.45 mmol) and (Pb).

1 H-NMR (DMSO-d ₆ ): δ 10.46 (s, 1H), 7.91 (m, 4H), 7.77 (m, 2H), 7.45 (d, J = 7.9 Hz) , 1H), 5.84 (t, J = 4.6 Hz, 1H), 2.52 (q, J = 7.4 Hz, 2H), 2.17 (d, J = 4.6 Hz, 2H) ), 1.21 (s, 6H), 1.11 (t, J = 7.4 Hz, 3H).

¹³ C NMR (DMSO-d ₆ ): δ 166.97, 166.133, 148.61, 143.33, 136.36, 133.27, 132.54, 130.19, 126.72, 125.52 , 123.95, 122.80, 122.11, 119.50, 119.41, 37.62, 33.42, 27.94, 24.65, 12.86.

Preparation of the title compound in an analogous manner to that used for the preparation of the 8-phenyl derivative (XVIIa) provided 188 mg (60%) of the desired compound (292 mg, 1.26 mmol).

1 H-NMR (CDCl ₃ ): δ 8.29 (d, J = 2.0 Hz, 1H),

7.85 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H), 2, 0 (t, J = 7.0 Hz, 2H), 1.87 (t, J = 7.0 Hz, 2H), 1.60 (d, J = 1.3 Hz, 3H), 1.38 ( s, 6H).

Example 29

5,6-Dihydro-5,5,8-trimethyl-2-naphthalenecarboxylic acid (XVIIIc)

Preparation of the title compound in an analogous manner to the procedure described for the preparation of the (XVIIIa) 8-phenyl derivative afforded 188 mg (0.76 mmol) of XVIIc (154 mg, 94%).

1 H-NMR (DMSO-d 6): δ 7.96 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 5.87 (m, 1H), 2.27 (m, 2H), 2.17 (d, J = 1.3 Hz, 3H), 1.27 (s, 6H).

Example 30

Methyl 4 - {[(5,6-dihydro-5,5,8-trimethyl-2-naphthyl) carbonyl] amino} benzoate (Pc)

Preparation of the title compound in a manner analogous to that described for the preparation of the (Pa) 8-phenyl derivative 39

This gave 90 mg (36%) of the desired compound using 154 mg (0.713 mmol) of XVIIIc.

1 H-NMR (CDCl 3): δ 8.05 (d, J = 8.5 Hz, 2H),

7.90 (bs, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8) , 0 Hz, J = 2.0 Hz, 1H),

7.43 (d, J = 8.0 Hz, 1H), 5.87 (m, 1H), 3.92 (s, 3H),

2.27 (m, 2H), 2.18 (d, J = 1.3 Hz, 3H), 1.30 (s, 6H).

MS (DCI) m / e: 350 (MH +).

Example 31

4 - {[(5,6-Dihydro-5,5,8-trimethyl-2-naphthalenyl) carbonyl] -propionic acid (I ⁴ c)

(I ⁴ c)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation process to obtain the desired compound (70 mg, 81%) as a result of which the use of 90 mg (0.26 mmol) of (Pc) compounds.

1 H-NMR (DMSO-d ₆ ): δ 12.72 (bs, 1H), 10.46 (s, 1H), 7.89 (m, 5H), 7.79 (dd, J = 8.0). Hz, J = 2.0 Hz, 1H),

7.72 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H),

5.85 (m, 1H), 2.17 (m, 1H), 2.09 (d, J = 1.3 Hz, 3H),

1.22 (s, 6H).

¹³ C-NMR (DMSO-d ₆ ): δ 166.93, 166.13, 148.21, 143.38, 133.98, 132.58, 130.63, 130.22, 126.89, 125.36.124 , 90, 123.83, 122.48, 119.48, 119.39, 37.84, 33.54, 28,14,19,12.

MS (DCI) m / e: 336 (MH +).

IR (KBr): 2958,1674,1656,1416.

Elemental Analysis for: C ₂₁ H ₂₁ O ₃ N: Calculated: C, 75.20; H, 6.31; N, 4.1;

Found: C, 74.90; H, 6.36; N, 3.99.

Example 32

2-Acetyl-5,6-dihydro-5,5-dimethyl-8-phenyl-naphthalene (XIXa)

To a stirred solution of (XVilla) (816 mg, 2.94 mmol) in diethyl ether (15.0 mL) at -78 ° C was added 4.19 mL (5.88 mmol) of methyl lithium in 1.4 M diethyl ether. solution. The reaction mixture was stirred at room temperature for 1 hour and then 50 ml of 1M hydrochloric acid were added. The organic layer was separated, washed with 50 mL of saturated aqueous sodium chloride solution and 50 mL of 1 M aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated. This gave the title compound (600 mg, 74%).

1 H-NMR (CDCl 3): δ 7.83 (dd, J = 8.0 Hz, J = 1.7 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (m, 5H), 6.05 (t, J = 4.7 Hz, 1H),

2.44 (s, 3H), 2.37 (d, J = 4.7 Hz, 2H), 1.35 (s, 6H).

MS (DCI) m / e: 277 (MH +).

Example 33

Ethyl 4- (E, Z) - [2- (5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) -1-propenyl] -benzoate (Pa)

Methyl 4 - [(diethoxyphosphoryl) methyl] benzoate (1.02 g, 3.40 mmol) was added to a 1 M solution of dimethylsulfonic anion in 3.09 mL (3.09 mmol). 4 - [(diethoxyphosphoryl) methyl] benzoate was prepared according to the procedure described in Liebigs Ann. Chem., 929 (1985); dimethylsulfoxide dimethyl anion solution was prepared by heating sodium hydride at 65 ° C for 1 hour in dimethylsulfoxide}. After 30 minutes, the mixture was added at room temperature to a solution of (XIXa) (595 mg, 2.16 mmol) in dimethyl sulfoxide (6.50 mL). The reaction mixture was stirred at room temperature for 3 hours and then a solution of 1.74 mL (3.48 mmol) of 2 M sodium ethanolate in ethanol was added. The resulting mixture was stirred at room temperature for 16 hours, then diluted with 50 ml of 5% w / w sodium bicarbonate solution and extracted with 3 x 50 ml of ethyl acetate. The combined organic layers were concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). This gave the title compound (159 mg, 18%). NMR showed the product to have an E: Z isomer ratio of 4: 1.

Example 34

4- (E) - [2- (5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) propenyl] benzoic acid (I ⁶ a)

HU 218,963 Β

15.0 ml of ethanol, stirred solution of the compound (159 mg, 0.388 mmol) (S ⁵⁾ at room temperature was added 0.39 ml (3.90 mmol) of 10 M aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 48 hours, then diluted with excess 1M hydrochloric acid (40.0 mL) and then filtered. The solid was washed with water, dried and recrystallized from ethanol. This gave the title compound (60 mg, 40%).

1 H-NMR (DMSO-d ₆ ): δ 7.91 (d, J = 8.3 Hz, 2H),

7.42 (m, 9H), 7.06 (d, J = 1.7 Hz, 1H), 6.70 (s, 1H), 6.03 (t, J = 4.6 Hz, 1H), 2.34 (d, J = 4.6 Hz, 2H), 2.12 (s, 3H), 1.31 (s, 6H).

13 C NMR (DMSO-d ₆ ): δ 144.42, 140.58, 140.14, 138.94, 138.72, 133.12, 129.26, 129.07, 128.47, 128, 35, 127.32, 126.71, 125.89, 125.32, 124.07, 123.06, 38.25, 33.16, 27.94, 17.38.

MS (DCI) m / e: 395 (MH ⁺ ).

IR (KBr): 2958, 1680, 1602, 1292.

Example 35

4,4-Dimethyl-7 - [(tert-butyldimethylsilyl) oxy] -1-tetralone (XXla)

To a solution of (XIV) (2.00 g, 10.5 mmol) in N, N-dimethylformamide (16 mL) was added tert-butyldimethylsilyl chloride (1.90 g, 12.6 mmol) at room temperature and 1.79 g (26). 3 mmol) imidazole. The reaction mixture was stirred at room temperature for 5 hours, then 50 ml of a 5% aqueous sodium bicarbonate solution was added and the resulting mixture was extracted twice with 75 ml of benzene. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. This gave the title compound (3.22 g, 99%).

1 H-NMR (CDCl ₃ ): δ 7.44 (d, J = 8.7 Hz, 1H),

7.29 (d, J = 8.7 Hz, 1H), 7.01 (dd, J = 8.7 Hz, J = 2.8 Hz, 1H), 2.71 (t, J = 7.0) Hz; 2H), 1.99 (t, J = 7.0 Hz, 2H),

1.36 (s, 6H), 0.98 (s, 9H), 0.20 (s, 6H).

MS (DCI) m / e: 305 (MH ⁺ ).

Example 36

5,6-Dihydro-5,5-dimethyl-2 - [(tert-butyldimethylsilyl) oxy] -8 - [(trifluoromethanesulfonyl) oxy] naphthalene (XXIIa)

To a solution of (XXla) (2.73 g, 8.98 mmol) in tetrahydrofuran (80.0 mL) at -78 ° C was added 9.88 mL (9.88 mmol) of 1.0M sodium bis (trimethylsilyl) in THF - amide solution was added. The reaction mixture was stirred at -78 ° C for 1 hour, then at room temperature for 1.5 hours and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90 v / v). This gave the title compound (2.26 g, 58%).

1 H-NMR (CDCl 3): δ 7.15 (d, J = 8.4 Hz, 1H),

6.85 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 8.4 Hz, J = 2.5 Hz, 1H), 5.94 (t, J = 4.8 Hz, 1H), 2.38 (d, J = 4.8 Hz, 2H),

1.27 (s, 6H), 0.98 (s, 9H), 0.20 (s, 6H).

MS (DCI) m / e: 437 (MH ⁺ ).

Example 37

5,6-Dihydro-5,5-dimethyl-2- (tert-butyldimethylsilyl) oxy] -8-phenylnaphthalene (XXIIIa)

To a solution of XXIIa (2.26 g, 5.18 mmol) in 1-methyl-2-pyrrolidinone (25.0 mL) was added triphenylarzine (300 mg, 0.980 mmol), tris (dibenzylideneacetone dipalladium) (147 mg, 0.16 mmol) at room temperature. (0) and tributylphenylone (4.18 g, 11.4 mmol) were stirred at 85 ° C for 16 hours, water (50 mL) and ethyl acetate (50 mL) were added and the organic layer was separated and After stirring for one minute with a saturated aqueous solution of potassium fluoride, the organic phase was separated again, concentrated in vacuo and the residue chromatographed on silica gel using pure hexane as the eluent.

1.10 g (58%) of the title compound were obtained.

1 H-NMR (CDCl 3): δ 7.10 (m, 5H), 6.97 (d, J = 8.4 Hz, 1H), 6.41 (dd, J = 8.4 Hz, J = 2 , 5 Hz, 1H),

6.20 (d, J = 2.5 Hz, 1H), 5.68 (t, J = 4.8 Hz, 1H), 2.05 (d, J = 4.8 Hz, 2H), 1, O 2 (s, 6H), 0.60 (s, 9H), 0.00 (s, 6H).

MS (DCI) m / e: 365 (MH +).

Example 38

5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthol (XXVa)

HU 218,963 Β

Example 41 tert-Butyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) oxy] carbonyl} benzoate (I ⁷ a)

To a solution of XXIIIa (1.10 g, 3.02 mmol) in tetrahydrofuran (10.0 mL) was added a solution of tetrabutylammonium fluoride (3.32 mL, 3.32 mmol) in tetrahydrofuran at room temperature. After stirring for 5 minutes at room temperature, the reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90 v / v). This gave the title compound (575 mg, 76%).

1 H-NMR (CDCl ₃ ): δ 7.36 (m, 5H), 7.23 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.3 Hz, J = 2.7 Hz, 1H),

6.49 (d, J = 2.7 Hz, 1H), 5.99 (t, J = 4.6 Hz, 1H), 2.34 (d, J = 4.6 Hz, 2H), 1, 32 (s, 6H).

MS (DCI) m / e: 251 (MH +).

Example 39

Di (tert-butyl) terephthalate (XXVI)

SHE

(XXVI)

To a solution of terephthaloyl dichloride (2.00 g, 9.85 mmol) in dry pyridine (25.0 mL) was added tert-butyl alcohol (803 mg, 10.8 mmol). After stirring at 85 ° C for 16 hours, water (75.0 mL) was added and the solid filtered. The solid was dissolved in diethyl ether (40 mL) and washed with saturated aqueous sodium bicarbonate (2 x 75 mL). The organic phase was then dried over anhydrous magnesium sulfate and concentrated in vacuo. This gave 1.15 g (42%) of the title compound.

1 H-NMR (CDCl 3): δ 9.01 (s, 4H), 1.60 (s, 18H).

Example 40

Mono (tert-butyl) terephthalate (XXVII)

To potassium hydroxide (255 mg, 4.55 mmol) was added tert-butyl alcohol (4.0 mL) followed by water (0.5 mL) to aid dissolution. To the resulting solution was added a mixture of (XXVI) (1.15 g, 4.14 mmol) and tert-butyl alcohol (5.5 mL). After stirring at 50 ° C for 3 hours, diethyl ether (35 mL) was added and the mixture was filtered. The filtered solid was dissolved in water (35.0 mL), extracted with dichloromethane (2 x 50 mL), and acidified with 1M hydrochloric acid. The precipitate was filtered off to give the title compound (270 mg, 30%).

1 H-NMR (CDCl 3): δ 8.02 (m, 4H), 1.56 (s, 9H).

MS (DCI) m / e: 223 (MH +).

To a solution of compound XXVII (107 mg, 0.480 mmol) in dichloromethane (5 mL) was added oxalyl dichloride (0.15 mL) and N, A-dimethylformamide (2 drops) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. As a result, the corresponding acid chloride, compound XXIVa, was obtained.

To a solution of 0.480 mmol (XXIVa) in 5 mL of anhydrous pyridine was added 120 mg (0.48 mmol) of XXVa. The reaction mixture was stirred at room temperature for 16 hours and then diluted with 1M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (100 mL), and the organic layer was washed with 1M hydrochloric acid (4 x 100 mL) and brine (2 x 100 mL). The organic phase was then separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. This gave the title compound (137 mg, 63%).

1 H-NMR (CDCl 3): δ 8.16 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.35 (m, 6H), δ , 07 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.04 (t, J = 4.6 Hz) , 1H), 2.38 (d, J = 4.6 Hz, 2H), 1.61 (s, 9H), 1.36 (s, 6H).

MS (DCI) m / e: 455 (MH +).

Example 42 {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) oxy] carbonyl (benzoic acid (Pa)

To a solution of compound with methylene chloride (137 mg, 0.30 mmol) (I ⁷ a) with stirring at room temperature was added 0.270 mL of TFA. The reaction mixture was stirred at room temperature for 72 hours and 30 mL of 1M hydrochloric acid was added. The precipitate was collected by vacuum filtration, washed with 1M hydrochloric acid and then air dried. This gave the title compound (85 mg, 71%).

HU 218,963 Β

1 H-NMR (CDCl 3): δ 13.39 (bs, 1H), 8.15 (d, J = 7.6 Hz, 2H), 8.05 (d, J = 7.6 Hz, 2H), δ , 38 (m, 6H), 7.18 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.06 (t, J = 4.2 Hz, 1H), 2 , 35 (d, J = 4.2 Hz, 2H), 1.32 (s, 6H).

C-NMR (CDCl 3): δ 166.48, 163.99, 148.51, 142.55, 139.77, 138.17, 135.24, 134.59, 132.59, 132.45, 131, 61, 130.01, 129.66, 129.48, 128.57, 128.28, 127.63, 127.41, 125.24, 120.74, 118.36, 67.39, 38.24, 38.07, 33.12, 28.37.

MS (DCI) m / e: 399 (MH ⁺ ).

IR (KBr): 2964,1738,1698,1246.

Elemental analysis for C ₂₄ H ₂₂ O ₄ .0.5 H ₂ O:

Found: C, 76.64; H, 5.69;

Found: C, 76.66; H, 5.89.

Example 43 tert-Butyl 4-hydroxybenzoate (XXVIIIa)

To a solution of 2.00 g (14.5 mmol) of 4-hydroxybenzoic acid in 10.0 ml of 1,4-dioxane saturated with 2-methyl-1-propene was added 0.150 ml of concentrated sulfuric acid in a metal bomb at -78 ° C. The bomb was sealed and then warmed to room temperature. After keeping the bomb at room temperature for 72 hours, the reaction mixture was cooled to -78 ° C and poured into 30.0 ml of a saturated aqueous sodium bicarbonate solution. The mixture was extracted with diethyl ether (2 x 50.0 mL). The combined organic phases were concentrated and the residue was chromatographed on silica gel using methanol / dichloromethane (5:95) as eluent. This gave 290 mg (10%) of the title compound.

1 H-NMR (CDCl ₃ ): δ 7.89 (d, J = 8.8 Hz, 2H),

6.83 (d, J = 8.8 Hz, 2H), 1.57 (s, 9H).

Example 44 tert-Butyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] oxy} benzoate (Pa)

To a solution of XVIIIa (200 mg, 0.720 mmol) in dichloromethane (7.00 mL) was added oxalyl dichloride (0.075 mL) and N, N-dimethylformamide (2 drops) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in 5.00 mL of anhydrous pyridine and 154 mg (0.792 mmol) of XXVIIIa was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with 1M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (50 mL), and the organic layer was washed with 1M hydrochloric acid (4 x 100 mL) and brine (2 x 100 mL). The organic phase was then separated and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (3:97, v / v). This gave the title compound (203 mg, 61%).

1 H-NMR (CDCl 3): δ 8.05 (m, 3H), 7.85 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 8.1 Hz), 7.38 (m, 6H), 7.18 (d, J = 8.6 Hz, 1H), 6.07 (t, J = 4.6 Hz, 1H), 2.40 (d, J = 4.6 Hz) , 2H), 1.59 (s, 9H), 1.38 (s, 6H).

MS (DCI) m / e: 455 (MH +).

Example 45

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) oxy] -

Dissolved in 5.00 ml of methylene chloride The compound (203 mg, 0.480 mmol), (S ⁹⁾ at room temperature was added 0.400 mL of TFA. The reaction mixture was stirred at room temperature for 16 hours and 30 mL of 1M hydrochloric acid was added. The precipitate was collected by vacuum filtration, washed with 1M hydrochloric acid and then air dried. This gave the title compound (133 mg, 75%).

1 H-NMR (CDCl 3): δ 8.05-7.31 (m, 12H), 6.10 (t, J = 4.6 Hz, 1H), 2.39 (d, J = 4.6 Hz, 2H), 1.34 (s, 6H).

MS (DCI) m / e: 399 (MH +).

IR (KBr): 2962, 1742, 1684, 1602.

Elemental analysis for C ₂₄ H ₂₂ O ₄ .0.850 H ₂ O:

Found: C, 75.47; H, 5.77;

Found: C, 75.52; H, 5.43.

Example 46

Methyl 5,5-dimethyl-8-hydroxy-8- (2-fluorophenyl) 5,6,7,8-tetrahydronaphthalene-2-carboxylate (XVIld)

HU 218,963 Β

To a solution of (XVIa) (297 mg, 1.28 mmol) in tetrahydrofuran (7.0 mL) was added a solution of 2-fluorophenyl lithium (5.50 mL, 1.93 mmol) in THF at -78 ° C. [This reagent was prepared by adding a solution of 2-fluorobenzobenzene (552 mg, 3.15 mmol) in tetrahydrofuran (5.0 mL) at -78 ° C in 4.09 mL (2.41 mmol) of 1.7 M pentane butyl lithium solution. The reaction mixture was stirred for 5 minutes at -78 ° C, then 5.50 ml was added by syringe to a solution of compound (XVIa). A mixture of ethyl acetate / hexane (10:90 v / v) was used. This gave the title compound (280 mg, 67%).

1 H-NMR (CDCl ₃ ): δ (dd, J = 8.4 Hz, J = 1.7 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.50 ( m, 2H), 7.18 (m, 1H), 6.96 (m, 2H), 3.80 (s, 3H), 2.50 (m, 1H), 2.40 (d, J = 2 , 8 Hz, 1H), 2.05 (m, 2H), 1.60 (m, 1H), 1.43 (s, 3H), 1.35 (s, 3H).

MS (DCI) m / e: 329 (MH +).

Example 47

5,6-Dihydro-5,5-dimethyl-8- (2-fluorophenyl) -naphthalene-

Preparation of the title compound in an analogous manner to the procedure described for the preparation of the (XVIIIa) 8-phenyl derivative afforded 280 mg (0.85 mmol) of XVIId (209 mg, 83%).

1 H-NMR (DMSO-d ₆ ): δ 7.81 (dd, J = 8.0 Hz, J = 1.8 Hz, 1 H), 7.55-7.25 (m, 6H), 6, 09 (t, J = 4.5 Hz, 1H), 2.38 (d, J = 4.5 Hz, 2H), 1.32 (s, 6H).

MS (DCI) m / e: 297 (MH +).

Example 48

Methyl 4 - [{[5,6-dihydro-5,5-dimethyl-8- (2-fluorophenyl) -2-naphthyl] carbonyl} amino] benzoate (Pg)

To a solution of XVIIId (200 mg, 0.676 mmol) in CH 2 Cl 2 (5.0 mL) was added oxalyl dichloride (0.20 mL, 2.29 mmol) and N-dimethylformamide (2 drops) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in 5.0 ml of anhydrous pyridine and then 102 mg (0.68 mmol) of methyl 4-aminobenzoate (Aldrich) was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with 1M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with 1M HCl (3 x 100 mL) and brine (2 x 100 mL). The organic phase was then separated and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (20:80, v / v). This gave the title compound (226 mg, 78%).

