A substrate has a first thermal expansion coefficient and a piezoelectric thin film has a second thermal expansion coefficient. The piezoelectric thin film is mainly composed of a potassium sodium niobate (K,Na)NbO3 with a perovskite structure. A curvature radius of a warping of the substrate provided with the piezoelectric thin film due to difference between the first and the second thermal expansion coefficients is 10 m or more at room temperature.

The present application is based on Japanese Patent Application No. 2007-267858, the entire contents of which are incorporated herein by reference.
1. Field of the Invention
The present invention relates to a substrate with a piezoelectric thin film, particularly to a Pb-free substrate with a piezoelectric thin film.
2. Related Art
A piezoelectric element having a piezoelectric material is used for an actuator or a sensor etc. A Pb(Zr1−xTix)O3 based perovskite-type ferroelectric substance (piezoelectric lead zirconium titanate: PZT) has been widely used as a piezoelectric material for forming such a piezoelectric element. However, since the PZT contains lead (Pb), it is desired to use a piezoelectric material containing no lead, i.e. a Pb-free piezoelectric material for a piezoelectric element from a consideration of environmental point of view.
As a conventional Pb-free piezoelectric thin film element, for instance, there is a piezoelectric thin film element using a dielectric film comprising an alkali niobium oxide based perovskite compound. This piezoelectric thin film element comprises a substrate comprising MgO etc., a lower electrode formed on the substrate, a buffer layer comprising BaTiO3 etc. and formed on the lower electrode, a piezoelectric thin film comprising an alkali niobium oxide based perovskite compound expressed by a general formula of (NaxKyLiz)NbO3 (0<x<1, 0<y<1, and x+y+z=1) and formed on the buffer layer, and an upper electrode formed on the piezoelectric thin film. For instance, Japanese Patent Laid-Open No.2007-19302 (JP-A-2007-19302) discloses this type of Pb-free piezoelectric thin film element.
However, in the piezoelectric thin film element according to JP-A-2007-19302, a warping might be generated in the piezoelectric thin film element when forming the piezoelectric thin film comprising a potassium sodium niobate based material on the substrate of MgO etc. If a piezoelectric operation is continuously conducted for a long period in such a warped piezoelectric thin film element, a piezoelectric constant d31 of the piezoelectric thin film element will be decreased greatly.

Substrate with a piezoelectric thin film


Selectively BRS-3-agonistic compounds of formula I

The present invention relates to novel, non-peptidic compounds which exhibit a selective agonistic action on the bombesin receptor of subtype 3 (BRS-3), and to pharmaceutical preparations containing these compounds and also processes for the preparation of these compounds.
Bombesin (Bn) is a peptide consisting of 14 amino acids which was originally isolated from amphibians. The two peptides neuromedin B (NMB) and the "gastrin-releasing peptide" (GRP) which have been identified in mammals represent structurally similar peptides. These bombesin-like peptides are the naturally endogenous ligands of the corresponding bombesin receptors, the "neuromedin B receptor" (NMB-R, BB1) and the "gastrin-releasing peptide receptor" (GRP-R, BB2). The bombesin receptors belong to the group of the G-coupled receptors with 7 transmembrane domains.
Due to the homology of its amino acid sequence, the bombesin receptor of subtype 3 (BRS-3 or BB3) is assigned to this family of bombesin receptors [cf. Fathi et al. (1993) J. Biol. Chem. 268:5979-84; cited below as "Fathi et al."]. The natural ligand of BRS-3 is hitherto unknown. The expression of BRS-3 was demonstrated in various regions of the brain [cf. Yamada et al. (1999) Physiol. Behav. 66:863-7], in secondary spermatocytes [cf. Fathi et al.], in pancreatic islet cells [cf. Fleischmann et al. (2000) Lab. Invest. 80:1807-17] and in the uterine tissue of pregnant animals [cf. Gorbulev et al. (1992) Eur. J. Biochem. 208:405-10]. Furthermore, BRS-3 was identified in different human cancer cell lines (e.g. lung [cf. Fathi et al.], breast [cf. Gorbulev et al. (1994) FEBS Lett. 340:260-4], prostate [cf. Sun et al. (2000) Prostate. 42:295-303] or ovary [cf. Sun et al. (2000) Regul. Pept. 90:77-84]).
Genetically altered mice in which the BRS-3 gene had been knocked out ("BRS-3 Knockout Mice") exhibited a clinical picture which comprised obesity, hyperphagia and also hypertension and diabetes [cf. Okhi-Hamazaki et al. (1997) Nature 390:165-9]. According to this, BRS-3 appears to be an essential participant in the regulation of glucose metabolism and lipometabolism, in maintaining the energy status and in controlling blood pressure, and also in influencing eating behaviour. It can therefore be assumed of BRS-3 agonistic compounds that they are suitable in particular for the prophylaxis and/or treatment of pathological conditions such as obesity (=adiposity), diabetes, hyperinsulinism, cardiovascular diseases, eating disorders (hyperphagia, anorexia, bulimia) and/or metabolic syndrome (=syndrome X). Syndrome X manifests itself above all by Type II diabetes mellitus and/or reduced glucose tolerance, arterial hypertension, lipometabolism disorders, obesity and also coronary heart disease.
Furthermore, it is known that the activation of BRS-3 can have a neuro-protective action [cf. WO 01/68120]. Also BRS-3 appears to be connected to taste perception [cf. Yamada et al. (1999) Physiol. Behav. 66:863-7], influencing of social behaviour [cf. Yamada et al. (2000) Physiol. Behav. 68:555-61] and certain emotional behaviors [cf. Yamada et al. (2002) Mol. Psychiatry. 7:113-7]. It can therefore likewise be assumed that BRS-3-modulatory compounds may be suitable for the prophylaxis and/or treatment of psychic clinical pictures such as depression or anxiety states, taste perception disorders and/or degenerative diseases of the central nervous system, for example Parkinson's or Alzheimer's.
Some synthetic peptidic ligands are already known which bind with a certain affinity to BRS-3 and exert an agonistic action thereon, namely the BRS-3 selective octapeptide [D-Phe6, Phe13]Bn(6-13) propylamide [cf. Wu et al. (1996) Mol. Pharmacol. 50:1355-63] and also the less-selective nonapeptide [D-Tyr6, β-Ala11, Phe13, Nle14]Bn(6-14) [cf. Mantey et al. (1997) J. Biol. Chem. 272:26062-71] and its derivatives [cf. Pradhan et al. (1998) J. Pharmacol. 343:275-87; Mantey et al. (2001) J. Biol. Chem. 276:9219-29].
Low-molecular, non-peptidic bombesin-analogous compounds are furthermore already known from WO 98/07718, but these are selective antagonists of the other two subtypes of the bombesin receptor family (NMB-R and GRP-R). Low-molecular, non-peptidic compounds which have a selective agonistic effect with high affinity to BRS-3 on the other hand have not been described hitherto.

Abstract: wherein A1, A2, A3, R1, R2, R3, Ar1, Ar2, Ar3, m and n have the meanings given in the description, and also pharmaceutical compositions containing these compounds and a process for the preparation of compounds of Formula I are described.


The invention provides a swine which is homozygous for a major histocompatibility complex haplotype and at least 60% homozygous at all other genetic loci and such animal is propagatable, and a cell or an organ derived therefrom. The invention also provides a method for providing a swine which is homozygous at swine leukocyte antigens (SLA) A, B, C, DR, and DQ, and in which at least 60% of all other genetic loci are homozygous, as well as a method of inducing tolerance in a recipient mammal of a first species to a graft from a donor mammal of a second species.

The major histocompatibility complex (MHC) is a set of linked genes which code for cell surface proteins involved in transplant rejection. The MHC contains three types of genes, class I, II and III (Klein J. et al.: Immunology: The Science of Self-Nonself Discrimination, pp. 687, 1984,John Wiley, Somerset, N.J.).
In humans, class I genes encode polymorphic 44,000 dalton glycoprotein chains that associate with a nonpolymorphic 12,000 dalton light chain, β2-microglobulin, and which are expressed on most cells of the body. Typical class I MHC genes are involved in regulating immune to viral infections (Zinkernagal R. M. et al. (1979) Adv. Immunol. 27:52–72).
In humans, the class II MHC antigens are cell surface glycoproteins composed of an α chain of approximately 35,000 daltons and a β chain of about 28,000 that are expressed only on subsets of immunologically active cells, such as β lymphocytes and macrophages.
Class III MHC genes code for serum proteins such as complement (C′).
The MHC loci in swine are known as the swine leukocyte antigens (SLA). In 1970, Vaiman et al., (Vaiman M. et al. (1970) Transplantation 10:155–161) and Viza et al. (Viza D. et al. (1970) Nature 227:949–951) provided descriptions of the SLA complex. These groups developed panels of SLA typing reagents (Vaiman M. et al. (1979) Immunogenetics 9:353–361) by preparing antisera of a defined specificity as well as by characterizing cells of known SLA type (homozygous typing cells) for use in mixed lymphocyte complex, to chromosome 7 (Geffrotin C. et al. (1984) Ann Genet (Parix) 27:213–219). The class I swine MHC loci are designated SLA-A,B,C. The class II swine MHC loci are designated SLA-DR, DQ. Because there are numerous genes coded by the SLA complex and because usually they are inherited as a unit, haplotype designations have been developed. For example, the SLAa haplotype codes for SLA-AaBaCaDRaDQa alleles.
Miniature swine are a good model for organ transplantation studies because of their breeding characteristics which make them one of few large animals in which genetics can be manipulated in a reasonable time, and also because of their size which permits surgical manipulations similar to those humans.

