Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-11-08
2001-12-11
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S560000, C514S565000
Reexamination Certificate
active
06329545
ABSTRACT:
The present invention provides novel compounds and a novel method for treating: non-insulin dependent diabetes mellitus (NIDDM); diabetic complications resulting from excessive non-enzymatic glycosylation of proteins in non-insulin dependent and insulin-dependent diabetes mellitus; impaired glucose tolerance; and obesity.
BACKGROUND OF THE INVENTION
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).
Insulin-Dependent diabetes mellitus, IDDM, and Type I diabetes are synonymous. IDDM 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. IDDM is diagnosed based on recognized criteria (American Diabetes Association, Physician's Guide to Insulin-Dependent (Type I) 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, IDDM, 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 and 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).
While the relationship between these conditions is known, it would be an advantage to have a drug which can treat or prevent all 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 alkylide-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-(hydrazinoimino: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 &bgr;-Aryl-N-guanidino-(&bgr;-alanines or &agr;-carboxy-&bgr;-alanines) as MAO inhibitors and long acting hypotensives.
SUMMARY OF THE INVENTION
The present invention particularly provides:
A compound of the formulae I or II:
a pharmacologically acceptable salt thereof,
wherein AG is
a) N-aminoguanidine,
b) N,N′-diaminoguanidine, or
c) N,N′,N″-triaminoguanidine;
wherein n is an integer from 1-5;
wherein R
1
is
a) hydrogen,
b) phenyl,
c) C
1
-C
5
alkyl, or
d) C
1
-C
3
alkyl-phenyl; and
wherein R
2
is
a) hydrogen,
b) phenyl,
c) C
1
-C
10
alkyl, or
d) C
1
-C
5
alkyl-phenyl
with the following provisos:
a) in Formula II, when n is 2, R
1
is other than hydrogen;
b) in Formula II, when n is one, R
1
is other than methyl;
c) in Formula I, when R
2
is ethyl, R
1
is other than hydrogen;
d) in Formula I, when R
2
is phenyl, R
1
is other than hydrogen; and
e) in Formula II, when n is 3, R
1
is other than hydrogen.
(2) a method for treating or preventing non-insulin dependent diabetes mellitus in a patient suscepible to or experiencing said NIDDM comprising the systemic administration of an amount effective to treat or prevent NIDDM of a compound of the formula III
wherein R
3
is hydrogen, methyl, ethyl, CH
2
phenyl, or n-hexyl.
For the generic formulae I and II, attachment of the AG fragment is unspecified, i.e. bonding to the adjacent carbon may occur at any one of the nitrogens of the AG fragment. The remaining nitrogens of the AG fragment are unsubstituted.
The carbon atom content of the carbon containing moieties is indicated by a prefix “C
i
-C
j
” wherein i is the lowest number of carbon atoms and j is the highest number of carbon atoms.
Examples of alkyl groups having from 1 to 10 carbon atoms include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and other isomeric forms thereof.
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-III 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 and II. Known compounds claimed for use in the treatment of NIDDM are represented by formula III.
Of the compounds of this invention, represented by generic formulae I and II, the compounds listed in Table 1 are especially preferred and their preferred utility is in the treatment of NIDDM and its complications.
Table 2 contains a list of related compounds which are not claimed. They are included to demonstrate the surprising effect of the claimed compounds by showing that these compounds, which are closely related to the claimed compounds, are not considered active at the highest dose tested.
Table 3 contains a list of compounds within the generic scope embodied in the generic formula
Larsen Scott D.
May Paul D.
Meglasson Martin D.
Schostarez Heinrich J.
Tanis Steven P.
Fish & Richardson P.C.
Shippen Michael L.
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