The present invention relates to a method for detecting a line-to-ground fault location in power network, and more particularly, detecting the line-to-ground fault location by direct 3-phase circuit analysis without using a symmetrical component transformation, so even in an unbalanced 3-phase circuit, the line-to-ground fault location can be accurately detected. In the method using direct 3-phase circuit analysis of this invention, inverse lemma is used to simplify matrix inversion calculations, thus the line-to-ground fault location can be easily and accurately determined even in the case of an unbalanced network without symmetrical component transformation.

(a) Field of the invention
The present invention relates to a method for detecting a line-to-ground fault location in power network, and more particularly, detecting the line-to-ground fault location with direct 3-phase circuit analysis without using a symmetrical component transformation, whereby even in an unbalanced 3-phase circuit the line-to-ground fault location can be accurately detected.
b) Description of the Related Art
Rapid growth of economy has resulted in large scale of power systems, and an excessive increase in transmission and distribution networks of electric power systems causes many kinds of faults by various causes. Transmission and distribution networks of electric power systems are playing very important roles as the links between the power suppliers and the consumers. However, because most of lines are exposed to air, lightning, contact of animals or mal-functioning of protection devices causes many kinds of faults. When a line-to-ground fault occurs, detecting a fault location rapidly and precisely separating the part of the network including the fault location from the rest part of the network until repairing the fault being finished is very important to minimize power interruption rate and to provide highly reliable power supplying service and electric power of high quality.
Transformation of 3-phase networks to symmetrical component systems (symmetrical component transformation) is generally used in conventional methods for detecting the line-to-ground fault locations. A 3-phase balanced network can be transformed to a symmetrical component system, which has no coupling between sequences so that the systems of equation may be solved easily. In other words, diagonal sequence impedance matrices are obtained in case of the balanced networks, thus sequence voltage and current can be expressed without any coupling among the sequences ([1] G. B. Ancell, N. C. Pahalawaththa, xe2x80x9cMaximum Likelyhood Estimation of Fault Location on Transmission Lines Using Travelling Wavesxe2x80x9d, IEEE Transactions on PWRD, Vol. 9, No. 9, 1994, pp. 680-689; [2] T. Takagi, Y. Yamakoshi, J. Baba, K. Uemura, T. Sakaguchi, xe2x80x9cA New Algorithm of an Accurate Fault Location for EHV/UHV Transmission Lines: Partxe2x80x94Fourier Transform Methodxe2x80x9d, IEEE Trans. on PAS, Vol. PAS-100, No. 3, 1988, pp. 1316-1323; and [3] M. S. Sachdev, R. Agarwal, xe2x80x9cA Technique For Estimating Transmission Line Fault Locations form Digital Impedance Relay Measurementsxe2x80x9d, IEEE Trans. on PWRD, Vol. 3, No.1, 1988, pp 121-129).
Following is a detailed description of an example of the conventional method for detecting the line to ground fault location in a power system using the symmetrical component transformation. FIG. 1 shows a simplified diagram of a balanced 3-phase power network.
Assuming the capacitance in this network is so small that it is negligible, A-phase voltage at the measuring point (relay) is given as:
VSa=(1xe2x88x92d)Zl1xc3x97(ISa+kIS0)+IfRf xe2x80x83xe2x80x83(1)
where, VSa: a-phase voltage; ISa: a-phase current; IS0: zero sequence current; Zl0,Zl: zero and positive sequence impedance of line; kxe2x89xa1(Zl0xe2x88x92Zl1)/Z1; If: fault current; Rf: fault resistance; and d: fault distance from the other end.
In equation (1), all the impedances except fault resistance are known values. In addition, the phase voltage and current are also available from measurement. One of two unknown variables, a fault current can be obtained using the current distribution factor and another one, a fault resistance can be eliminated during derivation of fault location equation, whose details are described in the following.
For a single line-to-ground fault, the following relation holds: If=3If2, and the negative sequence component of the fault current If2 can be obtained from the distribution factor, Df=If2/IS2 and the negative sequence current (IS2) at the measuring point.
FIG. 2 is a negative sequence network obtained by symmetrical component transformation of a faulted network given in FIG. 1.
The negative sequence circuit for the balanced system in FIG. 2 is shown in FIG. 3. Applying KVL to the route A, the following voltage equation is obtained:
ZS2IS2+(1xe2x88x92d)Zl2IS2xe2x88x92dZl2Ir2xe2x88x92Zr2Ir2=0 xe2x80x83xe2x80x83(2)
where, ZS2,Zr2: equivalent negative sequence impedances for the source and load; IS2, Ir2: negative sequence current flowing into the fault from the source and load side; and Zl2: negative sequence line impedance.
From Equation (2), distribution factor Db can be obtained.                               D          b                =                                            I              r2                                      I              S2                                =                                                                                (                                          1                      -                      d                                        )                                                                          Zl                    2                                                  +                                  Z                  S2                                                                              dZl                  2                                +                                  Z                  r2                                                      =                                                            -                                      dA                    1                                                  +                                  B                  1                                                                              dA                  1                                +                                  D                  1                                                                                (        3        )
where, A1=Zl2, B1=ZS2+Zl2 and D1=Zr2.
Then a negative sequence current distribution factor Df is obtained using Eq. (3):                               D          f                =                                            I              f2                                      I              S2                                =                                                                      I                  S2                                +                                  I                  r2                                                            I                S2                                      =                                                            B                  1                                +                                  D                  1                                                                              dA                  1                                +                                  D                  1                                                                                (        4        )
Equation (4) provides a way to obtain negative sequence component of the fault current from the source current.
