A chromium steel alloy having 0.4 to 0.75% of carbon, 0.4 to 1.6% of manganese, 12 to 19% of chromium, up to 0.2% of nickel, up to 0.7% of silicon, 0.5 to 1.5% of molybdenum, up to 1.5% of tungsten, 0.05 to 0.3% of vanadium and (% Ti/% Nb), 0.02 to 0.15% of sulfur, up to 0.1% of nitrogen and up to 0.008% of boron, remainder iron including smelting-related impurities. This steel alloy is distinguished by good processability, resistance to corrosion, resistance to abrasion, a high resistance to heat up to 300xc2x0 C. and above, and a high rigidity.

Recent developments in sewing machines have also decisively changed the profile of demands imposed on industrial (sewing) needles. Hitherto, industrial needles for sewing machines have been produced from a carbon steel containing approximately 0.8 to 1.1% of carbon. In humid air, needles of this type tend to form rust spots, which very greatly limits their use. Therefore, to improve the resistance to corrosion and to avoid the formation of rust, the needles are coated by electrodeposition, for example in rotating drums. Nickel and/or chromium is applied as coating by cathode deposition. The layer thicknesses often differ very considerably, and critical areas, for example in the region of the eye, the point or the thread groove, can often only be provided with a very thin coating. However, it is in these very regions that, in operation, high levels of wear occur. Abrasion of the coating is also undesirable, since it is known that nickel is a highly allergenic metal even in very small concentrations.
A further drawback of the coating by electrodeposition is that during cathode deposition of metal in electrodeposition baths, hydrogen can be incorporated in the needle material. This hydrogen causes the brittleness to increase very considerably, with the result that there is a risk of needles breaking, with possible damage to the machine.
For economic production of the needles, the workability is a parameter of crucial importance. This applies in particular to the production of thin needles. The carbon steels containing up to 1.1% of carbon which have been used hitherto are just able to satisfy these conditions, but in the annealed state with carbon contents of over 1% there may already be difficulties with working the thread groove and the eye. With these carbon steels, it is possible to achieve a hardness of at most 800 to 840 HV1 after a special heat treatment.
However, the temperature stability, i.e. the maintenance of the hardness after heating, is insufficient. Even in the case of heating to 300xc2x0 C., a drop in hardness of more than 200 HV1 units (10 HRC units) is possible. Furthermore, at full hardness, there is a considerable susceptibility to uptake of hydrogen, for example during coating by electrodeposition. Even low hydrogen contents may embrittle the martensitic microstructure, which is stabilized only by carbon, and cause an increased risk of fractures. This is particularly critical in the case of thin needles. Because of difficulties in the micromachining and precision machining of the eye and the thread groove and because of insufficient matching of the alloying elements, it has hitherto been impossible to utilize the advantages of relatively high-alloy steels.
The demands imposed on new needle materials are determined primarily by the increases in performance in sewing machines. Developments are toward an increase in the economic viability of the production of seams combined, at the same time, with simple operation and a longer service life of the sewing machines. The following measures serve this purpose:
increasing the sewing speed,
improving the thread guidance,
optimizing the sewing foot pressure,
continuous adjustability of the stitch width,
highest possible stitching force of the needles
combined with lowest possible friction.
The desire for higher sewing speeds results solely from economic considerations, in order to reduce costs and increase production. For example, industrial sewing machines are currently already driven at more than 7000 rpm. The high sewing speeds (i.e. the high stitch numbers) lead to particular loads on the needles and require adjustment of the materials and of the materials properties.
The high sewing speeds and the associated particular loads on the needles therefore require improved materials properties. These relate to the heat resistance of the needle point, the wear resistance as a sum property of corrosion and abrasion resistance, the hardness, the rigidity, the maximum bending force and the maximum bending.
Recent tests have shown that when thick materials are being sewn at high sewing speeds, temperatures of up to 300xc2x0 C. occur at the needle point. Under these conditions, the wear resistance is significantly reduced after even a short period of use, a fact which is also attributable to insufficient protection by coatings applied by electrodeposition.
A major drawback of needles made from carbon steel is in particular the drop in the core hardness and the insufficient mechanical properties under extreme loads. The matrix, which is only stabilized by carbon, is often unable to resist deformation at elevated temperatures. As a result, the service life of the needle is reduced considerably. The deformation in turn significantly increases the risk of damage to the sewing machine.
An industrial needle should have a high core hardness and a high heat resistance, if possible to over 300xc2x0 C.
The wear resistance as a sum property of abrasion resistance and corrosion resistance should be good and as far as possible should not be adversely affected by the action of air and moisture and by contact with abraded fabric and fibers (finishing agents, dyes, chemicals, bleach residues and other substances).
The risk of a needle breaking should also be low when different materials are being sewn, in particular during sewing in the transition region between different materials and when sewing padding and reinforcements.
The numerical value of the rigidity S, expressed as a quotient Fmax/Smax (maximum bending force/maximum bending) should be high and have a scatter which is as low as possible. The bending of a needle until it breaks should be between 1.5 and 2.5 mm and should not exceed 3.0 mm.
The production of needles should be inexpensive, environmentally friendly and simple. The shaping and heat treatment should be possible with conventional installations. In the case of needles made from sintered carbide (German laid-open specification 38 19 481), this condition is not satisfied, since shaping requires diamond grinding tools and the eye has to be manufactured by means of spark erosion.
Needles for medium sewing speeds are produced from wire, which has a simple alloy structure and is easy to process. Inexpensive production is a crucial aspect in the selection of the materials. Carbon steels containing approx. 0.8 to 1.1% of carbon, approximately corresponding to a steel with materials number 1.1545, are customary. For high demands on the needles, wire from the upper carbon range is currently used. However, the limits of processability are encountered in this range.
To produce an industrial needle, a wire is processed predominantly by means of chipless shaping. In this case, first of all the needle stem and neck are processed and extruded by means of presses, and the eye is flattened and shaped out. Then, the needles are straightened and the thread groove is introduced by means of roll stamping. Precision machining of the eye and sharpening of the needle point follow as further processing stages. There then follows a hardening step with a subsequent tempering treatment, if appropriate also in combination with a deep cooling treatment. The sewing needles then achieve a hardness of approx. 60 HRC. This is followed by precision grinding of the needle points, cleaning and coating with nickel and/or chromium by electrodeposition. The coating by electrodeposition takes place in rotating plastic vessels with direct current being supplied, the negative supply conductor being introduced into the interior of the plastic vessel, where it makes contact with the needles. The electrolyte used is often the acid solution of a chromate (Cr6+) salt. From this solution, a thin film of chromium or hard chromium is deposited on a nickel layer which has often been deposited beforehand.
During the coating operation, it is very easy for hydrogen to diffuse into the lattice of the needle material, with the result that the hardened carbon steel can suffer considerable embrittlement. This in turn leads to a high susceptibility to breaking on the part of the needle and increases the risk of failure at high sewing speeds.
The drawback of hydrogen embrittlement can be avoided by using a physical coating process, for example the PVD (Physical Vapor Deposition) process. These processes predominantly operate in vacuum or at reduced pressure and require temperatures of 300 to 500xc2x0 C. However, the relatively high temperatures lead to excessive thermal loads being placed on the needlesxe2x80x94on account of their low content of alloying metalsxe2x80x94and to a drop in the substrate hardness (core hardness). As a result, the compressive strength of the point deteriorates.