This patent is subject to a terminal disclaimer.


A tensioning control device having a first motor that applies a torque to a first end of a substrate in a first direction and a second motor that applies a torque to a second end of the substrate in a second direction that is generally opposite the first direction is disclosed. In this manner, the first motor and the second motor apply torque to the substrate in opposing directions, thereby placing the substrate in tension. In one embodiment, the first motor applies a torque to the first end of the substrate that is equal to the torque applied to the second end of the substrate by the second motor. By placing the substrate in tension in this manner, an actuator is able to incrementally move the substrate in a forward direction and a backward direction independent of the tension applied to the substrate.

1. Field of the Disclosure
The present disclosure relates generally to a tensioning control device. More particularly, the present disclosure relates to a tensioning control device for a labeling device for a syringe.
2. Description of the Related Art
Syringes need to include information to help medical professionals identify the contents of the syringes. Errors such as giving an incorrect medication or an incorrect dose can easily be made if the contents of the syringe cannot be positively identified from the point of time that a medication is transferred to a syringe up to the moment of its administration.
The results of missed and unintended medication include adverse effects to patients and significant costs to the healthcare industry. Potential causes for these errors include unclear syringe contents due to unlabeled or poorly labeled syringes and poor record keeping of which drugs were administered and the concentration and quantity of the administered drug.
Identifying the content of a syringe based on the appearance of that content is unreliable. Visual identification of the medication is very difficult since several of the medications are identical or nearly identical in appearance.


A modular construction system and modular member are provided for the construction of concatenated structures having interconnected, overlapping, offset or parallel courses. The modular members are provided with substantially planar upper and lower surfaces with the thickness, width and hole spacing of each modular member being predetermined and interdependent. The modular members present holes which receive connectors, and may have holes presenting a plurality of bore diameters. The members may be cut perpendicular to the longitudinal axis of the member midway between adjacent holes to provide compatible modular member segments. The complementally shaped connectors are received in the holes and may include mechanical barbs or threads, or separate retainers for use with the connectors inhibit preventing vertical separation of overlapping adjacent modular members. The system and method permit the construction of structures such as playhouses which have window and door openings and may include cupolas, elevated floors, roofs and stairs of interconnected modular members. Such structures are uniquely adapted for disassembly and rearrangement or expansion.

1. Field of the Invention
This invention relates to a modular construction system and a corresponding method of erecting structures particularly useful for the average homeowner or "do-it-yourself" builder. More particularly, it is directed toward a prefabricated modular construction member which presents holes therethrough at particularly predetermined spacings to receive connectors, is adaptable to be cut into different lengths, and thereby enables rapid and precision assembly into a finished concatenated structure capable of future reconfiguration and expansion.
2. Description of the Prior Art
One of the favorite past-times of many homeowners is the tailoring of their residences and yards to meet their personal preferences and to express their own unique personalities and abilities. Although some people would prefer to hire professionals to do this work for them, there are many who would prefer to do such work themselves because of a sense of personal pride in the accomplishment of the task, to economize on the cost of the project, and for other reasons.
Among the many types of projects which may be undertaken are the design and building of concatenated structures such as planters, decks, children's playhouses, or storage facilities. These structures may enhance the beauty and value of the property and provide additional living and work space, as well as providing challenges and opportunities for personal expression. These projects are frequently constructed of lumber or rough timber as it is accessible and may be worked more readily than metal or stone. However, there are an increasing number of homeowners who lack the time, tools, talent or temperament necessary to tackle a construction project using dimension lumber or timbers as their starting material.
There have been many attempts in recent years to develop various premanufactured construction systems out of lumber products geared toward the average "do-it-yourselfer", particularly with large timbers such as landscape logs. In many instances, these products achieve noteworthy results, but in other instances fail to provide the working materials needed to achieve a particular goal.
One system heretofore developed is shown in U.S. Pat. No. 4,834,585, which uses a landscape timber module of a predetermined length and width with two flat surfaces and a plurality of uniformly spaced holes. This timber module is useful for constructing curvilinear berms and planters, but the single diameter hole without stopping means, long connectors requiring field fabrication in various lengths and lack of a module with only one hole significantly limits the usefulness of this module for above grade applications. The teaching of this invention does not recognize the advantages of arranging modules in overlapping, vertically spaced relationships nor does it recognize the advantages of using premanufactured, short, loose-fitting connectors which are either supplemented with mechanical connectors or specially adapted to resist vertical separation of the landscape timbers.
Both U.S. Pat. No. 4,897,955 and 5,168,678 disclose a landscaping structure with overlapping corner joints. These modules are useful for landscaping but are not readily adapted for creating openings between the timbers for playhouses and the like and may require irregular hole spacings or complex end shapes. U.S. Pat. No. 5,283,994 discloses another type of landscape timber utilizing a ball and socket joint to provide angled walls, but does not provide the ventilation or hole spacing which makes it readily adaptable to open construction.
Because of the complex shapes of the ends of the modules and/or the irregularities of the holes or spacings in the modules of these systems, the modules would need to be prefabricated in a number of different lengths. Field fabrication of complex shapes or particular spacings for a large quantity of modules in the various lengths which might be required by an end-user would defeat the module concept and not be practical. The necessity of fabricating, packaging, maintaining an inventory and selling modules of various lengths is a serious drawback to the economic viability of these systems and many other similar modular construction systems.
Currently, non-earth-contact structures such as children's playhouses are problems which present limited options for the do-it-yourself builder. Such a builder can either design and erect a structure from existing materials, such as landscape timbers or dimension lumber, or purchase and assemble a prefabricated kit. The option of designing and building a custom play structure definitely provides an opportunity for creative expression for the parent-builder, but as mentioned above, there are an increasing number of homeowners who do not have the time, tools, talent or temperament necessary for this option. The limited number of homeowners who do accept this challenge and complete a custom structure with conventional lumber products often find that the novelty of the static structure is soon gone, or the children may grow and require a larger playhouse.
Most parents thus resort to the option of purchasing a prefabricated structure or a kit with a multitude of different components and connecting hardware which can only be assembled into a single configuration. However, many children, like their parents, would prefer to express their individuality with a unique, customized playhouse, fort or clubhouse of their own making. The fancy "gingerbread" of a prefabricated plastic playhouse is no substitute for the personal satisfaction of expressing one's own budding engineering and construction talent. Another disadvantage of most prefabricated play structures is that they are typically fairly permanent structures which can only be assembled into a single configuration. Even the most elaborate of commercially available structures soon lose their novelty and are short-lived in their ability to fulfill the imagination and appetite of most children for new challenges and adventures.
There are also a number of different log-cabin type construction systems with various configurations of notched or specially designed interlocking ends which could be used for the construction of children's playhouses, but none of these have enjoyed very broad commercial success for playhouse applications. These systems typically have the same disadvantages as the aforementioned retaining wall systems. The specialized ends and/or other design features of the systems often require the end user to purchase a number of different lengths of factory fabricated components or expend a considerable amount of time and effort field fabricating connections. Additionally, these systems are generally limited to square or rectangular structures since the components can only be interconnected in an orthogonal relationship and many systems are limited to solid wall structures which do not allow for the introduction of natural light and ventilation and require considerably more components than concatenated structures with vertical spaces between parallel members. Finally, these structures have limited flexibility of redesign, or future modification or expansion.
U.S. Pat. No. 4,521,203 to Rothenburg disclosed a toy construction kit of kraft paper blocks or logs with notched ends which could be interlocked in orthogonal, vertically spaced relationships to create a playhouse with spaces between the logs. However, it may be appreciated that a structure constructed in accordance with the teachings of this patent has a number of limitations. The components of Rothenburg are made of a material (kraft paper) which is unsuitable for outdoor applications and weather conditions, especially when exposed to precipitation. These components have limited structural capabilities which limits the design flexibility of the system; that is, larger structures with multiple floor levels and large structural spans are not an option. Furthermore, these components can only be interconnected at their ends in overlapping, orthogonal, vertically spaced relationships which significantly limits the design flexibility of the system, preventing or inhibiting the use of angled or curved walls, sloping walls, stairs, roofs, or the like. In addition, cantilevering members to form overhangs, soffits, or the like is not possible. Finally, the system cannot be fabricated from a single article of manufacture, and requires components of particular lengths and configurations. Thus, separate purchase of exactly the right components is required, with inventorying and storage of both flat panels and components of various lengths.

Concatenated structures of modular members


A long arm for an aircraft turnaround apparatus mounted at one end to the floor of an aircraft hanger for swinging about a vertical axis causing a nose-wheel carriage at the free end of the arm to follow a semicircular path. The nose-wheel of an incoming aircraft runs onto the carriage such that its imaginary lateral rotation axis is practically coincident with the arm axis so when the arm swings, the aircraft's ground supported landing gear traces a semicircle. The carriage has a chock bar which stops the aircraft from overtraveling the carriage. One chock bar version requires manual insertion and removal and another automatically latches in the stopping position but is unlatched by an aircraft leaving the carriage after which a spring restores the chock to the latched position. An optional spring system can restore the arm and carriage to a nose-wheel receiving position after a turned around aircraft has departed. A device is fastened to the hanger floor such that the oncoming carriage engages it upon approaching its final nose-wheel receiving position. The device gradually retards the rotational movement of the arm and carriage and finally stops their movement.