Substituting If in Equation (1) by If=3If2 and Equation (4), we obtain:                                                                         V                Sa                            =                              xe2x80x83                                                                                (                                          1                      -                      d                                        )                                                                          Zl                    1                                    xc3x97                                      (                                                                  I                        Sa                                            +                                              kI                        S0                                                              )                                                  +                                  3                                                        I                    f2                                                                          R                    f                                                                                =                              xe2x80x83                                                                                (                                          1                      -                      d                                        )                                                                          Zl                    1                                    xc3x97                                      (                                                                  I                        Sa                                            +                                              kI                        S0                                                              )                                                  +                                                                            3                                                                    (                                                                              B                            1                                                    +                                                      D                            1                                                                          )                                                                                I                        S2                                                                                dA                        1                                            +                                              D                        1                                                                                R                      f                                        .                                                                                (        5        )
Rearrangement of Equation (5) yields:
(VSaxe2x88x92(1xe2x88x92d)Zl1(ISa+kIS0))(dA1+D1)+3(B1D1)IS2Rf=0 xe2x80x83xe2x80x83(6)
Equation (6) is rearranged again to form a second order polynomial with respect to fault distance variable d as follows:
d2(ar+jai)+d(br+jbi)+(crjc1)+Rf(dr+jd1)=0 xe2x80x83xe2x80x83(7)
where, ar+jai=(ISa+kIS0)Zl1A1,
br+jbi=(ISa+kIS0)Zl1D1+(VSaxe2x88x92((ISa+kIS0)Zl1))A1,
cr+jci=(VSa+kIS0)Zl1))D1,
dr+jdi=3(B1+D1)IS2.
From the imaginary part of Equation (7), the fault resistance is obtained.
xe2x88x92(d2ai+dbici)/di=Rf xe2x80x83xe2x80x83(8)
Replacing Rf in the real part of Equation (7) by Equation (8),                                                         d              2                                                  (                                                a                  r                                -                                                                            d                      r                                                              d                      1                                                                                a                    1                                                              )                                +                      d                                      (                                                b                  r                                -                                                                            d                      r                                                              d                      1                                                                                b                    1                                                              )                                +                      c            r                    -                                                    d                r                                            d                1                                                                c              1                                      =        0                            (                  8                                -1)
is obtained. Then the fault distance 1xe2x88x92d can be obtained by solving Equation (8-1).
The advantage of the above method is that it can be easily applied to a balanced network. Zero sequence, positive sequence and negative sequence can be easily analyzed because they are not correlated, that is, there is no couplings, or equivalently, mutual impedances among the sequences. In the above example, the fault location can be simply determined by analyzing the negative sequence circuit only.
However, the above conventional method can only be applied to a balanced network, because the simplified equations of zero sequence, positive sequence and negative sequence, which are not correlated, can be obtained by symmetrical component transformation only in the balanced network. Thus, the conventional method is not available for unbalanced systems.
The present invention has been made in an effort to solve the above problems.
It is an object of the present invention to provide a method for detecting a line-to-ground fault location in a power network including a fault resistance, not using the symmetrical component transformation but using direct 3-phase circuit analysis. The line-to-ground fault location detecting method of the present invention requires voltage and current of a fundamental frequency measured at a relay.
In the method using direct 3-phase circuit analysis of the present invention, matrix inverse lemma is applied to simplify matrix inversion calculations, thus the line-to-ground fault location can be easily and accurately determined even in the case of an unbalanced network without using the symmetrical component transformation.
By using the method of the present invention, the line-to-ground fault location can be directly analyzed whether the 3-phase network is balanced or unbalanced.
To achieve the above object, the present invention provides a method for detecting a line-to-ground fault location in a power network comprising the steps of:
determining elements of a line impedance matrix and phase voltage and current at a relay;
determining a line-to-ground fault distance by substituting said elements of line impedance matrix, said phase voltage and current into a fault location equation based on direct circuit analysis;
wherein said fault location equation is derived from a model consisting of said phase voltage and current at the relay, a fault current, a fault resistance and the line-to-ground fault distance;
wherein the model is described by the equation: VSabc=(1xe2x88x92d)xc3x97Zlabcxc3x97ISabc+Vfabc,
where, VSabc=[VsaVSbVSc]xe2x80x2: phase voltage vector, ISabc=[ISaISbISc]xe2x80x2: phase current vector, Vfabc=[VfaVfbVfc]xe2x80x2: phase voltage vector at the fault location,             Zl      abc        =                  [                                                            Zl                aa                                                                    Zl                ab                                                                    Zl                                  a                                                        xe2x80x83                                                      c                                                                                Zl                ba                                                                    Zl                bb                                                                    Zl                bc                                                                                Zl                ca                                                                    Zl                cb                                                                    Zl                cc                                                    ]                          :                          xe2x80x83                  line                    xe2x80x83                  impedance                    xe2x80x83                  matrix        ,
xe2x80x83If: fault current, 1xe2x88x92d: fault distance;
wherein said fault location equation is derived by using the matrix inverse lemma: (Axe2x88x921+BCD)xe2x88x921=Axe2x88x92AB(Cxe2x88x921+DAB)xe2x88x921DA, to simplify an inverse matrix calculation; and
wherein the fault location equation is derived by direct circuit analysis without using the conventional symmetrical component transformation method.