To achieve the highest possible compressive strength and hardness, German laid-open specification 38 19 481 proposes producing the needle stem and the point of a machine needle from an ultrafine-grained sintered carbide. This high-strength needle stem is to be joined to the needle shank by means of cold extrusion, erosion taking place in order to form the thread groove and the eye. However, the high costs of this complex shaping and the considerable time required for erosion machining do not satisfy the criteria of economic mass production and therefore have also not gained acceptance in practice.
It has also already been attempted to use known stainless steels with additions of molybdenum and other alloying elements for the production of industrial needles. The intention was in particular to improve the resistance to corrosion. However, these needles made from conventional stainless steels were difficult to work and did not achieve the required surface hardness. Compared to the known carbon steels, in particular the lower rigidity combined, at the same time, with a high degree of plastic deformation was a considerable drawback.
Therefore, to increase the surface hardness, German laid-open specification 2 054 671 proposes produced machine needles from a stainless steel and subsequently hardening the parts which are exposed to wear by nitriding.
This embodiment too has failed to gain acceptance in practice, since the high nitriding temperatures cause distortion, and the layer, which is only a few pm thick, did not result in any improvement in the compressive strength. Correcting the distortion by means of a straightening operation is generally difficult to carry out, since it leads to incipient cracks forming in the layer and therefore to the formation of fracture points.
The invention is based on the object of proposing a nickel-free or low-nickel alloy for the production of rust-free and wear-resistant needles, in particular for industrial needles. The alloy has an improved processability, a rigidity which is improved in the hardened and heat-treated state, an improved heat resistance and an excellent resistance to abrasion and resistance to corrosion.
The alloy contains:
remainder iron and smelting-related impurities.
A preferred embodiment contains:
Furthermore, it is advantageous if the alloyxe2x80x94individually or in addition to one anotherxe2x80x94contains in each case at least 0.10% of silicon, 0.05% of tungsten, 0.01% of titanium and, in each case in total, 0.05% of vanadium and titanium and/or 0.05% of vanadium and niobium.
The alloy is preferably characterized by the following relationship:
K1=30xc3x97(%C+%N)/(%Cr+%Mo)=0.9 to 1.25.
A further characterization of the alloy may be the matching of the sulfide-forming elements manganese, titanium to sulfur and carbon and nitrogen. Particularly advantageous properties are given within the following limits:
K2=10xc3x97%S/(%C+%N)=0.35 to 1.50
and/or
K3=(%Mn+%Ti)/%S=5 to 30.
These relationships characterize the interaction of the sulfur as a function of the total carbon and nitrogen and manganese and titanium content.
The following properties of the alloy are particularly advantageous:
Good processability with shaping tools, in particular by means of stamping and punching tools.
High resistance to corrosion as a result of the alloying elements chromium and molybdenum. The high resistance to corrosion makes it possible to dispense with expensive, environmentally polluting coating processes using electrodeposition (chromium plating).
Elimination of the hydrogen embrittlement which is possible during coating by electro-deposition. The uptake of hydrogen may cause different levels of embrittlement to the needles, with the result that the risk of fractures increases considerably.
High resistance to wear and abrasion and high hardness after a standard heat treatment (hardening).
The good resistance to wear and the required hardness are achieved by a high strength of the matrix and carbides and/or carbonitrides which are finely distributed therein. The mechanical properties of the matrix are determined predominantly by the level of dissolved alloying elements and can be adjusted by specially matching the chromium, molybdenum, carbon and nitrogen contents, preferably with a nickel content of less than 0.1%.
Low plastic deformability of the hardened needles combined, at the same time, with a low scatter in the bending force, the bending and the needle rigidity.
The needle rigidity is characterized by the ratio of the maximum bending force to the maximum bending. These values are determined by the ratio of the alloying elements manganese and titanium to sulfur and of carbon end nitrogen to chromium and molybdenum.
Low scatter in the values for the maximum bending, the maximum bending force and the needle rigidity.
The alloy contains little or no nickel and is therefore distinguished by a particularly low allergenic potential; it is therefore also suitable for medical needles, which are exposed to aggressive chemical cleaning agents and disinfectants at elevated temperatures.
However, the material according to the invention is also suitable for the production of other needles, such as industrial needles.
The invention is explained in more detail below with reference to exemplary embodiments.
Table I compares conventional alloys A1 to A3 and C1 to C3 with six alloys E1 to E6 in accordance with the invention.
These test alloys have been used to carry out tests to determine the overall resistance to wear in a humid atmosphere using the condensation water test under changing conditions as laid down by DIN 50017 together with a subsequent 30-minute or 60-minute chafing test in a rotating vessel. The specimens used were wire pins which had been ground and hardened in the usual way, with a diameter of 1 mm, and industrial needles with a nickel coating applied by electrodeposition. The condensation water test under changing conditions was used to determine the resistance of the specimens to corrosion under these conditions established in a climate chamber. The specimens were stored for 8 hours at 40xc2x0 C. and 100% relative humidity in air. Then, the specimens were slowly cooled to room temperature over 16 hours and the rust coverage was determined. During the subsequent chafing test, the change in the specimen surface was optically assessed and the mass loss determined.
The bending characteristics of the specimens were determined using an F 33 test machine produced by Shimatzu at a bending rate of 2.5 mm/min. The rigidity S, Fmax and Smax was taken or calculated from the corresponding force/bending diagrams.
The test data are compiled in Tables III and IV below.
The data from the two tables demonstrate that the alloys E1 to E6 in accordance with the invention are distinguished by a high rigidity S combined, at the same time, with good processability.
In this connection, the graph illustrates the maximum bending force as a function of the bending, showing the allows E1 to E6 according to the invention compared to the conventional test alloys B1 to B3 and C1 to C3 and known sintered carbides in the tough-hard range.
The range of the invention is indicated by E. It is characterized in that after hardening the needles are in the tough-hard range. B indicates results of tests using a steel containing 0.88% to  greater than 1% of carbon. Bi indicates the range of embrittlement caused by hydrogen. In this brittle range, the maximum possible bending force and the bending are greatly reduced.
The range C, by contrast, relates to the characteristics of known stainless steels with a considerable plastic deformation level. In these steels, there is a risk of permanent bending of the needle at high sewing speeds causing considerable damage to the sewing machine.
For comparison purposes, the range D describes the performance of sintered carbide. However, this material is too brittle for practical uses as a needle material.


Compounds of formula I:

The present invention relates to compounds that are useful as antidiabetic agents.
Type II diabetes, or non-insulin dependent diabetes (NIDDM) is a significant healthcare problem whose incidence is on the rise. Between 1990 and 1998, the prevalence of NIDDM in the United States increased by 33 percent, to about 13 million persons. An additional 5 million persons are presumed to have undiagnosed NIDDM, while another 14 million persons have impaired glucose tolerance. Direct medical costs associated with diabetes were $44 billion in 1997, due mainly to hyperglycemia-related diabetic complications, including diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation, and glaucoma.
NIDDM is one of a number of disease states associated with the phenomenon of insulin resistance. Insulin resistance is defined as the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus. Insulin resistance syndrome (hereinafter IRS) refers to the cluster of manifestations that include insulin resistance; hyperinsulinemia; non insulin dependent diabetes mellitus (NIDDM); arterial hypertension; central (visceral) obesity; and dyslipidemia.
The primary goal of IRS therapy and thus diabetes therapy is to lower blood glucose levels so as to prevent acute and long-term disease complications. For some persons, modified diet and increased exercise may be a successful therapeutic option for achieving the goal of glucose control. When modified diet and increased exercise are not successful, drug therapy using oral antidiabetic agents is initiated.
