EP1276730A2 - Compositions et methodes destinees au traitement du diabete, de l'hyperlipidemie, de l'hypercholesterolemie et de l'atherosclerose - Google Patents

Compositions et methodes destinees au traitement du diabete, de l'hyperlipidemie, de l'hypercholesterolemie et de l'atherosclerose

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Publication number
EP1276730A2
EP1276730A2 EP01932617A EP01932617A EP1276730A2 EP 1276730 A2 EP1276730 A2 EP 1276730A2 EP 01932617 A EP01932617 A EP 01932617A EP 01932617 A EP01932617 A EP 01932617A EP 1276730 A2 EP1276730 A2 EP 1276730A2
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EP
European Patent Office
Prior art keywords
methyl
hydroxy
alkyl
pyridyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP01932617A
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German (de)
English (en)
Inventor
Pascal Druzgala
Peter G. Milner
Jurg R. Pfister
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ARYx Therapeutics Inc
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ARYx Therapeutics Inc
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Publication of EP1276730A2 publication Critical patent/EP1276730A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/12—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom

Definitions

  • Diabetes is one of the most prevalent chronic disorders worldwide with significant personal and financial costs for patients and their families, as well as for society. Different types of diabetes exist with distinct etiologies and pathogeneses.
  • diabetes mellitus is a disorder of carbohydrate metabolism, characterized by hyperglycemia and glycosuria and resulting from inadequate production or utilization of insulin.
  • Noninsulin-dependent diabetes mellitus is a form of diabetes that occurs predominantly in adults who produce adequate levels of insulin but who have a defect in insulin-mediated utilization and metabolism of glucose in peripheral tissues.
  • Overt NIDDM is characterized by three major metabolic abnormalities: resistance to insulin-mediated glucose disposal, impairment of nutrient-stimulated insulin secretion, and overproduction of glucose by the liver. It has been shown that for some people with diabetes a genetic predisposition results from a mutation in the gene(s) coding for insulin and/or the insulin receptor and/or insulin-mediated signal transduction factor(s), thereby resulting in ineffective insulin and/or insulin-mediated effects thus impairing the utilization or metabolism of glucose.
  • B-cells For people with Type II diabetes, insulin secretion is often enhanced, presumably to compensate for insulin resistance. Eventually, however, the B-cells fail to maintain sufficient insulin secretion to compensate for the insulin resistance. Mechanisms responsible for the B-cell failure have not been identified, but may be related to the chronic demands placed on the B-cells by peripheral insulin resistance and/or to the effects of hyperglycemia. The B-cell failure could also occur as an independent, inherent defect in "pre-diabetic" individuals.
  • PCOS polycystic ovary syndrome
  • This syndrome is characterized by hyperandrogenism and disordered gonadotropin secretion producing oligo- or anovulation.
  • Recent prevalence estimates suggest that 5-10% of women between 18- 44 years of age (about 5 million women, according to the 1990 census) have the fullblown syndrome of hyperandrogenism, chronic anovulation, and polycystic ovaries. Despite more than 50 years since its original description, the etiology of the syndrome remains unclear.
  • PCOS is associated with profound insulin resistance resulting in substantial hyperinsulinemia.
  • NIDDM also develops from the at risk population of individuals with gestational diabetes mellitus (GDM). Pregnancy normally is associated with progressive resistance to insulin-mediated glucose disposal. In fact, insulin sensitivity is lower during late pregnancy than in nearly all other physiological conditions.
  • the insulin resistance is thought to be mediated in large part by the effects of circulating hormones such as placental lactogen, progesterone, and cortisol, all of which are elevated during pregnancy.
  • pancreatic B-cell responsiveness to glucose normally increases nearly 3 -fold by late pregnancy, a response that serves to minimize the effect of insulin resistance on circulating glucose levels.
  • pregnancy provides a major "stress-test" of the capacity for B-cells to compensate for insulin resistance.
  • NIDDM neurodegenerative disease 2019
  • Other populations thought to be at risk for developing NIDDM include persons with Syndrome X; persons with concomitant hyperinsulinemia; persons with insulin resistance characterized by hyperinsulinemia and by failure to respond to exogenous insulin; and persons with abnormal insulin and/or evidence of glucose disorders associated with excess circulating glucocorticoids, growth hormone, catecholamines, glucagon, parathyroid hormone, and other insulin-resistant conditions.
  • NIDDM failure to treat NIDDM can result in mortality due to cardiovascular disease and in other diabetic complications including retinopathy, nephropathy, and peripheral neuropathy.
  • NIDDM neurodegenerative disease 2019
  • treatment of NIDDM can involve oral hypoglycemic agents, such as sulfonylureas alone or in combination with insulin injections.
  • alpha-glucosidase inhibitors such as a carboys, have been shown to be effective in reducing the postprandial rise in blood glucose (Lefevre, et al., Drugs 1992; 44:29-38).
  • metformin a biguanide.
  • Drug toxicity is an important consideration in the treatment of humans and animals. Toxic side effects resulting from the administration of drugs include a variety of conditions that range from low-grade fever to death. Drug therapy is justified only when the benefits of the treatment protocol outweigh the potential risks associated with the treatment. The factors balanced by the practitioner include the qualitative and quantitative impact of the drug to be used as well as the resulting outcome if the drug is not provided to the individual. Other factors considered include the physical condition of the patient, the disease stage and its history of progression, and any known adverse effects associated with a drug.
  • Drug elimination is typically the result of metabolic activity upon the drug and the subsequent excretion of the drug from the body. Metabolic activity can take place within the vascular supply and/or within cellular compartments or organs. The liver is a principal site of drug metabolism.
  • the metabolic process can be categorized into synthetic and nonsynthetic reactions. In nonsynthetic reactions, the drug is chemically altered by oxidation, reduction, hydrolysis, or any combination of the aforementioned processes. These processes are collectively referred to as Phase I reactions.
  • Phase II reactions also known as synthetic reactions or conjugations
  • the parent drug, or intermediate metabolites thereof are combined with endogenous substrates to yield an addition or conjugation product.
  • Metabolites formed in synthetic reactions are, typically, more polar and biologically inactive. As a result, these metabolites are more easily excreted via the kidneys (in urine) or the liver (in bile).
  • Synthetic reactions include glucuronidation, amino acid conjugation, acetylation, sulfoconjugation, and methylation.
  • troglitazone One of the drugs used to treat Type II diabetes is troglitazone.
  • the major side effects of troglitazone are nausea, peripheral edema, and abnormal liver function.
  • Other reported adverse events include dyspnea, headache, thirst, gastrointestinal distress, insomnia, dizziness, incoordination, confusion, fatigue, pruritus, rash, alterations in blood cell counts, changes in serum lipids, acute renal insufficiency, and dryness of the mouth.
  • Additional symptoms that have been reported, for which the relationship to troglitazone is unknown, include palpitations, sensations of hot and cold, swelling of body parts, skin eruption, stroke, and hyperglycemia. Accordingly, forms of glitazones which have fewer, or no, adverse effects (i.e., less toxicity) are desirable.
  • the presence of the carboxyl group has significant consequences for the biological behavior of these new compounds.
  • the present compounds are primarily metabolized by hydrolytic enzymatic systems, whereas compounds having an ether function are metabolized only by oxidative enzymes.