1 H-NMR (CDCl ₃ ): δ 8.02 (d, J = 8.7 Hz, 1H),

7.71 (m, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.40-7.10 (m , 7H), 6.11 (t, J = 4.5 Hz, 1H), 3.90 (s, 3H), 2.42 (d, J = 4.5 Hz, 2H), 1.39 (s) , 6H).

MS (DCI) m / e: 430 (MH +).

Example 49

4 - [{[5,6-Dihydro-5,5-dimethyl-8- (2-fluoro-phenyl) -2-naphthalenyl] carbonyl} amino] benzoic acid (I ⁴ g)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation procedure, to yield 180 mg (82%) of the desired compound using the compound (226 mg, 0.527 mmol) (Pg).

1 H-NMR (DMSO-d 6): δ 12.73 (s, 1H), 10.43 (s, 1H), 7.89-7.78 (m, 5H), 7.53 (d, J = 8.0 Hz, 1H), 7.48-7.19 (m, 5H), 6.10 (t, J = 4.5 Hz, 1H), 2.38 (d, J = 4.5 Hz, 2H), 1.33 (s, 6H).

¹³ C-NMR (DMSO-d6: δ 166.89, 165.80, 161.12, 147.85, 143.24, 133.03, 08.132.95, 132.57, 131.54, 130.18, 129.93, 129.48, 126.91, 125.37, 124) , 88,124,29,123.86, 119.42,119,33,115,75,37,89, 33,48,27,75.

MS (DCI) m / e: 416 (MH +).

IR (KBr): 2962, 1688, 1594, 1520.

Elemental analysis for C ₂₆ H ₂₂ O ₃ NF.0.25 H ₂ O:

Found: C, 74.36; H, 5.40; N, 3.34;

Found: C, 74.50; H, 5.40; N, 3.17.

Example 50

Methyl 5,5-dimethyl-8-oxo-5,8-dihydronaphthalene-2-carboxylate (XXXa)

HU 218,963 Β

2.00 g (8.60 mmol) of the compound of formula XVI in Scheme XXL wherein R ⁷ is methyl, 1.12 g (10.3 mmol) of trimethylsilyl chloride (TMSC1), 1.70 g (11.2 mmol) of a mixture of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 10 ml of anhydrous dichloromethane was refluxed for one hour with stirring. The reaction mixture was diluted with diethyl ether (75 mL), washed with 0.1 M hydrochloric acid (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dried under vacuum. To the resulting material was added 30 ml of acetonitrile and 2.12 g (9.50 mmol) of palladium (II) acetate. After stirring for 16 hours, additional palladium (II) acetate (1.06 g, 4.75 mmol) was added and stirring was continued for 16 hours. The mixture was filtered through celite and washed with acetonitrile. The filtrate was evaporated and the residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). This gave 1.42 g (64%) of the title compound.

1 H-NMR (CDCl 3): δ 1.50 (s, 6H), 3.94 (s, 3H),

6.41 (d, J = 10.2 Hz, 1H), 6.94 (d, J = 10.2 Hz, 1H),

7.62 (d, J = 8.2 Hz, 1H), 8.22 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H), 8.82 (d, J = 2.0) Hz, 1H).

MS (DCI) m / e: 321 (MH +).

Example 51

Methyl 8-oxo-5,5,6-trimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate (XXXIa)

To a suspension of copper (I) cyanide (724 mg, 8.08 mmol) in anhydrous diethyl ether (40 mL) at -50 ° C was slowly added lithium (11.5 mL, 16.2 mmol) in diethyl ether (1.4 M). solution. After stirring for one hour, the reaction mixture was cooled to -78 ° C, boron trifluoride diethyl etherate (573 mg, 4.04 mmol) was added, followed by the slow addition of enone (XXXa) (930 mg, 4.04 mmol). A solution of the ester in diethyl ether (10 mL) was added. The reaction mixture was stirred for 45 minutes and then quenched with 30 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether (3 x 30 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). This afforded the title compound as a solid (251 mg, 25%).

1 H-NMR (CDCl 3): δ 1.05 (d, J = 6.9 Hz, 3H),

1.30 (s, 3H), 1.44 (s, 3H), 2.15-2.30 (m, 1H), 2.55 (dd, J = 9.3 Hz, J = 17.5 Hz) , 1H), 2.81 (dd, J = 4.5 Hz, J = 17.5 Hz, 1H), 3.93 (s, 3H), 7.55 (d, J = 8.3 Hz, 1H) ), 7.69 (dd, J = 1.9 Hz, J = 8.3 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H).

MS (DCI) m / e: 247 (MH +).

Elemental Analysis for: C ₁₅ H ₈ O ₃ Calculated: C, 73.15; Η 7.37;

Found: C, 72.78; H, 7.31.

Example 52

Methyl 8-phenyl-5,5,6-trimethyl-5,6-dihydronaphthalene-2-carboxylate (XXXIIIa)

To a solution of XXXIa (390 mg, 1.58 mmol) in anhydrous THF (10 mL) was added a solution of phenylmagnesium bromide (1.05 mL, 3.15 mmol) in diethyl ether at -30 ° C. The reaction mixture was stirred at -30 ° C for 10 minutes, then the solution was raised to 0 ° C and stirred at this temperature for a further 20 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined extracts were washed with water (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. To the residue were added 20 ml of anhydrous benzene and 50 mg of p-toluenesulfonic acid. The solution was stirred at reflux for 30 minutes and then concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1:10 v / v). This gave the title compound (380 mg, 78%).

1 H-NMR (CDCl ₃ ): δ 1.01 (d, J = 7.1 Hz, 3H),

1.29 (s, 3H), 1.36 (s, 3H), 2.35-2.43 (m, 1H), 3.82 (s, 3H), 5.94 (d, J = 5, 0 Hz, 1H), 7.33-7.42 (m, 5H),

7.43 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H),

7.90 (dd, J = 1.8 Hz, J = 8.1 Hz, 1H).

MS (DCI) m / e: 307 (MH ⁺ ).

Elemental analysis for C ₂ H ₂₂ O ₂ requires: Calculated% C, 82.32; H, 7.24;

Found: C, 82.10; H, 7.32.

HU 218,963 Β

Example 3

8-Phenyl-5,5,6-trimethyl-5,6-dihydronaphthalene-2-carboxylic acid (XVIIIe)

A solution of (XXXIIa) (224 mg, 0.73 mmol), 2M aqueous sodium hydroxide (3.7 mL, 7.4 mmol) and tetrahydrofuran (7 mL), and methanol (7 mL) was heated at 60 ° for 1.5 h. Stir at C. The reaction mixture was concentrated under reduced pressure, acidified with 10 ml of 1M hydrochloric acid and extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was crystallized from diethyl ether / hexane. This gave the product as a solid (220 mg, quantitative).

1 H-NMR (CDCl 3): δ 1.02 (d, J = 7.1 Hz, 3H),

1.31 (s, 3H), 1.37 (s, 3H), 2.35-2.45 (m, 1H), 5.95 (d, J = 5.1 Hz, 1H), 7.30 -7.40 (m, 5H), 7.46 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.94 (dd, J = 1.9 Hz, J = 8, 1 Hz, 1H).

MS (DCI) m / e: 293 (MH +).

Elemental C2oH the _two o0 .0,125 ₂ H ₂ O Calcd:

Found: C, 81.53; H, 6.93;

Found: C, 81.68; H, 6.86.

Example 54

Methyl 4 - {[(5,6-dihydro-8-phenyl-5,5,6-trimethyl-2-naphthyl) carbonyl] amino} benzoate (Pd)

(Pd)

To a solution of (XVIIIe) (206 mg, 0.71 mmol) in dichloromethane (4 mL) was added oxalyl dichloride (179 mg) and N, N-dimethylformamide (1 drop) at 0 ° C. The reaction mixture was stirred for 2 hours at 0 ° C and then for 1 hour at room temperature. The solvent was evaporated and dried under vacuum. To the residue was added a solution of methyl p-aminobenzoate (128 mg, 0.85 mmol) in dry pyridine (4 mL). The reaction mixture was stirred at room temperature for 18 hours and then diluted with 20 ml of 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:10 to 1: 5, v / v). As a result, the title compound was obtained as a foam (234 mg, 78%).

1 H-NMR (CDCl 3): δ 1.03 (d, J = 7.1 Hz, 3H),

1.30 (s, 3H), 1.37 (s, 3H), 2.35-2.45 (m, 1H), 3.90 (s, 3H), 5.98 (d, J = 5, 0 Hz, 1H), 7.30-7.41 (m, 5H),

7.46 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H),

7.65 (d, J = 8.7 Hz, 1H), 7.72 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 7.97 and 8.00 (s above d, J = 8.7 Hz, 3H).

MS (DCI) m / e: 426 (MH +).

Elemental analysis for C ₂₈ H ₂₇ O ₃ N.0,5 H ₂ O:

Found: C, 77.39; H, 6.50; N, 3.22;

Found: C, 77.34; H, 6.19; N, 3.33.

Example 55

4 - {[(5,6-Dihydro-8-phenyl-5,5,6-trimethyl-2-naphthalenyl) carbonyl] amino (benzoic acid (I ⁴ d)

A solution of (Pd) (224 mg, 0.53 mmol), 2M aqueous sodium hydroxide solution (2.65 mL, 5.30 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at room temperature for 16 h. The resulting solution was acidified with 1M hydrochloric acid and then concentrated under reduced pressure. The residue was diluted with water (20 mL) and filtered. The filtered solid was triturated under diethyl ether to give the title compound as a pale yellow powder (127 mg, 59%).

1 H-NMR (DMSO-d ₆ ): δ 0.97 (d, J = 7.1 Hz, 3H),

1.26 (s, 3H), 1.31 (s, 3H), 2.37-2.41 (m, 1H), 5.98 (d, J = 5.0 Hz, 1H), 7.31 -7.45 (m, 6H), 7.54 (d, J = 8.1 Hz, 1H), 7.79-7.89 (m, 6H), 10.43 (s, 1H), 12, 72 (s, 2H).

MS (DCI) m / e: 411 (MH ⁺ ).

Elemental analysis for C ₂₇ H ₂₅ O ₃ N.0,5 H ₂ O:

Found: C, 77.12; H, 6.23; N, 3.33; Found: C, 77.41; H, 6.05; N, 3.26.

Example 56

Methyl 8-oxo-5,5,7-trimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate (XXXVa)

HU 218,963 Β

A solution of 0.60 g (2.58 mmol) of the compound of formula XVI in Scheme XXL wherein R ⁷ is methyl in a mixture of 10 ml of anhydrous tetrahydrofuran and 1 ml of hexamethylphosphoric acid amide (HMPA) and under -78 Lithium bis (trimethylsilyl) 1M solution in hexane (2.71 mL, 2.71 mmol) was added at 0 ° C. After stirring for 2 hours at -78 ° C, the solution was warmed to -40 ° C and methyl iodide (0.73 g, 5.16 mmol) was added. The reaction mixture was stirred for 2.5 hours and then quenched with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL), and the combined extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:30 to 1:10 by volume). This gave the title compound as a white solid (516 mg, 81%).

1 H-NMR (CDCl 3): δ 1.27 (d, J = 6.6 Hz, 3H), 1.40 (s, 3H), 1.45 (s, 3H), 1.91 (d, J = 2.0 Hz, 1H), 1.94 (s, 1H), 2.78-2.91 (m, 1H), 3.93 (s, 3H), 7.50 (d, J = 8.2 Hz, 1H), 8.16 (dd, J = 1.9 Hz, J = 8.2 Hz, 1H), 8.64 (d, J = 1.9 Hz, 1H).

MS (DCI) m / e: 247.

Elemental Analysis for: C ₁₅ H ₁₈ O ₃ : Calculated: C, 73.15; H, 7.37;

Found: C, 73.15; H, 7.51.

Example 57

Methyl 8-phenyl-5,5,7-trimethyl-5,6-dihydronaphthalene-2-carboxylate (XXXVIa)

To a solution of (XXXVa) ketone (500 mg, 2.03 mmol) in tetrahydrofuran (20 mL) at 0 ° C was slowly added a solution of phenylmagnesium bromide (1.35 mL, 4.06 mmol) in diethyl ether. The red mixture was stirred at 0 ° C for 1 hour and then quenched with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 25 mL). The combined extracts were dried over anhydrous magnesium sulfate and evaporated. To the residue was added benzene (10 ml) and p-toluenesulfonic acid (0.1 g), and the reaction mixture was refluxed for 30 minutes with stirring. The solvent was then evaporated. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / hexane (1:30 to 1:20 by volume). This gave the title compound (380 mg, 61%).

1 H-NMR (CDCl ₃ ): δ 1.35 (s, 6H), 1.73 (s, 3H),

2.31 (s, 2H), 3.77 (s, 3H), 7.17 (d, J = 6.8 Hz, 2H), 7.29-7.45 (m, 5H), 7.80 (dd, J = 1.8 Hz, J = 8.0 Hz, 1H).

MS (DCI) m / e: 307. (MH +).

Example 58

8-Phenyl-5,5,7-trimethyl-5,6-dihydronaphthalene-2-carboxylic acid (XVIIIJ)

A solution of the ester XXXVIa (180 mg, 0.62 mmol), 1M aqueous sodium hydroxide solution (1.22 mL, 2 mmol) and tetrahydrofuran (5 mL), and methanol (2 mL) was stirred at 60 ° C for 3 h. The resulting solution was concentrated under reduced pressure to about 3 mL, diluted with 10 mL of 1M hydrochloric acid, and extracted twice with 30 mL of ethyl acetate. The combined extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate and concentrated. As a result, the title compound (150 mg, 83%) was obtained as a solid.

1 H-NMR (CDCl ₃ ): δ 1.35 (s, 6H), 1.73 (s, 3H),

2.32 (s, 2H), 7.15 (d, J = 6.7 Hz, 2H), 7.32 (d, J = 1.6 Hz, 1H), 7.35-7.45 (m , 4H), 7.86 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H).

MS (DCI) m / e: 293 (MH +).

Elemental analysis for C ₂₀ H ₂₀ O ₂ .0.25 H ₂ O:

Found: C, 80.91; H, 6.96;

Found: C, 81.01; H, 6.82.

Example 59

Methyl 4 - {[(5,6-dihydro-8-phenyl-5,5,7-trimethyl-2-naphthyl) carbonyl] amino} benzoate (Pe)

(Pe)

To a solution of (XVIIIf) acid (171 mg, 0.59 mmol) in CH 2 Cl 2 (4 mL) was added oxalyl dichloride (150 mg, 1.18 mmol) and a drop of N, N-dimethylformamide. The solution was allowed to stand at 0 ° C for one hour and then for 16 hours

HU 218 963 Β. The solvent was evaporated and the residue was dried under vacuum. Methyl p-aminobenzoate (98 mg, 0.65 mmol) and anhydrous pyridine (3 mL) were added to the residue. The mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was diluted with 1M hydrochloric acid (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). This gave the title compound as an oil (149 mg, 78%).

1 H-NMR (CDCl ₃ ): δ 1.37 (s, 6H), 1.75 (s, 3H),

2.34 (s, 2H), 3.90 (s, 3H), 7.09 (d, J = 1.8 Hz, 1H),

7.18 (bd, J = 6.8 Hz, 2H), 7.33-7.46 (m, 4H), 7.60 (d, J = 8.8 Hz, 2H), 7.65 and 7. , 67 (bs over d, J = 1.9 Hz, 1H), 8.00 (d, J = 8.7 Hz, 2H).

MS (DCI) m / e: 426 (MH ⁺ ).

Example 60

4 - {[(5,6-Dihydro-8-phenyl-5,5,7-trimethyl-2-naphthyl) carbonyl] amino (benzoic acid (He)

(I ⁴ e) mg (0.23 mmol) (Pe) of the compound, 1.15 ml (2.30 mmol) of 2M aqueous sodium hydroxide solution and 5 ml of a mixture of tetrahydrofuran and 5 ml of methanol is added 12 hours and stirred at room temperature. The resulting solution was acidified with 1M hydrochloric acid and then concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was triturated under diethyl ether / hexane to give the product as a white solid (77 mg, 82%).

1 H-NMR (DMSO-d 6): δ 1.33 (s, 3H), 1.69 (s, 3H), 2.31 (s, 2H), 7.02 (s, 1H), 7.15 (d, J = 7.9 Hz, 2H),

7.33-7.49 (m, 4H), 7.75 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.87 (d) , J = 8.6 Hz, 2H).

MS (DCI) m / e: 412 (MH +).

Elemental analysis for C 7 H _{25 2} O3N.0,25 _H2O Calcd:

Found: C, 77.95; H, 6.18; N, 3.37.

Found: C, 77.93; H, 6.01; N, 3.27.

Example 61

Methyl 10,10-dimethyl-9-oxo-5,8,8a, 9,10,10a-hexahydroanthracene-2-carboxylate (XXXVIIa)

A solution of (XXXa) enone (500 mg, 2.17 mmol) and aluminum chloride (260 mg, 1.95 mmol) in dry toluene (10 mL) was saturated with 1,3-butadiene at -78 ° C. The reaction mixture was stirred at room temperature for 18 hours and then diluted with 20 ml of 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 30 mL), and the combined extracts were washed with water (20 mL) and brine, then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5 by volume). As a result, the title compound was obtained as an oil (638 mg, quantitative).

1 H-NMR (CDCl 3): δ 1.45 (s, 3H), 1.49 (s, 3H),

1.60-1.75 (m, 1H), 2.10-2.30 (m, 3H), 2.99-3.06 (bd, J = 18 Hz, 1H), 3.29 (bs, 1H), 3.90 (s, 3H), 5.53-5.58 (m, 1H), 5.70-5.76 (m, 1H), 7.46 (d, J = 8.2 Hz) , 1H), 8.16 (dd, J = 1.8 Hz, J = 8.2 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H).

MS (DCI) m / e: 285 (MH ⁺ ).

Elemental analysis for C ₁₈ H ₂ o0 ₃ calcd: Calculated% C, 76.03; H, 7.09;

Found: C, 75.73; H, 7.25.

Example 62

Methyl 10,10-dimethyl-9-phenyl-5,8,10,10a-tetrahydroanthracene-2-carboxylate (XXXVIIIa)

To a solution of (XXXVIIa) (600 mg, 2.11 mmol) in dry tetrahydrofuran (5 mL) at -30 ° C was slowly added a solution of phenylmagnesium bromide (1.76 mL, 5.28 mmol) in diethyl ether. The mixture was stirred at -30 ° C for 15 minutes and then allowed to warm slowly to 0 ° C over about 20 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was partially purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). As a result, 520 mg

HU 218 963 Β was obtained in the form of a crude alcohol. Anhydrous benzene (10 ml) and ptoluenesulfonic acid (50 mg) were added to the alcohol, and the reaction mixture was refluxed for 3 hours with stirring. The solvent was then evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:30 to 1:20 v / v). This gave the title compound as an oil (265 mg, 36%).

1 H-NMR (CDCl 3); δ 1.34 (s, 3H), 1.44 (s, 3H),

1.92-2.05 (m, 1H), 2.25-2.45 (m, 2H), 2.65-2.80 (m, 2H), 3.78 (s, 3H), δ, 55-5.78 (m, 2H), 7.16 (d, J = 6.8 Hz, 2H), 7.31 (d, J = 1.7 Hz, 1H), 7.30-7.50 (m, 6H), 7.82 (dd, J = 1.7 Hz, J = 8.0 Hz, 1H).

Example 63

10,10-Dimethyl-9-phenyl-5,8,10,10a-tetrahydroanthracene-2-carboxylic acid (XVIIIg)

A solution of XXXVIIIa (260 mg, 0.75 mmol), 3M aqueous sodium hydroxide (2.5 mL, 7.5 mmol) and methanol (2 mL) was stirred at 80 ° C for 3 h. The solvent was evaporated, diluted with 1M hydrochloric acid and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. This gave the title compound (235 mg, 95%).

1 H-NMR (CDCl 3): δ 1.34 (s, 3H), 1.44 (s, 3H),

1.93-2.05 (m, 1H), 2.25-2.37 (m, 1H), 2.41 (dd, J = 5.0 Hz, J = 11, 9 Hz, 1H), 2 , 65-2.80 (m, 2H),

5.60-5.70 (m, 2H), 7.14 (d, J = 6.7 Hz, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.36-7 , 46 (m, 4H), 7.85 (dd, J = 1.8 Hz, J = 8.0 Hz, 1H).

MS (DCI) m / e: 331 (MH +).

Elemental Analysis for: C23H22O2: Calculated: C, 83.61; H, 6.71;

Found: C, 83.25; H, 6.86.

Example 64

Methyl 4 - {[(5,8,10,10a-tetrahydro-1 0,10-dimethyl-9-phenyl-2-anthracenyl) carbonyl] amino} benzoate (Pf)

To a solution of (XVIIIg) acid (225 mg, 0.68 mmol) in methylene chloride (4 mL) at 0 ° C was added oxalyl dichloride (172 mg, 1.36 mmol) and a drop of N, N-dimethylformamide. The solution was stirred at 0 ° C for 2 hours and then at room temperature for 1 hour. The solvent was evaporated and the residue was dried under vacuum. To the residue was added methyl p-aminobenzoate (122 mg, 0.81 mmol) and anhydrous pyridine (2 mL). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was diluted with 1M hydrochloric acid (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / hexane (1: 20 to 1: 5, v / v). 210 mg (67%) of the title compound were obtained.

