JP2001131173A - Double ring type heterocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a new double ring type hetrocyclic derivative exhibiting a potent blood sugar-reducing activity by binding with a human peroxisome-propagating medicine-activating receptor γ (PPAR γ) as its ligand to activate it. SOLUTION: This double ring type heterocyclic derivative expressed by the general formula (1) (wherein, the bonding form of the X-Y part expresses COO, CH2O and CH=CH) and its pharmaceutically permissible salt, and its method of production are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a human peroxisome proliferator-activated receptor (PPAR) agonist, particularly an agonist for human PPARγ isoform, for the prevention and treatment of metabolic diseases such as diabetes and hyperlipidemia. The present invention relates to an effective bicyclic heterocyclic derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof, a production method thereof, and a pharmaceutical composition containing the compound.

[0002]

BACKGROUND OF THE INVENTION Peroxisome proliferator-activated receptors (P
PAR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily like the steroid receptor, retinoid receptor, thyroid receptor, etc., and three isoforms with different tissue distributions so far. (α type, β (or δ)
Type and gamma type) have been identified in various animal species including humans
(Proc. Natl. Acad. Sci., 1992, 89 , 4653). PP
ARα is distributed in the liver, kidney, etc., which have high catabolic potential of fatty acids, and high expression is particularly observed in the liver (Endocrinolog
y, 1995, 137 , 354), genes related to fatty acid metabolism and intracellular transport (eg, acyl-CoA synthetase, fatty acid binding protein and lipoprotein lipase), and apolipoproteins (AI) related to cholesterol and neutral lipid metabolism. , AII, CIII) genes are positively or negatively regulated. PPARβ is ubiquitously expressed in various tissues in vivo, mainly in neurons. At this time, the physiological significance of PPARβ is unknown. PP
ARγ is highly expressed in adipose tissue, immune cells, adrenal glands, spleen, etc. and is involved in adipocyte differentiation (J. Lipid. Res., 199).
6, 37 , 907). Thus, each isoform of PPAR plays a specific function in a specific organ or tissue.

[0003]

2. Description of the Related Art PPARγ ligands
Affinity compounds include metabolites of prostaglandins
15-deoxy- △^12,14-Prostaglandin j_Two (1
5d-PGj _Two) And cis-parinaric acid have been reported (Cell.,
1995,83, 813, FEBS Lett., 1998,431, 476). But this
These endogenous unsaturated fatty acid derivatives are metabolically and chemically
Is also unstable and cannot be used as a medicine.

On the other hand, troglitazone, which is known as a therapeutic agent for type II diabetes (non-insulin-dependent diabetes), has an effect of improving hyperinsulinemia, improving glucose tolerance and lowering serum lipids,
Thiazolidine-2,4 such as pioglitazone, rosiglitazone
-Dione derivatives have been shown to bind to PPARγ and increase the transcriptional activity of PPARγ (Endocrinology., 199).
6, 137 , 4189, Cell., 1995, 83 , 803, Cell., 1995, 83 , 81
9), the main in vivo target protein of these drugs is PPAR
It is considered γ. Therefore, PPARγ activators (agonists) that increase the transcriptional activation of PPARγ are important as hypoglycemic agents and / or hypolipidemic agents.

By the way, as compounds having a similar structure of the bicyclic heterocyclic derivative of the present invention, JP-A-55-22636 and JP-A-60-511
No. 89, JP-A-61-85372, JP-A-61-286376, JP-A-1
-131169, JP-A-2-83384, JP-A-5-213913, European Patent Publication No. 0441605, WO-92 / 07839 and the like are known. However, all of the compounds described in these patents are 4-alkoxybenzylthiazolidine-2,4-dione derivatives and have different structures from the compounds of the present invention.

[0006] As a compound having a similar structure having a benzamide structure, a thiazolidine-2,4-dione derivative disclosed in JP-A-8-333355, JP-A-9-48771, JP-A-9-169746 is known. However, the compounds described in these patents are all monocyclic benzamide derivatives, and have different structures from the compounds of the present invention.