  • Hydrolytic enzymatic systems are ubiquitous, non-oxidative, not easily saturable, and non-inducible, and, therefore, reliable.
  • oxidative systems are mediated by the P-450 isozymes. These systems are localized, mainly, in the liver, saturable and inducible (even at low concentrations of therapeutic compounds) and therefore are highly unreliable.
  • the compounds of the subject invention do not rely on saturable hepatic systems for their metabolism and elimination, whereas the prior art compounds exert a heavy bio-burden on hepatic functions, especially in the presence of other drugs that rely on similar enzymes for detoxification.
  • the present compounds have a much more desirable toxicity profile than prior art compounds, especially when considering liver toxicity and potentially fatal drug-drug interactions.
  • the subject invention provides materials and methods for the safe and effective treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis.
  • the subject invention provides therapeutic compounds for the treatment of diabetes.
  • the compounds of the subject invention can be used to treat at-risk populations, such as those with PCOS and GDM, in order to prevent or delay the onset of NIDDM thereby bringing relief of symptoms, improving the quality of life, preventing acute and long-term complications, reducing mortality and treating accompanying disorders.
  • the subject invention provides compounds that are readily metabolized by the physiological metabolic drug detoxification systems.
  • the therapeutic compounds of the subject invention contain an ester group, which does not detract from the ability of these compounds to provide a therapeutic benefit, but which makes these compounds more susceptible to degradation by hydrolases, particularly serum and/or cytosolic esterases.
  • the subject invention further provides methods of treatment comprising the administration of these compounds to individuals in need of treatment for Type II diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis.
  • the subject invention pertains to the breakdown products that are formed when the therapeutic compounds of the subject invention are acted upon by esterases. These breakdown products can be used as described herein to monitor the clearance of the therapeutic compounds from a patient.
  • the subject invention provides methods for synthesizing the therapeutic compounds of the subject invention.
  • Figure 1 depicts exemplary metabolic breakdown products resulting from the actions of esterases on compounds of the invention.
  • Figures 2-3 provide an exemplary synthetic scheme for compounds 1 through
  • Figure 4 illustrates an alternative reaction scheme for the production of compound 1 (of Table I).
  • para-anisidine undergoes a diazotation reaction with sodium nitrite and hydrochloric acid.
  • the diazonium chloride salt undergoing, in turn, a radicalar reaction with methyl acrylate and then a cyclization reaction with thiourea, the product of which is hydrolyzed to the thiazolidinedione molecule.
  • Figure 5 shows an exemplary synthetic scheme for the compounds described in Table I (compounds 5 to 32). These compounds can be made via an esterif ⁇ cation reaction between 1 or 2 and an appropriately substituted carboxylic acid, or between 3 or 4 and an appropriately substituted alcohol.
  • Figure 6 depicts the synthesis of the 4-oxazoleacetic acid and the 4- oxazoleethanol moiety starting from aspartic acid derivatives in which R 2 and R 3 are methyl or hydrogen.
  • Figure 7 describes the synthesis of the 4-oxazolecarboxylic acid and 4- oxazolemethanol groups.
  • the synthesis starts from ethyl acetoacetate in which a 2- amino-group is introduced via oxime formation followed by reduction with zinc powder.
  • the synthesis then proceeds as before, where the R ⁇ group is introduced by acylating the amino group, followed by cyclization with sulfuric acid in ethyl acetate, and finally ester cleavage or reduction to the alcohol.
  • Figure 8 shows how steric hindrance can be introduced under the form of methyl groups on the 4-methanol moiety.
  • pentane-2,4-dione and following the same synthetic sequence as in Figure 7 leads to the 4-acetyloxazole compounds which can be reduced by sodium borohydride to the 4-(l-ethyl)oxazole, or which can be transformed to 4-(2-hydroxy-2-propyl) oxazole with a methyl Grignard reagent such as methyl magnesium iodide.
  • Figure 9 illustrates an alternative synthetic scheme wherein condensation of a thioamide with methyl 4-bromo-3-oxopentanoate gives methyl 4-thiazoleacetate. Ester cleavage with lithium hydroxide or reduction with lithium aluminum hydride gives the corresponding acid or the alcohol, respectively.
  • Figures 10-17 depict the synthesis of compounds 105 to 224 in Tables VI to XVII. These compounds contain an amino acid or an amino alcohol as part of their structure.
  • Figures 19-20 illustrate the activity of representative compounds on serum glucose and insulin levels in non-insulin dependent diabetic mellitus (NIDDM) KK- A y male mice.
  • Post-treatment data for each group were transferred to a percentage of pretreatment values and unpaired Student's t test was used for comparison between vehicle and test substance treated groups. Results show a significant reduction of both serum glucose and serum insulin relative to the vehicle control group. Reduction in serum glucose and serum insulin levels were comparable to the reduction observed in the troglitazone-treated animals.
  • Table XXI The results are also presented in Table XXI.
  • Tables I-XXII depict exemplary compounds according to the invention.
  • the term “db” indicates a double bond between P and Q.
  • Table XXIII illustrates the effects of exemplary compounds on serum glucose and insulin levels in NIDDM mice.
  • the subject invention provides materials and methods for the treatment of non-insulin dependent diabetes mellitus (NIDDM), hyperlipidemia, hypercholesterolemia, and atherosclerosis.
  • NIDDM non-insulin dependent diabetes mellitus
  • the therapeutic compounds of the subject invention are stable in storage but have a shorter half-life in the physiological environment than other drugs which are available for treatment of diabetes; therefore, the compounds of the subject invention can be used with a lower incidence of side effects and toxicity, especially in patients having elevated liver function or compromised liver function.
  • therapeutic compounds are provided which are useful in the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis and which contain an ester group which is acted upon by esterases thereby breaking down the compound and facilitating its efficient removal from the treated individual.
  • the therapeutic compounds are metabolized by the Phase I drug detoxification system and are exemplified by the compound of Formula I.
  • the compounds of Formula I can be generally described as 5 -benzyl- or 5- benzylidene-thiazolidine-2,4-dione compounds having a carboxyl group directly attached to the ? r ⁇ -position of the phenyl ring. These compounds represent a new class of chemical compounds having therapeutic properties for the treatment of type-
  • diabetes mellitus atherosclerosis, hypercholesterolemia, and hyperlipidemia.
  • a and B may be the same or different and are C, N, NO, NH, SO 0 . 2 , O;
  • D]-D 6 can be the same or different and are C, N, S, or O;
  • E can be attached to one or more of the atoms located at D J -D 6 ; P and Q can be a double bond; or
  • P, Q, and E can be the same or different and are a moiety selected from the group consisting of H, C ⁇ o alkyl, substituted alkyl groups, substituted or unsubstituted carboxylic acids, substituted or unsubstituted carboxylic esters, halogen, carboxyl, hydroxyl, phosphate, phosphonate, aryl, CN, OH, COOH, NO 2 , NH , SO 2 . 4 , C;f_ 2 o heteroalkyl, C 2 .
  • heterocyclic groups include, but not limited to, morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine or thiadiazoline.
  • Substituted carboxylic acids, substituted carboxylic esters, and substituted alkyl groups can be substituted at any available position with a moiety selected from the group consisting of d_ 10 alkyl, halogen, CN, OH, COOH, NO 2 , NH 2 , 802 ⁇ , C 1 .
  • heterocyclic groups include, but are not limited to, morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine, and thiadiazoline.