To date, a number of oral antidiabetic agents have been developed. For instance, sulfonylureas are generally used to stimulate insuln. The biguanide metformin is generally used to improve insulin sensitivity and to decrease hepatic glucose output. Acarbose is used to limit postprandial hyperglycemia, Thiazolidine 2,4 diones are used to enhance insulin action.
New drug therapies for the treatment of NIDDM have focused in part on the discovery of new Peroxisome Proliferator Activation Recpetor (PPAR) agonists. PPARs are members of the nuclear receptor superfamily of transcription factors that includes steroid, thyroid, and vitamin D receptors. PPARs play a role in controlling expression of proteins that regulate lipid metabolism. There are three PPAR subtypes: PPAR xcex1, PPAR xcex4, and PPAR xcex3.
Each PPAR receptor shows a different pattern of tissue expression, and differences in activation by structurally diverse compounds. PPAR xcex3, for instance, is expressed most abundantly in adipose tissue and at lower levels in skeletal muscle, heart, liver, intestine, kidney, vascular endothelial and smooth muscle cells as well as macrophages. Two isoforms of PPAR xcex3 exist, identified as xcex31 and xcex32, respectively. PPAR xcex3 mediates adipocyte signalling, lipid storage, and fat metabolism. Evidence gathered to date support the conclusion that PPAR xcex3 is the primary, and perhaps the only, molecular target mediating the insulin sensitizing action of one class of antidiabetic agents, the thiazolidine 2,4 diones.
In a monotherapeutic or combination therapy context, new and established oral antidiabetic agents are still considered to have non-uniform and even limited effectiveness. The effectivieness of oral antidiabetic therapies may be limited, in part, because of poor or limited glycemic control, or poor patient compliance due to unacceptable side effects. These side effects include edema weight gain, or even more serious complications. For instance, hypoglycemia is observed in some patients taking sulfonylureas. Metformin, a substituted biguanide, can cause diarrhea and gastrointestinal discomfort. Finally, edema, weight gain, and in some cases, hepatoxicity, have been linked to the administration of some thiazolidine 2,4 dione antidiabetic agents. Combination therapy using two or more of the above agents is common, but generally only leads to incremental improvements in glycemic control.
As a result, there is a need for oral antidiabetic agents that can be used alone or in combination, and that do not give rise to side effects such as fluid retention, peripheral edema, weight gain, or more severe complications.
These and other needs are addressed by the invention claimed by the instant application, which is directed to a compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
X is (CR1R2)x wherein x is 1, 2, 3, or X is
xe2x80x94(CR3R4)xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94(CR3R4)xe2x80x94,
xe2x80x94(CR3R4)xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94Cxe2x89xa1Cxe2x80x94(CR3R4)xe2x80x94,
wherein R1-R4 are each independently H, OH or (C1-C6) alkoxy, or R3 and R4 taken together are xe2x95x90O, or R3-R6 are each independently or (C1-C6)alkyl;
Y and Z are (CR1R2)n and (CR3R4)m wherein m and n are each independently 0, 1, 2, or 3;
B is H or (C1-C6)alkyl;
E is COR5, wherein R5 is (C1-C6)alkyl, OH, (C1-C6)alkoxy, NR6R7, wherein R6 and R7 are each independently H or (C1-C6)alkyl, or one of R6 and R7 is H or (C1-C6)alkyl and the other is SO2R8, wherein R8 is H or (C1-C6)alkyl, or E is substituted heteroaryl or
R9-R12 are each independently H, halo, aryl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkanoyl, halo(C1-C6)alkanoyl, benzoyl, or halo(C2-C6)alkanoyl; and
one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R9, R10, and R12 are absent at that position.
What is also provided is a compound which is:
8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-ynoic acid methyl ester;
8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-ynoic acid;
8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-4-ynoic acid;
8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-ynoic acid;
8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-6-en-4-ynoic acid;
8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-6-en-4-ynoic acid;
6-Hydroxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-4-ynoic acid;
6-Hydroxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-4-ynoic acid;
6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-4-ynoic acid;
6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-4-ynoic acid;
6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-ynoic acid;
6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-ynoic acid.
What is also provided is a pharmaceutical composition comprising a compound of formula I admixed with a carrier, diluent, or excipient.
What is also provided is a method of treating, preventing or controlling non-insulin dependent diabetes mellitus, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, or hyperinsulinemia in a mammal comprising administering to the mammal in need thereof an effective amount of a compound of formula I.
What is also provided is a method of treating a patient suffering from abnormal insulin and/or evidence of glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone, comprising administering to the patient a therapeutically effective amount of a compound of fomula I.
What is also provided is a method of reducing body weight in an obese mammal comprising administering to the mammal in need thereof an effective amount of a compound of formula I.
What is also provided is a method of preparing a compound of formula IA
wherein R9-R12 are each independently H, halo, aryl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkanoyl, halo(C1-C6)alkanoyl, (C3-C7)cycloalkylcarbonyl, benzoyl, or halo(C2-C6)alkanoyl; and one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R9, R10, and R12 are absent at that position comprising:
(a) Conversion of the mesylate to the nitrile;
(b) Conversion of the nitrile to the primary alcohol;
(c) Conversion of the primary alcohol to the halide;
(d) Displacement of the halide with TMSacetylide to to form the TMS acetylene;
(e) Removal of the TMS group by hydrolysis;
(f) Treatment of the acetylene with base and reaction with formaldehyde to form the propargyl alcohol;
(g) Conversion of the primary alcohol to the Halde;
(h) Alkylation with xe2x80x9cXxe2x80x9d follwed by decarboxylation to form the ester; and
(i) Hydrolysis of the ester.
What is also provided is a method of preparing a compound of formula IB
wherein Rxe2x80x2 is H or (C1-C6)alkyl;
R9-R12 are each independently H, halo, aryl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkanoyl, halo(C1-C6)alkanoyl, benzoyl, or halo(C2-C6)alkanoyl; and one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R9, R10, and R12 are absent at that position comprising:
(a) Oxidation of the alcohol to the aldehyde;
(b) Addition of TMS acetylide to the aldehyde;
(c) Removal of the TMS group by hydrolysis;
(d) Treatment of the acetylene with base and reaction with formaldehyde to form the propargyl alcohol;
(e) Conversion of the primary alcohol to the halide;
(f) Alkylation with xe2x80x9cXxe2x80x9d to followed byby decarboxylation to form the ester; and
(g) Hydrolysis of the ester to provide the compound of formula IB.
The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to.
The term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon radical having from 1 to 7 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, 2-isopropylheptyl.
The term xe2x80x9carylxe2x80x9d means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms, and being unsubstituted or substituted with up to 3 of the substituent groups recited above for alkyl, alkenyl, and alkynyl. Examples of aryl groups include phenyl, 2,6-dichlorophenyl, 3-methoxyphenyl, naphthyl, 4-thionaphthyl, tetralinyl, anthracinyl, phenanthrenyl, benzonaphthenyl, fluorenyl, 2-acetamidofluoren-9-yl, and 4xe2x80x2-bromobiphenyl.
The term xe2x80x9cheteroarylxe2x80x9d means an aromatic cyclic or fused polycyclic ring system having from 1 to 8 heteroatoms selected from N, O, and S. The heteroaryl groups or fused heteroaryl groups may be unsubstituted or substituted by 1 to 3 substituents selected from those described above for alkyl, alkenyl, and alkynyl, for example, cyanothienyl and formylpyrrolyl.
Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-, pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazoyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl.