EP 780 389 as a bicyclic heterocyclic derivative
No., JP-7173158, JP-10237049, US-5401761, WO
Thiazolidine-2,4-dione derivatives such as -98/42704 and WO-98 / 42704 are known. However, each of the compounds described in these patents is an indole derivative (EP78)
No. 0389, WO-98 / 42704), benzoisoxazole derivatives (JP-10237049), benzofuran derivatives (JP-717315)
No. 8, US-5401761), benzothiazole derivatives (WO-9
8/42704), which are all different in structure from the compound of the present invention.

[0008]

The metabolic diseases such as diabetes and hyperlipidemia are lifestyle-related diseases, and clinical development of an effective and highly safe therapeutic agent is desired.

[0009]

Means for Solving the Problems The present inventors have focused on the specific role of human PPARγ for the purpose of creating a structurally novel drug having high efficacy and safety as a therapeutic drug for metabolic diseases, As a result of intensive studies, they have found that a novel bicyclic heterocyclic derivative represented by the following general formula (1) has an excellent human PPARγ transcription activation effect, and exhibits a blood glucose lowering effect and a blood lipid lowering effect. The present invention has been completed.

That is, the present invention provides a compound represented by the general formula (1) [Wherein the binding mode of the YX moiety represents COO, CH ₂ O and CH = CH], a pharmaceutically acceptable salt thereof, and a hydrate thereof.

The salts of the compound represented by the general formula (1) in the present invention are conventional and include metal salts such as alkali metal salts (eg, sodium salt and potassium salt) and alkaline earth metal salts (eg, calcium salt). Pharmacologically acceptable salts such as aluminum salts and the like.

The compound represented by the general formula (1) in the present invention may include optical isomers based on a thiazolidine-2,4-dione ring moiety. Are intended to be included within the scope of this invention.

Further, various tautomers may be present in the compound represented by the general formula (1). For example, as shown in the following equation. [Wherein, YX is as described above] In the general formula (1), all of these isomers and mixtures thereof are included in the scope of the present invention.

According to the present invention, the compound (1a) of the above general formula (1) wherein the bonding mode of the YX moiety is COO can be produced, for example, by the following method (Scheme 1).

That is, the compound (1a) of the general formula (1) in which the bonding mode of the YX moiety is COO is the demethoxylation of the methoxy group of the compound (2) of the known compound (JP-A-8-333355). Step 2) A carbonyl group insertion reaction to the compound (3) obtained by the step (2)
It can be manufactured by performing.

The reaction in the first step can be carried out in a solvent such as tetrahydrofuran, dioxane, N, N-dimethylformamide or the like in the presence of carbonyldiimidazole or triphosgene. The reaction can be carried out at a temperature from room temperature to 200 ° C., preferably from 50 ° C. to 150 ° C.

In the general formula (1), the bonding mode of the YX moiety is CH ₂ O
Can be produced, for example, by the following method (Scheme 2).

That is, in the general formula (1), the compound (1b) in which the bonding mode of the YX moiety is CH ₂ O is produced by subjecting the compound (3) to a methylene insertion reaction (third step) under acidic conditions. can do.

The reaction in the third step can be carried out in a solvent such as methylene chloride or chloroform. Acetic acid, sulfuric acid, hydrochloric acid and the like can be used as the acid. The reaction can be carried out at a reaction temperature of -20 ° C to 100 ° C, preferably at 0 ° C to room temperature.

The compound (1c) of the general formula (1) wherein the bonding mode of the YX moiety is CH = CH can be produced, for example, by the following method (Scheme 3).

That is, the compound (1c) in the general formula (1) wherein the bonding mode of the YX moiety is CH = CH is known [for example, SW Li
Et al., J. Med. Chem. 2746 (1991)].
Compound (5) obtained by allowing (trifluoromethyl) benzylamine to undergo base presence reaction (fourth step) In the presence of peroxide, bromine the methyl group with N-bromosuccinimide (fifth step) The compound (7) can be produced by reacting a base-presented thiazolidine-2,4-dione on the obtained compound (7) (sixth step).

The reaction of the fourth step can be carried out in a solvent such as ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. The reaction is carried out in the presence of a base such as an alkali metal hydride such as sodium hydride, an alkali metal hydroxide such as sodium hydroxide, an alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine or triethylamine. Can do things. The reaction can be carried out at a reaction temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C.