  • X is -OH, -COOH, or a substituted carboxylic group having the carboxyl moiety OOC- or COO- directly attached to the phenyl ring of the compound of Formula 1.
  • the carboxylic acid group can be substituted with a moiety selected from the group consisting of alkyloxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, arylcarbonyloxy, heteroalkyloxycarbonyl, heteroalkylcarbonyloxy, heteroaryl- oxycarbonyl, and heteroarylcarbonyloxy, each of which is, optionally, substituted with C ⁇ - 10 alkyl, CN, COOH, NO 2 , NH 2 , SO 2 . , Q-20 heteroalkyl, C2-20 alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C 1 .
  • alkyl-aryl C2- 20 alkenyl-aryl, heteroaryl, d_ 2 o alkyl-heteroaryl, C2-20 alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, Q- 20 alkyl-heteroycloalkyl, and d_ 20 alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 6 alkyl, halogen, OH, NH 2 , CN, NO 2 , COOH, or SO 2 . 4 ..
  • the substituted carboxylic group can be substituted with at moiety selected from the group consisting of C W o alkyl, CN, COOH, NO 2 , NH 2 , SO 2 . 4 , C1.20 heteroalkyl, C 2 . 2 o alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, . 20 alkyl-aryl, C 2 - 20 alkenyl- aryl, heteroaryl, d. 20 alkyl-heteroaryl, C 2 - 20 alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, d.
  • alkyl-heteroycloalkyl and C 1 - 20 alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of d. 6 alkyl, halogen, OH, NH 2 , CN, NO 2 , COOH, or SO 2 ⁇ .
  • exemplary heterocyclic groups include, but are not limited to, morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine, and thiadiazoline.
  • X can be hydroxyl, hydroxycarbonyl, 1 -methyl- 1- cyclohexylcarbonyloxy, 1 -methyl- 1 -cyclohexylmethoxycarbonyl, 5-ethyl-2-pyridyl- acetoxy, 5-ethyl-2-pyridylmeth-oxy-carbonyl, (R)-6-hydroxy-2,5,7,8-tetramethyl- chroman-2-carboxy, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy, (R)-6- hydroxy-2,5,7,8-tetra-methylchroman-2-ylmethoxy -carbonyl, (S)-6-hydroxy-2,5,7,8- tetramethylchroman-2-ylmethoxy -carbonyl, (S)-6-hydroxy-2,5,7,8- tetramethylchroman-2-ylmethoxycarbonyl, (R)-5-hydroxy-2,2,4,6,7
  • X can be
  • Hetero is an aromatic, cyclic, or alicyclic moiety that can contain heteroatoms.
  • Hetero is an aromatic, cyclic, or alicyclic moiety that contains heteroatoms that are generally part of the structure of the statin-family of lipid lowering agents.
  • Preferred examples include, but are not limited to, 2-(4-fluorophenyl)-5-(l -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] -l-(lH-pyrrol)yl, a component of atorvastatin, and l,2,3,7,8,8a-hexahydro-l-(2- methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl, a component of lovastatin.
  • X can be
  • Fib is an aromatic, cyclic, or alicyclic moiety that can contain heteroatoms.
  • Fib moieties are part of the f ⁇ brate- family of lipid lowering agents.
  • Preferred examples include, but are not limited to 4- (4-chlorobenzoyl)phenoxy, a component of fenofibric acid, 4-chlorophenoxy, a component of clofibric acid, and 3-(2,5-xylyloxy)-l-propyl, a component of gemfibrozil.
  • X can be
  • R is hydrogen or methyl
  • NSAID means an aromatic, alkyl, or cycloalkyl moiety that may contain heteroatoms and that are generally part of the family of non-steroidal anti-inflammatory agents.
  • Preferred examples include, but are not limited to 4-(2-methyl-l-propyl)phenyl, 2-(2,6-dichloro-l-phenyl)aminophenyl, 6'-methoxy-2'-naphthyl, and 6'-methoxy-2'-naphthylmethyl.
  • X can be
  • ⁇ and ⁇ are hydrogen or ⁇ and ⁇ form a bond, and where ⁇ , ⁇ , and ⁇ , are independently hydrogen, hydroxy, fluoro, chloro, or methyl.
  • X can be
  • X can also be of the general formula
  • n 0 or 1
  • R 2 and R 3 are independently hydrogen or methyl
  • Z is N, O, or S
  • R ⁇ is aryl or heteroaryl, alkyl or heteroalkyl.
  • Preferred non-limiting examples include compounds where R ⁇ is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4- pyridyl, 2-pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl.
  • Other embodiments provide compounds wherein X is
  • n 0 or 1
  • R 2 and R 3 are independently hydrogen or methyl
  • Z is N, O, or S
  • Preferred non-limiting examples include compounds where Rl is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl- 2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, 2- pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl.
  • X is a 1 -substituted (R)-pyrrolidine-2- methoxycarbonyl, (S)-pyrrolidine-2-methoxycarbonyl, (R)-pyrrolidine-2-carboxy, or (S)-pyrrolidine-2 -carboxy, having the following formulas
  • Y is aryl or heteroaryl, alkyl or heteroalkyl.
  • Preferred non-limiting examples include compounds where Y is (R)-6-hydroxy-2,5,7,8-tetramethylchroman- 2-carboxy, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy, (R)-6-hydroxy- 2,5,7,8-tetrameth-ylchroman-2-ylmeth-oxycarbonyl, (S)-6-hydroxy-2,5,7,8-tetra- methylchroman-2-ylmeth-oxycarbonyl, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3- dihydrobenzofuran-3 -carboxy, (S)-5-hydroxy-2,2,4,6 ,7-pentamethyl-2,3-dihydro- be ⁇ zofuran-3 -carboxy, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3 -dihydr
  • X is an N-substituted 2-methylaminoethoxycarbonyl or a N- substituted 2-methylaminoacetoxy, having the following formulas:
  • Y is aryl or heteroaryl, alkyl or heteroalkyl.
  • Preferred non-limiting examples include compounds where Y is (R)-6-hydroxy-2,5,7,8-tetramethylchroman- 2-carboxy, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy, (R)-6-hydroxy- 2,5,7,8-tetramethylchroman-2-ylmeth-oxycarbonyl, (S)-6-hydroxy-2,5,7,8-tetra- methylchroman-2-ylmethoxycarbonyl, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3- dihydrobenzofuran-3 -carboxy, (S)-5-hydroxy-2,2,4,6, 7-pentamethyl-2,3-dihydro- benzofuran-3 -carboxy, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro- benzofuran-3 -carbox
  • X can also be a 1 -substituted (R)-pyrrolidine-2-methoxycarbonyl, (S)- pyrrolidine-2-methoxycarbonyl, (R)-pyrrolidine-2-carboxy, or (S)-pyrrolidine-2- carboxy, having the following formulas:
  • R ⁇ is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2- thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, or 2- pyrazinyl; or Y is
  • Preferred non-limiting examples include compounds where R] is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl- 2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, or 2-pyrazinyl; or Y is
  • Hetero is an aromatic, cyclic, or alicyclic moiety that usually contains heteroatoms.
  • these moieties are part of the structure of the statin-family of lipid lowering agents.
