Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-11
2001-04-10
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S369000, C546S178000, C546S180000, C548S183000
Reexamination Certificate
active
06214842
ABSTRACT:
BACKGROUND OF THE INVENTION
Diabetes mellitus is a syndrome characterized by abnormal insulin production, increased urinary output and elevated blood glucose levels. There are two major subclasses of diabetes mellitus. One is the insulin-dependent diabetes mellitus (IDDM or Type I), formerly referred to as juvenile onset diabetes since it was evident early in life, and non-insulin dependent diabetes mellitus (NIDDM or Type II), often referred to as maturity-onset diabetes. Exogenous insulin by injection is used clinically to control diabetes but suffers from several drawbacks. Insulin is a protein and thus cannot be taken orally due to digestion and degradation but must be injected. It is not always possible to attain good control of blood sugar levels by insulin administration. Insulin resistance sometimes occurs requiring much higher doses of insulin than normal. Another shortcoming of insulin is that while it may control hormonal abnormalities, it does not always prevent the occurrence of complications such as neuropathy, retinopathy, glomerulosclerosis, or cardiovascular disorders.
Orally effective antihyperglycemic agents are used to reduce blood glucose levels and to reduce damage to the nervous, retinal, renal or vascular systems through mechanisms affecting glucose metabolism. Such agents act in a variety of different mechanisms including inhibition of fatty acid oxidation, a-glycosidase inhibition, antagonism of a
2
-receptors and inhibition of gluconeogenesis. Two classes of compounds have predominated: the biguanides as represented by phenformin and the sulfonylureas as represented by tolbutamide (Orinase®). A third class of compounds which has shown antihyperglycemic activity are thiazolidinediones of which ciglitazone is the prototype. Ciglitazone suppresses the symptoms of diabetes—hyperglycemia, hypertriglyceridemia and hyperinsulinemia [Diabetes 32, 804-10 (1983)]. Rezulin, a member of the thiazolidinediones, has recently been used successfully in the treatment of type II diabetes mellitus.
DESCRIPTION OF THE INVENTION
This invention provides a compound of formula I having the structure
wherein:
R is hydrogen or alkyl of 1-6 carbon atoms;
A is
R
1
, R
2
, R
3
are each, independently, hydrogen, alkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, trifluoromethyl,
R
4
is hydrogen, alkyl of 1-6 carbon atoms, halogen, or alkoxy of 1-6 carbon atoms;
R
5
is phenyl, naphthyl, thienyl, furyl, wherein R
5
may be optionally mono-, di-, or tri-substituted with a sustituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms, nitro, cyano, —CO
2
H, alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbon atoms;
m=1-4;
n=1-4; and
or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, with the imidic acidic functionality of the thiazolidinedione moiety, and when a compound of this invention contains a carboxylate or phenolic moiety, or similar moiety capable of forming base addition salts.
Alkyl includes both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
Preferred compounds of this invention include:
5-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenylamino}-thiazolidine-2,4-dione;
5-[(4-methoxyphenyl)amino]-thiazolidine-2,4-dione;
5-[[(4-methylthio)phenyl]amino]-thiazolidine-2,4-dione;
5-[(4-methoxyphenyl)methylamino]-thiazolidine-2,4-dione;
5-(2-naphthalenylamino)-thiazolidine-2,4-dione;
5-(4-chloro-naphthalen-1-ylamino)-thiazolidine-2,4-dione;
5-(1-naphthalenylamino)-thiazolidine-2,4-dione;
5-{3-[2-(5-ethyl -pyridin-2 -yl)-ethoxy]-phenylamino}-thiazolidine-2,4-dione;
5-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-biphenyl-3-ylamino}-thiazolidine-2,4,-dione;
5-{3-[2-(quinolin-2-ylmethoxy)-ethyl]-phenylamino}-thiazolidine-2,4-dione;
5-{3-[naphthalen-2-ylmethoxy)-ethyl]-phenylamino}-thiazolidine-2,4-dione;
5-{3-[5-chloro-naphthalen-2-ylmethoxy)-ethyl]-phenylamino}-thiazolidine-2,4-dione;
5-{(5-[5-chloro-naphthalen-2-ylmethoxy)-ethyl]-naphthalen-2-ylamino}-thiazolidine-2,4-dione;
or a pharmaceutically acceptable salt thereof.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
The invention compounds of Formula I may be prepared from intermediates of the formula II below wherein the variables A and R are as previously defined.
5-Amino-thiazolidinediones of Formula I are prepared from a Formula II intermediate by reacting with 5-bromo-thiazolidinedione in the presence of a base, i.e. triethylamine.
The amines of Formula II are either commercially available or can be prepared according to standard literature procedures as described in the following reaction schemes I-II.
The starting oxazole intermediates can be prepared according to standard literature procedures. For example, 4-(1′-hydroxyethyl)-5-methyl-2-phenyl oxazoles and thiazoles can be prepared according to Scheme III (European Patent EP 0177353A2), and 2-phenyl-4-chloromethyl-5-methyloxazoles can be prepared by known methods conventional in the art Scheme IV (Heterocyclic Compounds 34, 1979, and Heterocyclic Compounds 45, 1986).
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of this invention in the following standard pharmacological test procedures.
Determination of Blood Glucose Lowering in db/db Mice
On the morning of Day 1, 35 mice [male diabetic db/db (C57BL/KsJ) mice (Jackson Laboratories), 2-7 months of age and 50-70 g] were fasted for 4 hours, weighed and a baseline blood sample (15-30 &mgr;l) was collected from the tail-tip of each mouse without anesthesia, and placed directly into a fluoride-containing tube, mixed and maintained on ice. Food was then returned to the mice. The plasma was an separated and levels of glucose in plasma determined by the
Gunawan Iwan
Malamas Michael S.
Milowsky Arnold S.
Seaman D. Margaret
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