The reaction of the fifth step can be carried out in carbon tetrachloride. As the peroxide, for example, benzoyl peroxide, hydrogen peroxide, peracetic acid and the like can be used. The reaction can be carried out at room temperature to 150 ° C., preferably at the reflux temperature of the solvent.

The reaction of the sixth step can be carried out in a solvent such as tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, and hexamethyltriamide phosphate. Examples of the base include alkali metal hydrides such as sodium hydride, organometallic compounds such as butyllithium, metal amides such as lithium diisopropylamide, and metal alkoxides such as sodium methoxide and potassium t-butoxide. it can. The reaction can be carried out at a reaction temperature of -100 ° C to 50 ° C, preferably at -80 ° C to room temperature.

The administration form of the novel compound of the present invention includes:
For example, there may be mentioned oral administration by tablets, capsules, granules, powders, inhalants or syrups or parenteral administration by injections or suppositories.

[0026]

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

<Reference Example 1>2-hydroxy-5-[(2,4-dioxothiazolidine-5-yl)
Methyl] -N-[(4-trifluorophenyl) methyl] benzure
Mid  Known (JP-A-9-48771) 2-methoxy-5-[(2,4-dioxo
Thiazolidine-5-yl) methyl] -N-[(4-trifluorophen
Nyl) methyl] benzamide (800 mg, 1.82 mmol)
Suspended in ren (30 ml), dry eye under argon atmosphere
It was cooled with su-acetone. 1.0 mol / l tribromide
Slowly add a solution of iodine in methylene chloride (2.20 ml, 2.2 mmol)
I dropped it. After returning to room temperature and stirring for 6 hours, leave at room temperature for 3 days.
Was. Water was added to the reaction solution, and the mixture was stirred for 30 minutes and concentrated. Vinegar to residue
Ethyl acid was added, washed with water, dried over anhydrous sodium sulfate and concentrated.
Shrank. The residue was purified by silica gel chromatography (eluent).
 Purified with methylene chloride: methanol = 40: 1 v / v), 618
mg (80%) of the title compound was obtained as a light brown powder. 146.0-148.0 ° C; mass spec.m / z 424.0719 (M⁺).

<Example 1>6-[(2,4-dioxothiazolidine-5-yl) methyl] -3-[(4-
Trifluorophenyl) methyl] -1,3-benzoxazine-
2,4-dione  2-hydroxy-5-[(2,4-dioxothiazolidine-5-yl)
Methyl] -N-[(4-trifluorophenyl) methyl] benzure
Mido (Reference Example 1; 300 mg, 0.707 mmol), N, N'-carboni
Ludiimidazole (115mg, 0.709mmol) and dehydrated tetra
Mix with hydrofuran (5 ml) and return for 1 hour under argon atmosphere
Shed. The solvent was distilled off at normal pressure and concentrated. 100 residues
The mixture was heated at ℃ C for 1 hour, cooled, and water (20 ml) was added. Another 0.5
Acidify with mol / l hydrochloric acid, wash the precipitated crystals with water and dry
And the residue is chromatographed on silica gel (eluate salt
Purified with methylene chloride: methanol = 10: 1 v / v, 257 mg (8
1%) of the title compound was obtained as a colorless powder. Melting point 107.0-110.0 ° C; mass spec.m / z 450 (M⁺); Elemental analysis value C₂₀H₁₃F_ThreeN_TwoO_FiveS: Calculated C, 53.34; H, 2.91; N, 6.22. Found C, 53.35; H, 2.75; N, 6.37.

<Embodiment 2>6-[(2,4-dioxothiazolidine-5-yl) methyl] -3-[(4-
Trifluorophenyl) methyl] -1,3-benzoxazine-
4-on  2-hydroxy-5-[(2,4-dioxothiazolidine-5-yl)
Methyl] -N-[(4-trifluorophenyl) methyl] benzure
Amide (Reference Example 1; 425 mg, 1.00 mmol), trioxane (6
1.0mg, 0.677mmol), acetic acid (20ml) and methylene chloride (30m
l), and concentrated sulfuric acid (1 ml) was slowly added dropwise with stirring under ice-cooling.
Was. The mixture was further stirred at room temperature for two days. About 10 ml of the reaction solution
And then poured into cooling water and extracted with ether. Athe
The aqueous layer was washed with water, dried over anhydrous sodium sulfate and concentrated. ,
The residue was purified by silica gel chromatography (eluent
Purified with Tylene: Methanol = 200: 1v / v), 184mg (42%)
Was obtained as a colorless amorphous. Mass spec.m / z 436 (M⁺). Elemental analysis value C₂₀H_FifteenF_ThreeN_TwoO_FourS: Calculated C, 55.04; H, 3.46; N, 6.42. Found C, 54.93; H, 3.50; N, 6.30.