  • Preferred examples include, but are not limited to, 2-(4-fluorophenyl)-5-(l -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] -l-(lH-pyrrol)yl, a component of atorvastatin, and 1, 2,3,7,8, 8a-hexahydro-l -(2- methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl, a component of lovastatin; or Y is
  • Fib is an aromatic, cyclic, or alicyclic moiety that contains heteroatoms.
  • these moieties are part of the fibrate-family of lipid lowering agents.
  • Preferred examples include, but are not limited to 4-(4- chlorobenzoyl)phenoxy, a component of fenofibric acid, 4-chlorophenoxy, a component of clofibric acid, and 3-(2,5-xylyloxy)-l-propyl, a component of gemfibrozil; or Y is
  • R is hydrogen or methyl
  • NSAID means an aromatic, alkyl, or cycloalkyl moiety that may contain heteroatoms and that are generally part of the family of non-steroidal anti-inflammatory agents.
  • Preferred examples include, but are not limited to 4-(2-methyl-l-propyl)phenyl, 2-(2,6-dichloro-l-phenyl)aminophenyl, 6'-methoxy-2'-naphthyl, and 6'-methoxy-2'-naphthylmethyl or Y ean be
  • X can be an N-substituted 2-methylaminoethoxycarbonyl or an N-substituted 2-methylaminoacetoxy, having the following formulas:
  • R ⁇ is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2- thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, or 2- pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl; or Y is
  • Preferred non-limiting examples include compounds where R;, is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl- 2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, 2- pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl; or Y is
  • Hetero is an aromatic, cyclic, or alicyclic moiety that contains heteroatoms.
  • these moieties are part of the structure of the statin- family of lipid lowering agents.
  • Preferred examples include, but are not limited to, 2- (4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-l-(lH- pyrrol)yl, a component of atorvastatin, and 1,2,3, 7,8, 8a-hexahydro-l-(2- methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl, a component of lovastatin; or Y is
  • Fib is an aromatic, cyclic, or alicyclic moiety that contains heteroatoms.
  • these moieties are part of the fibrate-family of lipid lowering agents.
  • Preferred examples include, but are not limited to 4-(4- chlorobenzoyl)phenoxy, a component of fenofibric acid, 4-chlorophenoxy, a component of clofibric acid, and 3-(2,5-xylyloxy)-l-propyl, a component of gemfibrozil; or Y is
  • R is hydrogen or methyl
  • NSAID means an aromatic, alkyl, or cycloalkyl moiety that may contain heteroatoms and that are generally part of the family of non-steroidal anti-inflammatory agents.
  • Preferred examples include, but are not limited to 4-(2-methyl-l-propyl)phenyl, 2-(2,6-dichloro-l-phenyl)aminophenyl, 6'-methoxy-2'-naphthyl, and 6'-methoxy-2'-naphthylmethyl; or
  • ⁇ and ⁇ are hydrogen or ⁇ and ⁇ form a bond, and where ⁇ , ⁇ , and ⁇ , are independently hydrogen, hydroxy, fluoro, chloro, or methyl; or Y can be
  • R 4 is hydrogen or methyl, and where R 5 is aryl or heteroaryl, alkyl or heteroalkyl.
  • R 5 is phenyl, 4- fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl, 5- methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, 2-pyrazinyl, (R)-6-hydroxy-2,5,7,8- tetramethyl-2-chromanyl, (S)-6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl, (R)-5- hydroxy-2,2,4,6,7-pentamethyl-2,3 -dihydro-3 -benzofuranyl, or (S)-5-hydroxy- 2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzo-furanyl.
  • X can also be
  • R4 is hydrogen or methyl
  • R5 is aryl or heteroaryl, alkyl or heteroalkyl.
  • Preferred non-limiting examples include compounds where R5 is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl, 5- methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, 2-pyrazinyl, (R)-6-hydroxy-2,5,7,8- tetramethyl-2-chromanyl, (S)-6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl, (R)-5- hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzofuranyl, or (S)-5-hydroxy- 2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzofuranyl.
  • analogs and derivatives refer to compounds which are substantially the same as another compound but which may have been modified by, for example, adding additional side groups.
  • analogs and derivatives as used in this application also may refer to compounds which are substantially the same as another compound but which have atomic or molecular substitutions at certain locations in the compound.
  • Analogs or derivatives of the exemplified compounds can be readily prepared using commonly known, standard reactions. These standard reactions include, but are not limited to, hydrogenation, methylation, acetylation, and acidification reactions.
  • new salts within the scope of the invention can be made by adding mineral acids, e.g., HC1, H 2 SO 4 , etc., or strong organic acids, e.g., formic, oxalic, etc., in appropriate amounts to form the acid addition salt of the parent compound or its derivative.
  • synthesis type reactions may be used pursuant to known procedures to add or modify various groups in the exemplified compounds to produce other compounds within the scope of the invention.
  • the subject invention further provides methods of treating disorders, such as diabetes, atherosclerosis, hypercholesterolemia, and hyperlipidemia, comprising the administration of a therapeutically effective amount of esterified thiazolidinedione analogs to an individual in need of treatment.
  • Thiazolidinedione based compounds include troglitazone (for example, REZULLN), pioglitazone, and rosiglitazone.
  • the subject invention provides esterified thiazolidinedione analogs and pharmaceutical compositions of these esterified compounds.
  • the compounds and compositions according to the invention can also be administered in conjunction with other therapeutic compounds, therapeutic regimens, compositions, and agents suitable for the treatment of disorders, such as diabetes, atherosclerosis, hypercholesterolemia, and hyperlipidemia.
  • the invention includes combination therapies wherein the compounds and compositions of the invention are used in conjunction with other therapeutic agents for the treatment of disorders, such as diabetes, atherosclerosis, hypercholesterolemia, and hyperlipidemia.
  • the compounds of this invention have therapeutic properties similar to those of the unmodified parent compounds. Accordingly, dosage rates and routes of administration of the disclosed compounds are similar to those already used in the art and known to the skilled artisan (see, for example, Physicians' Desk Reference, 54 th Ed., Medical Economics Company, Montvale, NJ, 2000).
  • compositions of the subject invention can be formulated according to known methods for preparing pharmaceutically useful compositions.
  • Formulations are described in detail in a number of sources that are well known and readily available to those skilled in the art.
  • Remington's Pharmaceutical Science by E.W. Martin describes formulations that can be used in connection with the subject invention.
  • the compositions of the subject invention are formulated such that an effective amount of the bioactive compound(s) is combined with a suitable carrier in order to facilitate effective administration of the composition.
  • compositions which comprise, as an active ingredient, an effective amount of one or more of the compounds of the invention and one or more non-toxic, pharmaceutically acceptable carriers or diluents.
  • carriers for use in the invention include ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch, and equivalent carriers and diluents.
  • Additional therapeutic agents suitable for the treatment of disorders such as diabetes, atherosclerosis, hypercholesterolemia, and hyper-lipidemia can also be incorporated into pharmaceutical agents according to the invention.
  • acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances that may act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.
  • the disclosed pharmaceutical compositions may be subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, such as packeted tablets, capsules, and powders in paper or plastic containers or in vials or ampoules.
  • the unit dosage can be a liquid based preparation or formulated to be incorporated into solid food products, chewing gum, or lozenge.
  • Compounds 1 through 4 can be conveniently prepared by the Knoevenagel reaction between an aldehyde and thiazolidine-2,4-dione, using for example sodium acetate in acetic anhydride, or piperidine and benzoic acid in methylene chloride as a reaction medium. This is illustrated in Figure 2 and Figure 3.