Method for detecting line-to-ground fault location in power network


Methods and systems for social functionality via a mobile communication device are presented. An example system may include an access device and a communication node. The access device may be located at a commercial venue and communicatively coupled via a local area network with a mobile communication device located at the venue. The communication node may be communicatively coupled to the access device via a wide area network to provide a social networking service related to the venue to a user of the mobile communication device. The access device may exchange information relating to the social networking service between the communication node and the mobile communication device.

On both satellite and cable television distribution systems, numerous sports programs and events, as well as other audio/video content of interest, may be transmitted and presented simultaneously over different broadcast channels. Given the varying interest of potential patrons, some public establishments, such as bars, sports books, and the like, may provide multiple televisions, video monitors, projection systems, and similar audio/video devices to provide many different such programs concurrently for the enjoyment of their clientele. Ordinarily, these devices are placed in relatively close proximity to each other, or are placed in the same large room, so any patron of the establishment may view any of multiple video devices without changing locations within the establishment.
However, given such an arrangement of the audio/video devices within the establishment, allowing each of the audio/video devices, or some related devices, to produce the audio for each program being displayed is impractical due to the confusing, and likely unintelligible, sounds that would result. To prevent such confusion, in some situations the audio associated with a single one of the programs being shown may be produced, such as the sound associated with the most popular program or event being presented in the establishment at the time. Additionally, in some cases, one or more of the audio/video devices may be placed in a "closed captioning mode," in which text reflecting the words spoken by sports announcers or others associated with the program is displayed on the screen to provide at least some reflection of the program audio to the patrons viewing that program.

This patent is subject to a terminal disclaimer.

Venue-oriented social functionality via a mobile communication device


A combination drinking glass lid and game includes a base which operates to cover and seal a drinking glass. The base includes an opening there through for passage of a drinking straw. Supported upon the base is a game of skill or chance, such as a target game.

As society becomes more mobile, the demand for carry out food and beverages is increasing. Cup lids are necessary in order to prevent spillage of beverages during transport and also during consumption, particularly by young children or by others who are at public events or in a mobile environment. Concomitant with the increase in volume of carry out food service, is increasing competitiveness among fast food merchandisers. Toward that end, merchants often offer purchase incentives, such as uniquely decorated serving materials, premiums and the like to consumers.
The present invention provides a drink cup lid which also functions as a game of skill or chance. As such, the present invention provides a unique marketing tool, particularly suited for the fast food industry. The lid of the present invention is uniquely configured to provide a game which may be played while the lid is attached to the drink, without spillage of the drink. Furthermore, the game lid provides a premium which may be removed from the drink after consumption and retained by the customer. As such, the present invention provides a purchase incentive for a customer. Additionally, the lid of the present invention may also be utilized as a souvenir at concerts, sporting events, amusement parks and the like, and as such, may constitute a value added item, allowing beverages to be sold at a premium price.
While the prior art has long employed drink lids of various configurations, such lids have not heretofore been integrated with games of the type described herein. U.S. Pat. No. 4,239,223 discloses a drinking glass having a game of skill integral with the base thereof. This item is relatively difficult to manufacture and does not lend itself to being used as a promotional premium; more importantly, the game cannot be played until after the drink is consumed, because of problems of spillage and the fact that any beverage in the glass will obscure the game portion. U.S. Pat. No. 933,429 discloses a cup having a chamber integral with the base thereof for containing a number of dice. This device is thus similar to that of the '223 patent. U.S. Pat. No. 1,280,300 discloses a flashlight case having a game of skill integral with one end thereof. None of the prior art provides any type of drink lid closure, much less a closure configured in accord with the principles and objectives of the present invention.