Aromatic fused heteroaryl groups of from 8 to 20 atoms include but are not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-, perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
Particualar heteroaryl groups of use in the context of the instant invention which may be substituted or unsubstituted include the following groups wherein xe2x80x9cxe2x80x9d indicates the point of attachment.
The alkyl, aryl, and heteroaryl can be substituted with 1 to 4 groups selected from halo, hydroxy, cyano, C1-C6 alkoxy, nitro, nitroso, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, carboxy, C1-C6 C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, aminocarbonyl, halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, tetrahaloethyl, pentahaloethyl, thiol, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, and aminosulfonyl. Examples of substituted alkyl groups include fluoromethyl, tribromomethyl, hydroxymethyl, 3-methoxypropyl, 3-carboxypentyl, 3,5-dibromo-6-aminocarbonyidecyl, and 4-ethylsulfinyloctyl.
The term xe2x80x9cprodrugxe2x80x9d denotes a compound that is converted in vivo to an active compound. The term xe2x80x9cprodrug groupxe2x80x9d denotes a moiety that is converted in vivo into the active compound of formula I wherein E is substituted heteroaryl or xe2x80x94CO2H. Such groups are generally known in the art and include ester forming groups, that form an ester prodrug, such as benzyloxy, di(C1-C6)alkylaminoethyloxy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl, 5-methyl-2-oxo-1,3-dioxol-4-yl methyl, and (C1-C6)alkoxy optionally substituted by N-morpholino and amide-forming groups such as di(C1-C6)alkylamino. Other prodrug groups include C1-C6 alkoxy, and O M+ where M+ represents a cation. Preferred cations include sodium, potassium, and ammonium. Other cations include magnesium and calcium. Further prodrug groups include Oxe2x95x90M++, where M++ is a divalent cation such as magnesium or calcium.
The term xe2x80x9cdiabetesxe2x80x9d refers to one metabolic disorder in which there is impaired glucose utilization inducing hyperglycemia. An overview of the pathogenesis and morphology of diabetes and its late complications is available to practitioneres of the art, for instance, in Robins"" Pathologic Basis of Disease (5th. Ed., pp. 910-922). Other metabolic disorders associated with impaired glucose utilization and insulin resistance include IRS, described previously. In addition to the major late-stage complications of NIDDM (diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma), many other conditions are linked to NIDDM, including dyslipidemia glucocortcoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholerteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman""s Medical Dictionary (Xth Ed.).
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity or cytotoxicity using the standard tests described herein, or using other similar tests which are well known in the art.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;.
(C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C1-C6)alkanoyl can be acetyl, propanoyl or butanoyl.
Halo(C1-C6)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl.
(C1-C6)alkanoyloxy can be formyloxy, acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy.
Aryl can be phenyl, indenyl, or naphthyl.
Heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
In one embodiment, in a compound of formula I, a value for X is
B is H.
E is CO2H.
Y isxe2x80x94CH2xe2x80x94.
R9-R12 are each independently H, halo, aryl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkanoyl, halo(C1-C6)alkanoyl, benzoyl, or halo(C2-C6)alkanoyl.
Also, one, two, or three of J, K, and L can be N, provided that when J, K, or L are N, R9, R10, and R12 are absent at that position.
In another embodiment of a compound of formula I, X is xe2x80x94CH2CH2CH2xe2x80x94.
B is H.
E is CO2H.
Y is xe2x80x94CH2xe2x80x94.
R9-R12 are each independently H, halo, aryl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkanoyl, halo(C1-C6)alkanoyl, benzoyl, or halo(C2-C6)alkanoyl.
Also, one, two, or three of J, K, and L can be N, provided that when J, K, or L are N, R9, R10, and R12 are absent at that position.
In another embodiment of a compound of formula I, X is xe2x80x94CH2CH2CH2xe2x80x94.
B is H.
E is CO2H.
Y is xe2x80x94CH2xe2x80x94.
R11 is H.
Jxe2x80x94R9 is N or CH.
Kxe2x80x94R12 is N or CH; and
Lxe2x80x94R10 is CH.
In another embodiment of a compound of formula I, X is xe2x80x94CH2CH2CH2xe2x80x94.
B is H.
E is CO2H.
Y is xe2x80x94CH2xe2x80x94.
R11 is H.
Jxe2x80x94R9 is N or CH.
Kxe2x80x94R12 is CH; and
Lxe2x80x94R10 is N.
In another embodiment of a compound of formula I, X is xe2x80x94CH2CH2CH2xe2x80x94.
B is H.
E is CO2H.
Y is xe2x80x94CH2xe2x80x94.
R11 is H.
Jxe2x80x94R9 is CH.
Kxe2x80x94R12 is N or CH; and
Lxe2x80x94R10 is N or CH.
In another embodiment of a compound of formula I, X is
B is H.
E is CO2H.
Y is xe2x80x94CH2xe2x80x94.
R9-R12 are each independently H, halo, aryl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkanoyl, halo(C1-C6)alkanoyl, benzoyl, or halo(C2-C6)alkanoyl.
Also, one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R9, R10, and R12 are absent at that position.
In another embodiment of a compound of formula I, X is
B is H;
E is CO2H.
Y is xe2x80x94CH2xe2x80x94.
R11 is H.
Jxe2x80x94R9 is N or CH.
Kxe2x80x94R12 is N or CH; and
Lxe2x80x94R10 is CH.
In another embodiment of a compound of formula I, X is
B is H;
E is CO2H.
Y is xe2x80x94CH2xe2x80x94.
R11 is H.
Jxe2x80x94R9 is CH.
Kxe2x80x94R12 is N or CH; and
Lxe2x80x94R10 is N or CH.
In another embodiment of a compound of formula I, X is
B is H;
E is CO2H.
Y is xe2x80x94CH2xe2x80x94.
R11 is H.
Jxe2x80x94R9 is N or CH.
Kxe2x80x94R12 is CH; and
Lxe2x80x94R10 is N.
Processes and novel intermediates for preparing compounds of formula I are provided as further embodiments of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as given above unless otherwise qualified.
Scheme 1 depicts one approach to preparing compounds of the invention which are compounds of formula IA. Thus, displacement of the mesylate group in 1-1 with cyanide provides the nitrile 1-2. The nitrile 1-2 is then hydrolyzed to the corresponding carboxylic acid 1-3. The acid 1-3 is reduced to the primary alcohol 1-4 and converted to the halide 1-5 (such as the bromide, although the chlorideor iodide can also be made), under Finkelstein-type conditions. The bromide 1-5 is them treated with lithium trimethylsilylacetylide to provided the TMS-protected acetylene 1-6. The TMS group is removed from 1-6, genereating the free acetylene 1-7. The acetyelene 1-7 is then treated with based and allowed to undergo reaction with formaldehyde to provide the propargyl alcohol 1-8. The primary alcohol 1-8 is then converted to the halide 1-9 using the conditions indicated earlier. The bromide is then used as the alkylating agent in the presence of xe2x80x9cXxe2x80x9d to prepare the target compound 1-10 as the ester, after decarboxylation of the malonate. The ester 1-10 is then converted to the invention compound IA.
An additional approach to invention compounds which are compounds of formula IB is provided in the Scheme 2. Thus, the primary alcohol in 1-1 is oxidized to the corresponding aldehyde 2-1 under conditions available to the skilled artisan. The aldehyde 2-1 is then treated with lithium trimethylsilyl acetylide to provide the secondary alcohol 2-2, which optionally may be protected as an acetate, or converted to the methyl ether. The trimenthylsilyl group in 2-2 is removed to provide the free acetylene 2-3. The acetylene 2-3 is treated with base, then quenched with formaldehyde to provide the propargyl alcohol 2-4. The primary alcohol 2-4 is then converted to the halide 2-5 using the conditions indicated earlier. The bromide 2-5 is then used as the alkylating agent in the presence of xe2x80x9cXxe2x80x9d to prepare the target compound 2-6 as the ester, after decarboxylation of the malonate. The ester 2-6 is then converted to the invention compound IA.