  • compound 1 can be prepared by the method described in Figure 4.
  • jr ⁇ r ⁇ -anisidine undergoes a diazotation reaction with sodium nitrite and hydrochloric acid.
  • the diazonium chloride salt undergoing, in turn, a radicalar reaction with methyl acrylate and then a cyclization reaction with thiourea, the product of which is hydrolyzed to the thiazolidinedione molecule.
  • the compounds described in Table I can all be made via an esterification reaction between 1 or 2 and an appropriately substituted carboxylic acid, or between 3 or 4 and an appropriately substituted alcohol.
  • the esterification reaction can be facilitated by the presence of a catalyst in the reaction medium, such as a small amount of concentrated sulfuric acid for example.
  • a catalyst such as a small amount of concentrated sulfuric acid for example.
  • an activated functional derivative of the carboxylic acid is made.
  • Numerous functional derivatives of carboxylic acids used in esterification reactions have been described in the scientific literature. The most commonly used activated functional derivatives are acyl chlorides, anhydrides and mixed anhydrides, and activated esters.
  • dicyclohexyl carbodiimide (DCC) was used as an activating agent ( Figure 5).
  • Compounds 33 to 104 are functionalized 5-methyloxazole and functionalized 5-methylthiazole derivatives. They all have various functional groups attached to the 2-position (R ⁇ in Tables II to V), and at the 4-position, which is the enzymaticaliy labile link with the thiazolidine portion of the molecule.
  • the enzymaticaliy labile link is either an ester (COO-) or a reverse ester (OOC-) and can be substituted with 0, 1 , or 2 methyl groups at the alpha-position from the oxazole or thiazole ring (R 2 and R 3 in Tables II to V).
  • Figure 6 describes the synthesis of the 4-oxazoleacetic acid and the 4- oxazoleethanol moiety starting from aspartic acid derivatives in which R 2 and R 3 are methyl or hydrogen.
  • ⁇ -benzyl aspartate is acetylated and then decarboxylated to benzyl 3-acetamido-4-oxovalerate using acetic anhydride as an acetylating agent followed by potassium hydroxide in order to obtain the decarboxylated product.
  • ester hydrolysis using lithium hydroxide in methanol gives the desired 4-oxazoleacetic acid derivatives
  • reduction of the ester with lithium aluminum hydride or reduction of the acid using diborane gives the 4-oxazoleethanol analogs.
  • Figure 7 describes the synthesis of the 4-oxazolecarboxylic acid and 4- oxazolemethanol groups.
  • the synthesis starts from ethyl acetoacetate in which a 2- amino-group is introduced via oxime formation followed by reduction with zinc powder.
  • the synthesis then proceeds as before, where the R] group is introduced by acylating the amino group, followed by cyclization with sulfuric acid in ethyl acetate, and finally ester cleavage or reduction to the alcohol.
  • Figure 8 shows how steric hindrance can be introduced under the form of methyl groups on the 4-methanol moiety.
  • pentane-2,4-dione following the same synthetic sequence as in Figure 7 leads to the 4-acetyloxazole compounds which can be reduced by sodium borohydride to the 4-(l-ethyl)oxazole.
  • the compounds can be transformed by methylmagnesium iodide into the tertiary alcohol analogs.
  • condensation of a thioamide with methyl 4-bromo-3-oxopentanoate gives methyl 4-thiazoleacetate, as described in Figure 9. Ester cleavage with lithium hydroxide or reduction with lithium aluminum hydride gives the corresponding acid or the alcohol, respectively.
  • Compounds 105 to 224 in Tables VI to XVII all have an amino acid or an amino alcohol as part of their structure. Their synthesis is described in Figures 10 to 18. Any amino acid can be used in the synthesis of compounds according to this aspect of the invention.
  • the amino acid group can be either proline or N-methyl glycine and the amino alcohol group is their alcohol equivalent, i.e., prolinol or N-methyl glycinol, respectively.
  • Carboxylic acid adducts react with 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione in the presence of DCC and DMAP to give compounds 115-118, 121, 122, 135-138, 141, 142, 195-198, 201, 202.
  • these adducts are alcohols, such as in Figures 11 and 13, they react with 5-(4-carboxybenzyl)thiazolidine-2,4-dione in the presence of DCC and DMAP to give compounds 145-148, 151, 152, 165-168, 171, 172, 205-208, 211, 212.
  • Alcohol adducts react with 5-(4-carboxybenzylidene)thiazolidine-2,4-dione in the presence of DCC and DMAP to give compounds 155-158, 161, 162, 175-178, 181, 182, 215-218, 221, 222.
  • the amino acid or amino alcohol group can be linked to another group via an amide function, such as described in Figures 14 to 17.
  • the synthesis of such compounds is straightforward.
  • the synthetic sequence is an amide bond formation, ester deprotection, and ester formation.
  • (R)-Trolox ® is combined with L-proline methyl ester, in the presence of DCC and DMAP in methylene chloride to form an amide intermediate.
  • the methyl ester of the proline group is then cleaved with lithium hydroxide in methanol, and the resulting carboxylic acid is combined with 5-(4- hydroxybenzyl)thiazolidine-2,4-dione in DCC/DMAP/methylene chloride to give compound 109.
  • the (S)-isomer, compound 110 is made in a similar way.
  • the synthetic sequence is an amide bond formation, followed by an ester bond formation.
  • (R)-Trolox ® is combined with L-prolinol in the presence of DCC and DMAP in methylene chloride to form an amide intermediate.
  • the resulting amide is combined with 5-(4-carboxybenzyl)thiazolidine-2,4-dione in DCC/DMAP/methylene chloride to give compound 149.
  • the (S)-isomer, compound 150 is made in a similar way.
  • Compounds 243 to 248 are thiazolidinedione molecules where X is a group containing a substituted 2-methyl-2-propionyl residue.
  • Examples include the 2-methyl-2-(4-chlorophenoxy)propionyl moiety (clofibryl moiety), the 2-methyl- 2-[4-(4-chlorobenzoyl)phenoxy]propionyl moiety (fenofibryl moiety), and 2,2- dimethyl-5-(2,5-xylyloxy)valeryl moiety (gemfibrozilyl moiety).
  • Compounds 249 to 252 are thiazolidinedione molecules where X is a group containing a substituted (R,R)-3,5-dihydroxyheptanoyl residue.
  • X is a group containing a substituted (R,R)-3,5-dihydroxyheptanoyl residue.
  • Examples include the ( ⁇ R, ⁇ R)-2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenyl- amino)carbonyl] lH-pyrrole-l-( ⁇ , ⁇ ,dihydroxy)heptanoyl group (atorvastatin), and the 1, 2,3,7,8, 8a-hexahydro-l-(2-methylbutanoyl)oxy-3,7-dimethylnaphthalenyl-8- [(3R,5R)-7-heptan]oyl group (lovastatin).
  • Compounds 253 to 260 are thiazolidinedione molecules where X is a group containing an arylacetic acid residue, such as in molecules that have non- steroidal anti-inflammatory properties.
  • the X group is an ibuprofen, ibufenac, naproxen, diclofenac, or nabumetone residue.
  • the synthesis of these compounds is a simple ester formation reaction between the X group and compound 1 (P and Q are hydrogen) or compound 2 (P and Q form a bond).