1 H-NMR (CDCl 3): δ 1.36 (s, 3H), 1.45 (s, 3H), 1.95-2.05 (m, 1H), 2.33 (dt, J = 4, 6 Hz, J = 16.1 Hz, 1H), 2.44 (dd, J = 5.1 Hz, J = 12.0 Hz, 1H), 2.65-2.82 (m, 2H), 3 , 89 (s, 3H), 5.60-5.73 (m, 2H), 7.09 (d, J = 1.9 Hz, 1H), 7.18 (bd, J = 6.7 Hz), 2 H),

7.33-7.47 (m, 4H), 7.59-7.65 (m, 3H), 7.70 (bs, 1H), 8.00 (d, J = 8.8 Hz, 2H). .

MS (DCI) m / e: 464 (MH +).

Example 65

4- {[(5,8,10,10a- Tetrahydro-10,10-dimethyl-9-phenyl-2antracenil) carbonyl / amino} benzoic acid (I ⁴ f)

A solution of (Pf) ester (210 mg, 0.45 mmol) and dibutyltin oxide (228 mg, 0.92 mmol) in dry toluene (5 mL) was heated at reflux for 2 days with stirring. The reaction mixture was then treated with 1M hydrochloric acid (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water (10 mL) and concentrated to about 20 mL. The solution was then stirred for 30 minutes with 10 ml of 20% potassium fluoride solution. The mixture was extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with methanol / dichloromethane (1: 100 to 1: 5, v / v). This gave the title product as a yellow solid (72 mg, 35%).

1 H-NMR (DMSO-d 6): δ 1.30 (s, 3H), 1.41 (s, 3H), 1.85 (bt, J = 12.1 Hz, 1H), 2.28-2 , 35 (m, 1H),

HU 218,963 Β

1 H-NMR (CDCl ₃ ): δ 8.00 (d, J = 8.4 Hz, 2H),

7.47 (d, J = 8.4 Hz, 2H), 6.76 (m, 1H), 5.87 (d,

J = 17.6 Hz, 1H), 5.38 (d, J = 11.0 Hz, 1H), 3.91 (s, 3H).

MS (DCI) m / e: 163 (MH ⁺ ).

2.41 (dd, J = 5.0 Hz, J = 11.5 Hz, 1H), 2.55 (bd, J = 19.1 Hz, 1H), 2.75 (bd, J = 19.1) Hz, 1H),

5.60-5.80 (m, 2H), 7.02 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 6.9 Hz, 2H), 7.35-7 , 48 (m, 4H), 7.73 (dd, J = 1.9 Hz, J = 8.2 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H),

7.86 (d, J = 8.8 Hz, 2H), 10.35 (s, 1H).

MS (DCI) m / e: 450 (MH +).

Elemental analysis for C ₃₀ H ₂₇ O ₃ N.0.75H ₂ O:

Found: C, 77.81; H, 6.20; N, 3.02;

Found: C, 78.09; H, 5.99; N, 3.14.

Example 66

4,4-Dimethyl-7-iodo-1-tetralone (XXXIX)

To a solution of 4,4-dimethyl-7-amino-1-tetralone (XII) (1.82 g, 10.0 mmol) in concentrated hydrochloric acid (4.69 mL) was added ice cold water (3.13 mL). The reaction mixture was then cooled to 0 ° C using a salted ice bath and diazotized by adding dropwise a solution of sodium nitrite (0.76 g, 11.0 mmol) in water (3.13 mL) while stirring at 0 ° C. The temperature was kept at -5 ° C. The reaction mixture was stirred for 15 minutes and then added to a solution of 3.63 g (21.9 mmol) in 18.8 mL of water. The resulting mixture was allowed to stand for 30 minutes and the dark gum was extracted once with 100 mL of ethyl acetate. The organic phase was then concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). This afforded the title compound (1.56 g, 54%).

1 H-NMR (CDCl ₃ ): δ 8.33 (d, J = 2.0 Hz, 1H),

7.82 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 2.72 (t, J = 6.8) Hz, 2H), 2.01 (t, J = 6.8 Hz, 2H),

1.37 (s, 6H).

MS (DCI) m / e: 301 (MH +).

Example 67

Methyl 4-vinyl benzoate

To a solution of 2.18 g (14.7 mmol) of 4-vinylbenzoic acid (Aldrich) in 14.0 ml of anhydrous acetonitrile at 0 ° C was added 2.46 g (16.2 mmol) of 1,8-diazabicyclo [5.4. .0] undec-7 (DBU; Aldrich) and

3.13 g (22.1 mmol) of methyl iodide (Aldrich). The reaction mixture was then warmed to room temperature and stirred for 3 hours. To the mixture was added ethyl acetate (100 mL) and the solution was washed with saturated brine (50 mL). The organic phase was then separated and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). This gave the title compound (1.05 g, 44%).

Example 68

Methyl 4 - {(E) - [2- (5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthyl)] - vinyl} benzoate (XLa)

4,4-Dimethyl-7-iodo-1-tetralone (XXXIX) (1.55 g, 5.17 mmol) and methyl 4-vinylbenzoate (1.67 g, 10.34 mmol) in ,0- To a solution of dimethylformamide, 58 mg (0.259 mmol) of palladium (II) acetate (Aldrich), 1.49 g (5.17 mmol) of tetrabutylammonium chloride hydrate (Aldrich) and 1.09 g (12 9 mmol) of sodium bicarbonate (Mallinckrodt). The reaction mixture was heated at 70 ° C for 4 hours and then stirred at room temperature for 16 hours. To the mixture was added ethyl acetate (50 mL) and the solution was washed with saturated aqueous sodium chloride solution (50 mL). The organic layer was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90). This gave the title compound (1.29 g, 75%).

1 H-NMR (CDCl ₃ ): δ 8.19 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 6.69 (dd, J = 8) , 1 Hz, J = 1.7 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8, 1 Hz, 1H),

7.21 (s, 2H), 3.93 (s, 3H), 2.76 (t, J = 6.8 Hz, 2H), 2.05 (t, J = 6.8 Hz, 2H), 1.41 (s, 6H).

MS (DCI) m / e: 335 (MH +).

Example 69

Methyl 4 - {(E) - [2- (5,5-dimethyl-8-phenyl-8-hydroxy-5,6,7,8-tetrahydro-2-naphthyl)] - vinyl} benzoate (XLla)

Preparation of the title compound in an analogous manner to that described for the preparation of the 8-phenyl derivative (XVIIa) afforded 1.39 g (87%) of the desired compound using 1.29 g (3.86 mmol) of XLa. .

HU 218,963 Β

1 H-NMR (CDCl 3): δ 7.98 (d, J = 8.1 Hz, 2H),

7.48 (m, 5H), 7.31 (s, 5H), 7.03 (m, 2H), 3.91 (s, 3H),

2.22 (m, 2H), 1.85 (m, 1H), 1.60 (m, 1H), 1.40 (s, 3H),

1.35 (s, 3H).

Example 70

4 - {(E) - [2- (5,6-Dihydro-5,5-dimethyl-8-phenyl-naphthalene-2-

To a solution of (XLIa) (1.38 g, 3.35 mmol) in toluene (20 mL) was added p-toluenesulfonic acid (p-TsOH) (20 mg). The reaction mixture was heated at 70 ° C for 30 minutes, then cooled and concentrated in vacuo. The residue was dissolved in 20.0 mL of a 1: 1 mixture of ethanol / tetrahydrofuran and then 3.37 mL (33.7 mmol) of 10 M aqueous sodium hydroxide was added at room temperature. After stirring at room temperature for 16 hours, an excess of 1M hydrochloric acid (75 mL) was added and the resulting precipitate was collected by vacuum filtration. This gave 1.23 g (97%) of the title compound.

1 H-NMR (DMSO-d ₆ ): δ 12.87 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H) ), 7.58 (dd, J = 8.1 Hz, J = 1.7 Hz, 1H), 7.47-7.24 (m, 7H), 7.07 (m, 2H), 6.00 (t, J = 4.5 Hz, 1H), 2.30 (d, J = 4.5 Hz, 2H),

1.28 (s, 6H).

3 C NMR (DMSO-d ₆ ): δ 167.02,145.09, 141.35, 140.16, 138.59, 134.22, 133.52, 130.96, 129.66, 129.23, 128 , 52, 128.33, 127.31, 126.87, 126.65, 126.45,125,30,124,69,124.46, 38,23,33,29,27,89.

MS (DCI) m / e: 381 (MH +).

IR (KBr): 2922, 2818, 1684, 1604 cm -1.

Elemental analysis for C ₂₇ H ₂₄ O ₂ .0.65 H ₂ O:

Found: C, 82.69; H, 6.50;

Found: C, 83.00; H, 6.41.

Example 71

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl) carbonyl] thio} benzoic acid (I ¹² a)

(I> ² a)

To a solution of XVIIIa (119 mg, 0.430 mmol) in dichloromethane (5.0 mL) at 0 ° C was added oxalyl dichloride (0.13 mL, 1.5 mmol) and N, N-dimethylformamide (2 drops). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in 5.0 ml of anhydrous pyridine and then 66 mg (0.43 mmol) of methyl 4-mercaptobenzoate (Apin) was added. The reaction mixture was stirred at room temperature for 3 hours and then diluted with 1M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (50 mL), and the organic layer was washed with 1M HCl (3 x 50 mL) and brine (2 x 100 mL). The organic phase was then separated and concentrated in vacuo. The residue was chromatographed on silica gel using methanol / dichloromethane (5:95) as eluent. This gave the title compound (40 mg, 23%).

1 H-NMR (DMSO): δ 7.98 (d, J = 8.3 Hz, 2H),

7.91 (dd, J = 8.1 Hz, J = 2.0 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2) Hz, 2H), 7.48-7.27 (m, 6H), 6.11 (t, J = 4.5 Hz, 1H), 2.38 (d, J = 4.5 Hz, 2H), 1.33 (s, 6H).

MS (DCI) m / e: 415 (MH ⁺ ).

IR (KBr): 3440, 2962, 1684, 1594.

Elemental analysis for C ₂₆ H ₂₂ O ₃ S.1.2 H ₂ O:

Found: C, 71.60; H, 5.64;

Found: C, 71.65; H, 5.44.

Example 72 tert-Butyl 4 - {[(5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-2-naphthyl) thio] carbonyl} benzoate (XLIVa)

(XLIVa)

To a solution of mono (tert-butyl) terephthalate (122 mg, 0.550 mmol) in dry methylene chloride (5.0 mL) at 0 ° C was added oxalyl dichloride (0.17 mL, 1.95 mmol) and 2 drops of N, N-dimethyl. formamide. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in 5.0 ml of anhydrous pyridine and 113 mg (0.550 mmol) of 4,4-dimethyl-7-mercapto-1-tetralone (XLIII) was added. After stirring for 2 hours at room temperature, the reaction mixture was diluted with 1M hydrochloric acid, extracted with 50 mL of ethyl acetate, and the organic layer was washed with 1M hydrochloric acid (3 x 50 mL) and saturated aqueous sodium bicarbonate (2 x 50 mL). The organic phase was then separated and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90 v / v). for this

HU 218 963 80 yielded the title compound (80 mg, 35%).

1 H-NMR (CDCl ₃ ): δ 8.16 (d, J = 1.8 Hz, 1H), 8.11-8.03 (m, 4H), 7.67 (dd, J = 8.3 Hz) , J = 2.1 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 2.77 (t, J = 6.8 Hz, 2H), 2.06 (t, J = 5.8 Hz, 2H), 1.63 (s, 9H), 1.44 (s, 6H).

MS (DCI) m / e: 355 (MC ₄ H ₉ + H) +.

Example 73 tert-Butyl 4 - {[(5,5-dimethyl-8-phenyl-8-hydroxy-5,6,7,8-tetrahydro-2-naphthyl) thio] carbonyl} benzoate

Preparation of the title compound in an analogous manner to the procedure for the preparation of the (XVIIa) 8-phenyl derivative afforded 46 mg (50% yield) of XLIVa (80 mg, 0.19 mmol).

1 H-NMR (CDCl ₃ ): δ 8.03 (m, 4H), 7.52 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 8.2 Hz, J = 2 , 1 Hz, 1H), 7.20 (m, 6H), 2.30-2.10 (m, 3H), 1.90 (m, 1H),

1.63 (s, 9H), 1.45 (s, 3H), 1.37 (s, 3H).

MS (DCI) m / e: 471 (MH ⁺ )

Example 74

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) thio]

To a solution of XLVa (5.0 mg, 0.094 mmol) in toluene (5.0 mL) was added a few milligrams (about 3 mg) of p-toluenesulfonic acid. The reaction mixture was heated at 70 ° C for 30 minutes, then cooled and concentrated in vacuo. The residue was dissolved in methylene chloride (2.0 mL) and trifluoroacetic acid (0.08 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours and then diluted with ethyl acetate (20 mL) and the resulting solution was washed with 1M hydrochloric acid (20 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. This gave the title compound (34 mg, 87%).

1 H-NMR (DMSO-d ₆ ): δ 8.03 (m, 4H), 7.53 (d, J = 8.1 Hz, 1H), 7.43-7.30 (m, 6H), δ , 96 (d, J = 1.9 Hz, 1H), 6.07 (t, J = 4.5 Hz, 1H), 2.36 (d, J = 4.5 Hz, 2H),

1.18 (s, 6H).

MS (DCI) m / e: 415 (MH +).

IR (KBr): 3432, 2962, 1680, 11202.

Elemental analysis for C ₂₆ H ₂₂ O ₃ S.0.35 H ₂ O:

Found: C, 74.21; H, 5.44;

Found: C, 74.18; H, 5.22.

Example 75

Ethyl 4- [2- (5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) -ethyl-benzoate

310 kPa (45 psi) of hydrogen with stirring was added 15 mg, poisoned with lead, 5% palladium / calcium carbonate catalyst (I ⁱ⁵ a) A compound in 7.0 ml of toluene (Lindlar 118 mg (0.290 mmol) catalyst, Aldrich). The reaction mixture was stirred for 16 hours and then filtered through a pad of celite. The filtrate was concentrated in vacuo. This gave the title compound (60 mg, 50%).

1 H-NMR (CDCl 3): δ 7.93 (d, J = 8.1 Hz, 2H),

7.30 (m, 6H), 7.18 (d, J = 8.1 Hz, 2H), 7.05 (dd, J = 7.9 Hz, J = 1.8 Hz, 1H), 6, 81 (d, J = 1.8 Hz, 1H), 5.97 (t, J = 4.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H),

2.84 (m, 4H), 2.34 (d, J = 4.5 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.33 (s, 6H).

MS (DCI) m / e: 411 (MH +).

Example 76

4- [2- (5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) -

To a solution of ethyl 4- [2- (5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) ethyl] benzoate (5.0 mg, 0.146 mmol) in ethanol (5.0 mL) was added 2 (0 mmol) in 10 M aqueous sodium hydroxide solution. The reaction mixture was heated at 70 ° C for one hour, then cooled and 1M hydrochloric acid (20 mL) was added in excess. The precipitate was filtered off with suction

HU 218,963 Β was recovered. This gave the title compound (59 mg, 99%).

1 H-NMR (DMSO-d ₆ ): δ 7.79 (d, J = 8.2 Hz, 2H), 7.38-7.29 (m, 3H), 7.25 (d, J = 8, 2 Hz, 2H),

7.21-7.10 (m, 4H), 6.62 (d, J = 1.7 Hz, 1H), 5.93 (t, J = 4.5 Hz, 1H), 2.78 (m , 4H), 2.25 (d, J = 4.5 Hz, 2H),

1.24 (s, 6H).

MS (DCI) m / e: 383 (MH +).

IR (KBr): 2956, 1688, 1610, 1422 cm -1.

Elemental Analysis for: C ₂₇ H ₂₆ O ₂ : Calculated: C, 84.78; H, 6.84;

Found: C, 84.53; H, 6.81.

Example 77

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) thiocarbonyl] amino} benzoate

To a solution of 6.0 mL tetrahydrofuran the compound (285 mg, 0.693 mmol), (I ³ a) was added phosphorous (205 mg, 0.461 mmol), (V) sulfide (Aldrich). The reaction mixture was refluxed for 45 minutes and then concentrated. The residue was diluted with dichloromethane (50 mL) and the resulting mixture was washed with 5% aqueous sodium carbonate (2 x 50 mL). The organic phase was then concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90 v / v). This gave the title compound (88 mg, 30%).

1 H-NMR (CDCl 3): δ 8.92 (s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.74 (dd, J = 8.2 Hz, J = 1 , 8 Hz, 1H),

7.43 (d, J = 8.1 Hz, 1H), 7.33 (m, 8H), 6.07 (t, J = 4.5 Hz, 1H), 3.92 (s, 3H), 2.38 (d, J = 4.5 Hz, 2H),

1.36 (s, 6H).

MS (DCI) m / e: 428 (MH +).

Example 78

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) thiocarb

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in the preparation of 8-phenyl derivative chromatography to give methyl 4 (80 mg, 0.186 mmol) - {[(5,6-dihydro-5,5-dimethyl-8-phenyl 69 mg (90%) of the desired compound were obtained using 2-naphthyl) thiocarbonyl] amino} benzoate.

1 H-NMR (DMSO-d ₆ ): δ 12.88 (s, 1H), 11.89 (s, 1H), 7.87 (m, 4H), 7.60 (dd, J = 8.0 Hz) , J = 1.7 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.35 (m, 6H), 6.07 (t, J = 4.5 Hz, 1H) ), 2.35 (d, J = 4.5 Hz, 2H),

1.32 (s, 6H).

MS (DCI) m / e: 414 (MH ⁺ ).

IR (KBr): 2922, 1688, 1606, 1514.

Elemental analysis for C ₂₆ H ₂₃ O ₂ NS.0,5 H ₂ O:

Found: C, 73.91; H, 5.73; N, 3.31;

Found: C, 73.60; H, 5.76; N, 3.21.

Example 79

5,6-Dihydro-5,5-dimethyl-8-phenyl-2- {1 - [(trimethylsilyl) oxy] vinyl} naphthalene (L Via)

To a solution of 2.32 g (9.89 mmol) of Example 32 (XIXa) in 10.0 mL of dry dichloromethane was added 1.80 g (11.87 mmol) of 1,8-diazabicyclo [5.4.0 ] undec-7-ene (Aldrich) and 1.18 g (10.8 mmol) of trimethylsilyl chloride. The reaction mixture was heated to gentle reflux for 2 hours and then cooled to room temperature for 16 hours. To the mixture was added pentane (100 mL) and washed with 0.1 M hydrochloric acid (50 mL) and dilute aqueous sodium bicarbonate (50 mL). The organic phase was then dried over anhydrous magnesium sulfate and concentrated in vacuo. As a result of this

3.17 g (92%) of the title compound were obtained.

1 H-NMR (CDCl 3): δ 7.45 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.39-7.24 (m, 7H), 5.99 (t, J = 4.5 Hz, 1H), 4.74 (d, J = 1.6 Hz, 1H), 4.30 (d, J = 1.6 Hz, 1H),

2.35 (d, J = 4.5 Hz, 2H), 1.34 (s, 6H), 0.14 (s, 9H).

Example 80

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) -

864 mg (2.48 mmol) of LVIa and 355 mg (1.65 mmol) of methyl 4-bromobenzoate (Aldrich) in 10.0 mL of water 53

To a solution of EN 218 963 Β in benzene-free benzene was added 806 mg (2.61 mmol) of tributyltin fluoride (Aldrich) and 59 mg (0.074 mmol) of PdCl ₂ [P (o-CH ₃ C ₆ H ₄ ) ₃ ] _2. complex previously obtained from 19.3 mg (0.074 mmol) of bis (acetonitrile) palladium (II) chloride (Aldrich) and

45.3 mg (0.149 mmol) of tris (o-tolyl) phosphine (Aldrich) were prepared. The reaction mixture was refluxed for 4 hours, then cooled, diluted with ethyl acetate (50 mL) and washed with 1M aqueous sodium hydroxide (50 mL). The organic phase was chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). This gave the title compound (265 mg, 39%).

1 H-NMR (CDCl ₃ ): δ 7.92 (d, J = 8.5 Hz, 2H),

7.87 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.41 (m, 3H), 7.29 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.03 (t, J = 4.5) Hz, 1H),

4.12 (s, 2H), 3.90 (s, 3H), 2.37 (d, J = 4.5 Hz, 2H),

1.35 (s, 6H).

MS (DCI) m / e: 411 (MH ⁺ ).

Example 81

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carboxylic acid]

To a solution of 200 mg (0.488 mmol) of (I ²² a) in anhydrous toluene was added dibutyltin oxide (Aldrich) (364 mg, 1.46 mmol). The reaction mixture was refluxed for 16 hours and then concentrated in vacuo. The residue was chromatographed on silica gel using methanol / dichloromethane (5:95) as eluent. In this way, 70 mg of product contaminated with tin by-products was obtained. A second purification by preparative thin layer chromatography afforded 10 mg (5%) of the title compound.

1 H-NMR (DMSO-d ₆ ): δ 7.99 (dd, J = 7.9 Hz, J = 1.9 Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.42 (m, 3H), 6.05 (t, J = 4.5 Hz, 1H), 4.30 (s, 1H), 4.28 (s, 1H), 2.34 (d, J = 4.5 Hz, 2H), 1.31 (s, 6H).