The invention disclosed herein pertains to apparatus for turning around an aircraft from a position, for example, where its nose is pointing inwardly of a hangar to a position wherein the nose is pointing outwardly of the hangar in readiness for taxying out of the hangar. The new turnaround apparatus is especially applicable to small aircraft that typically have a nose-wheel and a pair of main fuselage support or landing wheels located aft of the nose-wheel under the fuselage for the wheels to provide three-point support of the aircraft on the ground.
The traditional method of parking or storing an aircraft in a hangar is to engage a hand-held towbar to the steerable nose-wheel to first turn the aircraft around so its tail is leading into the hangar and then pushing the aircraft further with its tail pointed into the hangar and with its nose pointed out of the hangar. This operation must be performed very carefully because even superficial contact with a rigid object can damage the aircraft and make it unairworthy. Any repair to an aircraft is costly. Any but the smallest aircraft requires at least two persons to turn it around when the towbar method is used, one person to handle the towbar and one person or even another person for pushing and observing to assure that all points on the aircraft are passing obstacles with safe clearance.
Scaled down models of engine driven tugs and tractors of the type used for moving large aircraft are also available for turning around small aircraft in a hangar. However, these motorized drivers are expensive and are used so infrequently that they are not considered by many aircraft owners to be cost justified. Moreover, because the engines are operated infrequently and for short intervals they are inclined to rust and otherwise deteriorate rapidly.
Winches are also available for towing and turning an aircraft around. A winch is mounted in the rear region of the hangar opposite of the hangar door and the aircraft is towed in backwards with a cable leading from the winch. Even when using a winch it is desirable to have two persons collaborate in performing the task, one person for operating the winch and the other person for steering the nose-wheel. If only one person is performing the task, the aircraft is put in place slowly, inch-by-inch because that person is required to switch back and forth between operating the winch and alternatingly observing clearance and steering the nose-wheel.


An user interface for domestic appliances, particularly for cooking ovens, comprises input and display for showing menus and/or items selected by the user through said input. The input comprises a selection zone where the user's finger can move, the display having at least a portion with a shape substantially corresponding to the shape of the selection zone and showing the result of the finger movement in terms of item or menu selection.

1. Field of the Invention
The present invention relates to a user interface for domestic appliances, particularly for cooking ovens, comprising input and display for showing menus and items selected by the user through the input.
2. Description of the Related Art
It is well known in the art of domestic appliances to use electronic user interfaces with buttons or with a touch control panel in order to set functions and/or parameters according to the user's choice. There exist many styles of input devices for consumer products; in domestic appliances are mainly used knobs and switches, buttons and touch screens. Each technology has advantage and disadvantages that are taken in consideration in designing a new appliance. By pressing a button or by touching a zone of the touch control panel the user can set his choices.
The use of a touch sensitive display in domestic appliances, particularly in cooking appliances, presents the disadvantage of easily soiling the display if this latter is touched with not perfectly clean fingers. This can cause problems in reading correctly the various parameters and/or functions to be chosen by the user. In view of the several choices of parameters/functions of a modern appliance, it is often necessary to use big displays that have a negative impact on the overall cost of the appliance.

User interface and cooking oven provided with such user interface


A laminating structure includes a first magnetic layer, a second magnetic layer, a first spacer disposed between the first and second magnetic layers and a second spacer disposed on the second magnetic layer.

The present invention relates to on-chip magnetic devices, and more specifically, to systems and methods for laminating magnetic cores for on-chip magnetic devices such as inductors and transformers.
On-chip magnetic inductors/transformers are important passive elements with applications in the fields such as on-chip power converters and radio frequency (RF) integrated circuits. In order to achieve high energy density, magnetic core materials with thickness ranging several 100 nm to a few microns are often implemented. Ferrite materials that often used in bulk inductors have to be processed at high temperature (>800° C.), which is incompatible with complementary metal-oxide-semiconductor (CMOS) processing. Thus, a majority of magnetic materials integrated on-chip are magnetic metals such as nickel iron (Ni—Fe), cobalt iron (Co—Fe), cobalt zirconium titanium (Co—Zr—Ti) and the like. Magnetic metals can be deposited through vacuum deposition technologies (i.e., sputtering) or electrodepositing through an aqueous solution. Vacuum methods have the ability to deposit a large variety of magnetic materials and to easily produce laminated structures. However, they usually have low deposition rates, poor conformal coverage, and the derived magnetic films are difficult to pattern. Electroplating has been a standard technique for the deposition of thick metal films due to its high deposition rate, conformal coverage and low cost.

Laminating magnetic cores for on-chip magnetic devices

INTERNATIONAL BUSINESS MACHINES CORPORATION


With a view toward solving various problems of prior-art gas turbine plants by applying a tube-nested combustion chamber type combustor in place of the combustor of the prior-art gas turbine, a combustor of a gas turbine used in a gas turbine power plant is equipped with a heat-absorber-water-tube-inserted combustion chamber in which fuel is burnt with combustion air only. Consequently, the NO.sub.x generated from the gas turbine power plant is notably reduced, no CO and unburnt hydrocarbons (UHC) are produced and, moreover, the amount of power generated and the utilizable calories of the steam are increased for the benefit of an enhanced overall heat efficiency. This enables the combustion space of the gas turbine power plant to be greatly diminished, with a resultant widened utilization range of gas turbines.

1. Field of the Invention
The present invention relates to the improvement of conventional combustors by applying a tube-nested combustion system, which has a remarkable effect when applied to the combustion chamber of an ordinary boiler, to other types of combustors, in particular to those of an ordinary gas turbine system. The invention also relates to a great expansion of the field application of gas turbine equipment with such an improvement.
2. Description of the Prior Art
The features of combustors of conventional gas turbines are as follows. A gas turbine system is now widely used for electric generation and for industrial uses, or for a gas turbine - steam turbine combined cycle, or so-called gas turbine cogeneration. There are the following problems common to all of these gas turbine systems. The first problem is that, since the higher the gas temperature is at the inlet, the higher the thermal efficiency, as indicated by the so-called Carnot's theoretical efficiency, the temperature of the inlet gas which flows into the space around the blades of the gas turbine should be raised so far as is practical. In the present situation, however, for example, the gas temperatures around the turbine blades and the gas turbine inlet are controlled to 990.degree.-1,100.degree. C., so as to reduce the heat resistance as well as the heat loss due to the raised temperature of each part of the turbine blades and the combustor. Indeed, if complete combustion were made in the vicinity of the stoichiometric air ratio, the combustion temperature of the so-called fossil fuel would be on the order of 2,130.degree. C. In practice, however, the combustor and the turbine blades will not serve their practical ends unless their temperatures are lowered. On this account, of the air supplied into the combustor, the air which participates in the actual combustion, or the so-called combustion air, is only about 35-40% of the total. Another about 20% is charged in as dilution air for reducing the temperature of the combustion gas, and the balance of 40% is fed in as the cooling air for the prevention of damage by fire to each part of the combustor and the turbine blades, etc. This represents the bench mark of the present technology.
The aforementioned first problem is quite an important problem. The temperature of the combustion gas, which has once been elevated, is lowered with the dilution air. On the other hand, the cooling air is used for raising the heat resistive temperatures of the combustor and the turbine blades, etc. This involves, besides the large exergy (irreversible) loss due to the cooling of combustion gas with the dilution air, decrease of turbine work resulting from part of air that does not serve as the cooling air, aerodynamic characteristic loss caused by blowing the cooling air out through the blade surface and the walls of flow paths of the combustor, the turbine, and the like, pumping loss of the moving blade cooling air, the loss due to the fact that the cooling air comes to mix with the main stream gas so that the main stream gas is cooled, and so on. Further, there occurs an increase in the pressure loss resulting from an increased amount of combustion gas or a large exergy loss. The sum of all these losses well exceeds about 10%, as converted to the turbine work. Such a loss greatly offsets the benefits in the output and the thermal efficiency which otherwise would be expected to accrue from the raised gas temperature. What is more important, in the present situation heat recovery is made later from the combustion exhaust gas, swollen by a large amount of dilution air and cooling air as described above, which can be said to actually be a serious matter, as compared with normal boilers, in which the combustion is made with an exhaust gas containing 1-3% O.sub.2, 3-5 times as large an amount of exhaust gas is required. As a result, 3-5 times as large a volume is required for all equipment located downstream, including a waste heat boiler, ducts, de-NO.sub.x equipment and chimneys, etc., resulting in a marked economical disadvantage. Conversely, any ingenious contrivance could possibly reduce the combined cycle or cogeneration in the present situation to less than 1/3-1/5 in volume.
A more important fact is that as the gas temperature at the turbine blade inlet goes up above 1,300.degree. C., the necessary volume of cooling air needs to be drastically cut down from the present level. Accordingly, not only some innovation in the technique for cooling turbine blades, etc., is desired, but other techniques corresponding to this one, such as water cooling or steam cooling, are necessary.
The second problem is that of heat loss. Since about 3-5 times as large an amount of dilution air and cooling air as that of the combustion air of the normal boiler is charged in for reducing the combustion gas temperature, as described above, the amount of the exhaust gas increases 3-5 fold. Consequently, elements of the equipment should be increased to 3-5 times in size, with a correspondingly large heat radiation loss, and besides, the heat loss accounted for by the exhaust gas itself runs 3-5 times as large. Thus, conversely, such heat loss and exhaust gas loss could possibly be reduced to 1/3-1/5 of that in the present state by some ingeneous means. As described above, the oxygen (O.sub.2) concentration % in the exhaust gas from a gas turbine reaches 15-16%. In the present state, since the combustion temperature in the combustor is high, the concentration of NO.sub.x generated is high, being 95-240 ppm (O.sub.2 =16%) or 400-1,000 ppm, as converted to that at 0% O.sub.2, in normal city gas (13A) under the present unsuppressed state. How large this amount should be regarded may be discerned from the fact that the boiler's NO.sub.x concentration is regulated to be 60-200 ppm, as converted to that at 0% O.sub.2.
As a third problem, in a gas turbine plant (the so-called combined cycle or cogeneration) of this type, particularly, hereafter attachment of large de-NO.sub.x equipment will be indispensable, making problems involving its cost, dimensions and space, etc., important. These problems will probably increase in importance from now on because of the growing demand of users for elevating the gas turbine inlet temperature.
Where a fourth problem is concerned, in a conventional gas and steam turbine combined cycle, or cogeneration, O.sub.2 in the exhaust gas is as high as about 15-16%. Its discharge is uneconomical. Accordingly, there has been taken a measure in which a duct burner is placed on the upstream side of the waste heat boiler and fuel is fed therein, to be burned, using the residual O.sub.2 in the exhaust gas, to raise the combustion gas temperature, thereby increasing the amount of steam recovered from the waste heat boiler. According to this system, however, a large duct burner and a long duct as its burner chamber equivalent are required. Besides, the potential temperature rise is limited by the factors of the heat resistance of these parts the and that heat loss and the outlet O.sub.2 concentration can be reduced to only about 10%. Thus in the final analysis, the exhaust gas must be released at a high O.sub.2 %, as it is, without recovering the exhaust gas heat loss.