Certain compounds of formula I are useful as intermediates for preparing other compounds of formula I. It is also noted that compounds of formula I can be prepared using protecting groups and protecting group chemistry. The appropriate use and choice of protecting groups is well-known by one skilled in the art, and is not limited to the specific examples below. It is also to be understood that such groups not only serve to protect chemically reactive sites, but also to enhance solubility or otherwise change physical properties. A good general reference for protecting group preparation and deprotection is xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d by T. W. Green and P. G. Wuts. A number of general reactions such as oxidations and reductions etc. are not shown in detail but can be done by methods understood by one skilled in the art. General transformations are well-reviewed in xe2x80x9cComprehensive Organic Transformationxe2x80x9d by Richard Larock, and the series xe2x80x9cCompendium of Organic Synthetic Methodsxe2x80x9d published by Wiley-Interscience. In general, the starting materials are obtained from commercial sources unless otherwise indicated.
Some of the compounds of Formula I are capable of further forming pharmaceutically acceptable acid-addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d Journal of Pharmaceutical Science, 1977;66:1-19).
The acid addition salt of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, S. M., supra., 1977).
The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms, as well as the appropriate mixtures thereof.
The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient""s diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth. acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include orotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
Generally, the concentration of the compound(s) of formula I in a liquid composition, such as a lotion, will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
In general, however, a suitable dose will be in the range of from about 0.005 to about 100 mg/kg, e.g., from about 0.1 to about 75 mg/kg of body weight per day, such as 0.03 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.06 to 90 mg/kg/day, most preferably in the range of 0.15 to 60 mg/kg/day.
The compound may conveniently be administered in unit dosage form; for example, containing 0.05 to 1000 mg, conveniently 0.1 to 750 mg, most conveniently, 0.5 to 500 mg of active ingredient per unit dosage form.
Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.005 to about 75 xcexcM, preferably, about 0.01 to 50 xcexcM, most preferably, about 0.02 to about 30 xcexcM. This may be achieved, for example, by the intravenous injection of a 0.0005 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 0.01-1 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.0001-5 mg/kg/hr or by intermittent infusions containing about 0.004-15 mg/kg of the active ingredient(s).
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
The antidiabetes ability of a compound of the invention is demonstrated using pharmacological models that are well known to the art, for example, using models such as the tests described below.
This assay is used to determine the potential of putative PPAR-xcex3 ligands to induce fat cell differentiation. A quantitative method was established for determining the ability of potential PPAR-xcex3 ligands to promote adipogenesis of 3T3-L1 preadipocytes. 3T3-L1 preadipocytes are plated onto 96 well plates (20,000 cells per well). Upon confluency, the compounds which were initially scored as positives from the PPAR-xcex3 ligand displacement and PPAR-xcex3 chimeric receptor transcription assays were added for 4 days with the final concentrations of 2.5, 5.0 and 10 xcexcM (n=3). Each plate contains positive controls (5 uM BRL 49653 and 5 uM Troglitazone) and a vehicle control (DMSO). Cells are replenished with FBS containing media on day 5 of post-drug treatment and incubated for additional 4-6 days. Cells are stained with BODIPY a fluorescent lipophilic stain to quantitate the lipid content of the cells. The assay is optimized for a 96-well plate format. Approximately after 10 days of post-drug treatment, cells are fixed in 3% formalin solution for 15 min followed by staining with BODIPY (80 xcexcg/ml) for 20 min at room temperature. The plate is then put through the CYTOFLUOR instrument to measure the fluorescence of BODIPY (excitation=485/20; emission=530/25). A template is created in a spread sheet to calculate the average value of BODIPY measurements and reported as % of BRL 49653 at 5 xcexcM.
The ANTCV1 transcription assay is an in vitro assay in which CV-1 cells, an African green monkey kidney cell line, are transfected with a luciferase reporter construct comprised of a fragment of the fatty acid binding protein (FATP) promoter located upstream of the TK TATA box. Transfection efficiency is controlled by co-transfectionof the reference plasmid CMV xcex2-galactosidase. The DNAs are transiently transfected into the cells by electroporation and the cells are plated into 96-well dishes. Test compounds are diluted to final concentration of 25 xcexcM in individual wells containing 300 nM BRL. Control wells include either the 0.5% DMSO vehicle control, the antagonist PD 0157724-0000 at 25 xcexcM and 300 nM BRL, or 300 nM BRL alone. Cells are incubated with both the drugs for 48 hrs and then harvested. The lysates are measured for luciferase and xcex2-galactosidase activities using the dual luciferase kit from Tropix on a EGandG Berthold MicroLumat LB96P luminometer. The fold activation of BRL 49653 in each assay must be above 4 in order for the assay to be considered valid.
Raw numbers are transferred to an Excel spreadsheet and luciferase/xcex2-galactosidase ratios are determined for each compound. The percent BRL 49653 inhibition for each compound is calculated by dividing the luciferase/xcex2-galactosidase ratio for each compound by the luciferase/xcex2-galactosidase ratio of the DMSO vehicle control. This number is then plugged into the following equation:
% BRL inhibition=(BRL fold activationxe2x88x92test compound fold activation and BRL/BRL fold activationxe2x88x921)xc3x97100.
The purpose of this assay is to identify ligands that activate endogenous nuclear receptors in CV-1 cells. Protocol: CV-1 cells are co-transfected with a luciferase reporter containing a fragment of the FATP promoter upstream the TK TATA box and a CMV beta-galactosidase plasmid. Transfected cells are incubated with test ligands for 48 hours. Cell lysates are harvested and the luciferase and beta-galactosidase activities are determined. Description: Luciferase and beta-galactosidase activities in the cell lysates are measured using an EGandG Berthold luminometer. These values are entered into and Excel worksheet which calculates the luciferase to beta-galactosidase ratios and expresses the data as percent activity of the reference compound, BRL 49653.
Glucose is obtained 4 hours post dose via tail vein stick (5 xcexcl whole blood) in awake, 4 hour fasted animals. Blood is drawn by capillary action into a glucose cuvette and read in a HemoCue Glucose Analyzer (Ryan Diagnostics). Blood is diluted 1:2 with saline if glucose levels are greater than 400 mg/dl (meter high range) and results multiplied by two.
This assay is used to determine the potential of putative PPAR-xcex3 ligands to activate the promoter/enhancer of the murine aP2 gene. 3T3-L1 preadipocytes are cultured on collagen coated plates in DMEM containing 10% Calf serum for 48 hours post-confluence. The cells are then cultured for approximately 3 days in DMEM containing 10% Fetal Bovine Serum (FBS), 0.5-mM methyl isobutylxanthine, 0.25 xcexcM dexamethasone, and 1 xcexcg/ml of insulin. Cells are detached from the plates with Trypsin-EDTA and resuspended in Phosphate Buffered Saline (PBS).
The reporter construct used in this assay is comprised of the xe2x80x945.4 Kb 5xe2x80x2 flanking region of the murine aP2 gene inserted into the cloning site of the TKpGL3 luciferase vector. Transfection efficiency is controlled by co-transfection of the reference plasmid CMV-xcex2-galactosidase. The reporter construct and the reference plasmid are transiently co-transfected into the cells by electroporation. The transfected cells are plated into collagen coated 96-well plates and cultured overnight. Cells are then incubated for 48 hours with the test compounds and then harvested. The lysates are measured for luciferase and xcex2-galactosidase activities using the Dual-Light(copyright) luciferase kit from Tropix on a EGandG Berthold MicroLumat LB96P luminometer.