MS (DCI) m / e: 397 (MH +).

HRMS calcd = 397.1804; Found = 397.1816; 3.0 ppm deviation.

Example 82

5,6-Dihydro-5,5-dimethyl-8-phenyl-2- (hydroxymethyl) naphthalene (LVIIa)

A mixture of 95% by weight lithium aluminum hydride powder (LAH) (1.0 mmol) in dry diethyl ether (5.0 ml) was refluxed until most of the lithium aluminum hydride was dissolved. A solution of (XVIIIa) (485 mg, 1.66 mmol) in dry diethyl ether (5.0 mL) was added slowly to the resulting solution. After stirring for 30 minutes, ethyl acetate (20 mL) and 1M hydrochloric acid (20 mL) were added. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. This afforded the title compound (368 mg, 84%).

1 H-NMR (CDCl ₃ ): δ 7.36 (m, 6H), 7.26 (m, 1H), 7.02 (d, J = 1.8 Hz, 1H), 5.99 (t, J = 4.5 Hz, 1H), 4.55 (s, 2H), 2.05 (d, J = 4.5 Hz, 2H), 1.34 (s, 6H).

MS (DCI) m / e: 247 (M ⁺ -OH).

Example 83

5,6-Dihydro-5,5-dimethyl-8-phenyl-2- (bromomethyl) naphthalene (LVIIIa)

To a solution of carbon tetrabromide (Aldrich) (1.36 g, 4.09 mmol) and triphenylphosphine (Aldrich, 1.07 g, 4.09 mmol) in dry diethyl ether (20 mL) was added 900 mg (3.41 mmol). (LVIIa). The reaction mixture was stirred at room temperature for 16 hours, then filtered and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (3:97, v / v). This gave the title compound (790 mg, 71%).

1 H-NMR (CDCl ₃ ): δ 7.39 (m, 6H), 7.27 (dd, J = 8.1 Hz, J = 1.8 Hz, 1H), 7.04 (d, J = 1) , 8 Hz, 1H), 6.01 (t, J = 4.5 Hz, 1H), 4.39 (s, 2H), 2.35 (d, J = 4.5 Hz, 2H), 1, 34 (s, 6H).

MS (DCI) m / e: 327 (MH +).

Example 84

Ethyl 4 - [(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) ylmethoxy benzoate (I ²⁵ a)

HU 218,963 Β

Example 86

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) oxy] methyl} benzoic acid (I ²⁷ a)

A solution of ethyl 4-hydroxybenzoate (Aldrich) (152 mg, 0.917 mmol) in ethylene glycol dimethyl ether (6.0 mL) was treated with 60% sodium hydride (43 mg, 1.05 mmol) at room temperature. After stirring for 9 minutes, LVIIIa (330 mg, 1.01 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (50 mL) and washed with 1M hydrochloric acid (2 x 50 mL). The organic layer was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90). This afforded the title compound (64 mg, 17%).

1 H-NMR (CDCl ₃ ): δ 7.97 (d, J = 8.8 Hz, 2H),

7.36 (m, 7H), 7.06 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.01 (t, J = 4.5 Hz, 1H), 4.96 (s, 2H), 4.34 (q, J = 7.2 Hz, 2H), 2.36 (d, J = 4.5 Hz, 2H), 1.40 (t, J = 7 , 2 Hz, 3H),

1.35 (s, 6H).

MS (DCI) m / e: 413 (MH +).

Example 85

4 - [(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) methoxy] benzoic acid ( ¹² a)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation procedure, to afford 50 mg (84%) of the desired compound using the compound (64 mg, 0.155 mmol) (S ^25).

1 H-NMR (DMSO-d ₆ ): δ 12.59 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.33 (m, 7H), 6.97 ( d, J = 8.9 Hz, 2H), 6.96 (s, 1H), 5.99 (t, J = 4.5 Hz, 1H), 5.04 (s, 2H),

2.30 (d, J = 4.5 Hz, 2H), 1.27 (s, 6H).

MS (DCI) m / e: 385 (MH +).

IR (KBr): 2958,1682,1604,1252 cm -1.

Elemental analysis for C ₂₆ H ₂₄ O ₃ .0.25 H ₂ O:

Found: C, 80.28; H, 6.35;

Found: C, 80.41; H, 6.23.

To a solution of this compound in ethylene glycol dimethyl ether (5.0 mL) was added sodium hydride (60 mg, 0.888 mmol, 60%) at room temperature. After stirring for 15 minutes at room temperature, methyl 4- (bromomethyl) benzoate (Aldrich) (195 mg, 0.848 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then 60 mg of sodium hydride (60 mg, 0.888 mmol) was added again. The reaction mixture was then refluxed for 24 hours, then diluted with 50 mL of ethyl acetate and washed twice with 50 mL of 1M hydrochloric acid. The organic phase was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). This gave 170 mg of slightly impure material. The crude product was dissolved in 3 mL of ethanol and 20 mL of 1M hydrochloric acid was added. The precipitate was collected by vacuum filtration. As a result, the title compound was isolated in 50 mg (16% yield).

1 H-NMR (DMSO-d 6): δ 12.95 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H) ), 6.44 (d, J = 2.7 Hz, 1H), 5.97 (t, J = 4.5 Hz, 1H), 5.04 (s, 2H),

2.27 (d, J = 4.5 Hz, 2H), 1.24 (s, 6H).

MS (DCI) m / e: 385 (MH +).

IR (KBr): 3442, 1682, 1282 cm -1.

Elemental analysis for C ₂₆ H ₂₄ O ₃ .0.5 H ₂ O:

Found: C, 80.59; H, 6.50;

Found: C, 80.31; H, 6.26.

Example 87

Methyl 5,5-dimethyl-8- (2,4-dimethylphenyl) -8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (XVIIe)

Preparation of the title compound according to the procedure for the preparation of (XVIId) 8- (2-fluorophenyl) derivative

This was carried out analogously to afford the title compound (281 mg, 63%) using 311 mg (1.34 mmol) of XVIa.

1 H-NMR (CDCl 3): δ 7.91 (dd, J = 8.3 Hz, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.49 (d, J = 8 , 3 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 3.80 (s, 3H),

2.76 (m, 1H), 2.34 (m, 1H), 2.32 (s, 3H), 2.08 (m, 1H),

1.63 (m, 1H), 1.55 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H).

MS (DCI) m / e: 339 (MH ⁺ ).

Example 88

5,6-Dihydro-5,5-dimethyl-8- (2,4-dimethyl-phenyl) -naphthalene-2-carboxylic acid (XVHIh)

Preparation of the title compound in an analogous manner to that described for the preparation of the (XVIIIe) 8-phenyl derivative afforded 311 mg (1.34 mmol) of XVIIa (285 mg, 63% yield).

1 H-NMR (CDCl 3): δ 7.78 (dd, J = 8.0 Hz, J = 1.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7 18 (d, J = 1.6 Hz, 1H), 7.06 (m, 3H), 5.86 (t, J = 4.5 Hz, 1H),

2.35 (m, 2H), 2.33 (s, 3H), 1.99 (s, 3H), 1.39 (s, 3H),

1.28 (s, 3H).

MS (DCI) m / e: 307 (MH +).

Example 89

Methyl 4 - [{[5,6-dihydro-5,5-dimethyl-8- (2,4-dimethylphenyl) -2-naphthyl] carbonyl} amino] benzoate (Ph)

The title compound was prepared analogously to the procedure described for the preparation of 8- (2-fluorophenyl) derivative ( ¹³ g), which afforded 221 mg (0.722 mmol) of XVIIIh (67 mg, 21%). the desired compound.

1 H-NMR (CDCl ₃ ): δ 8.00 (d, J = 8.7 Hz, 2H),

7.77 (s, 1H), 7.68 (dd, J = 8.2 Hz, J = 1.7 Hz, 1H),

7.63 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H),

7.15 (d, J = 1.7 Hz, 1H), 7.06 (m, 3H), 5.93 (t,

J = 4.5 Hz, 1H), 3.90 (s, 3H), 2.43 (m, 2H), 2.36 (s, 3H), 2.08 (s, 3H), 1.45 ( s, 3H).

MS (DCI) m / e: 440 (MH +).

Example 90

4- [{[5,6-Dihydro-5,5-dimethyl-8- (2,4-dimethylphenyl) -2-naphthalenyl] carbonyl} amino] benzoic acid (I ⁴ h)

(I ^4h )

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation procedure, to afford 61 mg (94%) of the desired compound using the compound (67 mg, 0.153 mmol) (Ph).

1 H-NMR (DMSO-d ₆ ): δ 12.72 (s, 1H), 10.40 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.80 ( m, 3H), 7.52 (d, J = 8.0 Hz, 1H), 7.04 (m, 4H), 5.88 (t, J = 4.5 Hz, 1H),

2.38 (m, 2H), 2.31 (s, 3H), 1.99 (s, 3H), 1.41 (s, 3H),

1.29 (s, 3H).

MS (DCI) m / e: 426 (MH ⁺ ).

IR (KBr): 2960.1688, 1594.1518 cm -1.

Elemental analysis for C ₂₈ H ₂₇ O ₃ N.0,5 H ₂ O:

Found: C, 77.39; H, 6.50; N, 3.22;

Found: C, 77.57; H, 6.50; N, 3.22.

Example 91

Methyl 5,5-dimethyl-8- (4-methylphenyl) -8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (XVIIf)

The title compound was prepared analogously to the procedure described for the preparation of the (XVIId) 8- (2-fluorophenyl) derivative, which afforded 260 mg (1.12 mmol) of XVIa (189 mg, 52%). the desired compound.

1 H-NMR (CDCl 3): δ 7.92 (dd, J = 8.4 Hz, J = 1.7 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7 47 (d, J = 8.4 Hz, 1H), 7.10 (s, 4H), 3.82 (s, 3H), 2.34 (s, 3H),

2.18 (m, 2H), 1.80 (m, 1H), 1.60 (m, 1H), 1.39 (s, 3H), 1.34 (s, 3H).

MS (DCI) m / e: 325 (MH +).

HU 218,963 Β

Example 92

5,6-Dihydro-5,5-dimethyl-8- (4-methylphenyl) -naphthalene-2-carboxylic acid (XVIIIi)

(XVIIIa)

The title compound was prepared analogously to the procedure described for the preparation of the (XVIIIa) 8-phenyl derivative to afford the title compound (155 mg, 91%) using 189 mg (0.583 mmol) of XVIIf.

1 H-NMR (CDCl ₃ ): δ 7.81 (dd, J = 8.0 Hz, J = 1.7 Hz, 1H), 7.51 (d, J = 1.7 Hz, 1H), δ , 49 (d, J = 8.0 Hz, 1H), 7.23 (m, 4H), 6.00 (t, J = 4.5 Hz, 1H), 2.35 (s, 3H), 2 , 33 (d, J = 4.5 Hz, 1H), 1.30 (s, 6H).

MS (DCI) m / e: 293 (MH +).

Example 93

Methyl 4 - [{[5,6-dihydro-5,5-dimethyl-8- (4-methylphenyl) -2-naphthyl] carbonyl] amino] benzoate (Pi)

(Pi)

Preparation of the title compound in an analogous manner to the procedure for the preparation of (Pg) 8- (2-fluorophenyl) afforded 143 mg (63%) of XVIIIi (155 mg, 0.531 mmol). compound.

1 H-NMR (CDCl 3): δ 8.02 (d, J = 8.8 Hz, 2H),

7.74 (s, 1H), 7.72 (dd, J = 8.0 Hz, J = 1.8 Hz, 1H),

7.66 (d, J = 8.8 2H), 7.53 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.23 ( m, 4H), 6.06 (t, J = 4.5 Hz, 1H),

3.90 (s, 3H), 2.40 (s, 3H), 2.39 (d, J = 4.5 Hz, 2H), 1.54 (s, 3H), 1.37 (s, 3H) ).

MS (DCI) m / e: 426 (MH +).

Example 94

4 - [{[5,6-Dihydro-5,5-dimethyl-8- (4-methylphenyl) -2naftil] carbonyl} amino] benzoic acid (I ⁴ i)

(Pi)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation process to yield the desired compound using the compound (143 mg, 0.336 mmol) (Pi) in an amount of 123 mg (89% yield).

1 H-NMR (DMSO-d 6: δ 12.72 (s, 1H), 10.42 (s, 1H), 7.85 (m, 5H), 7.52 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.21 (s, 4H), 6.02 (t, J = 4.5 Hz, 1H),

2.33 (s, 3H), 2.33 (d, J = 4.5 Hz, 2H), 1.31 (s, 6H).

¹³ C-NMR (DMSO-d 6): δ 166.90,166.06,148.77, 143.28, 138.16, 136.93, 136.60, 133.49, 132.48, 130.19, 129.12 , 128.21, 126.75, 125.35, 125.03, 123.92, 119.38, 119.29, 37.98, 33.52, 27.75, 20.79.

MS (DCI) m / e: 412 (MH ⁺ ).

IR (KBr): 2960, 1688, 1594, 1518 cm -1.

Elemental analysis for C ₂₇ H ₂₅ O ₃ N.0.25 H ₂ O:

Found: C, 77.96; H, 6.18; N, 3.37.

Found: C, 77.73; H, 6.09; N, 3.29.

Example 95

4,4-Dimethyl-7-bromo-1-tetralone (XL VIII)

To a solution of sodium nitrate (2.18 g, 13.92 mmol) in concentrated sulfuric acid (28.4 mL) and glacial acetic acid (26.72 mL) cooled to 10 ° C was added 5.0 g (26.46 mmol) under stirring over about 10 minutes. A solution of 4,4-dimethyl-7-amino-1-tetralone (XII) in glacial acetic acid (89 ml) was prepared by addition of sodium nitrate to concentrated sulfuric acid cooled to 10 ° C, and heated to dissolution, cooled, and then glacial acetic acid was added). The resulting solution was added slowly (over about 10 minutes) to a solution of copper (I) bromide (16.66 g) in concentrated hydrogen bromide (159 mL) heated to 60 ° C. The mixture was heated at 90 ° C for 10 minutes, cooled, diluted with water (250 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (3:97, v / v). This gave 1.95 g (29%) of the title compound.

1 H-NMR (CDCl ₃ ): δ 8.13 (d, J = 2.3 Hz, 1H),

7.62 (dd, J = 8.5 Hz, J = 2.3 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 2.73 (t, J = 7.0) Hz, 2H), 2.01 (t, J = 7.0 Hz, 2H),

1.38 (s, 6H).

MS (DCI) m / e: 253 (MH ⁺ ).

HU 218,963 Β

Example 96

4.4- Dimethyl-7 - [(trimethylsilyl) ethynyl] -1-tetralone (IL)

To a gasified solution of 1.53 g (6.04 mmol) of XLVIII, 15.4 mg (0.975 mmol) of palladium (II) acetate (Aldrich) and 31 mg (0.118 mmol) of triphenylphosphine in 30 mL of anhydrous triethylamine (Trimethylsilyl) acetylene (Aldrich) (3.0 mL, 21.23 mmol) was added and the reaction mixture was heated to 100 ° C for 30 min and kept at this temperature for 4 h. The reaction mixture was then cooled to room temperature and stirred for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (3:97, v / v). 1.24 g (76%) of the title compound were obtained.

1 H-NMR (CDCl ₃ ): δ 8.11 (d, J = 1.8 Hz, 1H),

7.58 (dd, J = 8.2 Hz, J = 1.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 2.72 (t, J = 7.0) Hz, 2H), 2.01 (t, J = 7.0 Hz, 2H),

1.37 (s, 6H), 0.24 (s, 9H).

MS (DCI) m / e: 271 (MH ⁺ ).

Example 97

4.4- Ditnethyl-7-ethynyl-1-tetrailone (L)

To a solution of (IL) (1.24 g, 4.59 mmol) in absolute ethanol (8.0 mL) was added potassium carbonate (170 mg, 1.21 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo, diluted with 25 mL of saturated aqueous sodium bicarbonate and extracted with 2 x 25 mL of methylene chloride. The organic phases were combined, concentrated in vacuo and the residue chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). This gave the title compound (694 mg, 76%).

1 H-NMR (CDCl 3): δ 8.15 (d, J = 1.9 Hz, 1H),

7.62 (dd, J = 8.2 Hz, J = 1.9 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 3.07 (s, 1H), 2, 73 (t, J = 7.0 Hz, 2H), 2.02 J = 7.0 Hz, 2H), 1.39 (s, 6H).

MS (DCI) m / e: 199 (MH +).

Example 98

Ethyl 4 - [(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthyl) ethynyl] benzoate (LIA)

Compound (L) (153 mg, 0.773 mmol), ethyl 4-iodobenzoate (Lancester) (160 mg, 0.58 mmol), bis (triphenylphosphine) palladium (II) chloride (923 mg, 0.013 mmol) Aldrich) and copper (I) iodide (4.5 mg, 0.02 mmol) in triethylamine (3.0 mL) were stirred at room temperature for 2 hours. The reaction mixture was diluted with 25 mL of ethyl acetate and washed once with 25 mL of water. The organic phase was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90). This gave 183 mg (91%) of the title compound.

1 H-NMR (CDCl 3): δ 8.20 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.67 (dd, J = 8) , 2 Hz, J = 1.8 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1H),

4.39 (q, J = 7.1 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.04 (t, J = 6.8 Hz, 2H), 1, 41 (t, J = 7.1 Hz, 3H), 1.41 (s, 6H).

MS (DCI) m / e: 347 (MH +).

Example 99

Ethyl 4 - [(5,5-dimethyl-8-phenyl-8-hydroxy-5,6,7,8-tetrahydro-2-naphthyl) ethynyl] benzoate (Purple)

Preparation of the title compound was analogous to the procedure described for the preparation of the (XVIIa) 8-phenyl derivative to afford 177 mg (79% yield) of the title compound (183 mg, 0.529 mmol) in (LIa).

1 H-NMR (CDCl 3): δ 7.98 (d, J = 8.3 Hz, 2H),

7.50 (d, J = 8.3 Hz, 2H), 7.47-7.26 (m, 8H), 4.37 (q, J = 7.0 Hz, 2H), 2.20 (m , 2H), 1.89 (m, 1H), 1.60 (m, 1H), 1.41 (s, 6H), 1.39 (t, J = 7.0 Hz, 3H).

MS (DCI) m / e: 425 (MH &lt; + &gt;).

Example 100

4 - [(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl) ethynyl] benzoic acid (I ¹⁶ a)

To a solution of (Lila) (177 mg, 0.42 mmol) was added a few milligrams (about 10-20 mg) of p-toluenesulfonic acid. The reaction mixture was heated at 70 ° C for 30 minutes, then cooled and concentrated in vacuo. As a result, ethyl 4 - [(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphth58)

Yield 211,963 (ethyl) ethynyl] benzoate (I ' ⁵ a). The residue was dissolved in 5.0 mL of ethanol and then 0.65 mL (6.5 mmol) of 10 M aqueous sodium hydroxide was added at 70 ° C. After 30 minutes, 1M hydrochloric acid was added in excess (20 mL) and the precipitate was collected by vacuum filtration. 142 mg (90%) of the title compound were obtained.

1 H-NMR (DMSO-d ₆ ): δ 13.13 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz) 2H), 7.39 (m, 6H),

7.30 (d, J = 6.6 Hz, 1H), 6.99 (s, 1H), 6.03 (t, J = 4.5 Hz, 1H), 2.33 (d, J = 4) , 5 Hz, 2H), 1.29 (s, 6H).

³ C NMR (DMSO-d ₆ ): δ 166.64, 146.14, 139.79, 137.96, 133.75, 131.50, 130.98, 130.37, 129.48, 128 , 63, 128.38, 127.88, 127.60, 127.49, 126.54, 124.69, 119.23, 91.96, 88.11, 37.98, 33.40, 27.75 .

MS (DCI) m / e: 379 (MH +).

IR (KBr): 2958, 1684, 1604, 1420 cm -1.

Elemental analysis for C ₂₇ H ₂₂ O ₂ .0,15 H ₂ O:

Found: C, 85.08; H, 5.90;

Found: C, 85.06; H, 5.97.

Example 101

4,4-Dimethyl-7 - {[(dimethylamino) thiocarbonyl] oxy} 1-tetralone (XLII)

To a solution of 3.07 g (16.16 mmol) of 4,4-dimethyl-7-hydroxy-1-tetralone in 90.7 mg of potassium hydroxide in 10.77 ml of water cooled to below 10 ° C was added 2.67 g. (21.6 mmol) of N, N-dimethylthiocarbamoyl chloride in 4.30 mL of tetrahydrofuran while maintaining the reaction temperature below 12 ° C. After 10 minutes, the reaction mixture was basified by the addition of 5.39 ml of 10% w / w aqueous potassium hydroxide solution. The product was extracted with ethyl acetate (2 x 50 mL), the organic phases were concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90). This gave the title compound (3.74 g, 84%).

1 H-NMR (CDCl ₃ ): δ 7.68 (dd, J = 8.5 Hz, J = 2.6 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), δ , 27 (dd, J = 8.5 Hz, J = 2.6 Hz, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.73 (t, J = 6, 8 Hz, 2H), 2.04 (t, J = 6.8 Hz, 2H), 1.41 (s, 6H).

MS (DCI) m / e: 278 (MH ⁺ ).