Gas turbine system with a tube-nested combustion chamber type combustor


A pretreatment agent was provided for ink jet textile printing. The pretreatment agent contains a polyvalent metal compound, an anionic resin emulsion, a fluorinated water and oil repellent, and water.

1. Technical Field
The present invention relates to a pretreatment agent for ink jet textile printing, an ink jet textile printing ink set including the pretreatment agent, and an ink jet textile printing method using the pretreatment agent.
2. Related Art
Various techniques are applied to recording processes for forming images on paper and other recording media according to image data signals. Among such techniques is an ink jet technique in which images are formed directly on a recording medium by ejecting an ink only onto desired image portions, using an inexpensive apparatus. In the ink jet technique, inks are efficiently used, and accordingly running cost can be reduced. In addition, little noise is produced when the ink jet technique is used, and the ink jet technique is thus advantageous as a recording method.
In recent years, approaches using an ink jet technique have been attempted for forming glossy images having high water fastness and rub fastness, and further high hiding power on the surface of a recording medium by ejecting a white pigment ink onto a recording medium.
For example, in a technique disclosed in JP-A-60-99081 (Example 1), a hard twist textile made of polyester fiber is pretreated by padding of a pretreatment agent (water repellent) of a fluorine-containing compound (Asahi Guard AG-710, manufactured by Asahi Glass) at a drawing rate of 62% and drying at 100° C. for 10 minutes, and a dye ink containing 4 parts of a dispersed dye, 1 part of a sizing agent sodium alginate (viscosity: 40 cps, produced by KIMICA) and 95 parts of ion-exchanged water is splayed to the pretreated hard twist textile by an on-demand ink jet method, thus producing a printed article.
Also, JP-A-2008-195767 (Paragraphs 0056, 0061 and 0069) discloses an aqueous white ink for ink jet textile printing. For preparing the aqueous white ink, 19 parts by mass of water is added to 36 parts by mass of a solution containing a specific polymer dispersant to yield a resin varnish for dispersing titanium oxide, and 45 parts by mass of titanium oxide is added to and mixed with the resin varnish, followed by dispersing the mixture in a wet mill to yield an aqueous white ink base (titanium oxide/dispersant=1/0.2) for ink jet textile printing. Then, to 33.3 parts by mass of the aqueous white ink base are added 33.3 parts by mass of nonionic acrylic resin emulsion (Mowinyl 966A, produced by Nichigo Mowinyl, solid content: 45% by mass) having a glass transition temperature of −30° C., 20 parts by mass of glycerol, 1 part by mass of acetylene glycol ethylene oxide adduct (Acetylenol E 100 produced by Kawaken Fine Chemicals), and 12.4 parts by mass of water. The materials are mixed and stirred to yield the aqueous white ink for ink jet textile printing.
However, when the techniques of the above-cited documents are applied to a white pigment ink, the whiteness of the resulting printed cloth may be very low, and the ink may not be reliably ejected.

Pretreatment agent for ink jet textile printing, ink jet textile printing ink set, and method of ink jet textile printing


The present invention relates to compounds of the formula I, in which R1, R2, A, B, D, F, n, m and o have the meanings indicated herein. The compounds of the formula I are valuable pharmacologically active compounds. They are reversible inhibitors of the interaction between the plasma protein von Willebrand factor (vWF) and the blood platelet receptor glycoprotein Ib-IX-V complex (GPIb). They exhibit an antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of atherothrombotic diseases

