WO2006029436A1

WO2006029436A1 - Cox-ii inhibitor compounds

Info

Publication number: WO2006029436A1
Application number: PCT/AT2005/000374
Authority: WO
Inventors: Thomas Erker; Norbert Handler; Walter Jäger; Beatrix Kuen-Krismer; Stephanie Parth
Original assignee: Universität Wien
Priority date: 2004-09-17
Filing date: 2005-09-16
Publication date: 2006-03-23

Abstract

The invention relates to the compounds of the general formula (I), wherein X = -CH- or -N=, n = 0 or 1, R1 = -H, -F, -OCH3 or -COOCH3, R2 = -H or -F, R3 = -H, or R2 and R3 together represent -CH2-CH2-, R4 = -H or -OCH3, R5 = -H, -OCH3 or -SO2CH3, and R6 = -H or -OCH3, with the proviso that at least two of the substituents R1, R4, R5 and R6 are not hydrogen. The inventive compounds are selective COX-II inhibitors.

Description

COX-II inhibitor compounds

The present invention relates to novel COX-II inhibitor compounds and their use as medicaments and for the preparation of medicaments.

In the early 1990s, two different isoforms of cyclooxygenase (COX) were discovered, COX-I and COX-II. These two enzymes are distributed differently in the body.

COX-I acts predominantly in the mucous membrane of the gastrointestinal tract as well as in the platelets. This enzyme has a protective effect on the gastric mucosa and promotes blood clotting. It should therefore experience no restriction in the treatment with anti-inflammatory drugs in its effect.

COX-II is u.a. in the development of tumors, e.g. Colon carcinoma, and neurodegenerative diseases, such as Alzheimer's disease, as well as in inflammatory processes formed and therefore represents a significant goal in the treatment of these diseases.

In the prior art several highly selective inhibitors of COX-II known, for example, Celecoxib ^®, ^® rofecoxib, valdecoxib ^®, etc. are high selective COX-II inhibitors may be used for the treatment verschiedenster state images and disorders. The following list shows some of the major effects and uses of such inhibitors:

Antitumour effect

Treatment and prevention of malignancies

Use in combination with radiotherapy

Use in combination with chemotherapeutic agents

Reduction of invasiveness and metastatic potential of tumors

Induction of apoptosis

Inhibition of NfkappaB

Inhibition of uterine contraction

Inhibition of platelet aggregation

Anti-inflammatory effect

Antipyretic effect

Treatment of asthma Treatment of osteoarthritis and rheumatoid arthritis

Improving effect on bone repair

Antiangiogenic effect

Prevention and treatment of connective tissue and bone diseases, including

osteoporosis

Anti-oestrotic effects

Treatment of glaucoma

Reduction of edema

Pain reduction

Effect on NO synthase

Prevention of blood vessel diseases

Prevention and treatment of heart attack

Prevention and treatment of diabetes and diabetes complications

Prevention and treatment of Helicobacter pylori gastritis

Prevention and treatment of Parkinson's disease

Prevention of ischemic proliferative retinopathy

Prevention of reperfusion damage

Antiviral, antibacterial and antifungal activity

Treatment of malaria

Treatment of sickle cell anemia

Treatment of skin diseases, such as psoriasis

Treatment of actinic keratosis

Treatment of amyotrophic lateral sclerosis

Treatment of multiple sclerosis

Treatment of M. Alzheimer's

In today's known COX-II inhibitors may be the problem that cardiovascular implications occur.

In the course of the investigations leading to the present invention, the inventors synthesized resveratrol, a natural selective COX-I inhibitor, based compounds. Compounds of this type are described, inter alia, in the Journal of Biological Chemistry (2004), 279 (21): 22727-22737, in WO 2001/042231 A, WO 2001/021165 A, CN 1 466 943 A, WO 1993/23357 A, FR 2 262 513 A, EP 1 418 164 A, WO 2003/018013 A, in the Journal of Research (2004), 41 (3): 365-368, in Heterocycles (1989), 29 (6): 1 199-207, in the Journal of Applied Physics (1992), 71 (1): 410-17, in Drug Development Research (2002), 55 (2): 79-90, in the Journal of Porphyrins and Phthalocyanines (2000), 4 (3): 233-242, in Synthetic Communications (1995), 25 (5): 667-80 and in WO 2005/016860 A.