<Embodiment 3>7-methyl-2-[[4- (trifluoromethyl) phenyl] methyl
R] isoquinoline-1 (2H) -one  Known [eg S.W.Li et al., J. Med. Chem. 2746 (199
1)] 7-Methylquinolin-1 (2H) -one (1.31 g, 8.23 mmol)
And N, N-dimethylformamide (20 ml)
Potassium (2.27 g, 16.4 mmol) and 4- (trifluoromethyl)
Add benzylamine (2.36 g, 9.87 mmol) and stir at room temperature for 8 hours.
Stirred. The reaction solution was poured into ice water and extracted with ether. Extraction
The washed ether is washed with water, dried over anhydrous sodium sulfate and concentrated.
did. The residue was purified by silica gel chromatography (eluent).
Hexane: ethyl acetate = 4: 1 v / v) to purify, 2.48 g (95%)
Was obtained as pale yellow prisms. Mass spec.m / z 317 (M⁺).¹ H-NMR (400MHz, CDCl_Three) δ2.50 (3H, s), 5.26 (2H,
s), 6.50 (1H, d, J = 7.3 Hz), 7.02 (1H, d, J = 7.3
 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.43 (1H, d, J = 8.
3 Hz), 7.49 (1H, dd, J = 8.3, 1.5 Hz), 7.58 (2H,
d, J = 8.3 Hz), 8.26 (1H, s).

<Embodiment 4>7-bromomethyl-2-[[4- (trifluoromethyl) phenyl]
Methyl] isoquinolin-1 (2H) -one  7-methyl-2-[[4- (trifluoromethyl) phenyl] methyl
Ru] isoquinolin-1 (2H) -one [Example 3] (2.48 g, 7.82 mm
ol) and carbon tetrachloride (300 ml).
Amide (1.40 g, 7.87 mmol), benzoyl peroxide (94.6 mg, 0.39
1 mmol) and refluxed for 8 hours. After cooling, the precipitated crystals are filtered.
The filtrate was concentrated. Silica gel chromatography of the residue
Raffy (eluent n-hexane: ethyl acetate = 8: 1 v / v)
Purify and obtain 1.40 mg (45%) of the title compound as a pale yellow powder.
Obtained. Mass spec.m / z 395 (M)⁺, 397 (M)⁺ .¹ H-NMR (400MHz, CDCl_Three) δ4.62 (3H, s), 5.27 (2H,
s), 6.52 (1H, d, J = 7.3 Hz), 7.10 (1H, d, J = 7.3
 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.
3 Hz), 7.59 (2H, d, J = 7.8 Hz), 7.69 (1H, dd, J
= 8.3, 1.5 Hz), 8.45 (1H, s).