A wavelength-converting wheel has a light incident side. The wavelength-converting wheel includes a disc, a heat conductive glue, a reflective layer, a plurality of protrusions, a heat conductive glue, and a wavelength-converting layer. The disc has an inner ring portion and an annular portion. The annular portion is connected to an outer edge of the inner ring portion. The annular portion includes a protrusion structure region. The protrusions are disposed in the protrusion structure region and protrude toward the light incident side. The heat conductive glue is disposed on the protrusion structure region. The reflective layer is disposed on the heat conductive glue. The wavelength-converting layer is disposed on the reflective layer and has a light receiving surface facing the light incident side.

With the market demands for brightness, color saturation, service life, non-toxicity and environmental protection of the projection apparatus, the type of the light source applied on the projection apparatus is evolved from an ultra-high pressure mercury lamp (UHP lamp), a light emitting diode (LED) to a laser diode (LD).
Currently, the costs of high-brightness red laser diodes and green laser diodes are still high. To decrease the cost, a part of the blue light of a blue laser diode is usually applied to excite the phosphor powders on the phosphor wheel to generate a yellow light or a green light, and another part of the blue light of the blue laser diode is reflected by or penetrates through the phosphor wheel. A desired red light is filtered from the yellow light, and then combined with the reflected or penetrated blue light to constitute the three primary colors of red, green, and blue required for the projection images.
Conventionally, a heat conductive glue is applied to adhere a sheet-like phosphor layer made by sintering to a substrate to fabricate a phosphor wheel, or further arranging a reflective layer, such as a sintered reflective layer, between the sheet-like phosphor layer and the substrate. However, the heat conductivity (K) of the heat conductive glue is about 2 W/(m·K) [Watt/(meter·degree)] to 10 W/(m·K), and the heat conduction of the heat conductive glue decreases sharply with the increase in the thickness of the heat conductive glue. If the thickness control of the heat conductive glue is unstable, the heat conductions of the fluorescent layer and the reflective layer will be affected obviously; thereby affecting the wavelength conversion efficiency of the phosphor layer and the reflection efficiency of the reflective layer. Moreover, the material may be deteriorated and damaged (blackened) due to the excessive temperature of the phosphor layer and the reflective layer.
In addition, transparent silicon is also applied to replace the heat conductive glue conventionally. A reflective coating film is disposed on the substrate to replace the reflective layer, and the thickness of silicon is controlled to less than 0.05 mm. However, the heat conductivity of silicon is merely about 0.2 W/(m·K) to 0.3 W/(m·K). Therefore, even if the thickness of the silicon is very thin, the heat conduction of silicon is limited, and thereby the wavelength conversion efficiency of the phosphor layer is poor, and the material may be deteriorated or damaged.
The information disclosed in this "BACKGROUND OF THE INVENTION" section is only for enhancement understanding of the background of the invention and therefore it may contain information that does not form the prior art that is already known to a person of ordinary skill in the art. Furthermore, the information disclosed in this "BACKGROUND OF THE INVENTION" section does not mean that one or more problems to be solved by one or more embodiments of the invention were acknowledged by a person of ordinary skill in the art

Wavelength-converting wheel and projection apparatus


Provided herein include compositions comprising a primer having the nucleic acid sequence of ACeIN-F3_c, a primer having the nucleic acid sequence of ACeIN-B3_a, a primer having the nucleic acid sequence of ACeIN-B3_b, a primer having the nucleic acid sequence of ACeIN-FIP_e, a primer having the nucleic acid sequence of ACeIN-FIP_f, a primer having the nucleic acid sequence of ACeIN-BIP (or ACeIN-BIP-song), a primer having the nucleic acid sequence of ACeIN-LF; and a primer having the nucleic acid sequence of ACeIN-LB. Also provided are methods of detecting human immunodeficiency virus (HIV) nucleic acids in a sample comprising performing reverse transcription-based loop mediated isothermal amplification (RT-LAMP) on a sample using the previously disclosed compositions.

Despite the introduction of efficient antiretroviral therapy, HIV infection and AIDS continue to cause a world-wide health crisis. Further, there is a lack of quantitative viral load assays in the developing world. Thus, there is a need in the art for rapid and quantitative assays that can be used at the point of care with minimal infrastructure.

Compositions, kits, and methods to detect HIV virus

The Trustees of the University of Pennsylvania


A hybrid robotic manipulator adapted to move objects includes a base and a waist mounted on the base. The waist is configured to rotate on the base. The hybrid robotic manipulator further includes a pair of arms mounted on the waist. Each arm includes an upper arm, a forearm serially coupled to the upper arm at an elbow, and a wrist configured to couple the pair of arms at a distal end through a pair of connecting elements. The wrist further includes an end-effector mounted thereon and configured to grip the object and move the object to a desired position.