Example 102

4,4-Dimethyl-7-mercapto-1-tetralone (XLIII)

Compound (XLII) (3.74 g, 13.50 mmol) was heated under nitrogen in a gas outlet flask for 45 minutes in a potassium nitrate / sodium nitrite salt bath (270: 275 ° C, 1: 1). After cooling, 1.13 g of potassium hydroxide

A solution of water (1.35 ml) and ethylene glycol (10.0 ml) was added to the flask and the mixture was refluxed for 1 hour. The cooled reaction mixture was then poured onto 30 g of ice. The mixture was washed with dichloromethane (2 x 50 mL), acidified with 1M hydrochloric acid, and extracted with dichloromethane (2 x 50 mL). The organic layer was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). 1.22 g (44%) of the title compound are obtained.

1 H-NMR (CDCl ₃ ): δ 7.91 (d, J = 2.2 Hz, 1H),

7.41 (dd, J = 8.2 Hz, J = 2.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 3.48 (s, 1H), 2, 71 (t, J = 6.8 Hz, 2H), 2.00 (t, J = 6.8 Hz, 2H), 1.37 (s, 6H).

MS (DCI) m / e: 207 (MH +).

Example 103

Methyl 4 - {[(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthyl) thio] methyl} benzoate (XL Via)

(XLVII)

264 mg (1.27 mmol) of 4,4-dimethyl-7-mercaptol-tetralone (XLIII), 291 mg (1.27 mmol) of methyl 4- (bromomethyl) -benzoate (Aldrich) and 179 mg (1.38) A solution of diisopropylethylamine (Aldrich) in anhydrous methylene chloride was stirred at room temperature for 90 minutes. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). This afforded the title compound (402 mg, 89%).

1 H-NMR (CDCl ₃ ): δ 7.98 (d, J = 2.1 Hz, 1 H),

7.95 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 8.3 Hz, J = 2.1 Hz, 1H), 7.38 (d, J = 8.5) Hz, 2H), 7.29 (d, J = 8.3 Hz, 1H),

HU 218,963 Β

4.17 (s, 2H), 3.90 (s, 3H), 2.71 (t, J = 6.8 Hz, 2H),

1.99 (t, J = 6.8 Hz, 2H), 1.36 (s, 6H).

MS (DCI) m / e: 355 (MH +).

Example 104

Methyl 4 - {[(5,5-dimethyl-8-phenyl-8-hydroxy-5,6,7,8-tetrahydro-2-naphthyl) thio] methyl} benzoate (XLIIa)

(XLVIII)

Preparation of the title compound in an analogous manner to that described for the preparation of the 8-phenyl derivative (XVIIa) afforded 415 mg (85% yield) of the title compound (400 mg, 1.13 mmol) (XLVIa).

1 H-NMR (CDCl 3): δ 7.87 (d, J = 8.2 Hz, 2H), 7.30-7.18 (m, 9H), 7.02 (d, J = 2.0 Hz) , 1H), 3.97 (s, 2H), 3.91 (s, 3H), 2.22-2.08 (m, 3H), 1.85 (m, 1H),

1.36 (s, 3H), 1.28 (s, 3H).

MS (DCI) m / e: 433 (MH +).

Example 705

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) thio] methyl} benzoic acid ( ^14a )

The title compound was prepared in a manner analogous to that described for 4 - {(E) - [2- (5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl)] - vinyl} benzoic acid (I a). to yield 365 mg (95% yield) of compound (XLVIIa) (415 mg, 0.96 mmol).

1 H-NMR (DMSO-d ₆ ): δ 12.87 (s, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.37 (m, 3H), 7.29 (s , 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.13 (m, 2H), 6.67 (d, J = 1.9 Hz, 1H),

5.95 ( _t , J = 4.5 Hz, 1H), 4.09 (s, 2H), 2.27 (d, J = 4.5 Hz, 2H), 1.24 (s, 6H).

MS (DCI) m / e: 401 (MH +).

IR (KBr): 2956, 1684, 1610, 1422, 1286 cm-1.

Elemental analysis for C ₂₆ H ₂₄ O ₂ S.0,5 H ₂ 0:

Found: C, 76.25; H, 6.15;

Found: C, 76.20; H, 6.15.

Example 106

5,6-Dihydro-5,5-dimethyl-8-phenyl-2- (N-methyl-N-methoxycarbamoyl) -naphthalene (Lilla)

To a solution of (XVIIIa) (1.04 g, 3.74 mmol) in dichloromethane (15.0 mL) was added oxalyl dichloride (0.39 mL, 4.49 mmol) and 2 drops of N, N-dimethyl at 0 ° C. formamide. After stirring for 2 hours at room temperature, 401 mg (4.11 mmol) of Ν, Ο-dimethylhydroxylamine hydrochloride (Aldrich) and 650 mg (0.665 mL) of anhydrous pyridine are added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed with brine (2 x 50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. 1.13 g (94%) of the title compound were obtained.

1 H-NMR (CDCl 3): δ 7.55 (dd, J = 8.0 Hz, J = 1.9 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7 37 (m, 5H),

7.32 (d, J = 1.8 Hz, 1H), 6.01 (t, J = 4.5 Hz, 1H), 3.49 (s, 3H), 3.27 (s, 3H), 2.37 (d, J = 4.5 Hz, 2H), 1.35 (s, 6H).

MS (DCI) m / e: 322 (MH +).

Example 107

5,6-Dihydro-5,5-dimethyl-8-phenyl-2-formylnaphthalene (LIVa)

To a solution of (Lilla) (1.13 g, 3.52 mmol) in THF (32 mL) was added 5.28 mL (5.28 mmol) of 1.0 M diisobutylaluminum hydride (DIBAH) in hexane at -78 ° C. . The reaction mixture was stirred for 1 hour and then diluted with 10 ml of 5% w / w aqueous hydrochloric acid and 10 ml of a saturated aqueous sodium chloride solution. The mixture was then extracted with ethyl acetate (2 x 40 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. This afforded the title compound (720 mg, 78%).

1 H-NMR (CDCl 3): δ 9.86 (s, 1H), 7.76 (dd, J = 8.0 Hz, 1.7 Hz, 1H), 7.54-7.52 (m, 2H) , 7.52-7.26

HU 218,963 Β (m, 5H), 6.07 (t, J = 4.5 Hz, 1H), 2.40 (d, J = 4.5 Hz, 2H), 1.38 (s, 6H) .

MS (DCI) m / e: 263 (MH ⁺ ).

Example 108

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) methyl] amino} benzoate (P a)

To a solution of methyl 4-aminobenzoate (505 mg, 3.35 mmol) in acetic acid (1% in methanol, 6.0 mL) was added LIVa (720 mg, 2.75 mmol) in 1% (w / w). methanolic acetic acid solution. Subsequently, a total of 174 mg (2.75 mmol) of sodium cyanotride hydroborate (1 -) was added (6 x 29 mg in portions every 10 minutes) over 1 hour. After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90, v / v). This afforded the title compound (856 mg, 78%).

1 H-NMR (CDCl ₃ ): δ 7.83 (d, J = 8.9 Hz, 2H),

7.34 (m, 6H), 7.21 (dd, J = 7.8 Hz, J = 2.0 Hz, 1H),

6.99 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 8.9 Hz, 2H), 5.99 (t, J = 4.5 Hz, 1H), 4, 37 (m, 1H), 4.23 (d, J = 5.5 Hz, 2H),

3.84 (s, 3H), 2.35 (t, J = 4.5 Hz, 2H), 1.34 (s, 6H).

MS (DCI) m / e: 398 (MH +).

Example 109

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) methylamino} benzoic acid hydrochloride ( ^12Ia )

To a solution of 5.0 ml of ethanol The compound (197 mg, 0.496 mmol) (S ²⁰⁾ was added 2.2 mL (22.0 mmol) of 10 M aqueous sodium hydroxide solution. The reaction mixture was refluxed for 4 hours and then treated with an excess of 1M hydrochloric acid (40 mL). The precipitate was collected by vacuum filtration to give the title compound (175 mg, 92%).

1 H-NMR (DMSO-d ₆ ): δ 7.60 (d, J = 8.8 Hz, 2H),

7.32 (m, 4H), 7.20 (m, 3H), 6.90 (d, J = 1.6 Hz, 1H),

6.49 (d, J = 8.8 Hz, 2H), 5.96 (t, J = 4.5 Hz, 1H), 4.16 (s, 2H), 2.27 (d, J = 4) , 5 Hz, 2H), 1.24 (s, 6H).

MS (DCI) m / e: 384 (MH +).

IR (KBr): 3418, 2960, 1672, 1602, 1176.

Elemental analysis for C ₂₆ H ₂₅ O ₂ Nl, 0 HCl:

Found: C, 74.36; H, 6.24; N, 3.34; Found: C, 74.39; H, 6.19; N, 3.29.

Example 110

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) amino] thiocarbonyl} benzoate

The title compound was prepared in a manner analogous to that described for methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) thiocarbonyl] amino} benzoate, to give 190 mg (0.462). 104 mg (52%) of compound (I'c) were obtained (mmol).

1 H-NMR (CDCl 3): δ 8.84 (s, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.91 (dd, J = 8.8 Hz, J = 2 , 4 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.8 Hz, 1H),

7.35 (m, 5H), 7.13 (d, J = 2.4 Hz, 1H), 6.04 (t, J = 4.5 Hz, 1H), 3.94 (s, 3H), 2, 38 (d, J = 4.5 Hz, 2H),

1.35 (s, 6H).

MS (DCI) m / e: 428 (MH +).

Example 111

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) amino] thioxomethyl} benzoic acid ^{(I, 9)}

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in the preparation of 8-phenyl derivative in the procedure to give 104 mg (0.240 mmol) of methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl 2-Naphthyl) thiocarbonyl] amino} benzoate (80 mg, 80%) was obtained.

1 H-NMR (DMSO-d 6: δ 11.80 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H),

HU 218,963 Β

7.43 (d, J = 8.4 Hz, 1H), 7.34 (m, 6H), 6.02 (t, J = 4.5 Hz, 1H), 2.33 (d, J = 4) , 5 Hz, 2H), 1.30 (s, 6H).

MS (DCI) m / e: 414 (MH +).

IR (KBr): 2958, 1694, 1490, 1410 cm ^-1 . Elemental analysis for C ₂₆ H ₂₃ O ₂ NS.0,5 H ₂ O:

Found: C, 73.91; H, 5.73; N, 3.31;

Found: C, 73.78; H, 5.55; N, 3.22.

Example 112

Methyl 4-mercaptobenzoate

To a solution of 4-mercaptobenzoic acid (Apin) (1.72 g, 11.17 mmol) in dry methanol (20.0 mL) was added sulfuric acid (0.43 mL). The reaction mixture was then refluxed for 16 hours, concentrated in vacuo, diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2 x 100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. This afforded the title compound (712 mg, 38%).

1 H-NMR (CDCl ₃ ): δ 7.89 (d, J = 8.7 Hz, 2H),

7.29 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H), 3.60 (s, 1H).

Example 113

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) methyl] thio} benzoate (P ⁴ a)

(I ²⁴ a) mg (0.528 mmol) of methyl 4-mercaptobenzoate To a solution of 3.0 ml of ethylene glycol dimethyl ether at room temperature was added (0.607 mmol) of 60% sodium hydride, 24 mg. The mixture was stirred for 15 minutes and then (LVilla) (190 mg, 0.581 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate (50 mL) and washed with 1M hydrochloric acid (2 x 50 mL). The organic phase was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane (10:90, v / v). This gave the title compound (30 mg, 13%).

1 H-NMR (CDCl 3): δ 7.88 (d, J = 8.5 Hz, 2H),

7.28 (m, 9H), 6.98 (d, J = 1.4 Hz, 1H), 5.98 (t, J = 4.5 Hz,

1H), 4.07 (s, 2H), 3.90 (s, 3H), 2.33 (d, J = 4.5 Hz, 2H),

1.32 (s, 6H).

MS (DCI) m / e: 415 (MH +).

Example 114

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) methyl] thio} benzoic acid (P ⁴ a)

(I ³⁴ a)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation procedure, to give the title compound 21 mg (72%) as a result of which the application (30 mg, 0.07 mmol) (I ²⁴ a) .

1 H-NMR (DMSO-d ₆ ): δ 12.87 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.35 (m, 7H), 7.28 ( d, J = 1.8 Hz, 1H),

7.19 (dd, J = 7.9 Hz, J = 1.8 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H), 5.95 (t, J = 4.5) Hz, 1H), 4.19 (s, 2H), 2.27 (d, J = 4.5 Hz, 2H), 1.24 (s, 6H).

MS (DCI) m / e: 401 (MH ⁺ ).

IR (KBr): 3436, 2960, 1688, 1592 cm -1.

Calcd for C ₂₆ H ₂₄ O ₂ SH ₂ O:% C, 76.93; H, 6.11;

Found: C, 76.91; H, 6.03.

Example 115

1,2-Dihydro-1,1-dimethyl-6-nitro-8 - [(trifluoromethanesulfonyl) oxy] naphthalene (LXI)

SHE

To a solution of 4,4-dimethyl-7-nitro-1-tetralone (VI) (2.4 g, 10.96 mmol) in tetrahydrofuran (10 mL) at -78 ° C was added 12.05 mL (12.05 mmol) 1, Lithium bis (trimethylsilyl) amide solution in hexane (0 M) and then N, N- (2-pyridyl) trifluoride (4.30 g, 12.05 mmol) at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes, then diluted with water and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (5:95, v / v). As a result of this

2.68 g (70%) of the title compound are obtained.

GB 218,963 Β • H-NMR (CDC1 _3): δ 8.20 (m, 2H), 7.49 (d, J = 8.2 Hz, 1H), 6.15 (t, J = 4.5 Hz, 1H), 2.50 (d, J = 4.5 Hz, 2H), 1.37 (s, 6H).

MS (DCI) m / e: 352 (MH +).

Example 116

1,2-Dihydro-1,1-dimethyl-4-phenyl-6-nitro-naphthalene (LXIIa)

To a solution of (LXI) (2.68 g, 7.64 mmol) in dry 1-methyl-2-pyrrolidinone (30.0 mL) was added triphenylarzine (442 mg, 1.44 mmol), tris (dibenzylidene) (217 mg, 0.237 mmol). acetone) dipalladium (0) and a mixture of 6.17 g (16.78 mmol) of tributylphenyltin in 5.0 ml of 1-methyl-2-pyrrolidinone. The reaction mixture was stirred at 60 ° C for 16 h, then diluted with water and extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, stirred for 30 minutes over saturated aqueous potassium fluoride solution, then separated and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (20:80, v / v). 1.93 g (90%) of the title compound were obtained.

1 H-NMR (CDCl 3): δ 8.07 (dd, J = 8.5 Hz, J = 2.5 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), δ, 50 (d, J = 8.5 Hz, 1H), 7.36 (m, 5H), 6.12 (t, J = 4.5 Hz, 1H),

2.41 (d, J = 4.5 Hz, 2H), 1.39 (s, 6H).

MS (DCI) m / e: 280 (MH +).

Example 117

5,5-Dimethyl-8-phenyl-5,6-dihydronaphthylamine (LXIIIa)

To a solution of (LXIIa) (1.75 g, 6.27 mmol) in benzene (15 mL) was added a solution of ferric chloride (33% in water, 2.94 mL) and water (11.9 mL). The reaction mixture was heated to reflux temperature and then, in 90 equal portions, in four equal portions

3.50 g of iron were added. The resulting mixture was then refluxed for 16 hours. The reaction mixture was cooled to room temperature and then filtered through a pad of celite. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. This gave 1.56 g (99%) of the title compound.

1 H-NMR (CDCl 3): δ 7.35 (m, 5H), 7.15 (d, J = 8.1 Hz, 1H), 6.57 (dd, J = 8.1 Hz, J = 2 , 5 Hz, 1H),

6.37 (d, J = 2.5 Hz, 1H), 5.95 (t, J = 4.5 Hz, 1H),

3.45 (bs, 2H), 2.31 (d, J = 4.5 Hz, 2H), 1.30 (s, 6H).

MS (DCI) m / e: 250 (MH ⁺ ).

Example 118

Methyl 4- {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) amino] methyl} benzoic acid (I ²⁸ a)

The preparation of the title compound, methyl 4 - {[(5,6-dihidro5,5-dimethyl-8-phenyl-2-naphthyl) methyl] amino} benzoic acid (I ²⁰ a) was carried out analogously as in the production process, with 1.38 g (79%) of the desired compound (1.35 g, 5.38 mmol) were obtained.

1 H-NMR (CDCl 3): δ 7.95 (d, J = 8.5 Hz, 2H),

7.29 (m, 7H), 7.16 (d, J = 8.3 Hz, 1H), 6.47 (dd, J = 8.3 Hz, J = 2.6 Hz, 1H), 6.29 ( d, J = 2.6 Hz, 1H), 5.94 (t, J = 4.5 Hz, 1H), 4.53 (s, 2H), 3.91 (s, 3H),

2.30 (d, J = 4.5 Hz, 2H), 1.29 (s, 6H).

MS (DCI) m / e: 398 (MH +).

Example 119

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) amino] methyl} benzoic acid (I ²⁹ a)

to a solution of ethanol / tetrahydrofuran in a ratio of tooth was added at room temperature

3.5 ml (35.0 mmol) of 10 M aqueous sodium hydroxide solution. After stirring at room temperature for 16 hours, an excess of 1M hydrochloric acid (100 mL) was added and the resulting precipitate was collected by vacuum filtration. This gave the title compound as the hydrochloride salt (1.28 g, 96%).

HU 218,963 Β

1 H-NMR (DMSO-d ₆ ): δ 7.84 (d, J = 8.2 Hz, 2H),

7.36 (d, J = 8.2 Hz, 1H), 7.31 (m, 5H), 7.15 (m, 4H),

6.99 (bs, 1H), 6.36 (bs, 1H), 5.90 (t, J = 4.5 Hz, 1H),

4.32 (s, 2H), 2.21 (d, J = 4.5 Hz, 2H), 1.19 (s, 6H).

MS (DCI) m / e: 384 (MH +).

IR (KBr): 3420, 2958, 1694, 1606 cm-1.

Elemental analysis for C ₂₆ H 25 O ₂ Nl, 0 HCl:

Found: C, 72.80; H, 6.34; N, 3.27; Found: C, 72.98; H, 6.09; N, 3.14.

Example 120

3,3-Dimethyl-6-nitro-l-indanone

16.3 g (50.9 mmol) of 3,3-dimethyl-1-indanone [Harms, W. M. and Eisenbraum, E. J., Org. Prep. Proc. Int., 4, 67-72 (1972)] at 0-5 ° C was slowly added 4.10 ml of 70% nitric acid and 20 ml sulfuric acid at 0-5 ° C. The reaction mixture was stirred for 1 hour and then poured onto 600 g of ice. The precipitate was filtered off and washed with water. The filtered solid was dissolved in 600 mL of ethyl acetate and the solution was washed twice with 80 mL of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated. The residue was triturated under methanol to give the title compound as a yellow solid (22.2 g).

1 H-NMR (CDCl 3): δ 1.49 (s, 6H), 2.71 (s, 2H),

7.68 (d, J = 8.4 Hz, 1H), 8.48 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 8.53 (d, J = 2.0) Hz, 1H).

MS (DCI) m / e: 206 (MH +).

Elemental Analysis for: C 11 H 10 O 3 N: Calculated: C, 64.38; H, 5.40; N, 6.83;

Found: C, 64.33; H, 5.33; N, 6.86.

Example 121

6-Amino-3,3-dimethyl-1-indanone (LXV)

A mixture of 22.3 g (54.1 mmol) of 3,3-dimethyl-6-nitro-1-indanone, 0.44 g (1.94 mmol) of platinum oxide + 30 ml of ethyl acetate and 60 ml of methanol is added Hydrogenate in a Parr hydrogenator for 40 minutes. The reaction mixture was filtered through a pad of celite, then the filtrate was evaporated and the residue was triturated under hexane. This gave the title compound as a yellow solid (18.4 g, 97%).

1 H-NMR (CDCl 3): δ 1.38 (s, 6H), 2.56 (s, 2H), 6.98 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 2.3 Hz, J = 8.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H).

MS (DCI) m / e: 176 (MH ⁺ ).

Elemental Analysis for: C _n H _n O _{N N} % Calculated: C, 75.40; H, 7.48; N, 7.99; Found: C, 75.07; H, 7.45; N, 7.94.

Example 122

3,3-Dimethyl-6-hydroxy-1-indanone (LXVI)

To a solution of 14.0 g (85.8 mmol) of 6-amino-3,3-dimethyl-1-indanone in 30 ml of a 48% aqueous solution of tetrafluoroboric acid and 30 ml of water is slowly added at 0-5 ° C. a solution of sodium nitrite (14.8 g, 214 mmol) in water (30 mL) was added. The reaction mixture was stirred for 30 minutes and then filtered. The filtered solid was washed with cold 5% aqueous tetrafluoroboric acid solution and dried under vacuum. The solid was then added in portions to a boiling solution of 50 mL of sulfuric acid and 0.5 L of water. The reaction mixture was heated at reflux for 1 hour, cooled to room temperature, and extracted with ethyl acetate (3 x 100 mL). The combined extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:10 to 1: 2 by volume). This afforded the title compound as a solid (7.60 g, 50%).

1 H-NMR (CDCl 3): δ 1.40 (s, 6H), 2.64 (s, 2H),

7.13 (s, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H).

MS m / e: 177 (MH +).

Elemental Analysis for: C _n H ₁₂ O ₂ : Calculated:% C, 74.98; H, 6.86;

Found: C, 74.81; H, 6.76.