The present invention relates to compounds of the formula I,
in which R1, R2, A, B, D, E, n, m or o have the meanings indicated below.
The compounds of the formula I are valuable pharmacologically active compounds. They are reversible inhibitors of the interaction between the plasma protein von Willebrand factor (vWF) and the blood platelet receptor glycoprotein Ib-IX-V complex (GPIb). This interaction causes primary adhesion of platelets to the injured subendothelial matrix and consequently platelet aggregation and thrombus formation. Inhibitors of this intraction exhibit an antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of athero-thrombotic diseases (for example: prevention of myocardial infarction, unstable angina, acute coronary syndromes, coronary artery disease, reocclusion following coronary thrombolysis, occlusion during thromboplasty and coronary restenosis, stroke, trasient ischemic attacks, pulmonary embolism, left ventricular dysfunction, secondary prevention of clinical vascular complications in patients with cardiovascular and cerebrovascular disease, atherosclerosis, comedication to vascular interventional strategies, etc.). They can in general be applied in conditions in which the interaction between GPIb and vWF leads to undesired physiological impact or for the cure or prevention of which an inhibition of the interaction between GPIb and vWF is intended. WO 98/27815 discloses particular aminoquinolines as modulators of chemokine receptor activity for modulating eosinophil and/or lymphocyte function for the prevention and/or treatment of inflammatory and immunoregulatory disorders and diseases as well as autoimmune pathologies. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
Platelet adhesion and thrombus formation are complex processes crucial to haemostasis. The formation of a blood clot is normally the result of tissue injury which initiates the platelet adhesion/aggregation and the coagulation cascade and has the effect of slowing or preventing blood flow in wound healing. However, in certain disease states the formation of blood clots within the circulatory system reaches an undesired extent and is itself the source of morbidity potentially leading to pathological consequences.
Many adhesive proteins and various receptors are involved in this complex progress. Circulating platelets become adherent and form an occlusive thrombus either by exposure to atherosclerotic lesions following plaque rupture or in response to pathological shear stress. An important adhesive plasma protein is vWF, a multimeric glycoprotein with a mature subunit of 2050 amino acids.
Two platelet membrane glycoprotein receptors for vWF have been identified. Unactivated platelets bind vWF through the platelet GPIb complex. This interaction is induced physiologically by high shear or by binding of vWF to any surface. Subsequently vWF changes the conformation of the binding domain in such a way that interaction becomes possible. After activation, platelets express a second binding site for vWF, the GPIIb-IIIa complex, which is also a binding site for fibrinogen. Platelet activation induces amplification mechanisms which finally lead to a firm platelet attachment.
The essential role of GPIb in platelet adhesion was established with the use of antibodies and by observations on a genetic defect the Bernard-Soulier syndrome in which GPIb is absent from platelets. Platelets from Bernard-Soulier patients poorly adhere and moderately aggregate in response to vWF. Also a lot of snake venom proteins are reported which modulate the interaction ob GPIb and vWF.
Specific inhibition of the interaction of GPIb to vWF using monoclonal antibodies or snake venom proteins is an effective means of controlling thrombus formation caused by arterial injury or thrombotic complications. There is also experimental evidence suggesting that inhibition of the GPIb-vWF interaction inhibits thrombus formation with a wider safety window than abciximab an antibody for GPIIb-IIIa which is already launched (Kageyama, S.; Yamamoto, H.; Nakazawa, H., Yoshimoto, R. Thromb. Res. 101 (2001) 395–404). However these type of drugs are only qualified for an intravenous application.
There continues to be a need for safe and effective therapeutic antithrombotic agents to limit or prevent thrombus formation. It is most desirable to develop agents that inhibit an early step in thrombogenesis like inhibition of the GPIb-vWF interaction. A specific inhibitor for the GPIb-vWF interaction which is suitable for oral long term use would have substantial practical value in the practice of medicine.
The present invention satisfies the above needs by providing novel compounds of the formula I, which are low molecular weight compounds and inhibit the GPIb-vWF interaction.
Thus, the present invention relates to compounds of the formula I,
wherein    n is the integer zero, 1,2,3 or 4;    m is the integer zero, 1,2,3 or 4;    o is the integer zero, 1,2,3 or 4;    R1 is —(C1–C8)-alkyl;    R2 is —NR4R5, wherein    R4 and R5 are identical or different and are hydrogen atom or —(C1–C8)-alkyl;    A is —NH—CO— or —CO—NH—;    B is 1. a covalent bond,    2. a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3,    3. (C3-C8)-cycloalkyl or    4. Het, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3,    D is —NH—CO—, —CO—NH— or —NH—;    E is a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3, or Het wherein Het is a saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocyclic ring system containing 3 to 10 ring atoms of which 1,2,3 or 4 are identical or different heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3;with the proviso that, when B is a covalent bond and Het is a bicyclic heterocyclic ring system, the ring of Het to which -D-(CH2)o— is attached contains at least one hetero atom;    R3 is 1. —(C1–C8)-alkyl,    2. (C1–C8)-alkoxy,    3. hydroxyl,    4. trifluoromethoxy,    5. trifluoromethyl,    6. halogen,    7. nitro,    8. —NR4R5, wherein R4 and R5 are as defined above,    9. —(C1–C8)-alkylcarbonyl,    10. —CN,    11. aminosulfonyl-,    12. amidino,    13. guanidino,    14. tri-((C1–C4)-alkyl)ammonio-,    15. di-((C1–C8)-alkyl)amino-,    16. (C1–C8)-alkylaminosulfonyl-,    17. di-((C1–C8)-alkyl)aminosulfonyl,    18. —O-Het, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3 and R3 is as defined above under 1. to 17., or    19. Het-, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3 and R3 is as defined above under 1. to 17.,in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically tolerable salts and as further specified in the attached claims.
The present invention also relates to the compounds of the formula I, wherein    n is the integer zero or 1,    m is the integer zero or 1,    o is the integer zero or 1,    R1 is —(C1–C4)-alkyl;    R2 is —NR4R5, wherein    R4 and R5 are identical or different and are hydrogen atom or —(C1–C4)-alkyl;    A is —NH—CO— or —CO—NH—;    B is 1. a covalent bond,    2. a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R3, or    3. (C3-C7)-cycloalkyl,    D is —NH—CO—, —CO—NH— or —NH—;    E is 1. aryl selected from the group phenyl, naphthyl, biphenylyl, fluorenyl and anthracenyl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R3, or    2. Het selected from the group aziridine, oxirane, azetidine, pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine, 1,4-dioxine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, indole, isoindole, benzofuran, benzothiophene, 1,3-benzodioxole, benzo[1,4]dioxine, 4H-benzo[1,4]oxazine, indazole, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, chromane, isochromane, cinnoline, quinazoline, quinoxaline, phthalazine, pyridoimidazoles, pyridopyridines, pyridopyrimidines or ring systems which result from the listed heterocycles by fusion or condensation of a carbocyclic ring, for example benzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane, 2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol, 1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine (=morpholine), 2,3-dihydrobenzo[1,4]dioxine, indoline, isoindoline, 3,4-dihydro-2H-benzo[1,4]oxazine, perhydro-1,4-thiazine, perhydroazepine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and wherein Het is unsubstituted or mono-, di- or trisubstituted independently of one another by R3;    R3 is 1. —(C1–C4)-alkyl,    2. hydroxyl,    3. halogen,    4. —NR4R5, wherein R4 and R5 are as defined above,    5. aminosulfonyl-,    6. (C1–C8)-alkylaminosulfonyl-,    7. di-((C1–C8)-alkyl)aminosulfonyl,    8. —(C1–C8)-alkoxy,    9. —O-Het, wherein Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R3 and R3 is as defined above under 1. to 8., or    10. Het-, wherein Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R3 and R3 is as defined above under 1. to 8.
The present invention also relates to the compounds of the formula I, wherein    n is the integer zero or 1,    m is the integer zero or 1,    o is the integer zero or 1,    R1 is methyl;    R2 is amino;    A is —NH—CO— or —CO—NH—;    B is phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R3,    D is —NH—CO—, —CO—NH— or —NH—;    E is 1. phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R3, or    2. Het, which is selected from the group pyridine, pyrimidine, pyrazine, quinoline, benzimidazole, benzthiazole, isoquinoline, chromane, indazole, isochromane, cinnoline, quinazoline, quinoxaline, phthalazine, pyridoimidazoles, pyrroline, pyrrolidine, tetrahydropyridine, piperidine, imidazolidine, 1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, piperazine, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and wherein Het is unsubstituted or mono-, di- or trisubstituted independently of one another by R3;    R3 is 1. methyl,    2. hydroxyl,    3. halogen,    4. —NH2,    5. aminosulfonyl-,    6. methoxyl,    7. —O-Het, wherein Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R3 and R3 is as defined above under 1. to 6., or    8. Het-, wherein Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R3 and R3 is as defined above under 1. to 6.
The present invention also relates to the compounds of the formula I selected from the group 3-(2-Amino-6-methyl-pyrimidin-4-ylamino)-N-(4-amino-2-methyl-quinolin-6-yl)-propionamide, 2-Amino-4-[3-(4-amino-2-methyl-quinolin-6-ylcarbamoyl)-phenylamino]-1,6-dimethyl-pyrimidin-1-ium, 2-Amino-4-[4-(4-amino-2-methyl-quinolin-6-ylcarbamoyl)-benzylamino]-1,6-dimethyl-pyrimidin-1-ium, Pyrazine-2-carboxylic acid 4-(4-amino-2-methyl-quinolin-6-ylcarbamoyl)-benzylamide, 6-Amino-N-[4-(4-amino-2-methyl-quinolin-6-ylcarbamoyl)-benzyl]-nicotinamide, 6-Pyrrolidin-1-yl-pyrazine-2-carboxylic acid 4-(4-amino-2-methyl-quinolin-6-ylcarbamoyl)-benzylamide, 2-Amino-4-[(4-{[(4-amino-2-methyl-6-quinolinyl)-carbonyl]amino} phenyl)amino]-1,6-dimethylpyrimidin-1-ium, 2-Amino-4-[(3-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}phenyl)amino]-1,6-dimethylpyrimidin-1-ium, 2-Amino-4-[(4-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}benzyl)amino]-1,6-dimethylpyrimidin-1-ium, 2-Amino-4-[(4-{[(4-amino-2-methyl-6-quinolinyl)-carbonyl]amino}benzyl)amino]-6-methylpyrimidine, 4-Amino-N-[4-({[(6-chloro-3-pyridinyl)carbonyl]amino}methyl)phenyl]-2-methyl-6-quinolinecarboxamide, 4-Amino-2-methyl-N-(4-{[(2-pyridinylcarbonyl)amino]methyl}phenyl)-6-quinoline-carboxamide, 4-Amino-N-[4-({[(2-chloro-4-pyridinyl)carbonyl]amino}methyl)phenyl]-2-methyl-6-quinolinecarboxamide, 4-Amino-N-[4-({[(3-bromo-5-pyridinyl)carbonyl]-amino}methyl)phenyl]-2-methyl-6-quinolinecarboxamide, 4-Amino-N-[4-({[(3-amino-2-pyrazinyl)carbonyl]amino}methyl)phenyl]-2-methyl-6-quinolinecarboxamide, 4-Amino-N-{4-[(2-pyridinylcarbonyl)amino]phenyl}-2-methyl-6-quinolinecarboxamide, 4-Amino-N-{4-[(3-pyridinylcarbonyl)amino]phenyl}-2-methyl-6-quinoline-carboxamide, 4-Amino-N-(4-{[(2-chloro-3-pyridinyl)carbonyl]amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(5-bromo-3-pyridinyl)carbonyl]-amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-amino-3-pyrazinyl)carbonyl]amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-amino-3-pyridinyl)carbonyl]amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-amino-5-pyridinyl)carbonyllaminolphenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-hydroxy-5-pyridinyl)carbonyl]amino}-phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-pyrazinyl)carbonyl]-aminophenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2,3-dichloro-5-pyridinyl)carbonyl]amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[3-(aminosulfonyl)-4-chlorobenzoyl]amino}phenyl)-2-methyl-6-quinolinecarbox-amide, 4-Amino-N-{4-[(3-dimethylaminobenzoyl)amino]phenyl}-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-methyl-1H-benzimidazol-5-yl)carbonyl]-amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[4-(4-piperidinyloxy) benzoyl]amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-amino-1H-benzimidazol-5-yl)carbonyl]amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-amino-1,2-benzthiazol-6-yl)carbonyl]-amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-amino-N-{4-[(1H-benzimidazol-5-ylcarbonyl)amino]phenyl}-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-amino-6-quinolinyl)carbonyl]amino}phenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-amino-6-quinolinyl)carbonyl]amino}-2-methoxyphenyl)-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(2-methoxy-4-{[(2-methyl-1H-benzimidazol-5-yl)carbonyl]amino}phenyl)-2-methyl-6-quinolinecarboxamide, 1,4-Di-{[(4-amino-2-methylquinolin-6-yl)carbonyl]amino}benzene, 4-Amino-N-{4-[(1H-indazol-6-ylamino)methyl]phenyl}-2-methyl-6-quinolinecarboxamide, 4-Amino-N-(4-{[(2-amino-1,3-benzothiazol-6-yl)carbonyl]amino}cyclohexyl)-2-methyl-6-quinolinecarboxamide and 4-Amino-N-(4-{[(2-amino-6-quinolinyl)carbonyl]amino}-cyclohexyl)-2-methyl-6-quinolinecarboxamide.
In general, the meaning of any group, residue, heteroatom, number etc. which can occur more than once in the compounds of the formula I, is independent of the meaning of this group, residue, heteroatom, number etc. in any other occurrence. All groups, residues, heteroatoms, numbers etc. which can occur more than once in the compounds of the formula I can be identical or different.
As used herein, the term alkyl is to be understood in the broadest sense to mean hydrocarbon residues which can be linear, i. e. straight-chain, or branched and which can be acyclic or cyclic residues or comprise any combination of acyclic and cyclic subunits. Further, the term alkyl as used herein expressly includes saturated groups as well as unsaturated groups which latter groups contain one or more, for example one, two or three, double bonds and/or triple bonds, provided that the double bonds are not located within a cyclic alkyl group in such a manner that an aromatic system results. All these statements also apply if an alkyl group occurs as a substituent on another residue, for example in an alkyloxy residue, an alkyloxycarbonyl residue or an arylalkyl residue. Examples of alkyl residues containing 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl, the n-isomers of all these residues, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-pentyl, sec-butyl, tert-butyl or tert-pentyl.
Unsaturated alkyl residues are, for example, alkenyl residues such as vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl, or alkynyl residues such as ethynyl, 1-propynyl, 2-propynyl (=propargyl) or 2-butynyl. Alkyl residues can also be unsaturated when they are substituted.
Examples of cyclic alkyl residues are cycloalkyl residues containing 3, 4, 5 or 6 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which can also be substituted and/or unsaturated. Unsaturated cyclic alkyl groups and unsaturated cycloalkyl groups like, for example, cyclopentenyl or cyclohexenyl can be bonded via any carbon atom.
Of course, a cyclic alkyl group has to contain at least three carbon atoms, and an unsaturated alkyl group has to contain at least two carbon atoms. Thus, a group like (C1–C8)-alkyl is to be understood as comprising, among others, saturated acyclic (C1–C8)-alkyl, (C3–C6)-cycloalkyl, and unsaturated (C2–C8)-alkyl like (C2–C8)-alkenyl or (C2–C8)-alkynyl. Similarly, a group like (C1–C4)-alkyl is to be understood as comprising, among others, saturated acyclic (C1–C4)-alkyl, and unsaturated (C2–C4)-alkyl like (C2–C4)-alkenyl or (C2–C4)-alkynyl.