Commercial and industrial robots are in widespread use for performing complex tasks. Robots perform tasks economically and precisely as compared to human beings. Further, robots are also employed to perform certain jobs that are dangerous, difficult, unsuitable and unsafe for human beings.
The structure of the robots includes kinematic chain having links, actuators and joints, each of which are configured to allow one or more degrees of freedom. Robot mechanisms with six degrees of freedom have been designed, and used in industry for accurately locating an object in a workspace. Conventional mechanisms in robots with six degrees of freedom use either a serial link mechanism or a parallel link mechanism to locate an object. The six degrees of freedom of any solid object include a position of the object's centre of gravity in an orthogonal three dimensional space denoted by x, y, and z co-ordinates, and the object's orientation about the centre of gravity denoted by three angles, often designated as yaw, pitch and roll. Position and orientation are often combined, and are collectively referred to as location.
Serial link mechanisms, which are generally open loop chains, provide for locating an object by means of an arm linkage for position, and a wrist linkage for the orientation. As each successive link in the serial chain is carried by its predecessor, the power required to move each link is compounded by the mass of the actuators powering its successors. Therefore, there is an increase in size and cost of all the actuators except for the last one in the chain. The additional power required does not contribute to the motion of the object being located by the robot. This results in a large ratio of the mass of the robot to the mass of the object or the payload that the robot can locate.
Parallel link mechanisms, which are generally closed loop chains, provide for locating an object by six arm links. In such mechanisms, all the actuators combine to contribute to the motion of the object. However, practically, the space within which the object can be located is limited due to interference of one link with a neighboring link. Parallel link robots have a smaller weight to payload ratio than serial link robots, and are used when their limited workspace is sufficient for the application.
Further, attempts have been made to build a manipulator employing a combination of serial link and parallel link mechanisms. One such manipulator is disclosed in a U.S. Pat. No. 6,047,610 granted to Stocco et al. (hereinafter US '610). FIG. 1 shows a structure of a robotic manipulator M having six degrees of freedom as disclosed by US '610. The manipulator M of US '610 includes first and second five-bar linkages 2 and 3 set on a rotatable base 4 and 5, respectively. Each of the five-bar linkages 2 and 3 are attached to a platform P via respective universal joints U2 and U3. Further, it is apparent from FIG. 1 that the links which form the five-bar linkage 2 are serially connected to each other by using serial link mechanism. Similarly, the links which form the five-bar linkage 3 are serially connected to each other by using serial link mechanism. Further, each of the five-bar linkages 2 and 3 is engaged with the platform P so as to form a closed loop chain or a parallel link.
It should be noted that a movement of each of the five-bar linkages 2 and 3 is limited due to interference of link 2 with link 3 and vice versa. Therefore, the amount of workspace maneuvered by the manipulator M, as disclosed in US '610, is substantially less and is identical to that of a parallel link robot.
Therefore, there is a need for a mechanism which enables a robot to maneuver substantially more amount of workspace than a parallel link robot and has a smaller weight to payload ratio than a serial link robot.

Hybrid serial-parallel linkage based six degrees of freedom robotic manipulator


The present invention is directed to methods of causing malignant B-cells and treating malignant B-cells. These methods involve the use of an inhibitor of PKK activity, whether active directly against PKK or effective to knockdown PKK expression, which when introduced into a malignant B cell (or administered to a patient) is effective to cause cell death of the malignant B cell, thereby treating the B-cell malignancy.