Example 123

3,3-Dimethyl-6 - {[(trifluoromethyl) sulfonyl] oxy} -l-indanone

3,3-Dimethyl-6-hydroxy-1-indanone (4.01 g, 24.4 mmol) and 4- (dimethylamino) pyridine (DMAP) (5.97 g, 48.9 mmol) in methylene chloride (30 mL). dichloride solution 64

Trifluoromethanesulfonic anhydride (9.65 g, 34.2 mmol) was added slowly at -78 ° C. The reaction mixture was stirred for one hour, then diluted with dichloromethane (60 mL), washed with 1M hydrochloric acid (2 x 10 mL) and water (10 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:10 to 1: 5, v / v). This gave the title compound (5.58 g, 74%).

1 H-NMR (CDCl 3): δ 1.46 (s, 6H), 2.67 (s, 2H),

7.51 (dd, J = 2.3 Hz, J = 8.4 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H).

MS m / e: 309 (MH +).

Elemental Analysis for: C ₁₂ H _h F ₃ O ₄ S: Calculated: C, 46.75; H, 3.60;

Found: C, 46.83; H, 3.58.

Example 124

Methyl 1,1-dimethyl-3-oxo-5-indanecarboxylate (LXVII)

3.08 g (10.0 mmol) of 3,3-dimethyl-6 - {[(trifluoromethyl) sulfonyl] oxy} -1-indanone, 2.02 g (20.0 mmol) of triethylamine, 0.11 g (0.50 mmol) of palladium (II) acetate, 0.21 g (0.50 mmol) of 1,3-bis (diphenylphosphino) propane + 30 ml of anhydrous dimethyl sulfoxide and 20 ml of methanol solution was saturated with carbon monoxide for 10 minutes, and the reaction mixture was stirred at 65-70 ° C for 2 hours under a balloon filled with carbon monoxide. Methanol was evaporated and the resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (4 x 40 mL). The combined extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). This gave the title compound as a pale yellow solid (1.98 g, 91%).

1 H-NMR (CDCl 3): δ 1.45 (s, 6H), 2.65 (s, 2H), 3.94 (s, 3H), 7.58 (dd, J = 8.1 Hz, 1H). , 8.30 (dd, J = 1.6 Hz, J = 8.1 Hz, 1H), 8.36 (d, J = 1.6 Hz, 1H).

MS m / e: 219 (MH +).

Elemental Analysis for: C ₁₃ H ₁₄ O ₃ : Calculated: C, 71.54; H, 6.47;

Found: C, 71.71; H, 6.46.

Example 125

Methyl 1,1-dimethyl-3 - {[(trifluoromethyl) sulfonyl] oxy} -1H-indene-5-carboxylate

SHE

Methyl 1,1-dimethyl-3-oxo-5-indanecarboxylate (0.90 g, 4.12 mmol) and 2,6-di (tert-butyl) -4-methylpyridine (1.10 g, 5.36 mmol) To a solution of dichloromethane (10 mL) was added trifluoromethanesulfonic anhydride (1.39 g, 4.94 mmol) at -78 ° C. The reaction mixture was stirred at room temperature for 16 hours, then diluted with diethyl ether (70 ml), 1M hydrochloric acid (20 ml), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). This gave 1.23 g (85%) of the title compound.

1 H-NMR (CDCl ₃ ): δ 1.41 (s, 6H), 3.95 (s, 3H),

6.30 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.99 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H).

MS m / e: 351 (MH +).

Example 126

Methyl 1,1-dimethyl-3-phenyl-1H-indene-5-carboxylate

Methyl 1,1-dimethyl-3 - {[(trifluoromethyl) sulfonyl] oxy} -1H-indene-5-carboxylate (580 mg, 1.86 mmol), Tris (dibenzylidene) (17 mg, 0.02 mmol) acetone) dipalladium (0) (Pd ₂ dba ₃ ), triphenylarzine 46 mg (0.15 mmol), lithium chloride 240 mg (5.59 mmol), and phenyl tributyl 680 mg (1.86 mmol) and a solution of 5 ml of 2-methylpyrrolidinone solution was stirred at 55 ° C for 1.5 days. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). This afforded the title compound as a white solid (0.43 g, 83%).

1 H-NMR (CDCl ₃ ): δ 1.41 (s, 6H), 3.91 (s, 3H), 6.48 (s, 1H), 7.39-7.62 (m, 6H), δ , 99 (d, J = 6.8 Hz, 1H), 8.14 (s, 1H).

HU 218,963 Β

MS m / e: 279 (-) -

Elemental analysis for C ₁₉ H ₁₈ O ₂ .0.25 H ₂ O:

Found: C, 80.68; H, 6.49;

Found: C, 80.76; H, 6.41.

Example 127

Methyl 4 - {[(1,1-dimethyl-3-phenyl-1H-inden-5-yl) carbonyl] amino} benzoate

Methyl 1,1-dimethyl-3-phenyl-1H-indene-5-carboxylate (315 mg, 1.13 mmol), 10 M aqueous sodium hydroxide (1.1 mL, 11.0 mmol), 5 mL methanol and 10 ml of tetrahydrofuran were stirred at 60 ° C for 1.5 hours. The solution was then concentrated under reduced pressure, acidified by addition of 15 ml of 1M hydrochloric acid solution and extracted three times with 15 ml of ethyl acetate. The combined organic extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was dried under vacuum and then dissolved

2.5 ml of methylene chloride. Oxalyl dichloride (348 mg, 2.74 mmol) and 2 drops of Α, Α-dimethylformamide were added at 0 ° C. The resulting solution was stirred at 0 ° C for 30 minutes and then at room temperature for 30 minutes. The mixture was evaporated and the residue was dried under vacuum. The residue was stirred with a solution of methyl 4-aminobenzoate (181 mg, 1.32 mmol) in dry pyridine (2 mL) for 18 h. The excess pyridine was evaporated and the residue was diluted with 20 ml of 2M hydrochloric acid and extracted with four 30 ml portions of diethyl ether. The combined organic extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). This gave 372 mg (85%) of the title compound as a glass.

1 H-NMR (CDCl 3): δ 1.43 (s, 6H), 3.91 (s, 3H),

6.52 (s, 1H), 7.40-7.50 (m, 4H), 7.59-7.61 (m, 2H), 7.72-7.75 (m, 3H), 7. 96 (s, 1H), 8.00 (bs, 1H), 8.05 (d, J = 8.7 Hz, 2H).

MS m / e: 398 (MH +).

Elemental analysis for C ₂₆ H ₂₃ O ₃ N.0,125 H ₂ O:

Found: C, 78.12; H, 5.93; N, 3.50;

Found: C, 77.97; H, 5.50; N, 3.24.

Example 128

4 - {[(1,1-Dimethyl-3-phenyl-1H-inden-5-yl) carbonyl] amino} benzoic acid (P a)

(° P)

359 mg (0.90 mmol) of methyl 4 - {[(l, l-dimethyl-3-fenillff-inden-5-yl) carbonyl] amino} benzoic acid (I ³⁰ a) 10 hours 4.5 2 mL of a 2M aqueous sodium hydroxide solution, 5 mL of methanol and 5 mL of tetrahydrofuran. The solution was then acidified with 1M hydrochloric acid and then concentrated under reduced pressure. To the residue was added water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was triturated under diethyl ether / hexane. This afforded the title compound as a solid (326 mg, 94%).

1 H-NMR (DMSO-d 6): δ 1.39 (s, 6H), 6.68 (s, 1H), 7.39-7.53 (m, 3H), 7.64-7.68 (m , 3H),

7.85-7.97 (m, 6H), 10.54 (s, 1H), 12.75 (bs, 1H).

MS m / e: 384 (MH ⁺ ).

Elemental analysis for C ₂₅ H ₂₁ O ₃ N.0.25 H ₂ O:

Found: C, 77.39; H, 5.46; N, 3.61; Found: C, 77.26; H, 5.51; N, 3.52.

Example 129 1,1-Dimethyl-5-nitro-3 - [[(trifluoromethylsulfonyl) oxy] -1H-indene

1.00 g (4.65 mmol) of 3,3-dimethyl-6-nitro-1-indanone (LXIX) and 1.19 g (5.80 mmol) of 2,6-di (tert-butyl) -4-methyl- To a solution of pyridine in 10 mL of dichloromethane was added trifluoro-methanesulfonic anhydride (1.57 g, 5.58 mmol) at -78 ° C. The reaction mixture was stirred at room temperature for 16 hours, then diluted with 20 ml of 1M hydrochloric acid and extracted three times with 30 ml of diethyl ether. The combined organic extracts were washed with water (20 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1:10). This afforded the title compound as an oil (1.37 g, 87%).

HU 218,963 Β 1 H-NMR (CDCl ₃ ): δ 1.45 (s, 6H), 6.43 (s, 1H),

7.53 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H),

8.24 (dd, J = 2.0 Hz, J = 8.3 Hz, 1H).

MS m / e: 338 (MH +).

Elemental Analysis for: C ₁₂ H ₁₀ O ₅ NS Calculated:% C, 42.73; H, 2.99; N, 4.15;

Found: C, 42.70; H, 2.80; N, 4.10.

Example 130

3-Phenyl-1,1-dimethyl-5-nitro-1H-indene (LXXa)

(LXXa)

1,32 g (2.89 mmol) of 1,1-dimethyl-5-nitro-3 - {[(trifluoromethyl) sulfonyl] oxy} -1 H -indene, 21 mg (0.02 mmol) of tris ( dibenzylideneacetone dipalladium (0) (Pd ₂ dba ₃ ), triphenylarzine (70 mg, 0.23 mmol), lithium chloride (0.37 g, 8.67 mmol), and 1.06 g (2, A mixture of phenyl tributylone (89 mmol) was stirred at 60 ° C for 48 hours. The reaction mixture was then diluted with water (30 mL) and extracted with diethyl ether (3 x 30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 5, v / v). The resulting solid was recrystallized from hexane to give the title compound as pale yellow-white crystals (575 mg, 75%).

1 H-NMR (CDCl 3): δ 1.44 (s, 6H), 6.58 (s, 1H),

7.40-7.60 (m, 6H), 8.18 (d, J = 2.0 Hz, J = 8.2 Hz, 1H),

8.32 (d, J = 2.0 Hz, 1H).

MS m / e: 266 (MH +).

Elemental Analysis for: C ₁₇ H ₁₅ O ₂ N: Calculated: C, 76.96; H, 5.70; N, 5.28; Found: C, 76.71; H, 5.69; N, 5.22.

Example 131

5-Amino-1,1-dimethyl-3-phenyl-1H-indene (LXXla)

To a mixture of 0.56 g (2.11 mmol) of 1,1-dimethyl-3-phenyl-5-nitro-1/7-indene (LXXa) and 5 mL of benzene was added 1 mL of 33% w / w aqueous ferric chloride solution and 4 ml of water. The resulting mixture was then stirred at reflux temperature and a total of 1.00 g (5.28 mmol) of iron powder was added in four portions over 2 hours. The resulting reaction mixture was refluxed for a further 18 hours with stirring. The mixture was diluted with water (20 mL) and ethyl acetate (20 mL) and filtered through a pad of celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. 0.49 g (98%) of the crude title compound were obtained; the product was used in the next reaction without further purification.

1 H-NMR (CDCl 3): δ 1.37 (s, 6H), 6.40 (s, 1H),

6.71 (dd, J = 2.0 Hz, J = 7.9 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 7.9) Hz, 1H), 7.36-7.58 (m, 5H).

MS m / e: 236 (MH +).

Example 132

Methyl 4 - {[(l, l-dimethyl-3-phenyl-lH-inden-5-yl) amino-benzoate karbonilf

A mixture of 0.49 g (2.06 mmol) of 5-amino-1,1-dimethyl-3-phenyl177-indene, 0.49 g (2.47 mmol) of terephthalic acid monomethyl ester chloride and 5 ml of pyridine was stirred for 18 hours. . After the solvent was evaporated, the residue was diluted with 20 ml of 1M hydrochloric acid solution and extracted three times with 20 ml of ethyl acetate each time. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:10 to 1: 5, v / v). This gave 772 mg (94%) of the title compound, which was crystallized from ethyl acetate / hexane to give 720 mg of crystalline product.

1 H-NMR (CDCl 3): δ 1.41 (s, 6H), 3.96 (s, 3H), 6.47 (s, 1H), 7.37-7.60 (m, 7H), δ , 68 (s, 1H),

7.84 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 8.16 (d, J = 8.3 Hz, 2H).

MS m / e: 398 (MH +).

Elemental Analysis for: C ₂₆ H ₂₃ O ₃ N: Calculated: C, 78.57; H, 5.83; N, 3.52;

Found: C, 78.45; H, 5.76; N, 3.41.

Example 133

4 - {[(1,1-Dimethyl-3-phenyl-1H-inden-5-yl) -amino] -carbonyl] -benzoic acid ( ^IIIa )

HU 218,963 Β

(P'a)

325 mg (0.82 mmol) of methyl 4 - {[(1,1-dimethyl-3-phenyl-N-inden-5-yl) -amino] carbonyl} -benzoate, 4.1 mL of 2M aqueous sodium hydroxide solution and 10 ml of tetrahydrofuran and 10 ml of methanol were stirred for 2 hours. The reaction mixture was concentrated, acidified with 1N hydrochloric acid (20 mL) and extracted with ethyl acetate (2 x 35 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was triturated under diethyl ether / hexane to give the title compound as a white solid (246 mg, 78%).

1 H-NMR (DMSO-d 6: δ 1.35 (s, 6H), 6.58 (s, 1H), 7.38-7.70 (m, 7H), 7.73 (d, J = 7, 9 Hz, 1H),

7.90 (s, 1H), 8.04 (s, 4H), 10.38 (bs, 1H), 13.25 (bs, 1H).

MS (DCI) m / e: 384 (MH +).

Elemental analysis for C ₂₅ H ₂₁ O ₃ N.0.25 H ₂ O:

Found: C, 77.40; H, 5.59; N, 3.61; Found: C, 77.24; H, 5.33; N, 3.41.

Example 134

Methyl 4 - {[(1,1-dimethyl-3-oxo-5-indanyl) oxy] methyl} benzoate (LXXIIa)

To a solution of 3,3-dimethyl-6-hydroxy-1-indanone (0.72 g, 4.37 mmol) in N, N-dimethylformamide (5 mL) was added 0.16 g (6.55 mmol) at 0 ° C. ) sodium hydride. The mixture was stirred for 30 minutes and then methyl 4-bromomethylbenzoate (1.00 g, 4.37 mmol) was added. The resulting reaction mixture was stirred at 0 ° C for 1 hour, then at room temperature for 2 hours, then cooled to 0 ° C and acidified by the addition of 1M hydrochloric acid. The solvent was evaporated and the residue was acidified with 20 ml of 1M hydrochloric acid solution and extracted three times with 30 ml of ethyl acetate each time. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1: 4, v / v).

As a result, the solids and

1.42 g (64%) of the title compound are obtained.

1 H-NMR (CDCl ₃ ): δ 1.41 (s, 6H), 2.61 (s, 2H), 3.93 (s, 1H), 5.15 (s, 2H), 7.18 (d , J = 2.5 Hz, 1H),

7.30 (d, J = 2.5 Hz, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.3) Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H).

MS m / e: 325 (MH ⁺ ).

Elemental Analysis for: C ₂₀ H ₂₀ O ₄ : Calculated: C, 74.06; H, 6.21;

Found: C, 73.99; H, 6.24.

Example 135

Methyl 4 - [{[l, l-dimethyl-3 - {[(trifluoromethyl) sulfonyl] oxy} -lH-inden-5-yl] oxy} methyl] benzoate

674 mg (2.08 mmol) of methyl 4 - {[(1,1-dimethyl-3-oxo-5-indanyl) oxy] methyl} benzoate (LXXIIa) and 534 mg (2.60 mmol) of 2.6 To a solution of di-tert-butyl-4-methylpyridine in 5 mL of dichloromethane was added 705 mg (2.50 mmol) of trifluoromethanesulfonic anhydride at -78 ° C. The reaction mixture was stirred at room temperature for 16 hours, then diluted with 20 ml of 1M hydrochloric acid and extracted three times with 30 ml of diethyl ether. The combined organic extracts were washed with water (20 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1:10). This gave the title compound as a solid (849 mg, 95%).

1 H-NMR (CDCl ₃ ): δ 1.37 (s, 6H), 3.93 (s, 1H),

5.15 (s, 2H), 6.24 (s, 1H), 6.90-6.94 (m, 2H), 7.25 (da above chloroform, J = 8.8 Hz, 1H), 7 , 53 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.7 Hz, 2H).

MS m / e: 457 (MH ⁺ ).

Elemental Analysis for: C ₂₁ H ₁₉ F ₃ O ₆ S: Calculated: C, 55.26; H, 4.20;

Found: C, 55.39; H, 4.08.

Example 136

Methyl 4 - {[(l, l-dimethyl-3-phenyl-lH-inden-5-yl) oxy] methyl} benzoate

HU 218,963 Β

Elemental analysis for C ₂₅ H ₂₂ O ₃ .0.25 H ₂ O:

Found: C, 80.08; H, 6.05;

Found: C, 80.17; H, 5.86.

Example 138

6-Bromo-m-3,3-dimethyl-1-indanone (LXXIV)

838 mg (1.84 mmol) of methyl 4 - [{[1,1-dimethyl-3 {[(trifluoromethyl) sulfonyl] oxy} -17 H -inden-5-yl] oxy} methyl] Benzoate, 17 mg (0.02 mmol) of tris (dibenzylideneacetone) dipalladium (O), 64 mg (0.20 mmol) of triphenylarazine, 234 mg (5.51 mmol) of lithium chloride, and 676 mg (1.84) a mixture of phenyl tributyltin) was stirred at 60 ° C for 18 hours. The reaction mixture was then diluted with water (30 mL) and extracted with diethyl ether (3 x 30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel flash chromatography eluting with 1; A mixture of ethyl acetate / hexane (25 to 1:10 by volume) was used. The resulting solid was recrystallized from ethyl acetate / hexane (1: 20- + 1: 10) to give the title compound in crystalline form (454 mg, 64%).

1 H-NMR (CDCl ₃ ): δ 1.38 (s, 6H), 3.93 (s, 1H),

5.13 (s, 2H), 6.44 (s, 1H), 6.86 (dd, J = 2.2 Hz, J = 8.1 Hz, 1H), 7.11 (d, J = 2) , 2 Hz, 1H), 7.27-7.55 (m, 8H), 8.06 (d, J = 8.1 Hz, 2H).

MS m / e: 385 (MH +).

Elemental analysis for C ₂₆ H ₂₄ O ₃ .0,125 H ₂ O:

Found: C, 80.75; H, 6.32;

Found: C, 80.76; H, 6.19.

Example 137

4 - {[(1,1-Dimethyl-3-phenyl-1H-inden-5-yl) oxy] methyl} -

300 mg (0.78 mmol) of methyl 4 - {[(1,1-dimethyl-3-phenylH-inden-5-yl) oxy] methyl} benzoate, 3.9 mL of 2M aqueous sodium hydroxide solution of tetrahydrofuran and 5 ml of methanol was stirred at room temperature for 16 hours. The reaction mixture was concentrated, acidified with 10 ml of 1M hydrochloric acid and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from diethyl ether / hexane to give the title compound as a white crystalline solid (247 mg, 85%).

1 H-NMR (DMSO-d 6): δ 1.31 (s, 6H), 5.20 (s, 2H), 6.57 (s, 1H), 6.89 (dd, J = 1.1 Hz) , J = 8.2 Hz, 1H), 7.02 (d, J = 1.1 Hz, 1H), 7.36-7.57 (m, 8H), 7.95 (d, J = 8, 3 Hz, 2H), 12.94 (bs, 1H).

MS m / e: 371 (MH +).

To aluminum chloride (4.16 g, 31.2 mmol) at 90-100 ° C was added 2.00 g (12.5 mmol) of 3,3-dimethyl-1-indanone. The mixture was stirred for 15 minutes and then bromine (2.39 g, 15.0 mmol) was added slowly. The reaction mixture was stirred at 100 ° C for 1 hour, quenched with 200 g of ice water and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:20 to 1:15 v / v). As a result, a crude product was obtained which was recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (1.23 g, 41%).

1 H-NMR (CDCl 3): δ 1.42 (s, 6H), 2.61 (s, 2H),

7.39 (d, J = 8.2 Hz, 1H), 7.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H), 7.82 (d, J = 2.0) Hz, 1H).

MS m / e: 239 (MH +).

Elemental Analysis for: C _H H _H Br O ₃ : Calculated: C, 55.26; H, 4.64;

Found: C, 55.19; H, 4.61.

Example 139

Methyl 4- [2- (1,1-dimethyl-3-oxo-5-indanyl) vinyl] benzoate (LXXVa)

(LXXV)

6-bromo-3,3-dimethyl-1-inadone (1.20 g, 5.02 mmol),

Methyl 4-vinyl benzoate (1.63 g, 10.0 mmol), palladium (II) acetate (56 mg, 0.25 mmol), tetrabutylammonium chloride hydrate (1.53 g, 5.52 mmol) A mixture of 1.05 g (12.6 mmol) of sodium bicarbonate and 10 ml of anhydrous N, N-methylformamide was stirred at 80-100 ° C for 8 hours. The reaction mixture was diluted with water (100 mL) and methylene chloride (3 x 50 mL)

HU 218 963 Β dichloride. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using a 1: 1 by volume mixture of dichloromethane / hexane as eluent. This afforded the title compound as a yellow solid (1.12 g, 70%).