The object of the invention is to provide novel compounds which act as highly selective COX-II inhibitors. Preferably, however, these compounds should show little or no inhibitory effect on COX-I.

This object is achieved by compounds of the general formula I.

solved, where X = -CH- or -N =, n = 0 or 1

R i = -H, -F, -OCH ₃ or -COOCH ₃ ,

R ₂ = -H or -F,

R ₃ = -H, or R ₂ and R ₃ together are -CH ₂ -CH ₂ -,

R ₄ = -H or -OCH ₃ ,

R ₅ = -H, -OCH ₃ or -SO ₂ CH ₃ , and

R ₆ = -H or -OCH ₃ , with the proviso that at least two of R 1, R ₄ , R ₅ and R _{6 are} not hydrogen.

These compounds have been shown, as shown below, to be highly selective COX II inhibitors with little or negligible COX-I inhibitory activity. These compounds are thus useful for the manufacture of a medicament for the treatment of condition patterns and diseases in whose formation and / or symptoms COX-II is involved.

Preferred embodiments of the present invention are compounds in which:

X = -N =, n = O, R, = -OCH ₃ , R ₂ = -H, R ₃ = -H, R ₄ = -OCH ₃ , R ₅ = -H and R ₆ = - X = -CH-, n = 0, R ₁ = -H, R ₂ + R ₃ = -CH ₂ -CH ₂ -, R ₄ = -H, R ₅ = -OCH ₃ and R ₆ = - OCH ₃

X = -CH-, n = 0, R ₁ = -F, R ₂ = -F, R ₃ = -H, R ₄ = -OCH ₃ , R ₅ = -H and R ₆ = -OCH ₃

X = -CH-, n = 1, R ₁ = -OCH ₃ , R ₂ = -H, R ₃ = -H, R ₄ = -OCH ₃ , R ₅ = -H and R ₆ = - OCH ₃

X = -CH-, n = O, R ₁ = -OCH ₃ , R ₂ = -H, R ₃ = -H, R ₄ = -H, R ₅ = -SO ₂ CH ₃ and R ₆ = -H

X = -CH-, n = O, R 1 = -COOCH ₃ , R ₂ = -H, R ₃ = -H, R ₄ = -OCH ₃ , R ₅ = -H and R ₆ = - OCH ₃

Another aspect of the invention relates to the compounds of general formula I as a medicament. Furthermore, the invention relates to the use of the compounds of general formula I for the preparation of a medicament with COX-II inhibitory activity.

The invention will be explained in more detail by way of examples. Examples:

Synthesis of preferred representatives of the compounds of the invention

Example 1: 3,5-Dimethoxy-N- (4-methoxyphenyl) benzalimine

In a round bottom flask, 3 mmol (0.498 g) of 3,5-dimethoxybenzaldehyde and 3 mmol (0.369 g) of p-anisidine were refluxed in about 15 ml of toluene at an oil bath temperature of about 120 ° C under argon. By means of thin-layer chromatography in toluene, the end of the reaction was determined, the solvent removed in vacuo and the crystalline product recrystallized from ethanol. Yield: 0.560g (68.9%); Mp 70 ° C. ¹ H-NMR (200 MHz, CDCl _3): δ 8:40 to 8:35 (m, IH), 7:28 to 7:18 (m, 2H), 7:07 to 7:01 (m, 2H), 6.98-6.88 ( m, 2H), 6.60-6.52 (m, IH), 3.85 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H). ¹³ C-NMR (50 MHz, CDCl _3): δ 161.0, 158.3, 158.3, 144.7, 138.4, 122.2, 1 14.3, 106.1, 103.8, 55.5, 55.4. MS m / z 271 (M ⁺ , 95%), 234 (100%). CHN analysis for C ₁₆ H ₁₇ NiO _3: Calcd. C 70.83, H 6.32, N 5.16; Gef. C 70.65, H 6.59, N 4.90.