<Embodiment 5>7-[(2,4-dioxothiazolidine-5-yl) methyl] -2-[[4-
(Trifluoromethyl) phenyl] methyl] isoquinoline-1
(2H) -ON  Thiazolidine-2,4-dione (319 mg, 2.72 mmol), dehydrated tet
Lahydrofuran (4 ml) and dehydrated hexamethylphosphorua
Mix (4 ml) and dry ice-air under an argon atmosphere.
Cooled in Seton. 2.5 mol / l n-butyllithium under stirring
Hexane solution (2.33 ml, 5.83 mmol) was added slowly.
The mixture was stirred for 1 hour as it was. Next, 7-bromomethyl-2-[[4- (to
Trifluoromethyl) phenyl] methyl] isoquinoline-1 (2
H) -one [Example 4] (1.40, 3.53 mmol), dehydrated tetrahydric
Lofuran (12 ml) and dehydrated hexamethylphosphoramide (3
ml), and the mixture was stirred on an ice bath for 30 minutes. Add concentrated hydrochloric acid (1 ml)
After that, the mixture was poured into water and extracted with ethyl acetate. The extract is water,
Wash sequentially with saturated saline, then dry over anhydrous sodium sulfate and concentrate.
Shrank. The residue was purified by silica gel chromatography (eluent).
Purified with methylene chloride: ethyl acetate = 20: 1 v / v), 735 mg
 (62%) of the title compound was obtained as a colorless powder. 113.0-115.0 ° C; elemental analysis C_{twenty one}H_FifteenF_ThreeN_TwoO_ThreeS (432.42): Calculated C, 58.33; H, 3.50; N, 6.48. Found C, 58.34; H, 3.39; N, 6.43 .; Mass spec m / z 432 (M)⁺.¹ H-NMR (400MHz, DMSO-d₆) δ3.50 (1H, dd, J = 14.
2, 4.9 Hz), 5.00 (1H, dd, J = 8.3, 4.9 Hz), 5.28
(1H, s), 6.68 (1H, d, J = 7.3 Hz), 7.51 (2H, d, J
= 7.8 Hz), 7.60 (1H, d, J = 7.3 Hz), 7.61 (1H, dd,
 J = 8.3, 1.5 Hz), 7.65 (1H, d, J = 8.3 Hz), 7.71
(2H, d, J = 8.3 Hz), 8.10 (1H, s), 12.05 (1H, s).

<< Bioactivity >> <Test Example 1>For peroxisome proliferator-activated receptors γ and α
Transcription activation test  Ham's F-12 containing 10% fetal bovine serum from which free fatty acids have been removed
DNA binding of yeast transcription factor to CHO cells cultured in medium
Region and ligand binding region of human PPARγ or human PPARα
(Biochemistry, 1993,32, 5598)
Receptor plasmid and its reporter plasmid (STR
ATAGENE) and β-galactosidase plastic for internal standard
Sumid (Promega) serum-free with Lipofectamine
Co-transfection. Then test compound
And the control compound was dissolved in DMSO and the final concentration of DMSO was 0.01
10% fetal bovine serum from which free fatty acids have been removed
Prepared and cultured in Ham's F-12 medium, and after 24 hours, CAT activity
Sex and β-galactosidase activity were measured.

Table 1 shows the results. These results indicate that the compound of the present invention has a strong transcriptional activating effect on human peroxisome proliferator-activated receptor γ.

【table 1】

[0035]

According to the above results, the bicyclic heterocyclic derivatives of the present invention are a group of novel compounds having an excellent human PPARγ transcription activation activity. In these compounds of the present invention, human PP
It can be said that it is an effective compound for the prevention and treatment of the above-mentioned metabolic diseases such as diabetes because it has an agonistic activity against ARγ.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C063 AA01 BB03 CC62 DD15 DD54 EE01 4C086 AA01 AA02 AA03 BC82 GA07 GA09 MA01 NA14 ZC33 ZC35 ZC41

Claims (7)

[Claims] (1) General formula (1) [Wherein the binding mode of the YX moiety represents COO, CH ₂ O and CH = CH], and a pharmaceutically acceptable salt thereof and a hydrate thereof. 2. The binding mode of the YX moiety is COO.
And the pharmaceutically acceptable salts and hydrates thereof. 3. The method according to claim 1, wherein the bonding mode of the YX moiety is CH ₂ O.
And the pharmaceutically acceptable salts and hydrates thereof. 4. The bonding mode of the YX moiety is CH = CH.
2. The bicyclic heterocyclic derivative according to 1, and a pharmaceutically acceptable salt thereof and a hydrate thereof. 5. The general formula (1) [Wherein the binding mode of the YX moiety represents COO, CH ₂ O and CH = CH], and at least one or more of a pharmaceutically acceptable salt thereof and a hydrate thereof. A therapeutic agent for type II diabetes, comprising: 6. The general formula (1) [Wherein the binding mode of the YX moiety represents COO, CH ₂ O and CH = CH], and at least one or more of a pharmaceutically acceptable salt thereof and a hydrate thereof. A blood lipid-lowering drug comprising, as an active ingredient. 7. General formula (1) [Wherein the binding mode of the YX moiety represents COO, CH ₂ O and CH = CH], and at least one or more of a pharmaceutically acceptable salt thereof and a hydrate thereof. Peroxisome Proliferator-Activated Receptor Containing Glycine
(PPAR) gamma agonist.