Data are summarized in Table 1.
In general, compounds of the invention may induce fat cell differentiation as described in test A. Results from test B, in particular, demonstrate that the compounds of the invention may lower glucose levels in mice.
Compounds of the invention induce adipocyte differentiation and lower blood glucose levels. As such, they may be useful in treating disorders associated with insulin resistance. Such disorders include: NIDDM, diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, as well as glucocortcoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholerteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension.
Accordingly, the invention also includes a method for treating a disease in a human or other mammal in need thereof in which insulin resistance has been implicated and glucose lowering is desired, comprising administering to said human or mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The invention also includes a method for treating or preventing insulin resistance in a mammal comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. Additionally, compounds of the invention can be used in vitro or in vivo as pharmacological and biochemical tools to assist in the discovery and evaluation of other glucose lowering agents and PPAR xcex3 agonists.
Esters of the general formula 1-10 or 2-6 (see Schemes 1 and 2) are readily hydrolyzed to compounds of the invention. Accordingly, the invention also includes a method of preparing a compound of formula I by hydrolyzing a compound of formula 1-10 or 2-6
Additionally, esters of the general formula 1-10 or 2-6 may be determined to function as prodrugs for compounds of formula I. Accordingly, the invention also includes a method for treating a disease in a human or other mammal in need thereof in which insulin resistance has been implicated and glucose lowering is desired, comprising administering to said human or mammal an effective amount of a compound of formula 1-10 or 2-6; or a pharmaceutically acceptable salt thereof.
The following non-limiting examples and related biological data are meant to further demonstrate the invention.
To a solution of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethanol (12.5 g, 61 mmol) in dichloromethane (200 mL) at xe2x88x9220xc2x0 C. under N2 atmophere was added triethylamine (26 mL, 184 mmol) and catalytic amount of 4-dimethylamino pyridine (50 mg). This solution was then treated with toluenesulfonyl chloride (14.1 g, 73.8 mmol) and the reaction was allowed to equilibrate to 23xc2x0 C. over 16 hours. Reaction was washed with water, 5% Na2CO3, saturated NH4Cl, and brine. Solvent was removed in vacuo and crude tosylate 1 (21.3 g) was carried on to the next step without further purification. M+1=358.2
Methanesulfonate 1-1 (21 g, 59 mmol) was added to a suspension of KCN (7.8 g, 120 mmol) in DMSO (100 mL) and stirred at 23xc2x0 C. for 16 hours then heated to 50xc2x0 C. for 2 hours. The reaction was further diluted with water and extracted with dichloromethane (3xc3x97200mL). Organic layers were combined, dried over MgSO4, and removed in vacuo to give 12.4 g of crude nitrile 1-2 which was carried on to the next step without further purification. M+1=213.1
KOH (13g, 235 mmol) was added to a mixture of ethanol/water (100 mL/100 mL) containing nitrile 1-2 (12.4 g, 58.68 mmol) and refluxed for 8 hours. Ethanol was removed in vacuo and the residue was acidified to pH=2 with aqueous HCl. The precipitated solid was filtered, washed with water, and dried in a vacuum oven overnight. The recoverd 13.5 g of acid 1-3 was used in the following step with no further purification. NMR CDCl3 (xcex4): 7.97 (2H, m); 7.45 (3H, m); 2.84 (4H, m); 2.35 (3H, s). M+1=232.1
Acid 1-3 (4.6 g, 20 mmol) was dissolved in 300 mL of a 1:1 mixture of methanol/toluene at 23xc2x0 C. under N2 atmosphere. Trimethylsilyl diazomethane (20 mL, 40 mmol), added dropwise until color persisted and stirred for an additional 4 hours. Solvent was removed in vacuo and residue dried under vacuum for 1 hour. Residue was then redissolved in 300 mL methanol and placed under N2 atmosphere. NaBH4 (10 g, 264 mmol)and the reaction stirred for 4 hours. When complete, solvent was removed in vacuo and residue taken up in ethyl acetate and washed with water, brine and dried over MgSO4. SiO2 chromatography with 40% EtOAc/Hexanes gave 3.1 g of the product 1-4 as white crystals (71%) M.P. NMR CDCl3 (xcex4): 8.01 (2H, m); 7.44 (3H, m); 3.75 (2H, t, J=5.8, 11.4 Hz); 2.68 (2H, t, 6.8, 13.7 Hz); 2.35 (3H, s); 1.91 (2H, m).
Alcohol 1-4 (3 g, 13.8 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0xc2x0 C. under N2 atmosphere. Triphenylphosphine (4.35 g, 16.6 mmol) was added followed by CBr4 (5.5 g, 16.6 mol) in small portions. Reaction temperature was allowed to equilibrate to 23xc2x0 C. over 8 hours. 20 g of SiO2 gel was added and solvent removed in vacuo. The dried silica gel was placed in a filter and washed with 10% EtOAc/Hexanes. The filtrate was reduced to minimum volume and chromatographed with 5-10% EtOAc/Hexanes to give 3.5 g of the product 1-5 as a clear oil (90% yield). M+1=280.0/282.1.
Bromide 1-5 (3.2 g, 12.2 mmol) was dissolved in a 1:1 mixture of THF:DMPU (200 mL) and cooled to 0xc2x0 C. under N2 atmosphere. Trimethylsilyl lithium acetylide (50mL, 25 mmol) was added to the solution via syringe and allowed to equilibrate to 23xc2x0 C. for 16 hours. The solution was partitioned between water and EtOAc in a separatory funnel. Organic layer was washed with water, brine, and dried over MgSO4. Solvent removed in vacuo and residue chromatographed with 5% EtOAc/hexanes to give 1.9 g of the product as a clear oil (50% yield). NMR CDCl3 (xcex4): 7.82 (2H, m); 7.27 (3H, m);2.46 (2H, m); 2.20 (3H, s); 2.10 (2H, m); 1.76 (2H, m); 0.01 (9H, s). M+1=298.1
Alkyne 1-6 (1.9 g, 6.3 mmol) was dissolved in methanol (100 mL) at 23xc2x0 C. under N2 atmosphere. An aqueous solution of 10% KOH (10 mL) was then added and the reaction stirred for 12 hours. Solvent removed in vacuo and residue partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water, brine and dried over MgSO4. The crude product 1-7 was used in the following step without further purification.
Alkyne 1-7 (1.44 g, 6.4 mmol) was dissolved in THF (100 mL) at xe2x88x9278xc2x0 C. under N2 atmosphere. nBuLi (5.6 mL, 9.0 mmol) was then added and the reaction stirred at xe2x88x9278xc2x0 C. for 1 hour. Paraformaldehyde (320 mg, 9.6 mmol) was then added in one portion and the reaction stirred while allowing equilibration to 23xc2x0 C. over 16 hours. Reaction was washed with dilute aqueous HCl, water, brine, and dried over MgSO4. After removing solvent in vacuo chromatography of the residue with 25% EtOAc/Hexanes gave 1.5 g of the product 1-8 as a clear yellowish oil (92%). NMR CDCl3 (xcex4): 7.97 (@H, m); 7.43 (3H, m); 4.25 (2H, t, J=2.2, 4.4 Hz); 2.60 (2H, t, J=7.3, 14.6 Hz); 2.33 (3H, s); 2.27 (2H, m); 1.89 (2H, m). M+1=256.2.