1 H-NMR (CDCl ₃ ): δ 1.45 (s, 6H), 2.64 (s, 2H),

5.30 (s, 3H), 7.18 (d, J = 16.5 Hz, 1H), 7.26 (d, J = 16.5 Hz, 1H), 7.52 (d, J = 8) , 1 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 1.7 Hz, J = 8, 1 Hz, 1H), 7.86 ( d, J = 1.7 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H)

MS m / e: 321 (MH ⁺ ).

Elemental Analysis for: C ₂₁ H ₂₀ O ₃ : Calculated: C, 78.18; H, 6.32;

Found: C, 78.22; H, 6.26.

Example 140

Methyl 4- {2- [1,1-dimethyl-3 - {[(trifluoromethyl) sulfonyl] oxy} -1H-inden-5-yl] vinyl} benzoate

450 mg (1.40 mmol) of methyl 4- [2- (1,1-dimethyl-3-oxo-5-indanyl) -vinyl] -benzoate (LXXVa) and 345 mg (1.68 mmol) of 2,6-di To a solution of tert -butyl 4-methylpyridine in 5 mL of dichloromethane was added 434 mg (1.54 mmol) of trifluoromethanesulfonic anhydride at -78 ° C. After stirring at room temperature for 16 hours, the reaction mixture was diluted with 20 ml of 1M hydrochloric acid and extracted three times with 20 ml of diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel flash chromatography eluting with dichloromethane / hexane (1: 2 to 1: 1, v / v). This afforded the title compound as a solid (606 mg, 95%).

1 H-NMR (CDCl ₃ ): δ 1.41 (s, 6H), 3.94 (s, 3H), 6.27 (s, 1H), 7.15 (d, J = 16.3 Hz, 1H ), 7.27 (d, J = 16.3 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.49 and 7.50 (s above d, J = 8, 2Hz, 2H), 7.59 (d, J = 8.4Hz, 2H), 8.05 (d, J = 8.4Hz, 2H).

MS m / e: 453 (MH +).

Elemental Analysis for: C ₂₂ H ₁₉ F ₃ O ₅ S: Calculated: C, 58.40; H, 4.23;

Found: C, 58.38; H, 4.00.

Example 141

Methyl 4- [2- (l, l-dimethyl-3-phenyl-lH-inden-5-yl) vinyl] benzoate

Methyl 4- {2- [1,1-dimethyl-3 - {[(trifluoromethyl) sulfonyl] oxy} -17 H -inden-5-yl] vinyl} benzoate (590 mg, 1.30 mmol) , 48 mg (0.05 mmol) tris (dibenzylideneacetone) dipalladium (0), 64 mg (0.20 mmol) triphenylarzine, 166 mg (3.91 mmol) lithium chloride, and 525 mg (1), A mixture of phenyl tributyltin (43 mmol) was stirred at 95 ° C for 16 h. The reaction mixture was then diluted with water (75 mL) and extracted with ethyl acetate (2 x 20 mL) and diethyl ether (2 x 20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1:25 to 1:10). The resulting solid was recrystallized from ethyl acetate / hexane to give the title compound as a yellow solid (311 mg, 63%).

1 H-NMR (CDCl 3): δ 1.42 (s, 6H), 3.93 (s, 3H),

6.45 (s, 1H), 7.11 (d, J = 16.3 Hz, 1H), 7.29 (d, J = 16.3 Hz, 1H), 7.41-7.65 (m , 10H), 8.02 (d, J = 8.4 Hz, 2H).

Example 142

4- [2- (l, l-Dimethyl-3-phenyl-lH-inden-5-yl) vinyl] benzene

294 mg (0.77 mmol) of methyl 4- [2- (1,1-dimethyl-3-phenyl-17 H -inden-5-yl) -vinyl] -benzoate, 0.77 mL of 10 M aqueous sodium hydroxide were added. A mixture of a solution of 1 M solution in water and 7 ml of tetrahydrofuran and 5 ml of methanol was heated at reflux for 1 hour with stirring. The reaction mixture was concentrated, acidified with 10 ml of 1M hydrochloric acid and extracted with ethyl acetate (2 x 30 ml). The combined organic extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was triturated under hot methanol to afford the title compound (276 mg, 90%) as a molecule containing methanol.

1 H-NMR (DMSO-d 6: δ 1.34 (s, 6H), 3.14 (s, 3H), 6.58 (s, 1H), 7.25 (d, J = 16.4 Hz, 1H ), 7.37-7.71 (m, 11H), 7.90 (d, J = 8.3 Hz, 2H).

HU 218,963 Β

MS m / e: 367 (MH +).

Elemental analysis for C ₂ 6 H ₂₆ O ₃ .CH ₃ OH:

Found: C, 81.38; H, 6.58;

Found: C, 81.18; H, 6.78.

Example 143

N- (2-pyridyl) triflimide

o = s = o

I

The title compound was prepared using the procedure described in Comins and Dehghani, Tetrahedron Letters, 33 (42), 6299 (1992).

1 H-NMR (CDCl 3): δ 8.66 (m, 1H), 7.95 (m, 1H), 7.56 (m, 1H), 7.48 (d, 1H).

MS (DCI) m / e: 359 (MH +).

Example 144

Phenyl-4- {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl) carbonyl] amino} -2-hydroxybenzoate (I ³ j)

The title compound was prepared analogously to the procedure described for the preparation of 8- (2-fluorophenyl) derivative ( ¹³ g), which afforded 230 mg (0.83 mmol) of XVIIIa and 190 mg (0.83 mmol) of phenyl. 193 mg (48% yield) of the desired compound were obtained using -4-amino salicylate (Aldrich).

1 H-NMR (CDCl 3): δ 8.03 (d, J = 9.3 Hz, 1H), 7.75-7.71 (m, 2H), 7.51-7.19 (m, 13H). , 6.09 (t, J = 4.5 Hz, 1H), 2.40 (d, J = 4.5 Hz, 2H), 1.38 (s, 6H).

MS (DCI) m / e: 490 (MH ⁺ ).

Example 145

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl-amino} -2-hydroxybenzoic acid (I ⁴ j)

(I ⁴ j)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation procedure, to yield 135 mg (83%) of the desired compound using the compound (193 mg, 0.39 mmol) (Pj).

1 H-NMR (DMSO-d 6): δ 11.33 (bs, 1H), 10.38 (s, 1H), 7.83 (dd, J = 8.0 Hz, J = 1.7 Hz, 1H )

7.71 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.45-7.29 (m, 7H), 7.24 (dd) , J = 8.7 Hz, J = 1.8 Hz, 1H), 6.06 (t, J = 4.5 Hz, 1H), 2.35 (d, J = 4.5 Hz, 2H),

1.32 (s, 6H).

MS (DCI) m / e: 400 (MH ⁺ ).

IR (KBr): 2960, 1668, 1600, 1508.

Elemental analysis for C ₂₆ H ₂₃ O ₄ N.0,5 H ₂ O:

Found: C, 73.92; H, 5.73; N, 3.32; Found: C, 73.91; H, 5.73; N, 2.99.

Example 146

2-Fluoro-4-nitrobenzoic acid

To a solution of 2-fluoro-4-nitrotoluene (Janssen) (3.95 g, 25.5 mmol) in water (200 mL) was added potassium permanganate (24.6 g, 0.15 mmol) in portions at 80 ° C. The reaction mixture was stirred at 80 ° C for 2 hours, filtered hot, acidified with 5M hydrochloric acid and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. 1.15 g (24%) of the title compound are obtained.

1 H-NMR (DMSO-d ₆ ): δ 8.21 (d, J = 10.5 Hz, 1H),

8.16-8.08 (m, 2H).

MS (DCI) m / e: 186 (MH ⁺ ).

Example 147

Ethyl 2-fluoro-4-nitrobenzoate

To a solution of 2-fluoro-4-nitrobenzoic acid (1.15 g, 6.22 mmol) in absolute ethanol (20 mL) was added p-toluenesulfonic acid monohydrate (100 mg). The reaction mixture was refluxed for 16 hours, then concentrated in vacuo and the residue chromatographed on silica gel, eluting with ethyl acetate / hexane (5:95, v / v). This afforded the title compound (770 mg, 58%).

¹H-NMR (CDClj): δ 8.16-8.00 (m, 3H), 4.45 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).

MS (DCI) m / e: 214 (MH +).

Example 148

Ethyl 4-amino-2-fluorobenzoate

A solution of 770 mg (3.62 mmol) of ethyl 2-fluoro-4-nitrobenzoate in 15 ml of methanol was reacted with 75 mg of platinum (IV) oxide under 40 psi of hydrogen. After 30 minutes, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. This gave 700 mg (99%) of the title compound.

1 H-NMR (CDCl ₃ ): δ 7.76 (t, J = 8.3 Hz, 1H), 6.42 (d, J = 8.5 Hz, 1H), 6.35 (d, J = 12.9 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.20 (bs, 2H), 1.36 (t, J = 7.1 Hz, 3H).

MS (DCI) m / e: 184 (MH +).

Example 149

Ethyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -2-fluorobenzoate (Pk)

The title compound was prepared analogously to the procedure for the preparation of 8- (2-fluorophenyl) derivative ( ¹³ g), which afforded 250 mg (0.90 mmol) of XVIIIa and 181 mg (0.99 mmol) of ethyl. 240 mg (60%) of the desired compound were obtained using -4-amino-2-fluorobenzoate.

1 H-NMR (CDCl 3): δ 7.91 (t, J = 8.5 Hz, 1H), 7.72 (d, J = 10.1 Hz, 1H), 7.66 (d, J = 1) , 8 Hz, 1H), 7.51-7.48 (m, 1H), 7.44-7.35 (m, 6H), 7.20 (d, J = 8.6 Hz, 1H), 6 , 08 (t, J = 4.5 Hz, 1H), 4.37 (q, 7.1 Hz, 2H), 2.40 (d, J = 4.5 Hz, 2H), 1.38 (t , J = 7.1 Hz, 3H), 1.37 (s, 6H).

MS (DCI) m / e: 444 (MH +).

Example 150

4- {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl) carbonyl] amino} -2-fluorobenzoic acid (I ⁴ k)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in 8-phenyl derivative in the preparation procedure, to yield 175 mg (78%) of the desired compound using the compound (240 mg, 0.54 mmol) (Pk).

1 H-NMR (DMSO-d 6): δ 12.98 (bs, 1H), 10.58 (s, 1H), 7.89-7.77 (m, 2H), 7.73 (d, J = 1.5 Hz, 1H),

7.54 (d, J = 8.1 Hz, 1H), 7.44-7.30 (m, 7H), 6.06 (t, J = 4.5 Hz, 1H), 2.34 (d , J = 4.5 Hz, 2H), 1.31 (s, 6H).

MS (DCI) m / e: 416 (MH +).

IR (KBr): 2960, 1692, 1596, 1526.

Elemental analysis for C ₂₆ H _{2 2} O ₃ NF.0.25 H ₂ O:

Found: C, 74.36; H, 5.40; N, 3.34; Found: C, 74.16; H, 5.74; N, 3.13.

Example 151

N- (4-Methyl-3-nitro-phenyl) -acetamide

A solution of 4-methyl-3-nitroaniline (3.60 g, 23.7 mmol) in acetic anhydride (28 mL) was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo, ethyl acetate (25 mL) was added to the residue, washed with saturated aqueous sodium bicarbonate (2 x 50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. As a result of this

The title compound was obtained in a yield of 4.20 g (99% yield).

1 H-NMR (CDCl 3): δ 8.10 (d, J = 1.7 Hz, 1H),

7.75 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 7.38 (bs, 1H),

7.29 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H), 2.21 (s, 3H).

MS (DCI) m / e: 195 (MH +).

Example 152

4- (Acetylamino) -2-nitrobenzoic acid

To a solution of N- (4-methyl-3-nitrophenyl) acetamide (4.20 g, 23.6 mmol) in water (200 mL) was added potassium permanganate (22.77 g, 0.144 mmol) in portions at 80 ° C. The reaction mixture was stirred at 80 ° C for 2 hours, filtered hot, acidified with 5M hydrochloric acid and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. 1.80 g (34%) of the title compound were obtained.

1 H-NMR (CDCl 3): δ 10.63 (s, 1H), 8.19 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 2.10 (s, 3H).

MS (DCI) m / e: 225 (MH +).

HU 218,963 Β

Example 153

Ethyl 4-amino-2-nitrobenzoate

A solution of 4- (acetylamino) -2-nitrobenzoic acid (1.80 g, 8.0 mmol) in 14 mL of 12 M hydrochloric acid and 10 mL of absolute ethanol was heated at 90-100 ° C for 5 h. Only ethanol was removed in vacuo and the mixture was concentrated to pH 4 with 1 N aqueous sodium hydroxide solution and the resulting precipitate was filtered off. This gave 140 mg (8%) of the title compound.

1 H-NMR (CDCl 3): δ 7.61 (d, J = 8.5 Hz, 1H),

6.82 (d, J = 2.1 Hz, 1H), 6.74 (dd, J = 8.5 Hz, J = 2.1 Hz, 1H), 6.52 (bs, 2H), 4, 17 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H).

MS (DCI) m / e: 211 (MH +).

Example 154

Ethyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -2-nitrobenzoate (P1)

Preparation of the title compound was analogous to the procedure for the preparation of (Pg) 8- (2-fluorophenyl) derivative, which afforded 199 mg (0.71 mmol) of XVIIIa and 140 mg (0.78 mmol) of ethyl 4 155 mg (46%) of the desired compound was obtained using amino-2-nitrobenzoate.

1 H-NMR (CDCl 3): δ 8.15 (s, 1H), 7.84 (s, 1H), 7.79 (s, 1H), 7.73 (dd, J = 8.1 Hz, J = 1.9 Hz, 1H), 7.52-7.49 (m, 2H), 7.41-7.26 (m, 5H), 6.09 (t, J = 4.5 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.40 (d, J = 4.5 Hz, 2H), 1.37 (s, 6H), 1.34 (t, J = 7 , 2 Hz, 3H).

MS (DCI) m / e: 471 (MH ⁺ ).

Example 755

4- {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl) carbonyl] amino} -2-nitrobenzoic acid (I ⁴ l)

(E.g)

Preparation of the title compound in analogy to the procedure described for the preparation of the (Pa) 8-phenyl derivative afforded 105 mg (72% yield) of compound (P1) (155 mg, 0.33 mmol).

1 H-NMR (DMSO-d 6): δ 13.65 (bs, 1H), 10.76 (s, 1H), 8.31 (d, J = 1.7 Hz, 1H), 7.99 (dd, J = 8.3 Hz, J = 1.7 Hz, 1H), 7.90-7.84 (m, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.47 ( d, J = 1.7 Hz, 1H), 7.44-7.30 (m, 5H), 6.07 (t, J = 4.5 Hz, 1H), 2.33 (d, J = 4). , 5 Hz, 2H), 1.31 (s, 6H).

MS (DCI) m / e: 443 (MH +).

IR (KBr): 2960, 1702, 1542, 1518.

Elemental analysis for C ₂₆ H ₂₂ O ₅ N ₂ .0.5 H ₂ O:

Found: C, 69.17; H, 5.14; N, 6.20;

Found: C, 69.55; H, 4.93; N, 5.94.

Example 756

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -2-methoxybenzoate (Pm)

Preparation of the title compound was analogous to the procedure for the preparation of (Pg) 8- (2-fluorophenyl) derivative, which afforded 415 mg (1.49 mmol) of XVIIIa and 297 mg (1.64 mmol) of methyl 4 570 mg (90%) of the desired compound were obtained using amino-2-methoxybenzoate (Apin).

1 H-NMR (CDCl 3): δ 7.82 (d, J = 8.5 Hz, 1H),

7.77 (d, J = 1.7 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.51 (m, 1H), 7.48 (s, 1H), 7.41-7.33 (m, 4H), 6.80 (dd, J = 8.5 Hz, J = 1.9 Hz, 1H), 6.08 (t , J = 4.5 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.39 (d, J = 4.5 Hz, 2H),

1.38 (s, 6H).

MS (DCI) m / e: 442 (MH ⁺ ).

Example 757

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl) carbonyl] amino} -2-methoxybenzoic acid (I ⁴ m)

The title compound was prepared in a manner analogous to that described for the preparation of the (Pa) 8-phenyl derivative, which yielded 135 mg (0.31 mmol).

100 mg (77%) of the title compound were obtained using compound Pm (Pm).

1 H-NMR (DMSO-d ₆ ): δ 12.32 (bs, 1H), 10.36 (s, 1H), 7.85 (dd, J = 8.1 Hz, J = 1.7 Hz, 1H ), 7.79 (s, 1H),

7.64 (d, J = 1.7 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H),

7.44-7.30 (m, 7H), 6.06 (t, J = 4.5 Hz, 1H), 3.76 (s, 3H), 2.34 (d, J = 4.5 Hz) , 2H), 1.31 (s, 6H).

MS (DCI) m / e: 428 (MH +).

IR (KBr): 2960, 1718, 1592, 1524.

Elemental analysis for C ₂ 7 H ₂ 5 O ₄ N.0.25 H ₂ O:

Found: C, 75.07; H, 5.95; N, 3.24; Found: C, 75.04; H, 5.86; N, 3.04.

Example 158

4 - [{[5,6-Dihydro-5,5-dimethyl-8- (2-naphthyl) -2-naphthyl] carbonyl} -amino] -benzoic acid (Pn)

The preparation of the title compound was carried out in analogy to the compounds (I ⁴ g) 8- (2-fluorophenyl) preparation method, the compound (XVIa), the title compound in which the.

1 H-NMR (DMSO-d ₆ ): δ 12.69 (s, 1H), 10.41 (s, 1H), 7.95-7.88 (m, 5H), 7.85 (d, J = 8.7 Hz, 2H),

7.77 (d, J = 8.7 Hz, 2H), 7.57-7.40 (m, 5H), 6.20 (t, J = 4.5 Hz, 1H), 2.40 (d , J = 4.5 Hz, 2H), 1.35 (s, 6H).

MS (DCI) m / e: 448 (MH +).

IR (KBr): 2960, 1686, 1596, 1518.

Elemental analysis for C ₃₀ H ₂₅ O ₃ N.0.90 H ₂ O:

Found: C, 77.70; H, 5.83; N, 3.02; Found: C, 78.10; H, 5.55; N, 3.13.

Example 159

4 - {[(5,6-Dihydro-8-phenyl-2-naphthyl) carbonyl] amino} benzoic acid (Po)

(I ⁴ o)

The preparation of the title compound was carried out in analogy to the compounds (I ⁴ g) 8- (2-fluorophenyl) preparation process in which the starting material

6-methoxytetralone was used.

1 H-NMR (DMSO-d 6: δ 12.73 (s, 1H), 10.42 (s, 1H), 7.91-7.81 (m, 5H), 7.55-7.25 (m, 7H), 6.18 (t, J = 4.5 Hz, 1H), 2.86 (t, J = 7.6 Hz, 2H), 2.41-2.34 (m, 2H).

MS (DCI) m / e: 370 (MH +).

IR (KBr): 2950, 1680, 1648, 1518.

Elemental Analysis for: C ₂₄ H ₁₉ O ₃ N: Calculated: C, 78.03; H, 5.18; N, 3.79; Found: C, 77.61; H, 5.14; N, 3.81.

Example 160

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -3-fluorobenzoate (Pp)

(Pp)

The title compound was prepared analogously to the procedure described for the preparation of (Pg) 8- (2-fluorophenyl) derivative, whereby 300 mg of compound (XVIIIa) and 245 mg of methyl 4-amino-3-fluorobenzoate were obtained in an amount of 320 mg. (69% yield) of the title compound was obtained.

1 H-NMR (CDCl ₃ ): δ 1.38 (s, 6H), 2.40 (d, J = 4.7 Hz, 2H), 3.90 (s, 3H), 6.08 (t, J = 4.7 Hz, 1H), 7.32-7.42 (m, 5H), 7.49 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 1.9 Hz) , 1H), 7.73 (d, J = 1.9 Hz, J = 8.0 Hz, 1H), 7.74 (d, J = 1.8 Hz, J = 11.5 Hz, 1H), 7.84 (dd, J = 1.8 Hz, J = 8.5 Hz, 1H), 8.11 (bd, J = 3.8 Hz, 1H),

8.55 (t, J = 8.5 Hz, 1H).

Example 161

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -3-fluorobenzoic acid (Pp)

(Pp)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in the preparation of 8-phenyl derivative chromatography to yield 170 mg (54%) of the desired compound using the compound (310 mg, Pp).

1 H-NMR (CDCl ₃ ): δ 1.23 (s, 6H), 2.39 (d, J = 4.7 Hz, 2H), 6.07 (t, J = 4.7 Hz, 1H), 7.30-7.42 (m, 5H), 7.49 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H),

7.49 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H),

7.72 (d, J = 2.0 Hz, J = 8.1 Hz, 1H), 7.79 (d, J = 1.8 Hz, J = 11, 4 Hz, 1H), 7.90 ( d, J = 8.5 Hz, 1H), 8.06 (bd, J = 4.2 Hz, 1H), 8.59 (t, J = 8.6 Hz, 1H).

HU 218,963 Β

MS (DCI) m / e: 416 (MH +).

Elemental analysis for C ₂₆ H _{2 2} O ₃ NF:

Found: C, 75.17; H, 5.34; N, 3.37.