Example 2: 2- (3,4-Dimethoxyphenyl) -3,4-dihydronaphthalene

This compound was prepared by the Suzuki reaction:

In a 50 ml three-necked flask were 2 mmol (0.416 g) of 3-bromo-l, 2-dihydronaphthalene, 2.2 mmol (0.400 g) 3,4-Dimethoxyphenylboronsäure and 4 mmol (0.552 g) K ₂ CO ₃ as a 2-molar solution in water and submitted to 12 ml of toluene. The solubilizers were 0.8 ml Ethanol was added and allowed to stir for 30 minutes at room temperature under argon. Thereafter, 0.06 mmol (0.068 g) of tetrakis (triphenylphosphine) palladium (0) were rinsed as a catalyst with about 0.6 ml of ethanol in the reaction solution and stirred under argon at an oil bath temperature of 90 ° C. By means of thin-layer chromatography in toluene / ethyl acetate 9 + 1, the end of the reaction was determined. The reaction mixture was then washed with 5% NaHCO ₃ solution, saturated NaHCO ₃ solution, saturated NaCl solution and several times with water. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated by rotary evaporation. The crystalline product was recrystallized from ethanol. Yield: 0.144g (27%); Mp = 74-76 ° C ¹ H-NMR (200 MHz, CDCl _3): δ 7:23 to 7:03 (m, 6H), 6.92-6.73 (m, 2H), 3.94 (s, 3H), 3.90 ( s, 3H), 3.00-2.85 (m, 2H), 2.80-2.63 (m, 2H). ¹³ C-NMR (50 MHz, CDCl _3): δ 148.8, 148.6, 138.3, 134.8, 134.6, 134.0, 127.1, 126.7, 126.6, 126.3, 122.9, 117.7, 1 1 1.0, 108.3, 55.9, 55.9, 28.2, 26.4 , MS m / z 266 (M ⁺ , 100%). CH analysis for Ci ₈ Hi ₈ O ₂ : Ber. C 81.17, H 6.81; Gef. C 80.83, H 6.78.

Example 3: 1- [2- (3,5-Dimethoxyphenyl) -1-ethenyl] -2,4-difluorobenzene

This compound was synthesized according to Horner-Emmons-Wadsworth: In a dry three-necked flask, 2 mmol (0.576 g) of diethyl (3,5-dimethoxybenzyl) phosphonate were cooled to 0 ° C. under argon. Then, 5 ml of dry DMF, 10 mmol (0.540 g) of sodium methoxide and 2 mmol (0.284 g) of 2,4-difluorobenzaldehyde were added and stirred for one hour at room temperature. The reaction mixture was heated to 100 ° C under argon for 24 hours. Then it was poured onto 250 ml of ice water, the precipitate was filtered off with suction and recrystallized from ethanol. Yield: 0.190 g (34%); Mp = 78-79 ° C ¹ H-NMR (200 MHz, CDCl _3): δ 7.61-7.49 (m, IH), 7.16 (d, J = 16.4 Hz, IH), 7:01 (d, J = 16.4 Hz , IH), 6.92-6.77 (m, 2H), 6.66 (d, J = 2.1 Hz, 2H), 6.41 (t, J = 2.1 Hz, IH), 3.82 (s, 3H). ¹³ C-NMR (50 MHz, CDCl _3): δ 161.0, 139.0, 130.5 (q, J _c, _F = 2.3 Hz), 127.8 (q, Jc _1F = 5.0 Hz), 121.5, 120.4 (q, J _{C; F} = 1.5 Hz), 11 1.6 (dd, J _C , _F = 3.8 Hz and 21.46 Hz, respectively), 104.6, 103.8 (d, J _CjF = 25.7 Hz), 100.3, 55.3. MS m / z 276 (M ⁺ , 100%). CHN analysis for C ₁₆ H ₁₄ O ₂ F _2: Calc. C 69.54, H 5.11; Gef. C 69.29, H 5.16.