B cells are a critical component of the immune response in mammals, as they are the cells responsible for antibody production (humoral immunity). Each B cell within the host expresses a different antibody—thus, one B cell will express antibody specific for one antigen, while another B cell will express antibody specific for a different antigen. Accordingly, B cells are quite diverse, and this diversity is critical to the immune system. In humans, each B cell can produce an enormous number of antibody molecules (i.e., about 107 to 108). The maturation of B cells (and thus antibody production) most typically ceases or substantially decreases when the foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell or plasma cell will continue unabated; such proliferation can result in a cancer referred to as "B cell lymphoma or multiple myeloma."
B cell lymphomas include both Hodgkin's lymphoma and a broad class of non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma encompasses over 29 types of lymphoma. The distinctions are based on the type of cancer cells, and often the cancers are classified by cell type and rate of growth.
The incidence of non-Hodgkin's lymphoma is much greater than the incidence of Hodgkin's lymphoma: about 8 in 9 cases. According to the American Cancer Society, an estimated 54,000 new non-Hodgkin's lymphoma cases will be diagnosed, 65% of which will be classified as intermediate- or high-grade lymphoma. Patients diagnosed with intermediate-grade lymphoma have an average survival rate of two to five years, and patients diagnosed with high-grade lymphoma survive an average of six months to two years after diagnosis.
Diffuse large B cell lymphoma (DLBCL) is an aggressive and the most common subtype of non-Hodgkin's lymphoma, accounting for 30-40% of lymphoid malignancy. Although DLBCL represents one of the most therapy-responsive malignancies, only approximately 40% of the patients can be cured by the current treatments with multiple therapeutic agents (Abramson et al., "Advances in the Biology and Therapy of Diffuse Large B-cell Lymphoma: Moving Toward a Molecularly Targeted Approach," Blood 106:1164-1174 (2005); Staudt et al., "The Biology of Human Lymphoid Malignancies Revealed by Gene Expression Profiling," Adv Immunol 87:163-208 (2005)). As a result, nearly 10,000 patients die from DLBCL each year in the United States, (Staudt et al., "The Biology of Human Lymphoid Malignancies Revealed by Gene Expression Profiling," Adv Immunol 87:163-208 (2005)), underscoring the importance of better molecular understanding of DLBCL and identifying proper therapeutic targets. Based on gene expression profiles, DLBCL can be divided into at least three subgroups: activated B cell-like (ABC) DLBCL, germinal center B cell-like (GCB) DLBCL, and primary mediastinal B cell lymphoma (PMBL), with the ABC and PMBL subgroups exhibiting higher levels of expression of NF-κB target genes than the GCB subgroup (Rosenwald et al., "Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma," J Exp Med 198:851-862 (2003); Wright et al., "A Gene Expression-based Method to Diagnose Clinically Distinct Subgroups of Diffuse Large B Cell Lymphoma," Proc Natl Acad Sci USA 100:9991-9996 (2003); Alizadeh et al., "Distinct Types of Diffuse Large B-cell Lymphoma Identified by Gene Expression Profiling," Nature 403:503-511 (2000); Savage et al., "The Molecular Signature of Mediastinal Large B-cell Lymphoma Differs from That of Other Diffuse Large B-cell Lymphomas and Shares Features with Classical Hodgkin Lymphoma," Blood 102:3871-3879 (2003)). It was shown that constitutive NF-κB signaling is required for survival of ABC and PMBL DLBCL cells (Feuerhake et al., "NFκB Activity, Function, and Target-gene Signatures in Primary Mediastinal Large B-cell Lymphoma and Diffuse Large B-cell Lymphoma Subtypes," Blood 106:1392-1399 (2005); Davis et al., "Constitutive Nuclear Factor κB Activity is Required for Survival of Activated B Cell-like Diffuse Large B Cell Lymphoma Cells," J Exp Med 194:1861-1874 (2001)), and that small molecules that inhibit IκB kinases (IKK) are selectively toxic for these two DLBCL subgroup cells (Lam et al., "Small Molecule Inhibitors of IκB Kinase Are Selectively Toxic for Subgroups of Diffuse Large B-cell Lymphoma Defined by Gene Expression Profiling," Clin Cancer Res 11:28-40 (2005)). These studies highlight the NF-κB pathway as a promising therapeutic target in B-lymphomas that depend on NF-κB activity for proliferation and survival.
Multiple myeloma ("MM") is a B cell malignancy characterized by the latent accumulation in bone marrow of secretory plasma cells with a low proliferative index and an extended life span. The disease ultimately attacks bones and bone marrow, resulting in multiple tumors and lesions throughout the skeletal system. Approximately 1% of all cancers, and slightly more than 10% of all hematologic malignancies, can be attributed to multiple myeloma. Incidence of MM increases in the aging population, with the median age at time of diagnosis being about 61 years. Current treatment protocols, which include a combination of chemotherapeutic agents such as vincristine, β-chloro-nitrosourea (BCNU), melphalan, cyclophosphamide, Adriamycin, and prednisone or dexamethasone, yield a complete remission rate of only about 5%, and median survival is approximately 36-48 months from the time of diagnosis. Recent advances using high dose chemotherapy followed by autologous bone marrow or peripheral blood progenitor cell (PBMC) transplantation have increased the complete remission rate and remission duration. Yet overall survival has only been slightly prolonged, and no evidence for a cure has been obtained. Ultimately, all MM patients relapse, even under maintenance therapy with interferon-α (IFN-α) alone or in combination with steroids.