Alcohol 1-8 (1.2 g, 4.7 mmol) was treated in a manner similar to the preparation of bromide 1-5. Chromatography with 10% EtOAc/Hexanes gave the product 1-9 as a colorless oil (1.7 g) in 80% yield. NMR CDCl3 (xcex4): 7.97 (2H, m); 7.40 (3H, m); 3.93 (2H, s); 2.60 (2H, m); 2.34 (3H, s); 2.28 (2H, m); 1.89 (2H, m).
To a solution of Methyl 2-pyrrolo-acetate (182 mg, 1.31 mmol) in THF/DMF (10 mL/10 mL) at xe2x88x9278xc2x0 C. under N2 atmosphere was added LiHMDS (1.65 mL, 1.57 mmol) and stirred for 45 min at xe2x88x9278xc2x0 C. A solution of bromide 9 (500 mg, 1.57 mmol) in THF (10 mL) was added via syringe and the solution was allowed to equilibrate to 23xc2x0 C. over 0.5 hours. Solution poured into water and extracted with EtOAc. The organic layer was washed with water, brine, and dried over MgSO4. Chromatography with 5% EtOAc gave 190 mg of the product 1-10 as a yellowish oil (38%).NMR CDCl3 (xcex4): 7.97 (2H, dd, J=1.9, 8.0 Hz); 7.43 (3H, m); 6.78 (2H, t, J=2.2, 4.4 Hz); 6.16 (2H, t, J=2.2, 4.4 Hz); 4.74 (1H, dt, J=7.3, 14.6 Hz); 3.74 (3H, s); 2.92 (2H, M); 2.51 (2H, t, J=7.1, 14.4 Hz); 2.30 (3H, s); 2.15 (2H, q, J=4.4, 6.8, 9.2, 13.6 Hz) M+1=377.
Ester 1-10 (150 mg, 0.4 mmol) was dissolved in a 1:1 mixture of the product 1-11 as a THF:water at 23xc2x0 C. LiOH.H2O (20 mg, 0.48 mmol) was added and the solution stirred for 1 hour. Solvent was removed in vacuo and the residue partitioned between EtOAc and aqeous HCl. The organic layer was washed with water, brine, and dried over MgSO4. Removal of solvent in vacuo gave 140 mg of yellowish oil (98%). NMR CDCl3 (xcex4): 7.92 (2H, m); 7.42 (3H, m); 6.96 (2H, t, J=1.9, 3.6 Hz); 6.19 (2H, t, J=2.2, 3.6 Hz); 4.90 (1H, dd, J=6.3, 8.0 Hz); 2.96 (2H, m); 2.84 (2H, m); 2.33 (3H, s); 2.23 (2H, m); 1.81 (2H, m). M+1=363. CHN (Theor) C=72.91%, H=6.12%, N=13.24%; Obs. 72.11%, H=5.6%, N=7.42%. Biological Data: EC50=89 nM in AD3T3-L1 reporter assay. Maximal response of 108% rosiglitazone
Prepared in a manner similar to ester 1-10 with the exception that Ethyl 2-thiophene acetate was used instead of Methyl 2-pyrrolo-acetate. Chromatography gave 206 mg of the ethyl ester 1-12 (38% yield) as a yellow oil. NMR CDCl3 (xcex4): 7.99 (2H, m); 7.43 (3H, m); 7.21 (1H, dd, J=1.0, 5.1 Hz); 6.98 (1H, m); 6.94 (1H, m); 4.22 (2H, m); 4.03 (1H, t, J=7.0, 8.0 Hz), 2.92 (1H, m); 2.71 (1H, m); 2.54 (2H, t, J=7.3, 7.3 Hz); 2.31 (3H, s); 2.14 (2H, m); 1.81 (2H, m); 1.25 (3H, t, J=7.1, 7.1 Hz). M+1=408.2.
The ester 1-12 was then hydrolyzed in a manner similar to the preparation of 1-11 with LiOH.H2O to provide 90 mg of acid 1-13 (47% yield). NMR CDCl3 (xcex4): 7.97 (2H, m); 7.43 (3H, m); 7.21 (1H, d, J=5.1 Hz); 7.06 (1H, d, J=3.1 Hz); 6.96 (1H, m); 4.21 (1H, dd, J=5.3, 10.7 Hz); 2.89 (2H, m); 2.62 (2H, m); 2.34 (3H, s); 2.23 (2H, m); 1.82 (2H, m). M+1=363.2. Biological Data: EC50=303 nM in AD3T3-L1 reporter assay. Maximal response of 97% rosiglitazone.
Potassium t-butoxide (2.6 mL, 2.6 mmol) was added to a to a solution of [1,2,3]triazol-2-yl-acetic acid ethyl ester (355 mg, 2.3 mmol) in THF (30 mL) at xe2x88x9278xc2x0 C. under N2 atmosphere and stirred for 1 hour. A solution of bromide 1-9 (1.5 g, 4.5 mmol) in THF (30 mL) was then added and the solution allowed to equilibrate to 0xc2x0 C. for 1 hour. Reaction was then poured into dilute aqueous HCl and diluted with EtOAc. The organic layer was washed with water, brine, and dried over MgSO4. Chromatography with 20% EtOAc/Hex gave 550 mg of a mixture of mono-1-4 and bis-alkylated products. The mixture was not separated, and was taken on to hydrolysis step.
The crude ethyl ester 1-14 was then hydrolyzed in a manner similar to the preparation of 1-14 with LiOH.H2O to provide 350 mg of a mixture of acid PD342716 and di-alkylated product. Chromatography with 20% EtOac/Hexanes 1% Acetic acid) gave 130 mg the of desired acid 1-15 as a white powder (15% overall yield for both steps). NMR CDCl3 (xcex4): 7.92 (2H, m); 7.70 (2H, m); 7.42 (3H, m); 5.53 (1H, m); 3.43 (1H, dd, J=4.8, 16.5 Hz), 3.16 (1H, dd, 2.9, 14.6 Hz); 2.73 (1H, m); 2.63 (1H, m); 2.31 (3H, s); 2.24 (2H, m); 1.76 (2H, m). M+1=365.2 Biological Data: EC50=15 nM in AD3T3-L1 reporter assay. Maximal response of 103% rosiglitazone Normalized blood glucose in Ob/Ob diabetic mouse model in 3 days at 20 mg/Kg

Abstract: Compounds of formula I:

Abstract: wherein X, Y, B, E, J, K, L, Z, and R9-R12 have any of the meanings described herein, their pharmaceutically acceptable salts, lower blood glucose levels and are useful for treating diseases in mammals such as Non-Insulin Dependent Diabetes Mellitus. Also disclosed are pharmaceutical compositions, processes for preparing compounds of formula (I) and intermediates useful for preparing compounds of formula I.


The invention relates to a child-proof capsule with a security strip (12) the capsule comprises an internal cap (4) which can be removably applied on a neck (2) of a container (1). An external cap (5) is applied and constrained on the internal cap (4). The external cap (5) is free to move in an axial direction from a first position in which free rotation is possible between the external cap (5) and the internal cap (4) to second position in which the external cap (5) and the internal cap (4) are solid in rotation. The security strip (12) is made in a single piece with the internal cap (4) and is of annular shape with a V-section. When the capsule is mounted on the container, a free circumference (12b) of the security strip (12) engages with an annular projection (15) fashioned on the container (1). In a connection zone between the security strip (12) and the peripheral edge (4a) of the internal cap (4) there is a plurality of circumferential cuts (16), not conjoined, which occupy all of the connection zone.