  • Compounds 261 to 268 are thiazolidinedione molecules where X is a group containing a cortienic acid residue, such as in molecules that have glucocorticoid anti-inflammatory properties.
  • the X group is a cortienic acid, 1,2-dihydrocortienic acid, 6 , 9 ⁇ -difluoro- 1,2-dihydrocortienic acid, and a 9 ⁇ -fluoro-16o.-methyl- 1,2-dihydrocortienic acid residue.
  • the synthesis of these compounds is a simple ester formation reaction between the X group and compound 1 (P and Q are hydrogen) or compound 2 (P and Q form a bond).
  • Cortienic acid one of the many metabolites of hydrocortisone in man, can be synthetized from hydrocortisone by oxidation with sodium periodate.
  • the substituted cortienic acid analogs can be made in an identical manner from the corresponding substituted glucocorticoids. This oxidation procedure is described in detail in [Druzgala P.: Novel Soft Anti-inflammatory Glucocorticoids for Topical Application. Ph.D. Dissertation (1985), University of Florida, Gainesville, FL, hereby incorporated by reference in its entirety].
  • Example 1- To (S)-2-pyrrolidinemethanol (3.96g) in THF (30ml) is added 2- chlorobenzoxazole (5.90g) also in THF (80ml) and then, dropwise, triethylamine (3.96g). Stir at 50°C for 4 hours. Cool to room temperature and filter out the solid. Evaporate the solvent and dissolve the crude product in 5ml of methylene chloride. Pass through a silica plug (50g) in a fritted filter funnel, and elute with methanol/methylene chloride (10:90), applying suction until the product has been collected. The yield of (S)-l-(2-benzoxazolyl)-2-hydroxymethylpyrrolidine is 8.2g.
  • Example 4- 2-chloropyridine (12g) and 2-(methylamino)ethanol (100ml) are stirred under nitrogen at 120°C for 18 hours. Cool to room temperature and then pour into iced water (250ml). Extract with ethyl acetate (2x200ml). Dry over sodium sulfate. Filter. Evaporate to dryness. The crude product is distilled in vacuo to give 10.3g of N-methyl-N-(2-pyridinyl)-2-aminoethanol, boiling at 110°C/1.0mmHg.
  • Example 5- A solution of 2-chlorobenzoxazole (15.3g) in THF (100ml) is added dropwise to an ice-cold solution of 2-(methylamino)ethanol (8.0g) and triethylamine (10. lg) also in THF (100ml). The mixture is stirred at room temperature for 4 hours and the solid is filtered off. The solvent is evaporated and the residue is dissolved in methylene chloride and passed through a silica plug (lOOg), eluting with methanol/methylene chloride (10:90) until the product has been collected. The yield ofN-methyl-N-(2-benzoxazolyl)-2-aminoethanol is 15.7g.
  • Example 6- Thionyl chloride (2.5ml) was added dropwise to an ice-cold solution of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylcarbinol (5.1g) in anhydrous methylene chloride (50ml). The solution was stirred at 0°C for 1 hour and then at room temperature for another period of 2 hours. Wash with saturated sodium bicarbonate solution (2x25ml), then with brine (25ml), and then with water (25ml). Dry over sodium sulfate, filter, and evaporate to dryness. The crude product, (R)-6- hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl chloride (5.2g) is used as is in the next step.
  • Example 7- Thionyl chloride (2.5ml) was added dropwise to an ice-cold solution of (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylcarbinol (5.1g) in anhydrous methylene chloride (50ml). The solution was stirred at 0°C for 1 hour and then at room temperature for another period of 2 hours. Wash with saturated sodium bicarbonate solution (2x25ml), then with brine (25ml), and then with water (25ml). Dry over sodium sulfate, filter, and evaporate to dryness. The crude product, (S)-6- hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl chloride (5.0g) is used as is in the next step.
  • Example 8 A mixture of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl chloride (8.43g), triethylamine (2.6g), and 2-(methylamino)ethanol (40ml) is stirred at 120°C under nitrogen for 16 hours. Cool to room temperature and pour into iced water (100ml). Extract with ethyl acetate (3x100ml) and wash the combined organic extracts with brine (100ml). Dry over sodium sulfate. Filter. Evaporate to dryness. The product, (R)-2-[N-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl)-N- methylaminojethanol weighs 9.0g.
  • Example 9 A mixture of (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl chloride (8.43g), triethylamine (2.6g), and 2-(methylamino)ethanol (40ml) is stirred at 120°C under nitrogen for 16 hours. Cool to room temperature and pour into iced water (100ml). Extract with ethyl acetate (3x100ml) and wash the combined organic extracts with brine (100ml). Dry over sodium sulfate. Filter. Evaporate to dryness. The product, (S)-2-[N-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl)-N- methylaminojethanol weighs 8.9g.
  • Example 10- A mixture of 2-chlorobenzoxazole (3.7g), (L)-proline methyl ester, hydrochloride salt (4.0g), and triethylamine (4.9g) in anhydrous THF (50ml) is stirred at room temperature for 18 hours. The solid is filtered off and washed with THF (10ml). The solution is evaporated to dryness and the crude product is dissolved in methylene chloride (5ml) and passed through a plug of silica (50g), eluting with ethyl acetate/methylene chloride (10:90). The product, (L)-N-(2-benzoxazolyl)-proline methyl ester (5.0g) is a crystalline solid.
  • Example 11- A mixture of 2-chlorobenzoxazole (3.7g), (D)-proline methyl ester, hydrochloride salt (4.0g), and triethylamine (4.9g) in anhydrous THF (50ml) is stirred at room temperature for 18 hours. The solid is filtered off and washed with THF (10ml). The solution is evaporated to dryness and the crude product is dissolved in methylene chloride (5ml) and passed through a plug of silica (50g), eluting with ethyl acetate/methylene chloride (10:90). The product, (D)-N-(2-benzoxazolyl)-proline methyl ester (5.5g) is a crystalline solid.
  • Example 12- (L)-N-(2-benzoxazolyl)-proline methyl ester (5.0g) is suspended in a mixture consisting of methanol (50ml), water (5ml), and lithium hydroxide (0.5g). Stir for 18 hours at room temperature. Acidify to pH 4.5 with citric acid. Extract with ethyl acetate (4x50ml). Dry over sodium sulfate, filter, and evaporate to dryness. The product, (L)-N-(2-benzoxazolyl)-proline (4.3 g) is an off-white solid.
  • Example 13- A mixture of (L)-proline (4.6g), 2-chlorobenzoxazole (6.6g), and triethylamine (4.45g) in anhydrous THF (100ml) is stirred at reflux temperature for 18 hours. Cool down to room temperature, filter off the solid and wash it with a THF (10ml). Evaporate the solvent. Add ethyl acetate (50ml) and then IN sodium hydroxide (50ml). Stir for 5 minutes. Keep the aqueous phase. Wash again with ethyl acetate (50ml). Acidify with citric acid to pH 4.5. Isolate the precipitate by filtration. The aqueous filtrate is extracted with ethyl acetate (4x30ml).