MM has been previously associated with enhanced NF-κB activity (Berenson et al., "The Role of Nuclear Factor-κB in the Biology and Treatment of Multiple Myeloma," Semin. Oncol. 28(6):626-33 (2001). New evidence on the molecular mechanisms that underlie aberrant NF-κB activity in MM tumor cells has been found recently (Annunziata et al., "Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma," Cancer Cell 12(2):115-30 (2007); Keats et al., "Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma," Cancer Cell 12(2):131-44 (2007)). The results reported in these studies confirm that diverse mutations can lead to pathological activation of NF-κB signaling in MM, and result in a shift of plasma cells from dependence on the microenvironment to an environment-independent state during progression of MM.
The NF-κB family consists of five members in mammals: p65 (RelA), RelB, c-Rel, NF-κB1(p105/p50), and NF-κB2(p100/p52). Members of NF-κB proteins form homo- or heterodimers and are retained in the cytoplasm prior to activation by the associated IκB proteins, or the precursor proteins p100 or p105, which contain the ankyrin repeats present also in the IκB proteins and, thus, can also function as IκB proteins. Extracellular signals induce NF-κB activation through two major pathways: the classical (also called the canonical pathway) and the alternative (the non-canonical) pathways. Activation of these pathways leads to activation of IKK and degradation or processing of IκB proteins, resulting in the release of sequestered NF-κB proteins and their subsequent translocation into the nucleus and target gene activation (Hayden et al., "Signaling to NF-κB," Genes Dev 18:2195-2224 (2004); Karin, "NF-κB and Cancer: Mechanisms and Targets," Mol Carcinog 45:355-361 (2006); Scheidereit, "IκB Kinase Complexes: Gateways to NF-κB Activation and Transcription," Oncogene 25:6685-6705 (2006)). Abnormal activation of NF-κB contributes to tumor development and progression, as well as to the resistance of cancer cells to chemotherapeutic agents and radiation therapy (Kim et al., "NF-κB and IKK as Therapeutic Targets in Cancer," Cell Death Differ 13(5):738-47 (2006); Karin, "Nuclear Factor-κB in Cancer Development and Progression," Nature 441:431-436 (2006)). Thus, inhibition of NF-κB activation represents a promising approach for cancer therapy (Karin et al., "The IKK NF-κB System: A Treasure Trove for Drug Development," Nat Rev Drug Discov 3:17-26 (2004)). However, as NF-κB is expressed ubiquitously and is involved in a wide variety of normal cellular functions, a general inhibition of NF-κB activity would likely cause serious side effects (Kim et al., "NF-κB and IKK as Therapeutic Targets in Cancer," Cell Death Differ 13(5):738-47 (2006); Luo et al., "IKK/NF-κB Signaling: Balancing Life and Death—A New Approach to Cancer Therapy," J Clin Invest 115:2625-2632 (2005); Li et al., "Inflammation-associated Cancer: NF-κB is the Lynchpin," Trends Immunol 26:318-325 (2005)). To achieve the specificity required for effective therapeutic intervention, it may be necessary to target cancer cell- or signal-specific regulators of NF-κB activation pathways.
The B cell-activating factor belonging to the tumor necrosis factor family (BAFF, also known as BlyS, TALL-1, THANK, zTNF-4, CD257 and TNFSF-13B) is critical for the development and survival of normal B lymphocytes, and activates NF-κB through both the classical and the alternative activation pathways in B cells (Kayagaki et al., "BAFF/BLyS Receptor 3 Binds the B Cell Survival Factor BAFF Ligand Through a Discrete Surface Loop and Promotes Processing of NF-κB2," Immunity 17:515-524 (2002); Claudio et al., "BAFF-induced NEMO-independent Processing of NF-κB2 in Maturing B cells," Nat Immunol 3:958-965 (2002); Schneider, P., "The Role of APRIL and BAFF in Lymphocyte Activation," Curr Opin Immunol 17:282-289 (2005); Sutherland et al., "Targeting BAFF: Immunomodulation for Autoimmune Diseases and Lymphomas," Pharmacol Ther 112:774-786 (2006); Hatada et al., "NF-κB1 p50 is Required for BLyS Attenuation of Apoptosis but Dispensable for Processing of NF-κB2 p100 to p52 in Quiescent Mature B Cells," J Immunol 171:761-768 (2003)). Dysregulated BAFF signaling has been associated with various B-cell malignancies. Elevated levels of BAFF have been detected in the serum of patients with various types of B-cell malignancies, and malignant B cells from patients express abnormally high levels of BAFF and one or more BAFF receptors (He et al., "Lymphoma B Cells Evade Apoptosis Through the TNF Family Members BAFF/BLyS and APRIL," J Immunol 172:3268-3279 (2004); Novak et al., "Expression of BLyS and its Receptors in B-cell non-Hodgkin Lymphoma: Correlation with Disease Activity and Patient Outcome," Blood 104:2247-2253 (2004); Novak et al., "Aberrant Expression of B-lymphocyte Stimulator by B Chronic Lymphocytic Leukemia Cells: A Mechanism for Survival," Blood 100:2973-2979 (2002); Briones et al., "BLyS and BLyS Receptor Expression in