Example 4: 1,3-Dimethoxy-5- [4- (4-methoxyphenyl) -1,3-butadienyl] benzene

This compound was synthesized according to Horner-Emmons-Wadsworth. In a dry three-necked flask, 5 mmol (1.44 g) of diethyl (3,5-dimethoxybenzyl) phosphonate were cooled to 0 ° C. under argon. Then, 5 ml of dry DMF, 10 mmol (0.540 g) of sodium methoxide and 5 mmol (0.81 1 g) of 4-methoxycinnamaldehyde were added and stirred for one hour at room temperature. The reaction mixture was added Argon heated to 100 ° C for 24 hours. Then it was poured onto 250 ml of ice water, the precipitate was filtered off with suction and recrystallized from ethanol. Yield: 0.825 g (55%); Mp = 101 ° C. ¹ H-NMR (200 MHz, CDCl _3): δ 7:37 (AB system, J = 8.7 Hz, 2H), 6.97-6.50 (m, 8H), 6:37 to 6:34 (m, IH) , 3.80 (s, 9H). ¹³ C-NMR (50 MHz, CDCl _3): δ 160.8, 159.2, 139.5, 132.7, 131.5, 130.0, 130.0, 127.6, 126.9, 114.1, 104.2, 99.7, 55.3. MS m / z 296 (M ⁺ , 100%). CHN analysis for Ci ₉ H ₂₀ O ₃ : Ber. C 76.99, H 6.80; Gef. C 76.67, H 6.88.

Example 5: 1-Methoxy-4- [2 - [(4-methylsulfonyl) phenyl] -1-ethenyl] benzene

As a precursor molecule, 1-methoxy-4- [2 - [(4-methylsulfanyl) phenyl] -1-ethenyl] benzene was prepared from 3 mmol (0.774 g) of diethyl (4-methoxybenzyl) phosphonate and 3 mmol (0.456 g) of 4-methylmercaptobenzaldehyde synthesized in the manner described in Examples 3 and 4. Yield: 0.500 g (65%); Mp = 195-196 ° C. ¹ H-NMR (200 MHz, CDCl _3): δ 7:45 to 7:38 (m, 4H), 7.22 (AB-system, B-part, JA _B = 8.4 Hz, 2H), 7:07 -6.86 (m, 4H), 3.82 (s, 3H), 2.49 (s, 3H). ¹³ C-NMR (50 MHz, CDCl _3): δ 159.2, 137.2, 134.6, 130.0, 127.6, 126.7, 126.6, 125.9, 114.1, 55.3, 15.9. MS m / z 256 (M ⁺ , 100%). CHN analysis for Ci ₆ Hi ₆ OiSi: Ber. C 74.97, H 6.29; Gef. C 75.04, H 6.08.

In a beaker, 1 mmol (0.256 g) of the just obtained l-methoxy-4- [2 - [(4-methylsulfanyl) phenyl] -1-ethenyl] benzene was dissolved in a large amount of acetone and 2 mmol (1230 g) Oxone® was added , The mixture was stirred for 24 hours at room temperature, then 10 ml of 10% ammonia was added and stirred for a further 30 minutes. The reaction mixture was brought to dryness on a rotary evaporator and taken up in water. The insoluble product was filtered with suction and recrystallized from acetone to obtain 1-methoxy-4- [2 - [(4-methylsulfonyl) phenyl] -1-ethenyl] benzene. Yield: 0.250 g (87%); Mp = 253-254 ° C. ¹ H NMR (200 MHz, d ₆ -DMSO): δ 7.90-7.78 (m, 4H), 7.60 (AB system, A part, JAB = 8.3 Hz, 2H), 7.43 (d, J _E = 16.0 Hz), 7.21 (d, J _E = 16.0 Hz), 7.98 (AB system, B part, JAB = 7.8 Hz, 2H), 3.79 (s, 3H), 3.21 (s , 3H). ¹³ C NMR (50 MHz, d ₆ -DMSO): δ 159.5, 142.6, 138.6, 131.7, 129.0, 128.3, 127.4, 126.6, 124.3, 114.2, 55.2, 43.6. MS m / z 288 (M ⁺ , 100%). CHN analysis for C ₁₆ Hi ₆ O ₃ Si: Ber. C 66.64, H 5.59; Gef. C 66.66, H 5.61.

