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Substituted 1,3-dioxanes and their uses

a technology of 1,3-dioxanes and substituted dioxanes, which is applied in the field of substituted dioxanes containing 1, 3-dioxanes, and can solve problems such as unsatisfactory treatmen

Inactive Publication Date: 2012-06-07
EVOLVA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides compounds with a 1,3-dioxane moiety that can be used to treat diseases such as cancer, diabetes, and obesity. These compounds are potent modulators of thromboxane A2 and peroxisome proliferator-activated receptors (PPAR). The compounds can be used as PPAR agonists or antagonists, and can be synthesized using a progroup that is metabolized under specific conditions. The compounds can be used in the treatment and prevention of diseases associated with these receptors. The invention also provides methods for using the compounds for the treatment and prevention of these diseases.

Problems solved by technology

Although, the responses observed in the context of the various methods for treating and / or preventing diseases or pathological conditions are encouraging, for example, the thiazolidinedione, TZD, class of medications (e.g., rosiglitazone or pioglitazone) unambiguously plays a critical role in improving insulin sensitivity in patients with type 2 diabetes (see Cheng lai and Levine, 2000, Heart Dis., 2, 326-333), they are not fully satisfactory treatments because of the occurrence of numerous serious undesirable side effects (for example, weigh gain, hypertension, cardiac hypertrophy, haemodilution, liver toxicity and oedema; see Haskins et al., 2001, Arch Toxicol., 75, 425-438; Yamamoto et al., 2001, Life Sci., 70, 471-482; Scheen, 2001, Diabetes Metab., 27, 305-313; Gale, 2001, Lancet, 357, 1870-1875; Forman et al., 2000, Ann. Intern. Med., 132, 118-121 and Al Salman et al., 2000, Ann. Intern. Med., 132, 121-124).

Method used

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  • Substituted 1,3-dioxanes and their uses
  • Substituted 1,3-dioxanes and their uses
  • Substituted 1,3-dioxanes and their uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

General Synthesis of the Compounds

[0122]A genera synthetic scheme for the compounds is shown below:

Esterification of Methoxy-Paraconic Acid

[0123]193 g of methoxy-paraconic acid was dissolved in 600 mL of THF, then CDI (145 g, 899 mmol, 1.1 eq) was added at room temperature over a 10 min period. Absolute ethanol 65 mL (or methanol to make the methyl ester) was added and the reaction mixture was stirred for about 120 min to give 188g of compound 23. (Yield 87%).

Reduction of Racemic Methoxy-Paraconic Acid, Ethyl Ester

[0124]105 g of compound 23 (397 mmol) was dissolved in 700 mL of toluene at 5° C. Then 3 eq. DIBAL-H (1.19 mol, 1.19 L 1M solution) was added, the reaction mixture was stirred for 60 min at room temperature and quenched with methanol. The product compound 24 recrystallized as an oily residue from chloroform / hexanes. Yield: 53 g (237 mmol, 59%).

Wittig Reaction Employing Racemic Lactol-Synthesis of Racemic Diol

[0125]191 g carboxypropyltriphenylphosphonium bromide, anhydrous ...

example 2

Synthesis of Compound 1

[0130]

[0131]Compound 1, shown in Table 1, was synthesized using the method of Example 1. HPLC showed that the compound had greater than 99% purity, and the mass spectra corresponded with the molecular ion and the fragmentation pattern expected for compound 1.

example 3

Synthesis of Compound 4

[0132]

[0133]Compound 4, shown in Table 1, was synthesized using the method of Example 1. HPLC showed that the compound had greater than 99% purity, and the mass spectra corresponded with the molecular ion and the fragmentation pattern expected for compound 4.

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Abstract

The present invention relates to compounds containing 1,3-dioxane moiety, pharmaceutical compositions thereof, and the use of the compounds and compositions for the modulation of thromboxane A2 or a peroxisome proliferator-activated receptor. The compounds, analogs, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions can be used in the treatment and prevention of cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of and claims priority from U.S. provisional Application Ser. No. 60 / 989,805, filed Nov. 21, 2007, U.S. provisional Application Ser. No. 60 / 989,806, filed Nov. 21, 2007, U.S. provisional Application Ser. No. 60 / 989,808, filed Nov. 21, 2007, and PCT Application No. PCT / US07 / 60724, filed Jan. 18, 2007, all of which are incorporated herein by reference in their entirety.FIELD OF INVENTION[0002]The invention relates to compounds containing the 1,3-dioxane moiety, compositions comprising the compounds, and methods of using the compounds and compositions for the modulation of thromboxane A2 and / or peroxisome proliferator-activated receptors. The compounds and compositions are useful for treating or modulating disease in which thromboxane A2 and / or peroxisome proliferator-activated receptors may be involved, symptoms of such disease, or the effect of other physiological events mediated by thromboxane A2 and / or...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/357A61P35/00A61P9/10A61P27/02A61P35/04A61P29/00A61P3/00A61P3/04A61P9/12A61P11/06C07D319/06A61P3/10
CPCA61K31/357A61K31/36A61K31/4433A61K31/453A61K31/77C07D319/06C07D405/06C07D407/04C07D407/06C07D491/10C07D405/04C07D491/113C07D319/08A61P1/00A61P1/04A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P3/12A61P7/02A61P9/00A61P9/10A61P9/12A61P11/00A61P11/02A61P11/06A61P13/12A61P15/00A61P17/00A61P17/04A61P17/06A61P19/00A61P19/02A61P19/10A61P25/00A61P25/28A61P27/02A61P29/00A61P31/00A61P31/04A61P31/16A61P31/18A61P35/00A61P35/02A61P35/04A61P37/00A61P37/04A61P37/08A61P43/00
Inventor SORENSEN, ALEXANDRA SANTANAMEYER, JEAN-PHILIPPEALBERTS, PETERISPRATHAMA, MAINKAR S.
Owner EVOLVA SA