  • Example 14- A mixture of (D)-proline (4.6g), 2-chlorobenzoxazole (6.6g), and triethylamine (4.45g) in anhydrous THF (100ml) is stirred at reflux temperature for 18 hours. Cool down to room temperature, filter off the solid and wash it with a THF (10ml). Evaporate the solvent. Add ethyl acetate (50ml) and then IN sodium hydroxide (50ml). Stir for 5 minutes. Keep the aqueous phase. Wash again with ethyl acetate (50ml). Acidify with citric acid to pH 4.5. Isolate the precipitate by filtration. The aqueous filtrate is extracted with ethyl acetate (4x30ml).
  • Example 15- A mixture of 4-hydroxybenzaldehyde (122.12g), 2,4-thiazolidinedione (117.13g), piperidine (5.1 lg), and benzoic acid (6.1 lg) in toluene (1,000ml), is stirred at 80°C for 16 hours. Cool to room temperature and filter off the yellow solid. Wash the solid with methylene chloride (3x100ml) and then with methanol/methylene chloride (30:70) (2x100ml). Dry in vacuo at 35°C until constant weight. The yield of product, 5-(4-hydroxybenzylidene)-2,4-thiazolidinedione, is 217.8g.
  • Example 16 To p-anisidine (25g) in acetone (400ml) at between 0 and 5°C, add dropwise a solution of sodium nitrite (15.41g) in water (50ml) and 12N hydrochloric acid (50ml) from 2 different funnels over a 15-minute period. Stir for another 5 minutes at 0°C. Add methyl acrylate (104.9g) and then warm up the solution to 35°C. Transfer into a 2-L Erlenmeyer flask and stir vigorously. While stirring, add copper(I) oxide (0.7g) in several portions. Keep stirring for as long as nitrogen gas evolves from the solution, then stir for another 4 hours.
  • Example 17- Methyl 2-chloro-3-(4-methoxyphenyl)propanoate (31.44g), thiourea (16.89g), and anhydrous sodium acetate (11.24g) in 2-methoxyethanol (100ml) is stirred at 100°C for 4 hours. Cool to room temperature and place the flask at 4°C for 16 hours. The pale yellow solid is filtered off and is washed with hexanes (50ml). Stir for 30 minutes in ethyl acetate/water (100ml: 10ml). Filter. Crystallize from hot ethanol (600ml).
  • Example 18- To a solution of 5-(4-methoxybenzyl)thiazolidine-2,4-dione (14.3g) in anhydrous methylene chloride (100ml) cooled to -40°C, add a 1.0M solution of boron tribromide in methylene chloride (63ml). The solution is left to warm up to 23°C and is then stirred for another 16 hours. Pour into iced water (700ml) and stir for 15 minutes. Isolate the precipitate by filtration. Wash the product with water (50ml) and then with methylene chloride (50ml). The yield of 5-(4-hydroxybenzyl)thiazolidine- 2,4-dione is 12.8g.
  • Example 20 A suspension of 5-(4-carbomethoxybenzylidene)-2,4-thiazolidinedione (26.3g) and magnesium turnings (24g) in anhydrous methanol (300ml) is stirred at 45°C for 8 hours. Acidify to pH 5.0 with 6N HC1 and then extract with methylene chloride (2x250ml). Dry over sodium sulfate, filter, and evaporate to dryness. The crude product is chromatographed on silica gel (l,300g), eluting with methanol/methylene chloride (02:98). The yield of 5-(4-carbomethoxybenzyl)-2,4- thiazolidinedione is 15.2g.
  • Example 21 A suspension of 5-(4-carbomethoxybenzylidene)-2,4-thiazolidinedione (50g) in 6N HC1 (200ml) is stirred at reflux for 4 hours. The mixture is cooled to 4°C and the product is filtered off. The product is then washed with water (2x100ml) and is dried in vacuo at 40°C. The yield of 5-(4-carboxybenzylidene)-2,4- thiazolidinedione is 45g.
  • Example 22 A suspension of 5-(4-carbomethoxybenzyl)-2,4-thiazolidinedione (50g) in 6N HC1 (200ml) is stirred at reflux for 4 hours. The mixture is cooled to 4°C and the product is filtered off. The product is then washed with water (2x100ml) and is dried in vacuo at 40°C. The yield of 5-(4-carboxybenzyl)-2,4-thiazolidinedione is 44g.
  • Example 23- (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (9.2g) and 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (8.3g) are dissolved in methylene chloride (100ml) and THF (50ml). To this add dicyclohexylcarbodiimide (7.6g) and DMAP (0.5g), and then stir for 4 hours at room temperature. The solid is removed by filtration and is washed with a small amount of THF (20ml). The solvent is removed and the solid residue is stirred with methylene chloride (100ml) and left at 4°C for 16 hours.
  • Example 24- (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (9.2g) and 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (8.3g) are dissolved in methylene chloride (100ml) and THF (50ml). To this add dicyclohexylcarbodiimide (7.6g) and DMAP (0.5g), and then stir for 4 hours at room temperature. The solid is removed by filtration and is washed with a small amount of THF (20ml). The solvent is removed and the solid residue is stirred with methylene chloride (100ml) and left at 4°C for 16 hours.
  • Example 25- (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (1.9g) and 5-(4- carboxybenzyl)thiazolidine-2,4-dione (1.8g) are dissolved in methylene chloride (20ml) and THF (10ml). To this add dicyclohexylcarbodiimide (1.6g) and DMAP (O.lg), and then stir for 4 hours at room temperature. The solid is removed by filtration and is washed with a small amount of THF (5ml). The solvent is removed and the solid residue is stirred with methylene chloride (20ml) and left at 4°C for 16 hours.
  • Example 26- (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (1.9g) and 5-(4- carboxybenzyl)thiazolidine-2,4-dione (1.8g) are dissolved in methylene chloride (20ml) and THF (10ml). To this add dicyclohexylcarbodiimide (1.6g) and DMAP (O.lg), and then stir for 4 hours at room temperature. The solid is removed by filtration and is washed with a small amount of THF (5ml). The solvent is removed and the solid residue is stirred with methylene chloride (20ml) and left at 4°C for 16 hours.
  • Example 27- (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (4.6g) and 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (4.2g) are dissolved in methylene chloride (50ml) and THF (25ml). To this add dicyclohexylcarbodiimide (3.8g) and DMAP (0.25g), and then stir for 4 hours at room temperature. The solid is removed by filtration and is washed with a small amount of THF (10ml). The solvent is removed and the solid residue is stirred with methylene chloride (50ml) and left at 4°C for 16 hours.
  • Example 29- (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (3.8g) and 5-(4- carboxybenzylidene)thiazolidine-2,4-dione (3.6g) are dissolved in methylene chloride (40ml) and THF (20ml). To this add dicyclohexylcarbodiimide (3.2g) and DMAP (0.2g), and then stir for 4 hours at room temperature. The solid is removed by filtration and is washed with a small amount of THF (10ml). The solvent is removed and the solid residue is stirred with methylene chloride (40ml) and left at 4°C for 16 hours.
  • Example 30- (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (3.8g) and 5-(4- carboxybenzylidene)thiazolidine-2,4-dione (3.6g) are dissolved in methylene chloride (40ml) and THF (20ml). To this add dicyclohexylcarbodiimide (3.2g) and DMAP (0.2g), and then stir for 4 hours at room temperature. The solid is removed by filtration and is washed with a small amount of THF (10ml). The solvent is removed and the solid residue is stirred with methylene chloride (40ml) and left at 4°C for 16 hours.