Example 6: Methyl 4- [2- (3,5-dimethoxyphenyl) -1-ethenyl] benzoate

This compound was synthesized from 5 mmol (1.44 g) of diethyl (3,5-dimethoxyphenyl) phosphonate and 5 mmol (0.820 g) of 4-formylbenzoic acid methyl ester according to Horner-Emmons-Wadsworth in the manner described above. Yield: 0.470 g (32%); M.p. = 1 19-120 ° C ¹ H-NMR (200 MHz, CDCl _3): δ 8:02 (AB-System, A part, J _m = 8.4 Hz, 2H), 7:55 (AB System, B part, J _AB = 8.4 Hz, 2H), 7.12-7.10 (m, 2H), 6.69-6.67 (m, 2H), 6.42 (t, J = 2.1 Hz, IH), 3.92 (s, 3H ), 3.83 (s, 6H). ¹³ C-NMR (50 MHz, CDCl _3): δ 166.8, 160.9, 141.5, 138.7, 131.1, 129.9, 128.9, 128.0, 126.3, 104.8, 100.5, 55.3, 52.0. MS m / z 298 (M ⁺ , 100%). CHN analysis for C ₇ Hi ₈ O ₄ : Ber. C 72.45, H 6.08; Gef. C 72.24, H 5.90.

Example 7: Methyl 4 - [(E) -2- (3-methoxyphenyl) -1-ethenyl] benzoate

₃₃

This compound was synthesized according to Horner-Emmons-Wadsworth. In a dry three-necked flask, 5 mmol (1.43 g) of methyl 4- [(diethoxyphosphoryl) methyl] benzoate was cooled to 0 ° C. under argon. Then, 10 ml of dry DMF, 10 mmol (0.540 g) of sodium methoxide and 5 mmol (0.680 g) of 2-methoxybenzaldehyde were added and stirred for one hour at room temperature. The reaction mixture was heated to 100 ° C under argon for 3 hours. Then it was poured onto 250 ml of ice water, the precipitate was filtered off with suction and recrystallized from ethanol. Yield: 0.625 g (46.6%); Mp = 94 ° C. ¹ H NMR (200 MHz, d ₆ -DMSO + CDCl ₃ ): δ 7.98 (AB system, A part, J _AB = 8.3 Hz, 2H), 7.60 (AB system, B part, J _AB ) 8.3 Hz, 2H), 7.32-7.08 (m, 5H), 6.86-6.81 (m, IH), 3.89 (s, 3H), 3.83 (s, 3H). ¹³ C NMR (50 MHz, d ₆ -DMSO + CDCl ₃ ): δ 166.3, 159.8, 141.6, 138.0, 131.1, 129.8, 129.7, 128.7, 127.6, 126.4, 119.4, 114.0, 11 1.9, 55.2, 52.0. MS m / z 268 (M ⁺ , 100%). CHN analysis for Ci ₇ Hi ₆ O ₃ : Ber. C 76.10, H 6.01; Gef. C 75.86, H 6.1 1. Example 8: Methyl 4 - [(IE, 3E) -4- (4-methoxyphenyl) -1,3-butadienyl] benzoate

This compound was synthesized according to Horner-Emmons-Wadsworth. In a dry three-necked flask, 5 mmol (1.43 g) of methyl 4- [(diethoxyphosphoryl) methyl] benzoate was cooled to 0 ° C. under argon. Then, 10 ml of dry DMF, 10 mmol (0.540 g) of sodium methoxide and 5 mmol (0.810 g) of 4-methoxycinnamaldehyde were added and stirred for one hour at room temperature. The reaction mixture was heated to 100 ° C under argon for 3 hours. Then it was poured onto 250 ml of ice water, the precipitate was filtered off with suction and recrystallized from ethanol. Yield: 0.685 g (47.9%); Mp = 218 ⁰ C. ¹ H-NMR (200 MHz, CDCl _3): δ 8.00-7.91 (m, 2H), 7.64-7.56 (m, 2H), 7:50 to 7:41 (m, 3H), 7:26 to 7:21 ( m, IH), 7.02-6.87 (m, 3H), 6.81-6.73 (m, IH), 3.87 (s, 3H), 3.77 (s, 3H). ¹³ C NMR no data as solubility too low. MS m / z 294 (M ⁺ , 100%). CHN analysis for Ci ₉ H ₁₈ O ₃ x 0.20 H ₂ O: Calcd. C 76.59, H 6.22; Gef. C 76.51, H 6.23.

