Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-07
2001-02-06
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S202000, C540S362000
Reexamination Certificate
active
06184216
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention provides novel compounds and a novel method for treating: non-insulin dependent diabetes mellitus (NIDDM); impaired glucose tolerance; and obesity.
Non-insulin dependent diabetes mellitus, or NIDDM, and Type II diabetes are synonymous. NIDDM patients have an abnormally high blood glucose concentration when fasting and delayed cellular uptake of glucose following meals or after a diagnostic test known as the glucose tolerance test. NIDDM is diagnosed based on recognized criteria (American Diabetes Association, Physician's Guide to Insulin-Dependent (Type I) Diabetes, 1988; American Diabetes Association, Physician's Guide to Non-Insulin-Dependent (Type II) Diabetes, 1988).
Impaired glucose tolerance occurs when the rate of metabolic clearance of glucose from the blood is less than that commonly occurring in the general population after a standard dose of glucose has been orally or parenterally administered (American Diabetes Association, Physician's Guide to Non-Insulin-Dependent (Type II) Diabetes, 1988). Impaired glucose tolerance can occur in NIDDM, insulin dependent diabetes mellitus, middle age onset diabetes mellitus of the young, gestational diabetes and obesity. Impaired glucose tolerance can also occur in individuals not meeting the diagnostic criteria for these disease states. Impaired glucose tolerance in non-diabetic individuals is a predisposing factor for the development of NIDDM.
Obesity is a condition in which there is an increase in body fat content resulting in excess body weight above the accepted norms for age, gender, height, and body build (Bray, Obesity, An Endocrine Perspective, p. 2303, Multihormonal Systems and Disorders (1989)). Accepted norms have been determined by life insurance mortality experience and by incidence of morbidity in relation to body composition. The excess mortality that occurs in obese individuals results from diseases that are predisposed by this condition. They include cancer, cardiovascular disease, digestive disease, respiratory disease and diabetes mellitus.
In patients with chronic hyperglycemia such as occurs in non-insulin dependent diabetes, glucose-dependent protein crosslinking occurs at a rate in excess of the norm (Bunn, American Journal of Medicine, Vol. 70, p. 325, 1981) resulting in altered tertiary protein structure (Brownlee, Chapter 18, Diabetes Mellitus, p. 279, 1990). Excessive non-enzymatic glycosylation of proteins contributes to diabetic complications and complications of aging in non-diabetic humans, such as neuropathy, nephropathy, retinopathy, hypertension, and atherosclerosis (Brownlee, 1990, supra).
Hyperglycemia is defined as blood glucose concentration in excess of the accepted norm for the general population (American Diabetes Association, Physician's Guide to Non-Insulin-Dependent (Type II) Diabetes, 1988).
Reducing the abnormally high blood glucose level of diabetic subjects benefits the patient by reducing the discomfort of glycosuria and the excessively high mortality and morbidity associated with diabetes mellitus (Kahn, Diabetes Mellitus Theory and Practice, 4th ed., Chapter 26, p. 450, 1990). Weight loss by patients with diabetes mellitus who are obese results in a long-term reduction of the excessively high blood glucose level (Wing, Archives of Internal Medicine, Vol. 147, p. 1749, 1987; Kahn, Diabetes Mellitus Theory and Practice, 4th ed., Chapter 26, p. 450, 1990). As a result of this beneficial effect of weight loss on diabetes mellitus, weight reduction is the treatment of choice for obese patients with diabetes (Karam, Chapter 33, Diabetes Mellitus and Obesity, p. 298, 1982). While the relationship between diabetes mellitus and obesity is known, it would be an advantage to have a drug which can treat or prevent both of them.
INFORMATION DISCLOSURE
3-(1-(Aminomethyl)hydrazino)) propanoic acid is reported in JP 54128523 (Chem. Abstr. 92:75899h) to be a fungicide and insecticide. The synthesis of N-(hydrazinoiminomethyl)-glycine is reported in: Gante,
J. Chem. Ber.
1968,101, 1195. Certain alkylidene-amino guanidine derivatives are described in U.S. Pat. No. 5,272,165 titled “Inhibiting advanced glycosylation of body proteins—using 2-alkylidene-amino:guanidine deriv., used e.g. for treating diabetic side-effects or esp. preventing tooth staining.” Aminoguanidine analogs of arginine are disclosed in DE 4244539-A1 and WO 9104-023-A. U.S. Pat. No. 5,132,453 discloses that N6-(hydrazino:imino:methyl)-lysine is useful as an inhibitor of nitric oxide formation and for treating hypertension. EP-230-037-A discloses certain new 2-substituted-guanidine derivatives having antiischaemic and cardioprotective activity. U.S. Pat. No. 3,412,105 discloses P-Aryl-N-guanidino-(&bgr;-alanines or &agr;-carboxy-&bgr;-alanines) as MAO inhibitors and long acting hypotensives. “Aminoguanidine carboxylates for the treatment of NIDDM” are disclosed in U.S. application Ser. No. 95/14126. Cyclic aminoguanidine carboxylates are disclosed in “Preparation and formulation of hydrazonothiazoles and imidazoles as physiological Maillard reaction inhibitors” (WO 9419335 A1,
Chem. Abstr.
122:314548).
The preparation of certain &agr;-hydrazonoimidazolidin-4-ones, -thiazolidine-4-ones and related compounds as Maillard reaction inhibitors is described in EP 531,812. The preparation of certain uracil derivatives is described in WO 89/10,701. Kokai Tokkyo Koho 79,128,590 describes certain 3-amino-5-hydroxy-6,7-dihydro-1[H]-1,2,4-triazepines.
SUMMARY OF THE INVENTION
The present invention particularly provides:
(1) A compound of the formulae I-VIII:
or a pharmacologically acceptable salt thereof,
wherein G is (CH
2
)
n
;
wherein G′ is (CH
2
)
m
;
wherein G″ is (CH
2
)
p
;
wherein R is H or NH
2
;
wherein n is an integer from 1-5;
wherein m is an integer from 0-4;
wherein p is an integer from 0-3;
with the proviso that in formulae II, at least one R group must be NH
2
, and when G is (CH
2
)
1
, formula II excludes the structure represented by formula XI
with the proviso that in formula I, when G is (CH
2
)
1
at least one R group must be NH
2
;
with the proviso that in formula VIII, when G is (CH
2
)
2
at least one R group must be NH
2
.
(2) a method for treating or preventing non-insulin dependent diabetes mellitus or obesity in a patient susceptible to or experiencing said NIDDM or obesity comprising the systemic administration of an amount effective to treat or prevent NIDDM or obesity of a compound of the formulae IX-XI.
Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
The dose of compounds of formula I-VIII to be used is between 0.1 and 100 mg/kg body weight daily. The preferred dose is 1-50 mg/kg/day. Administration may be by oral, parenteral, intranasal, buccal, sublingual, intrarectal, or transdermal routes. The oral route is preferred.
Novel compounds of the invention are given by the generic formulae I-VIII. Known compounds claimed for use in the treatment of NIDDM are represented by formula IX-XI.
Of the compounds of this invention, represented by generic formulae I-VIII, the compounds listed in Table 1 are especially preferred and their preferred utility is in the treatment of NIDDM and its complications. Procedures for their preparation are given in Section 4. Table 2 contains a list of compound specifically claimed by this invention.
Thus, the present invention provides novel and known compounds having surprising and unexpected antidiabetic
Larsen Scott D.
May Paul D.
Meglasson Martin D.
Vaillancourt Valerie A.
Dinsmore & Shohl LLP
Kifle Bruck
Pharmacia & Upjohn Company
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