Found: C, 74.96; H, 5.53; N, 3.33.

Example 162

Methyl 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -3-methylbenzoate (Pq)

The title compound was prepared analogously to the procedure for the preparation of 8- (2-fluorophenyl) derivative ( ¹³ g) using 300 mg of compound (XVIIIa) and 319 mg of methyl 4-amino-3-methylbenzoate as a glassy material. and 305 mg (66%) of the title compound were obtained.

1 H-NMR (CDCl 3): δ 1.39 (s, 6H), 2.20 (s, 3H), 2.41 (d, J = 4.7 Hz, 2H), 3.89 (s, 3H) , 6.09 (t, J = 4.7 Hz, 1H), 7.30-7.45 (m, 5H), 7.48 (d, J = 2.0 Hz, 1H),

7.51 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.79 (d, J = 2.0 Hz, J = 8.0 Hz, 1H), 7, 85 (s, 1H), 7.91 (dd, J = 2.0 Hz, J = 8.5 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H).

MS m / e: 426 (MH ⁺ ).

Example 163

4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -3-methylbenzoic acid (Pq)

The preparation of the title compound was carried out analogously to (S ⁴⁾ as described in the preparation of 8-phenyl derivative chromatography to yield 223 mg (82%) of the desired compound using the compound (280 mg, Pq).

1 H-NMR (CDCl ₃ ): δ 1.37 (s, 6H), 2.20 (s, 3H),

2.39 (d, J = 4.7 Hz, 2H), 6.07 (t, J = 4.7 Hz, 1H), 7.30-7.42 (m, 5H), 7.45 (d) , J = 2.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 7.78 (d, J = 2.0 Hz, J) = 8.1 Hz, 1H), 7.80 (s, 1H), 7.96 (dd, J = 1.9 Hz, J = 8.6 Hz, 1H), 8.36 (d, J = 8 , 6 Hz, 1H).

MS (DCI) m / e: 412 (MH +).

Elemental Analysis for: C ₂₇ H ₂₅ O ₃ N: Calculated: C, 78.81; H, 6.12; N, 3.40;

Found: C, 77.68; H, 6.12; N, 3.40.

The present invention is further illustrated by the following biological tests. The tests are for illustrative purposes only.

Rhino-mouse study

Some representative compounds of formula I were tested for their effect on the size of the utriculus in a rhino mouse. The results were directly compared with the activity of the fully trans isomeric retinoic acid.

Investigation of utriculus reduction in rhino mouse

Female rhino mice (hr ^rh / hr ^rh ) were bred at Bristol-Myers Squibb. A solution of the retinoids tested in 50 μΐ ethanol vehicle was applied to the dorsal area of rhino mice (approximately 0.5 χ 3 cm ² surface area) for 5 days (Monday to Friday) daily with one al15 cal. Dose responses were obtained for various retinoids at concentrations ranging from 0.00033 mM to 16.5 mM. The following Monday, the animals were sacrificed by inhalation of carbon dioxide. From the central dorsal area of the mice

A 2.22 cm (7/8 ”) section was taken. The section was incubated overnight at 4 ° C in 0.5% acetic acid and the epidermis was removed from the skin. The separated epidermis was then fixed in form, dehydrated with ethanol and lightened in xylene. To determine the diameter of the utricules, the epidermis layers were plated in xylene on a slide. In each case, 40 utricular diameters were measured with an image analysis system; during the measurement we used an IBM personal computer, Image Measure program and Olympos microscope equipped with a video camera. The utricular reduction was calculated using the following equation:

diameter of utriculus in test group (1 ------) χ100 diameter of utriculus in ethanol control group

Since the maximal effect in this assay corresponded to about 60% utricular reduction, the activity of the various 40 test compounds was expressed as ED ₃₀ and reported in Table 1 [ED ₃₀ is (corresponding to half of the maximum value) 30% means the concentration required to achieve utriculus reduction].

Table 1

Compound* ED ₃₀ (mM) I ⁴ a 1.25 I ⁴ d 0.931 I ⁴ e 0.123 I ⁴ f 0,038 P ° 2.35 I ³³ a 0.86 I ⁴ months 3.12

* The following compounds have been found to be inactive in the rhino-mouse model: Pc, I '° a, I ⁿ a, P ⁶ a, P'a, P ² a, I ⁴ p and I ⁴ q.

The following biological test confirms that the compounds of the present invention also possess retinoid75

HU 218 963 Β docking cytotoxic activity. Accordingly, the present invention also provides a method of treating various tumors.

Cytotoxicity results

The cytotoxicity assay was designed in a similar manner to that performed by the National Cancer Institute [D. A. Scudiero et al., "Evaluation of Soluble Tetrazolium / Formazan Assay for Cell Growth and Drug Sensitivity in Culture Using Human and Other Tumor Cell Lines", Cancer Research, 48, 4827-4833 (1988); MC Alley et al., "Feasibility of Drug Screening with Panels of Human Tumor Cell Lines Using a Microculture Tetrazolium Assay", Cancer Research, 48, 589-601 (1988)], with the exception that a new method for determining cellular viability, alamarBlue ™ vital dye was used. During the test, -1. On day 1, 1000 cells were inoculated into each well of a 96-well flat-bottom plate (Corning) with a volume of 120 μΐ. Twenty-four hours later, an appropriate dilution of a compound of formula (I) in 30 μΐ whole medium (150 μΐ final volume) was added to the wells. Plates were sealed with Dynatech Labs to prevent evaporation. The

On day 5, the protective plate was removed and 15 μΐ sterile alamarBlue ™ dye was added to each well and the cells were incubated in 5% carbon dioxide at 37 ° C for 2 hours. Using a Vmax plate reader, the optical density was determined by subtracting OD ₅₇₀ from OD ₆₀₀ . In the case of cell growth, the 100% signal was assigned to the value obtained on whole medium containing only 0.5% dimethylsulfoxide. For each well, triplicate experiments were performed; 1, 2 and

Figure 3 shows the mean values thus obtained. The IC ₅₀ values in Table 2 were determined from the results of the second experiment.

Table 2

Compound IC _S0 (pM) Fully trans isomeric retinoic acid 86 Pa 51 I '° 47 T * g 38 I ⁴ d 28 I ³⁰ a 60 I ²⁶ a 48 I ^{, 2} a > 100 I ⁶ a 28

Test for arthritis

Compound (I ⁿ a) was also evaluated in a classic animal model of rheumatoid arthritis; this model of collagen-induced arthritis (CIA) is described in Trentham et al., Collagen arthritis as a relevant model for rheumatoid arthritis. Evidence pro and contra ”, Arthritis Rheum.,

25: 911-916 (1982); and Trentham et al., "Autoimmunity to Type II Collagen: An Experimental Model of Arthritis," /. Exp. Med., 146, 857-868 (1977).

In our experiments, treatment with the drug was started 3 days before 100 µg II. The first intradermal injection of Freund's complete adjuvant solution of collagen type 1 collagen. On day 7, a second booster injection of collagen was given. The animals typically exhibited arthritis symptoms, such as swelling of the joints, around day 30. During treatment, Compound (I ⁿ a) was administered intraperitoneally at a concentration of 10 mg / kg and 30 mg / kg / day in a volume of 10 ml / kg. To determine the time of onset of symptoms, three clinical parameters (swelling, joint deformity and ankylosis) were monitored daily (Table 4). At the end of the experimental period (day 70), the animals were sacrificed and the joints were evaluated for histological lesions. The lesions were scored according to the following grades: 1. joint hypertrophy; 2. pannus erosion in the cartilage; 3. pannus erosion in bone; and 4. loss of joint integrity.

As shown in Figure 4, the clinical score per animal remained normal for approximately 30 days. The mean clinical score in vehicle treated animals increased linearly to about 2.5 by day 65 (maximum score 4.0), indicating that these animals developed well-established arthritis. In contrast, animals treated with (I ⁿ a) exhibited a significant decrease in mean clinical score over the same period. At day 65, the mean score was 0.6, which was due to the presence of (grade 1) joint swelling as the only obvious clinical symptom in a small number of animals. However, most of the limbs remained normal.

Preliminary data obtained with this model at treatment with 30 mg / kg demonstrated complete resolution of the disease at both visual and histological levels.

The compounds of formula (I) may be used topically or systemically as anticancer agents and for the treatment, amelioration or prevention of skin disorders in which retinoic acid or other retinoids are commonly used. The compounds of the present invention are thus useful in the treatment of epithelial cell lesions in pre-malignant epithelial cells in animals and humans, as well as in the treatment of dermatoses such as ichthyosis, follicular disorders, benign epithelial non-malignant conditions of cell proliferation or incomplete cell differentiation) such as acne, psoriasis, eczema, atopic dermatitis, non-specific dermatitis, etc. treatment. The compounds of formula (I) of the present invention may also be used for the prevention and / or treatment of radiation-induced damage. By (I) 76

The compounds of the invention are also useful in the treatment of rheumatic diseases including rheumatoid arthritis, psoriatic arthropathy, Reiter's disease and cutaneous lupus erythematosus. The compounds of the invention are also useful in the treatment of osteoarthritis.

If the compounds of the invention are to be used in the above treatments, the compounds of formula (I) are usually formulated with a pharmaceutically acceptable liquid, semisolid or solid carrier. Pharmaceutically acceptable carriers are substances which are non-toxic and generally inert and do not adversely affect the function of the active ingredients. Such materials are well known in the art. This includes substances sometimes referred to as diluents or carriers (adjuvants) in the pharmaceutical field. The carriers may be organic or inorganic. Examples of pharmaceutically acceptable carriers for use in the formulation of compounds of formula I include, but are not limited to, water, gelatin, lactose, starch, mineral oil, cocoa butter, dextrose, sucrose, sorbitol, mannitol, acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, and other commonly used pharmaceutical carriers. In addition to the compounds of Formula I and the carriers, the pharmaceutical compositions may also contain minor amounts of flavoring agents, coloring agents, thickening or gelling agents, emulsifying agents, wetting agents, buffers, stabilizers and preservatives such as antioxidants.

Dosage levels and dosage regimens during treatment with compounds of Formula I will be greatly influenced by the particular dosage form, the route of administration, the condition being treated, and the particular characteristics of the patient being treated. Accordingly, it is best to determine optimal concentrations at a given time and place by routine experimentation.

In the treatment of dermatosis, the active ingredient is preferably administered topically, although in some cases, for example, in the treatment of severe cystic acne, oral administration may also be employed. When used topically, the compounds of the invention are found to exhibit good activity in a wide dilution range; the active ingredient or compounds may be used in a concentration range of 0.0005 to 2% by weight. Of course, higher concentrations may be used if required in a particular treatment; however, a preferred concentration of the active ingredient is from 0.002% to 1% by weight.

For topical application of the compounds of Formula I, the following formulations may be advantageously used: creams, gels, creams, ointments, powders, coloring compositions, solutions, suspensions, emulsions, lotions, sprays, adhesive patches and impregnated pads. The compounds of the invention may be mixed with a liquid or creamy base for topical treatment. Such topical formulations are well known in the art, see, for example, Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa., USA. Additional active ingredients may be added to the topical formulations for secondary purposes, such as for the treatment of dry skin or protection against light. In addition to treating dermatosis, reducing infection, reducing irritation or inflammation, etc. Other pharmaceutical active ingredients may also be included in such compositions.

The compounds of the invention may also be administered enterally. For oral administration, the compounds of the present invention may be administered in a dosage range of from 2 pg to 100 mg per day and per kilogram of body weight. The required amount may be administered simultaneously or in several portions. Formulations suitable for oral administration include, but are not limited to, tablets, pills, dragees, syrups, suspensions, emulsions, solutions, powders, and granules. For oral administration, pills containing from 0.1 mg to about 1 mg of the active ingredient are preferably used.

U.S. Patent No. 4,876,381 to Retinoid Compounds can be used as a gel, balm, powder, cream and the like. formulations. The processes and compositions described in this patent can also be used to form compounds of formula (I).

Isotretinoin (Accutane®) and etretinate (Tegison®) are used clinically in the treatment of severe, persistent cystic acne such as erythroderma, and severe, persistent psoriasis such as common pustules. The application of these agents is described in detail, for example, in Physician's Desk Reference, 47th Edition, 1993 (published in Medical Economics Data). The compounds of formula (I) may also be used to treat severe, persistent cystic acne and severe, persistent psoriasis. In these cases, the compounds of the invention may be used in a manner similar to that of isotretinoin and etretinate. Referring to the chapters on isotretinoin and etretinate in the Physician's Desk Reference will provide good guidance for the use of the compounds of the invention, which may obviate the need for otherwise laborious experimental dose determination.

The compounds of the invention may also be administered parenterally by intravenous, intraperitoneal or intramuscular perfusion or injection. In these cases, the compounds of the invention will generally be administered in an amount of from 2 pg to 100 mg per kg body weight per day. In one preferred mode of administration, solutions or suspensions containing from about 0.01 mg to about 1 mg of active ingredient per ml are used.

Previous observations suggest that many retinoids have antitumor properties [Roberts,

A. B. and Spom, Μ. B., The Retinoids, (Spom, M.

B., Roberts, A. B., and Goodman, D. S., eds., 2, 209-286 (1984), Academic Press, New York, USA;

HU 218,963 Β

Lippman, S.M., Kessler, J.F., and Meyskens, F.L., Cancer Treat. Rep., 71, 391 (1987); and Lippman, S.M., Kessler, J.F., and Meyskens, F.L., Cancer Treat. Rep., 71.493 (1987)]. As used herein, the term "antitumor" includes both chemopreventive (prophylactic or anti-tumor growth) and therapeutic (curative) use. For example, fully trans isomeric retinoic acid can be used to treat acute promyelocytic leukemia (Huang, M. et al., Blood, 72, 567 (1988)). Isotretinoin has been shown to be useful in the prevention of the development of second primary tumors in squamous cell carcinoma of the head and neck [Hong, W. K. et al., Engl. J. Med., 323, 795 (1990)].

The compounds of formula I can be used in a manner substantially similar to retinoids for the treatment of various tumors (chemopreventive and therapeutic). The amount of the single, multiple or daily dose of antitumor agent to be administered for the compounds of the invention may vary depending on, among other factors, the potency of the compound, the route of administration chosen, the size of the recipient, the type of tumor and the condition. The dose to be administered is substantially non-fixed, but an effective amount will be used, or, if a dosage form is used that will metabolically release the pharmacologically active substance to produce the desired pharmacological and physiological effects, the composition will be in molar amount equivalent to the active form. contains the given compound. The cancer oncologist will be able to design a treatment program without undue experimentation, taking into account the results previously reported for retinoids with antitumor properties. For example, to prevent second primary tumors of squamous cell carcinoma of the head and neck, the oncologist can find guidance in Hong, W.K., et al., Engl. J. Med., 323, 795 (1990). The treatment of acute promyelocytic leukemia is described in Huang, M. et al., Blood, 72, 567 (1988).

Claims (47)

PATENT CLAIMS A compound of formula (I), or a non-toxic pharmaceutically acceptable salt, physiologically hydrolysable ester or solvate thereof, wherein: X is -O-CO-, -NH-CO-, -CS-CO-, -CS-NH-, -CO-O-, -CO-NH-, -COS-, -SCO-, -SCH ₂ -, -CH ₂ -CH ₂ -, -C = C-, -CH ₂ -NH-, -COCH ₂ -, -NHCS-, -CH ₂ S-, Or -CH ₂ O-, -OCH ₂ -, -NHCH ₂ - CR ⁵ = CR ⁶ -; R ^m and R ^k are each independently hydrogen, halogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, or nitro; n is 0 or 1; R ⁴ is - (CH ₂ ) -, -Y, -C 1-6 alkyl, or C 3-6 cycloalkyl; R &lt; 1 &gt; is -COOZ, (C1-C6) alkyl, hydroxymethyl, -CONHRy or formyl; R ² and R ³ are each independently hydrogen or C 1-6 alkyl; R ^a and R ^b are each independently hydrogen or C 1-6 alkyl; but when n is 1, R ^a and R ^b together form a group; Y is naphthyl or phenyl, each of which may be optionally substituted with 1 to 3 identical or different C 1-6 alkyl and / or halogen atoms; Z is hydrogen or C 1-6 alkyl; ^{R5, R6} and Ry are independently hydrogen or C1-6 alkyl; and t is 0, 1, 2, 3, 4, 5 or 6. A compound according to claim 1 having the formula R ¹ is carboxy; n is 1; R ² and R ³ are each independently hydrogen or methyl; as well as R ^a and R ^b are each independently hydrogen or C 1-6 alkyl. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-ethyl-2-naphthyl) amino] carbonyl} benzoic acid of claim 2. The 4 - {[(5,6-dihydro-5,5,8-trimethyl-2-naphthyl) amino] carbonyl} benzoic acid of claim 2. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) amino] carbonyl} benzoic acid of claim 2. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-ethyl-2-naphthyl) carbonyl] amino} benzoic acid of claim 2. The 4 - {[(5,6-dihydro-5,5,8-trimethyl-2-naphthyl) carbonyl] amino} benzoic acid of claim 2. The 4- (E) - [(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) -1-propenyl] benzoic acid according to claim 2. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) oxy] carbonyl} benzoic acid of claim 2. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino] benzoic acid of claim 2. 11. 4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] oxy} benzoic acid according to claim 2. HU 218,963 Β 12. The 4 - [{[5,6-dihydro-5,5-dimethyl-8- (2-fluorophenyl) -2-naphthyl] carbonyl} amino] benzoic acid of claim 2. 13. 4 - {[(5,6-Dihydro-5,5,6-trimethyl-8-phenyl-2-naphthyl) carbonyl] amino} benzoic acid according to claim 2. The 4 - {[(5,6-dihydro-5,5,7-trimethyl-8-phenyl-2-naphthyl) carbonyl] amino} benzoic acid of claim 2. 15. The 4 - {(E) - [2- (5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl)] vinyl} benzoic acid of claim 2. 16. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] thio} benzoic acid of claim 2. 17. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) thio] carbonyl} benzoic acid of claim 2. 18. 4- [2- (5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) ethyl] benzoic acid according to claim 2. 19. 4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) thiocarbonyl] anino} benzoic acid according to claim 2. 20. 4 - {[(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] methyl} benzoic acid according to claim 2. 21. 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) methyl] oxy} benzoic acid according to claim 2. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) oxy] methyl} benzoic acid according to claim 2. 23. The 4 - [{[5,6-dihydro-5,5-dimethyl-8- (2,4-dimethylphenyl) -2-naphthyl] carbonyl} amino] benzoic acid of claim 2. 24. The 4 - [{[5,6-dihydro-5,5-dimethyl-8- (4-methylphenyl) -2-naphthyl] carbonyl} amino] benzoic acid of claim 2. 25. The 4 - [(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) ethynyl] benzoate of claim 2. 26. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) thio] methyl} benzoic acid of claim 2. 27. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) methyl] amino} benzoic acid of claim 2. 28. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) amino] thiocarbonyl} benzoic acid of claim 2. 29. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) methyl] thio} benzoic acid of claim 2. 30. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) amino] methyl} benzoic acid of claim 2. 31. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -2-hydroxybenzoic acid of claim 2. 32. 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -2-fluorobenzoic acid according to claim 2. 33. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -2-nitrobenzoic acid of claim 2. 34. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -2-methoxybenzoic acid of claim 2. 35. The 4 - [{[5,6-dihydro-5,5-dimethyl-8- (2-naphthyl) -2-naphthyl] carbonyl} amino] benzoic acid of claim 2. 36. The 4 - {[(5,6-dihydro-8-phenyl-2-naphthyl) carbonyl] amino} -2-methoxybenzoic acid of claim 2. 37. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -3-fluorobenzoic acid of claim 2. 38. The 4 - {[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthyl) carbonyl] amino} -3-methylbenzoic acid of claim 2. A compound according to claim 1, wherein R ¹ is carboxy; X is -CONH-; R ² and R ³ is methyl; and R ^a and R ^b together form a group of the formula. 40. The 4 - {[(5,8,10,10a-tetrahydro-10,10-dimethyl-9-phenyl-2-anthracenyl) carbonyl] amino} benzoic acid of claim 39. 41. A compound according to claim 1, wherein R ¹ is carboxy; n is 0; and R ² and R ³ are methyl. 42. The 4 - {[(1,1-dimethyl-3-phenyl-1 H -inden-5-yl) amino] carbonyl} benzoic acid of claim 41. 43. The 4 - {[(1,1-dimethyl-3-phenyl-1 H -inden-5-yl) oxy] methyl} benzoic acid of claim 41. 44. The 4- [2- (1,1-dimethyl-3-phenyl-17 H -inden-5-yl) -vinyl] -benzoic acid of claim 41. 45. The 4 - {[(1,1-dimethyl-3-phenyl-1 H -inden-5-yl) carbonyl] amino} benzoic acid of claim 41. 46. A pharmaceutical composition for treating a tumor in a mammal comprising as an active ingredient a compound of formula (I), a nontoxic pharmaceutically acceptable salt thereof, a physiologically hydrolyzable ester or a solvate thereof, in association with a pharmaceutical carrier and / or carrier. 47. A pharmaceutical composition for treating rheumatoid arthritis in a mammal comprising as an active ingredient a compound of formula (I), a nontoxic pharmaceutically acceptable salt, a physiologically hydrolysable ester or a solvate thereof, preferably 4 - [[(E) - (5,6-dihydro-5,5-dimethyl) -8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid in association with pharmaceutical vehicles and / or carriers.