Measurement of the inhibitory effect of the compounds of general formula I.

COX (Human) Inhibitor Screening Assay:

An immunoassay from IBL Products, Hamburg, Germany, was used for the determination of the COX-I and COX-II activities. The assay quantifies prostaglandins F, E and D as well as thromboxane B-like prostaglandins formed by the cyclooxygenase reaction. COX-I and COX-II were used as so-called IC50, 50% enzyme inhibition, i. the substance concentration which inhibits 50% of the measured isoenzyme indicated.

For comparison, several compounds of related structure based on known COX inhibitors, of which, as a result, a selectivity for COX-II was assumed, were synthesized and investigated. The formulas of these compounds are given below: - (1H-2-indenyl) -1,3-benzodioxole (VB1):

- (2-methoxyphenyl) -H-indene (VB2):

- (2,3 ₁ 4-trimethoxyphenyl) -lH-indene (VB3):

, 2-Dihydro-3- (2,3,4-trimethoxyphenyl) naphthalene (VB4):

- (3,4-dihydro-2-naphthalenyl) -1,3-benzodioxole (VB5):

Table 1: COX inhibitors - IC50 [μM]

As can be seen from Table 1, compounds of the invention exhibit high selectivity for COX-II and hardly inflammatory ^"effects to COX-I. In the comparative examples, however, is contrary to all expectation no high selectivity for COX-II observed. Thus, it is not self-evident to presuppose a selectivity for one of the two COX isoforms for certain compound groups due to the structure.

Claims

Claims:

1. Compound of general formula I.

where X = -CH- or -N =, n = 0 or 1

R i = -H, -F, -OCH ₃ or -COOCH ₃ ,

R ₂ = -H or -F,

R ₃ = -H, or R ₂ and R ₃ together are -CH ₂ -CH ₂ -,

R ₄ = -H or -OCH ₃ ,

R ₅ = -H, -OCH ₃ or -SO ₂ CH ₃ , and

R ₆ = -H or -OCH ₃ , with the proviso that at least two of R ₁ , R ₄ , R ₅ and R _{6 are} not hydrogen.

2. A compound according to claim 1, characterized in that X = -N =, n = O, R ₁ = -OCH ₃ , R ₂ = -H, R ₃ = -H, R ₄ = -OCH ₃ , R ₅ = -H and R ₆ = -OCH ₃ (formula II).

3. A compound according to claim 1, characterized in that X = -CH-, n = O, Ri = -H, R ₂ + R ₃ = -CH ₂ -CH ₂ -, R ₄ = -H, R ₅ = - OCH ₃ and R ₆ = -OCH ₃ (Formula III).

4. A compound according to claim 1, characterized in that X = -CH-, n = O, Ri = -F, R ₂ = -F, R ₃ = -H, R ₄ = -OCH ₃ , R ₅ = -H and R ₆ = -OCH ₃ (Formula IV).

5. A compound according to claim 1, characterized in that X = -CH-, n = 1, R ₁ = -OCH ₃ , R ₂ = -H, R ₃ = -H, R ₄ = -OCH ₃ , R ₅ = -H and R ₆ = -OCH ₃ (Formula V).

6. A compound according to claim 1, characterized in that X = -CH-, n = O, R ₁ = -OCH ₃ , R ₂ = -H, R ₃ = -H, R ₄ = -H, R ₅ = - SO ₂ CH ₃ and R ₆ = -H (formula VI).

7. A compound according to claim 1, characterized in that X = -CH-, n = O, Ri = -COOCH ₃ , R ₂ = -H, R ₃ = -H, R ₄ = -OCH ₃ , R ₅ = - H and R ₆ = -OCH ₃ (formula VII).

8. A compound according to any one of claims 1 to 7 as a medicament.

9. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament with COX-II inhibitory activity.