The prior art comprises child-proof capsules in which the opening can be achieved only following a succession of co-ordinated movements which are difficult for a child below a certain age to perform.
These embodiments comprise an internal capsule, provided with means for connecting, normally of a screw-type, which enable the internal cap to be removably applied on a container, and an external cap which covers the internal cap when applied thereon. The external cap is constrained to the internal cap in such a way that there is freedom of rotation (a security situation known as child-proof) or solidarity of rotation with the internal cap according to distinct relative axial positions which the external cap can assume in relation to the internal cap. Child-proof capsules have existed for a considerable time in the prior art and on the market, which are provided with an easy-break security strip as proof of first opening, associated directly to the external cap of the capsule. One of the capsules is described in Italian patent IT 1.187.213 by the same applicant. This type of capsule, apart from requiring rather complex dies for its realisation, also exhibits the drawback of possible breakage of the easy-break ribs which keep the security strip joined to the external cap. Accidental pressure on the external cap, which can slide axially to activate the child-proof property, can also provoke a detachment of the security strip without the container being opened, or without there being any real intention to open the container.
There are other known types of child-proof capsule, which are however often assembled from a large number of individual pieces and therefore require the use of complex and expensive dies for their realisation.
The main aim in the manufacture of capsules in general, and in the realisation of the present capsule in particular, is to make realisation thereof ever-more economical, with embodiments that gradually reduce the number of separate pieces needed for their construction, using the simplest equipment possible, while not sacrificing working-life of the product and high productivity in its manufacture.
A further aim of the present invention is to provide a capsule of the child-proof kind which does not exhibit the risk of accidental breakage of the security strip. An advantage of the present invention is to provide a child-proof capsule made of only two parts.
This aim is achieved by the process of the invention, as it is characterised in the appended claims.
With reference to the figures of the drawings, 1 denotes a container with a mouth and a neck 2, which is closed by means of the child-proof capsule 3 of the invention, comprising an internal cap 4 with an internal thread 6 for screwing onto a corresponding thread 7 fashioned on the neck 2 of the container 1. An external cap 5 is applied on the internal cap 4.
In the position illustrated in the figures of the drawings, i.e. the child-proof safety condition, the external cap 5 is in a first position, in which it is free to rotate about the internal cap 4. This position is achievable depending on the relative axial positions of the external cap 5 and the internal cap 4—a position which is maintained by means 8 which elastically keep the external cap 5 raised with respect to the internal cap 4.
When pressure is exerted in the direction indicated by the arrow 13 on the external cap 5, the external cap 5 moves downwards into a second position, not illustrated, and an internal cogging 9 fashioned on the upper part of the internal surface of the external cap 5 meshes with an external cogging 10 fashioned on the upper external surface of the internal cap 4. In this second position no reciprocal rotation can be achieved between the external cap 5 and the internal cap 4; it is therefore possible, by pressing on the external cap 5, to unscrew or screw the internal cap 4 from or onto the neck 2 of the container 1. The above description is also true of other childproof capsules of known type, like those disclosed in EP-A-0 963 916, EP-A-0 127 943, U.S. Pat. No. 5,676,268, U.S. Pat. No. 6,372,167.
The capsule of the invention comprises a security strip 12 which is made in a single piece with the internal cap 4, as an appendix on the peripheral edge 4a thereof facing the container 1.
The security strip 12 exhibits an annular shape with a V-section. There are therefore two circumferences of the security strip 12: a first circumference 12a of which is connected in a connection zone, with the peripheral edge 4a of the internal cap 4; and a second circumference 12b of which is free and engages, when the capsule is mounted on the container 1, with an annular projection 15 which is fashioned on the outside of the neck 2 of the container 1.
The connection zone between the security strip 12 and the peripheral edge 4a of the capsule exhibits a plurality of circumferential cuts, not joined together, which occupy the whole connection zone between the strip 12 and the peripheral edge 4a of the capsule. The cuts 16 are in fact mechanical incisions in the connection zone between the peripheral edge 4a of the capsule and the security strip 12 and are separated by uncut zones 17, of a thickness comprised between 0.1 and 1.0 mm.
In this way in the connection zone between the peripheral edge 4a of the capsule and the security strip an easy-fracture line (or rather a circumference) is created, which will break when stressed as will be better described hereinafter, and thus cause a detachment of the strip 12 from the internal cap 4.
Manufacture of the internal cap 4 and the security strip 12 in a single piece, having the above-described characteristics, can be done by press-forming and subsequent mechanical operations, for example following the process described in Italian patent IT 1.292.751. To this end the internal cap 4 with connected security strip 12 is made of a pressable plastic material.
The internal capsule 4 and the security strip 12 as above-described could, however, be made using other processes.
The capsule of the invention further comprises an annular projection 18 which is fashioned on the internal upper part of the internal cap 4 and is coaxial to the internal cap 4. The annular projection 18 is arranged so as to interfere, when the capsule is mounted on the container 1, with the internal wall of the neck 2 of the container 1; in this way the annular projection 18 guarantees sealed closure of the container 1 when the capsule is mounted thereon. This means that it is not necessary to include a seal, which in known capsules is constituted by a small disc which realises a "top" seal on the mouth of the container, and which is generally inserted either as an individual piece or as a pressure-glued element on the upper internal wall of the internal cap 4. Thus with the present invention an even greater reduction in the number of pieces needed is achieved, with a reduction in manufacturing and work times, as the annular projection 18, differently to the "top" seal, can be fashioned directly during the press-forming stage of the internal cap 4. Obviously, however, a normal "top" seal disc can be used, although it calls for use of a further and separate element.
The capsule of the invention, provided with the annular projection 18, is made in two pieces only, which are assembled by pressing the internal cap 4 into the external cap 5. If a seal disc is to be added, it is inserted or afforded internally of the internal cap 4 before the internal cap 4 is press-inserted into the external cap 5.
As mentioned herein above, in the position of FIG. 1 the external cap 5 is free to rotate about the internal cap 4, since the coggings 9 and 10 are not enmeshed. By exerting a pressure in the direction indicated by the arrow 13 on the external cap 5, the external cap 5 is axially downwardly displaced and the cogging 9 enmeshes with the other cogging 10. In this situation, as all relative rotation between the internal cap 4 and the external cap 5 is now inhibited, by screwing or unscrewing the external cap 5 the internal cap 4 will screw onto or unscrew from the neck 2 of the container 1.
On first opening of the container 1, the raising of the internal cap 4 causes contrast between the second free circumference 12b of the security strip and the annular projection 15 on the outside of the neck 2 of the container 1, causing the uncut zones 17 to break and the detachment of the security strip from the internal cap 4, signifying that the container 1 has been opened.
As the security strip is solidly constrained to the internal cap 4, an accidental pressure, which is not intended to break open the container 1, causes no stress on the uncut zones 17 and therefore no accidental detachment of the security strip. The strip can only be detached from the internal cap 4 when, after the external cap 5 is lowered, there is a deliberate rotation thereof causing the internal capsule 4 to unscrew from the neck 2, i.e. when there is a deliberate intention to open the container 1.
Thus with the capsule of the invention the aim of preventing accidental detachment of the security strip is achieved; also attained is the aim of making a manufacturing economy during construction of the capsule, which is obtained thanks to a limited number of pieces constituting the capsule and to the possibility of obtaining these pieces directly through press-forming and with relatively simple dies, thanks to the special shape of the internal cap 4.