Unless stated otherwise, the term alkyl preferably comprises acyclic saturated hydro-carbon residues which have from one to six carbon atoms and which can be linear or branched. A particular group of saturated acyclic alkyl residues is formed by (C1–C4)-alkyl residues like methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tBu.
Unless stated otherwise, and irrespective of any specific substituents bonded to alkyl groups which are indicated in the definition of the compounds of the formula I, alkyl groups can in general be unsubstituted or substituted by one or more, for example one, two or three, identical or different substituents. Any kind of substituents present in substituted alkyl residues can be present in any desired position provided that the substitution does not lead to an unstable molecule. Examples of substituted alkyl residues are alkyl residues in which one or more, for example 1,2 or 3, hydrogen atoms are replaced with halogen atoms, in particular fluorine atoms.
The term aryl refers to a monocyclic or polycyclic hydrocarbon residue in which at least one carbocyclic ring is present that has a conjugated pi electron system. In a (C6–C14)-aryl group from 6 to 14 ring carbon atoms are present. Examples of (C6–C14)-aryl groups are phenyl, naphthyl, biphenylyl, fluorenyl or anthracenyl. Examples of (C6–C10)-aryl groups are phenyl or naphthyl. Unless stated otherwise, and irrespective of any specific substituents bonded to aryl groups which are indicated in the definition of the compounds of the formula I, aryl groups, for example phenyl, naphthyl or fluorenyl, can in general be unsubstituted or substituted by one or more, for example one, two, three or four, identical or different substituents. Aryl groups can be bonded via any desired position, and in substituted aryl groups the substituents can be located in any desired position.
In monosubstituted phenyl groups the substituent can be located in the 2-position, the 3-position or the 4-position. If a phenyl group carries two substituents, they can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenyl groups carrying three substituents the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position, or 3,4,5-position. Naphthyl groups can be 1-naphthyl and 2-naphthyl. In substituted naphthyl groups the substituents can be located in any positions, for example in monosubstituted 1-naphthyl groups in the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position and in monosubstituted 2-naphthyl groups in the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position. Biphenylyl groups can be biphenyl-2-yl, biphenyl-3-yl or biphenyl-4-yl. Fluorenyl groups can be bonded via the 1-, 2-, 3-, 4- or 9-position. In monosubstituted fluorenyl groups bonded via the 9-position the substituent is preferably present in the 1-, 2-, 3- or 4-position.
The above statements relating to aryl groups correspondingly apply to divalent groups derived 5 from aryl groups, i. e. to arylene groups like phenylene which can be unsubstituted or substituted 1,2-phenylene, 1,3-phenylene or 1,4-phenylene, or naphthylene which can be unsubstituted or substituted 1,2-naphthalenediyl, 1,3-naphthalenediyl, 1,4-naphthalenediyl, 1,5-naphthalenediyl, 1,6-naphthalenediyl, 1,7-naphthalenediyl, 1,8-naphthalenediyl, 2,3-naphthalenediyl, 2,6-naphthalenediyl or 2,7-naphthalenediyl.
The Het group comprises groups containing 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms in the parent monocyclic or bicyclic heterocyclic ring system. In monocyclic Het groups the heterocyclic ring preferably is a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered ring, particularly preferably a 5-membered or 6-membered ring. In bicyclic Het groups preferably two fused rings are present one of which is a 5-membered ring or 6-membered heterocyclic ring and the other of which is a 5-membered or 6-membered heterocyclic or carbocyclic ring, i. e. a bicyclic ring Het preferably contains 8, 9 or 10 ring atoms, particularly preferably 9 or 10 ring atoms.
Het comprises saturated heterocyclic ring systems which do not contain any double bonds within the rings, as well as unsaturated heterocyclic ring systems including mono-unsaturated and poly-unsaturated heterocyclic ring systems which contain one or more, for example one, two, three, four or five, double bonds within the rings provided that the resulting system is stable. Unsaturated rings may be partially unsaturated or non-aromatic, or they may be aromatic, i. e. double bonds within the rings in the Het group may be arranged in such a manner that a conjugated pi electron system results. Aromatic rings in a Het group may be 5-membered or 6-membered rings, i. e. aromatic groups in a Het group contain 5 to 10 ring atoms. Aromatic rings in a Het group thus comprise 5-membered and 6-membered monocyclic heterocycles and bicyclic heterocycles composed of two 5-membered rings, one 5-membered ring and one 6-membered ring, or two 6-membered rings. In bicyclic aromatic groups in a Het group one or both rings may contain heteroatoms. Aromatic Het groups may also be referred to by the customary term heteroaryl for which all the definitions and explanations above and below relating to Het correspondingly apply.
In a Het group preferably 1 or 2 identical or different ring heteroatoms selected from nitrogen, oxygen and sulfur atoms are present. In general, the ring heteroatoms can be present in any desired combination and in any desired positions with respect to each other provided that the resulting heterocyclic system is known in the art and is stable and suitable as a subgroup in a drug substance. Examples of parent structures of heterocycles from which the Het group any other heterocyclic groups can be derived are aziridine, oxirane, azetidine, pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine, 1,4-dioxine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, indole, isoindole, benzofuran, benzothiophene, 1,3-benzodioxole, benzo[1,4]dioxine, 4H-benzo[1,4]oxazine, indazole, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, chromane, isochromane, cinnoline, quinazoline, quinoxaline, phthalazine, pyridoimidazoles, pyridopyridines, pyridopyrimidines, etc. as well as ring systems which result from the listed heterocycles by fusion (or condensation) of a carbocyclic ring, for example benzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles.
The fact that many of the before-listed names of heterocycles are the chemical names of unsaturated or aromatic ring systems does not imply that the Het groups and other heterocyclic groups could only be derived from the respective unsaturated ring system. The names here only serve to describe the ring system with respect to ring size and the number of the heteroatoms and their relative positions. As explained above, for example a Het group can be saturated or partially unsaturated or aromatic, and can thus be derived not only from the before-listed heterocycles themselves but also from all their partially or completely hydrogenated analogues and also from their more highly unsaturated analogues if applicable. As examples of completely or partially hydrogenated analogues of the before-listed heterocycles from which a Het group and any other heterocyclic group may be derived the following may be mentioned: pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane, 2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol, 1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine (=morpholine), 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[1,4]oxazine, perhydro-1,4-thiazine (=thiomorpholine), perhydroazepine, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, etc.
The Het group and other any other heterocyclic group may be bonded via any ring carbon atom, and in the case of nitrogen heterocycles via any suitable ring nitrogen atom, if applicable. Thus, for example, a pyrrolyl group can be pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, a pyrrolidinyl group can be pyrrolidin-1-yl (=pyrrolidino), pyrrolidin-2-yl or pyrrolidin-3-yl, a pyridinyl group can be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, a piperidinyl group can be piperidin-1-yl (=piperidino), piperidin-2-yl, piperidin-3-yl or piperidin-3-yl. Furyl can be furan-2-yl or fur-3-yl, thienyl can be thiophen-2-yl or thiophen-3-yl, imidazolyl can be imidazol-1-yl, imidazol-2-yl, imidazol-4-yl or imidazol-5-yl, 1,3-oxazolyl can be 1,3-oxazol-2-yl, 1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl can be 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinyl can be pyrimidin-2-yl, pyrimidin-4-yl (=pyrimidin-6-yl) or pyrimidin-5-yl, piperazinyl can be piperazin-1-yl (=piperazin-4-yl=piperazino) or piperazin-2-yl. Indolyl can be indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl. Similarly benzimidazolyl, benzoxazolyl and benzothiazol groups can be bonded via the 2-position and via any of the positions 4, 5, 6, and 7. Quinolinyl can be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-5-yl, quinolin-7-yl or quinolin-8-yl, isoqinolinyl can be isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl. In addition to being bonded via any of the positions indicated for quinolinyl and isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl can also be bonded via the nitrogen atoms in 1-position and 2-position, and 2-position, respectively.
Unless stated otherwise, and irrespective of any specific substituents in aryl groups, Het groups or any other heterocyclic groups which are indicated in the definition of the compounds of the formula I, aryl groups, Het groups and other heterocyclic groups can be unsubstituted or substituted on ring carbon atoms with one or more, for example one, two, three or four, identical or different substituents like (C1–C4)-alkyl, (C1–C4)-alkyloxy, halogen, nitro, amino, (C1–C4)-alkylamino, di-((C1–C4)-alkyl)amino, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, hydroxymethyl, methylenedioxy, ethylenedioxy, cyano, methylsulfonyl, etc.
The substituents can be present in any desired position provided that a stable molecule results. Preferably not more than two nitro groups are present in the compounds of the formula I.
Further, unless stated otherwise, and irrespective of any specific substituents in Het groups or any other heterocyclic groups which are indicated in the definition of the compounds of the formula I, Het groups and other heterocyclic groups can on each suitable ring nitrogen atom independently of one another be unsubstituted, i. e. carry a hydrogen atom, or be substituted, for example, by (C1–C8)-alkyl, for example (C1–C4)-alkyl such as methyl or ethyl, optionally substituted phenyl, phenyl-(C1–C4)-alkyl, for example benzyl. Suitable nitrogen heterocycles can also be present as quaternary salts.
The explanations relating to the Het group correspondingly apply to divalent Het groups including divalent heteroaromatic groups which may be bonded via any two ring carbon atoms and in the case of nitrogen heterocycles via any carbon atom and any suitable ring nitrogen atom or via any two suitable nitrogen atoms. For example, a pyridinediyl group can be pyridin-2,3-diyl, pyridin-2,4-diyl, pyridin-2,5-diyl, pyridin-2,6-diyl, pyridin-3,4-diyl or pyridin-3,5-diyl, a piperidinediyl group can be, among others, piperidin-1,2-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, piperidin-2,3-diyl, piperidin-2,4-diyl or piperidin-3,5-diyl, a piperazinediyl group can be, among others, piperazin-1,3-diyl, piperazin-1,4-diyl, piperazin-2,3-diyl, piperazin-2,5-diyl, etc.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Physiologically tolerable salts of the compounds of formula I are nontoxic salts that are physiologically acceptable, in particular pharmaceutically utilizable salts. Such salts of compounds of the formula I containing acidic groups, for example a carboxy group COOH, are for example alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions such as tetramethylammonium or tetraethylammonium, and acid addition salts with ammonia and physiologically tolerable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. Basic groups contained in the compounds of the formula I, for example amino groups or amidino groups, form acid addition salts, for example with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. The present invention also includes acid addition salts of compounds of the formula I which contain, for example, two basic groups, with one or two acid equivalents.
Salts of compounds of the formula I can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the formula I with an inorganic or organic acid or base in a solvent or diluent, or from other salts by cation exchange or anion exchange. The present invention also includes all salts of the compounds of the formula I which, because of low physiologically tolerability, are not directly suitable for use in pharmaceuticals but are suitable, for example, as intermediates for carrying out further chemical modifications of the compounds of the formula I or as starting materials for the preparation of physiologically tolerable salts.
The anions of the mentioned acids that may be present in acid addition salts of the compounds of the formula I, are also examples of anions that may be present in the compounds of the formula I if they contain one or more positively charged groups like trialkylammonio-substituents, i. e. groups of the formula (alkyl)3N+ bonded via the positively charged nitrogen atom, representing R3, or quaternized ring nitrogen atoms in heterocyclic groups. In general a compound of the formula I contains one or more physiologically tolerable anions or anion equivalents as counterions if it contains one or more permanently positively charged groups like trialkylammonio.
Optically active carbon atoms present in the compounds of the formula I can independently of each other have R configuration or S configuration. The compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and/or diastereomers, for example in the form of racemates. The present invention relates to pure enantiomers and mixtures of enantiomers as well as to pure diastereomers and mixtures of diastereomers. The invention comprises mixtures of two or of more than two stereoisomers of the formula I, and it comprises all ratios of the stereoisomers in the mixtures. In case the compounds of the formula I can be present as E isomers or Z isomers (or cis isomers or trans isomers) the invention relates both to pure E isomers and pure Z isomers and to E/Z mixtures in all ratios. The invention also comprises all tautomeric forms of the compounds of the formula I.
Diastereomers, including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example by chromatography on chiral phases or by resolution, for example by crystallization of diastereomeric salts obtained with optically active acids or bases. Stereochemically uniform compounds of the formula I can also be obtained by employing stereochemically uniform starting materials or by using stereoselective reactions.