  • Example 31- (L)-N-(2-benzoxazolyl)-proline (3.26g) and 5-(4- hydroxybenzyl)thiazolidine-2,4-dione (3.1 lg) are suspended in methylene chloride (100ml). Add DCC (2.89g) and DMAP (0.12g) and stir at room temperature for 4 hours. Filter and purify on 114g of silica, eluting with methanol/methylene chloride (02:98). The yield of 5- ⁇ 4-[(S)-l-(2-benzoxazolyl)pyrrolidne-2- carboxy]benzyl ⁇ thiazolidine-2,4-dione is 4.55g.
  • Example 32- (L)-l-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26g) and 5-(4- carboxybenzyl)thiazolidine-2,4-dione (3.25g) are suspended in methylene chloride (100ml). Add DCC (2.88g) and DMAP (0.12g) and stir at room temperature for 4 hours. Filter and purify on 132g of silica, eluting with methanol/methylene chloride (02:98). The yield of 5- ⁇ 4-[(S)-l-(2-benzoxazolyl)pyrrolidinyl-2- methoxycarbonyl]benzyl ⁇ -thiazolidine-2,4-dione is 4.68g.
  • Example 33- (D)-l-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26g) and 5-(4- carboxybenzylidene)thiazolidine-2,4-dione (3.35g) are suspended in methylene chloride (100ml). Add DCC (2.91g) and DMAP (0.12g) and stir at room temperature for 4 hours. Filter and purify on 108g of silica, eluting with methanol/methylene chloride (02:98). The yield of 5- ⁇ 4-[(R)-l-(2-benzoxazolyl)pyrrolidinyl-2- methoxycarbonyl]benzylidene ⁇ -thiazolidine-2,4-dione is 4.32g.
  • Example 34- (D)-l-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26g) and 5-(4- carboxybenzyl)thiazolidine-2,4-dione (3.25g) are suspended in methylene chloride (100ml). Add DCC (2.93g) and DMAP (0.12g) and stir at room temperature for 4 hours. Filter and purify on 162g of silica, eluting with methanol/methylene chloride (02:98). The yield of 5- ⁇ 4-[(S)-l-(2-benzoxazolyl)pyrrolidinyl-2- methoxycarbonyl]benzyl ⁇ -thiazolidine-2,4-dione is 4.77g.
  • Example 35- Triethylamine (8.3ml) is added dropwise to a stirred cold solution of ethyl 2-aminoacetoacetate hydrochloride (5.4g) and 4-methoxybenzoyl chloride (5.2g) in dichloromethane (100ml). After stirring for 3 hours, the solution is washed with water (100ml), dried over sodium sulfate, filtered, and evaporated to dryness. The crude product, ethyl 2-(4-methoxy)phenylaminoacetoacetate weighs 6.7g.
  • Example 36 Ethyl 2-(4-methoxy)phenylaminoacetoacetate (5.9g) and phosphorus oxychloride (50ml) are stirred at 100C for 30 minutes. The phosphorus oxychloride is removed by evaporation, and the residue is diluted with aqueous sodium bicarbonate and extracted with methylene chloride. After drying over sodium sulfate, the solution is evaporated and the product is crystallized from hexane, giving ethyl 5-methyl-2-(4- methoxy)pheny 1-4-oxazolecarboxylate (4.5 g) .
  • Example 37- A solution of benzoyl chloride (17g) in ethyl acetate (40ml) is added dropwise, with stirring, in an ice-cold mixture of L-serine methyl ester, hydrochloride (15.5g), water (100ml), sodium bicarbonate (21.8g), and ethyl acetate (100ml). After stirring for 2 hours, the organic phase is separated, dried over sodium sulfate, and evaporated to give crystalline N-benzoyl-L-serine methyl ester (22. Og).
  • Example 39- A solution of benzoyl chloride (17g) in ethyl acetate (40ml) is added dropwise, with stirring, in an ice-cold mixture of L-threonine methyl ester, hydrochloride (16.5g), water (100ml), sodium bicarbonate (21.8g), and ethyl acetate (100ml). After stirring for 2 hours, the organic phase is separated, dried over sodium sulfate, and evaporated to give crystalline N-benzoyl-L-threonine methyl ester (21.5g).
  • Example 40- A stirred mixture of N-benzoyl-L-threonine methyl ester (21.0g), thionyl chloride (21. Og), and methylene chloride (150ml) is stirred at reflux for 1 hour. The solvent is evaporated and the residue is diluted with cold water. Neutralize with sodium bicarbonate, and extract with ethyl acetate. Purification on silica gel (250g), eluting with methanol :methylene chloride (01:99), yields methyl (R,S)-2-phenyl-2- oxazoline-5-methyl-4-carboxylate (14.8g).
  • Example 41- Activity in NIDDM KK-A y male mice Non-inslin dependent diabetic mellitus male mice, weighing 50 +/- 5g (9-10 weeks of age) were used. These animals exhibited hyperinsulinemia, hyperglycemia, and islet atrophy.
  • the test compounds 105, 115, and 155, and the positive control compound troglitazone were suspended in a 1% carboxymethylcellulose preparation and were given orally at a dose of lOmg/kg, twice a day, for 5 consecutive days. Blood sampling was performed before the first dose and then 90 minutes after the last dose. Serum glucose and insulin levels were measured. Percent reduction of serum glucose and insulin levels relative to the pre-treatment values are shown in Table XX and figures 20 and 21.

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Abstract

La présente invention concerne des composés pharmaceutiques utiles dans le traitement du diabète de type II. Ces composés présentent un avantage étant donné qu'ils sont rapidement métabolisés par les systèmes métaboliques de détoxication. Plus particulièrement, l'invention concerne des analogues de thiazolidinedione renfermant des esters dans la structure desdits composés. L'invention se rapporte également à des méthodes de traitement de troubles tels que le diabète. Ces méthodes consistent à administrer des compositions thérapeutiquement efficaces contenant des composés pouvant être métabolisés par un sérum ou des hydrolases et estérases intracellulaires. L'invention porte enfin sur les compositions de ces analogues de thiazolidinedione contenant des esters.
EP01932617A 2000-04-24 2001-04-24 Compositions et methodes destinees au traitement du diabete, de l'hyperlipidemie, de l'hypercholesterolemie et de l'atherosclerose Withdrawn EP1276730A2 (fr)

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US6680387B2 (en) 2000-04-24 2004-01-20 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6784199B2 (en) 2000-09-21 2004-08-31 Aryx Therapeutics Isoxazolidine compounds useful in the treatment of diabetes, hyperlipidemia, and atherosclerosis in mammals
US6768008B2 (en) 2000-04-24 2004-07-27 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6958355B2 (en) 2000-04-24 2005-10-25 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
WO2004009527A1 (fr) * 2002-07-19 2004-01-29 Aryx Therapeutics Substances et procedes pour le traitement de l'hypercholesterolemie
FR2856060A1 (fr) * 2003-06-12 2004-12-17 Centre Nat Rech Scient Groupement protecteur clivable par les albumines seriques
WO2005041951A2 (fr) * 2003-10-28 2005-05-12 Rigel Pharmaceuticals, Inc. Compositions de rhodanine utilisables comme agents antiviraux
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CN104306373B (zh) * 2014-09-29 2017-08-08 中国科学院成都生物研究所 一种苯基恶唑类化合物在制备治疗癌症的药中的应用
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