The invention also includes derivatives and modifications of the compounds of the formula I, for example prodrugs, protected forms and other physiologically tolerable derivatives, as well as active metabolites of the compounds of the formula I. The invention relates in particular to prodrugs and protected forms of the compounds of the formula I which can be converted into compounds of the formula I under physiological conditions. Suitable prodrugs for the compounds of the formula I, i. e. chemically modified derivatives of the compounds of the formula I having properties which are improved in a desired manner, for example with respect to solubility, bioavailability or duration of action, are known to those skilled in the art. More detailed information relating to prodrugs is found in standard literature like, for example, Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985, , Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115–130; or H. Bundgaard, Drugs of the Future 16 (1991) 443 which are all incorporated herein by reference. Suitable prodrugs for the compounds of the formula I are especially acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups and the guanidino group and also ester prodrugs and amide prodrugs of carboxylic acid groups which may be present in compounds of the formula I. In the acyl prodrugs and carbamate prodrugs one or more, for example one or two, hydrogen atoms on nitrogen atoms in such groups are replaced with an acyl group or a carbamate, preferably a (C1–C6)-alkyloxycarbonyl group. Suitable acyl groups and carbamate groups for acyl prodrugs and carbamate prodrugs are, for example, the groups Rp1—CO— and Rp2O—CO—, in which Rp1 is hydrogen, (C1–C18)-alkyl, (C3–C8)-cycloalkyl, (C3–C8)-cycloalkyl-(C1–C4)-akyl, (C6–C14)-aryl, Het-, (C6–C14)-aryl-(C1–C4)-alkyl- or Het-(C1–C4)-alkyl- and in which Rp2 has the meanings indicated for Rp1 with the exception of hydrogen.
Also with respect to all preferred compounds of the formula I all their stereoisomeric forms and mixtures thereof in any ratio and their physiologically acceptable salts explicitly are a subject of the present invention, as well as are their prodrugs. Similarly, also in all preferred compounds of the formula I all residues that are present more than one time in the molecule are independent of each other and can be identical or different.
The present invention also relates to processes of preparation by which the compounds of the formula I are obtainable. The compounds of the formula I can generally be prepared by linkage of two or more fragments (or building blocks) which can be derived retrosynthetically from the formula I. In the preparation of the compounds of the formula I it can generally be advantageous or necessary in the course of the synthesis to introduce functional groups which could lead to undesired reactions or side reactions in a synthesis step in the form of precursors which are later converted into the desired functional groups. As examples of precursor groups cyano groups may be mentioned which may later be converted into amidino groups, or nitro groups which may be converted into amino groups. Protecting groups (or blocking groups) that may be present on functional groups include allyl, tert-butyl, benzyl, allyloxycarbonyl (Alloc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) and 9-fluorenylmethoxycarbonyl (Fmoc) as protecting groups for hydroxy, carboxylic acid, amino, amidino and guanidino groups.
In particular, in the preparation of the compounds of the formula I building blocks can be connected by performing one or more condensation reactions and/or substitution reactions such as amide couplings, i. e. by forming an amide bond between a carboxylic acid group of one building block and an amino group of another building block, or by a nucleophilic substitution of a leaving group of one building block by an nucleophilic group of another building block, i. e. by substitution of an halogen of one building block by an amino group of another building block. For example, compounds of the formula I can be prepared by linking the building blocks of the formulae II, III, and IV
by means of forming in a manner known per se an amide bond between the carboxylic acid group G1 depicted in formula II and the NH2 group G2 depicted in formula III or between the carboxylic acid group G2 depicted in formula III and the NH2 group G1 depicted in formula II or    by means of forming in a manner known per se an amide bond between the carboxylic acid group G3 depicted in formula III and the NH2 group G4 depicted in formula IV or between the carboxylic acid group G4 depicted in formula IV and the NH2 group G3 depicted in formula III or    by means of forming a bonding between building block of the formula III and building block of the formula IV by nucleophilic substitution of an halogen atom G4 depicted in formula IV    by an amino group G3 depicted in formula III or    by means of forming a bonding between building block of the formula III and building block of the formula IV by nucleophilic substitution of an halogen atom G3 depicted in formula III    by an amino group G4 depicted in formula IV.
In the compounds of the formulae II, III and IV the groups and numbers m, n, o, R1, R2, B and E are as defined above. In general, in addition to the denotations of the groups and substituents given above, in the compounds of the formulae II, III and IV, functional groups can also be present in the form of precursor groups which are later converted into the groups present in the compounds of the formula I, or can be present in protected form.
The starting compounds of the formulae II, III and IV and other compounds which are employed in the synthesis of the compounds of formula I for introducing certain structural units, are commercially available or can be readily prepared from commercially available compounds by or analogously to procedures described below or in the literature which is readily available to those skilled in the art, i.e. building block of the formula II can be prepared by a procedure described in T. J. Lanza et al J. Med. Chem. 1992,35, 252–258.
For the preparation of the compounds of formula I first the compounds of the formulae II and III may be linked and the resulting intermediate product then be condensed or linked with a compound of the formula IV to give a compound of the formula I. Just so, first the compounds of the formulae III and IV may be condensed or linked and the resulting intermediate product then be linked to a compound of the formula II to give a compound of the formula I. After any such reaction step in the course of such syntheses protecting and deprotecting steps and conversions of precursor groups into the desired final groups may be carried out and further modifications may be made.
Various general methods for the formation of an amide bond that can be employed in the synthesis of the compounds of formula I are just so well known to those skilled in the art, for example from peptide chemistry. An amide coupling step can favorably be carried out by employing a free carboxylic acid, i. e. a compound of the formula II or an intermediate coupling product in which a group like G1 reacting in that step is a COOH group, activating that carboxylic acid group, preferably in situ, by means of a customary coupling reagent such as a carbodiimide like dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC), or an N,N′-carbonyldiazole like N,N′-carbonyldiimidazole, or a uronium salt like O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) or O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), or a chloroformic acid ester like ethyl chloroformate or isobutyl chloroformate, or tosyl chloride, or propylphosphonic acid anhydride, or others, and then reacting the activated carboxylic acid derivative with an amino compound of the formula III. An amide bond can also be formed by reacting an amino compound with a carboxylic acid halide, in particular a carboxylic acid chloride, which can be prepared in a separate step or in situ, from a carboxylic acid and, for example, thionyl chloride, or an carboxylic acid ester or thioester, for example a methyl ester, ethyl ester, phenyl ester, nitrophenyl ester, pentafluorophenyl ester, methylthio ester, phenylthio ester or pyridin-2-ylthio ester.
The activation reactions and coupling reactions are usually performed in the presence of an inert solvent (or diluent), for example in the presence of an aprotic solvent like dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), hexamethyl phosphoric triamide (HMPT), 1,2-dimethoxyethane (DME), dioxane, or others, or in a mixture of such solvents. Depending on the specific process, the reaction temperature may be varied over a wide range and be, for example, from about −20° C. to the boiling temperature of the solvent or diluent. Also depending on the specific process, it may be necessary or advantageous to add in a suitable amount one or more auxiliary agents, for example a base like a tertiary amine, such as N-ethylmorpholine, triethylamine or diisopropylethylamine, or an alkali metal alcoholate, such as sodium methoxide or potassium tert-butoxide, for adjusting the pH or neutralizing an acid that is formed or for liberating the free-base of an amino compound that is employed in the form of an acid addition salt, or an N-hydroxyazole like 1-hydroxybenzotriazole, or a catalyst like 4-dimethylaminopyridine. Details on methods for the preparation of activated carboxylic acid derivatives and the formation of amide bonds and ester bonds as well as source literature are given in various standard references like, for example, J. March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, 1992; or Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag.
Protective groups that may still be present in the products obtained in the coupling reaction are then removed by standard procedures. For example, tert-butyl protecting groups, in particular a tert-butoxycarbonyl group which is a protected form of an amino group, can be deprotected, i. e. converted into the amino group, by treatment with trifluoroacetic acid. As already explained, after the coupling reaction also functional groups can be generated from suitable precursor groups. In addition, a conversion into a physiologically tolerable salt or a prodrug of a compound of the formula I can then be carried out by known processes.
In general, a reaction mixture containing a final compound of the formula I or an intermediate is worked up and, if desired, the product is then purified by customary processes known to those skilled in the art. For example, a synthesized compound can be purified using well known methods such as crystallization, chromatography or reverse phase-high performance liquid chromatography (RP-HPLC) or other methods of separation based, for example, on the size, charge or hydrophobicity of the compound. Similarly, well known methods such as NMR, IR and mass spectrometry (MS) can be used for characterizing a compound of the invention.
The reactions described above and below that are carried out in the syntheses of the compounds of the formula I can generally be carried out according to the methods of conventional solution phase chemistry. Preferred methods include, but are not limited to those described in the examples.
The compounds of the present invention inhibit the initial step of the thrombogenesis. In particular, they are inhibitors of the interaction between the platelet surface glycoprotein GPIb complex and the plasma protein von Willebrand factor and preferably do not show an essential modulation of the chemokine receptor activity as e.g. measured in a CCR-1 and/or CCR-5 binding assay as disclosed e.g. in Van Riper et al. (1993) J. Exp. Med., 177, 851–856 or in a CCR-2 and/or CCR-3 binding assay as disclosed in e.g. Daugherty et al. (1996) J. Exp. Med., 183, 2349–2354.
Activity of compounds of the formula I was shown by an Eu based binding assay in which the binding of human von Willebrand factor to an europium (Eu)-chelate-labeled chimeric GPIb-Fc protein was induced by botrocetin. The preparation of the Eu-chelate-labeled chimeric GPIb-Fc protein is described in detail in a patent application (Fukuchi et al., EP1074564). IC50 (inhibition for 50%) values of all the compounds of the formula I were less than 100 microM.
In view of their ability to inhibit the interaction between GPIb and vWF the compounds of the formula I are useful pharmacologically active compounds which are suitable, for example, for influencing the platelet aggregation and for the treatment, including therapy and prophylaxis, of diseases such as, for example, cardiovascular disorders, thromboembolic diseases or restenoses.
The invention also relates to the treatment of disease states such as abnormal thrombus formation, myocardial infarction, acute myocardial infarction, unstable angina, acute coronary syndromes, coronary artery disease, reocclusion following coronary thrombolysis, occlusion during thromboplasty, coronary restenosis, thromboembolism, pulmonary embolism, left ventricular dysfunction, secondary prevention of clinical vascular complications in patients with cardiovascular and cerebrovascular disease,acute vessel closure associated with thrombolytic therapy or percutaneous transluminal coronary angioplasty, transient ischemic attacks, stroke, atherosclerosis, comedication to vascular interventional strategies,pathologic thrombus formation occurring in the veins of the lower extremities following abdominal, knee and hip surgery, a risk of pulmonary thromboembolism, or disseminated systemic intravascular coagulatopathy occurring in vascular systems during septic shock, certain viral infections or cancer.
The present invention also relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an effective amount of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs in addition to a customary pharmaceutically acceptable carrier, i. e. one or more pharmaceutically acceptable carrier substances or excipients and/or auxiliary substances or additives.
The compounds of the formula I and their physiologically tolerable salts and their prodrugs can be administered to animals, preferably to mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be administered on their own, or in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral administration and which contain, as active constituent, an effective amount of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs and a pharmaceutically acceptable carrier.
The pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
The pharmaceutical preparations according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Carrier substances for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carrier substances for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carrier substances for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to about 90% by weight of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs. The amount of the active ingredient of the formula I and/or its physiologically tolerable salts and/or its prodrugs in the pharmaceutical preparations normally is from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.
In addition to the active ingredients of the formula I and/or their physiologically acceptable salts and/or prodrugs and to carrier substances, the pharmaceutical preparations can contain one or more additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs. In case a pharmaceutical preparation contains two or more compounds of the formula I the selection of the individual compounds can aim at a specific overall pharmacological profile of the pharmaceutical preparation. For example, a highly potent compound with a shorter duration of action may be combined with a long-acting compound of lower potency. The flexibility permitted with respect to the choice of substituents in the compounds of the formula I allows a great deal of control over the biological and physico-chemical properties of the compounds and thus allows the selection of such desired compounds. Furthermore, in addition to at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
The present invention also relates to the use of the compound of the formula I for the inhibition of the GPIb-vWF interaction in vitro or in vivo. Consequently, the present invention additionally relates to a method for the inhibition of the GPIb-vWF interaction in a mammal comprising the administration of an effective amount of a compound of formula I in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically tolerable salts, as e.g. explained already above.
Provisional application No. 60/416,953 filed Oct. 8, 2002, including the specification, drawings, claims and abstract, is hereby incorporated by reference. All publications cited herein are incorporated in their entireties by reference.
It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are included within the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not limit the present invention.

Inhibitors of the GPIb—vWF interaction, their preparation and use


Various methods and arrangements for operating a skip fire engine control system are described. In one aspect of the invention, a distinct firing sequence is determined for each bank of working chambers that is used to operate the bank in a skip fire manner. Each firing sequence uses a different firing fraction. In another aspect of the invention, a determination is made as to whether a firing sequence should be dynamically generated or selected from a set of predefined firing sequences.

Most vehicles in operation today (and many other devices) are powered by internal combustion (IC) engines. Internal combustion engines typically have a plurality of cylinders or other working chambers where combustion occurs. Under normal driving conditions, the torque generated by an internal combustion engine needs to vary over a wide range in order to meet the operational demands of the driver. Over the years, a number of methods of controlling internal combustion engine torque have been proposed and utilized. Some such approaches contemplate varying the effective displacement of the engine. Engine control approaches that vary the effective displacement of an engine by sometimes skipping the firing of certain cylinders are often referred to as "skip fire" engine control. In general, skip fire engine control is understood to offer a number of potential advantages, including the potential of significantly improved fuel economy in many applications. Although the concept of skip fire engine control has been around for many years, and its benefits are understood, skip fire engine control has not yet achieved significant commercial success.
It is well understood that operating engines tend to be the source of significant noise and vibrations, which are often collectively referred to in the field as NVH (noise, vibration and harshness). In general, a stereotype associated with skip fire engine control is that skip fire operation of an engine will make the engine run significantly rougher than conventional operation. In many applications such as automotive applications, one of the most significant challenges presented by skip fire engine control is vibration control. Indeed, the inability to satisfactorily address NVH concerns is believed to be one of the primary obstacles that has prevented widespread adoption of skip fire types of engine control.

Split bank and multimode skip fire operation