non-Hodgkin's Lymphoma," Exp Hematol 30:135-141 (2002); Fu et al., "Constitutive NF-κB and NFAT Activation Leads to Stimulation of the BLyS Survival Pathway in Aggressive B Cell Lymphomas," Blood 107(11):4540-4548 (2006); Moreaux et al., "BAFF and APRIL Protect Myeloma Cells from Apoptosis Induced by Interleukin 6 Deprivation and Dexamethasone," Blood 103:3148-3157 (2004); Elsawa et al., "B-lymphocyte stimulator (BLyS) Stimulates Immunoglobulin Production and Malignant B-cell Growth in Waldenstrom's Macroglobulinemia," Blood 107(7):2882-2888 (2006); Kern et al., "Involvement of BAFF and APRIL in the Resistance to Apoptosis of B-CLL Through an Autocrine Pathway," Blood 103:679-688 (2004). It has been shown that BAFF functions as a crucial autocrine and paracrine survival factor for malignant B cells (Sutherland et al., "Targeting BAFF: Immunomodulation for Autoimmune Diseases and Lymphomas," Pharmacol Ther 112:774-786 (2006); He et al., "Lymphoma B Cells Evade Apoptosis Through the TNF Family Members BAFF/BLyS and APRIL," J Immunol 172:3268-3279 (2004); Novak et al., "Aberrant Expression of B-lymphocyte Stimulator by B Chronic Lymphocytic Leukemia Cells: A Mechanism for Survival," Blood 100:2973-2979 (2002); Fu et al., "Constitutive NF-κB and NFAT Activation Leads to Stimulation of the BLyS Survival Pathway in Aggressive B Cell Lymphomas Blood 107(11):4540-4548 (2006); Moreaux et al., "BAFF and APRIL Protect Myeloma Cells from Apoptosis Induced by Interleukin 6 Deprivation and Dexamethasone," Blood 103:3148-3157 (2004); Novak et al., "Expression of BCMA, TACI, and BAFF-R in Multiple Myeloma: A Mechanism for Growth and Survival," Blood 103:689-694 (2004); Elsawa et al., "B-lymphocyte Stimulator (BLyS) Stimulates Immunoglobulin Production and Malignant B-cell Growth in Waldenstrom's Macroglobulinemia," Blood 107(7):2882-2888 (2006); Kern et al., "Involvement of BAFF and APRIL in the Resistance to Apoptosis of B-CLL Through an Autocrine Pathway," Blood 103:679-688 (2004); Endo et al., "BAFF and APRIL Support Chronic Lymphocytic Leukemia B-cell Survival Through Activation of the Canonical NF-κB pathway," Blood 109:703-710 (2007); Nishio et al., "Nurselike Cells Express BAFF and APRIL, Which Can Promote Survival of Chronic Lymphocytic Leukemia Cells Via a Paracrine Pathway Distinct from That of SDF-1α," Blood 106:1012-1020 (2005), making the BAFF signaling pathway an attractive therapeutic target for B-cell malignancies. Despite the importance of BAFF signaling in both normal and malignant B cells, the mechanisms by which BAFF activates downstream events, including NF-κB activation, remain to be elucidated.
Protein kinase C-associated kinase PKK (also known as DIK and RIP4) was initially identified as a protein kinase C β- and δ-interacting protein (Bahr et al., "DIK, a Novel Protein Kinase that Interacts with Protein Kinase Cdelta. Cloning, Characterization, and Gene Analysis," J Biol Chem 36350-36357 (2000); Chen et al., "Protein Kinase C-associated Kinase (PKK), a Novel Membrane-associated, Ankyrin Repeat-containing Protein Kinase," J Biol Chem 276:21737-21744 (2001)). It belongs to the RIP kinase family, and shares high sequence homology at the N-terminal kinase domain with other members of this kinase family but contains unique C-terminal ankryin repeats (Meylan et al., "The RIP Kinases: Crucial Integrators of Cellular Stress," Trends Biochem Sci 30:151-159 (2005)). Mice deficient in PKK die soon after birth, likely due to suffocation caused by abnormal epidermal differentiation (Holland et al., "RIP4 is an Ankyrin Repeat-containing Kinase Essential for Keratinocyte Differentiation," Curr Biol 12:1424-1428 (2002)). It has been shown that PKK activates NF-κB when overexpressed in non-lymphoid cells (Moran et al., "Protein Kinase C-associated Kinase can Activate NFκB in Both a Kinase-dependent and a Kinase-independent Manner," J Biol Chem 278:21526-21533 (2003); Meylan et al., "RIP4 (DIK/PKK), a Novel Member of the RIP Kinase Family, Activates NF-κB and is Processed During Apoptosis," EMBO Rep 3:1201-1208 (2002); Muto et al., "Protein Kinase C-associated Kinase (PKK) Mediates Bcl10-independent NF-κB Activation Induced by Phorbol Ester," J Biol Chem 277:31871-31876 (2002)).
Despite these prior reports on the relationship between PKK and NF-κB activation, these prior reports fail to demonstrate any function of PKK in the proliferation/survival of cancer cells, particularly B cell malignancies such as lymphomas and multiple myeloma.
The present invention is directed to overcoming these and other deficiencies in the art.


A barrier device for an electrical connector is disclosed. In embodiments, the barrier device can comprise a first barrier element interposedly arranged between a substrate and a base assembly of the electrical connector. A second barrier element arranged for mating engagement with an upper surface of the substrate of the electrical connector; the second barrier element comprising a plurality of openings defined by a plurality of protruding structures that are configured and arranged to accommodate electronic components mounted to the upper surface of the substrate. The barrier device is designed such that the collective arrangement and positioning of the first barrier element and the second barrier element relative to substrate forms a thermal protection barrier and damping mechanism around the substrate.

High powered electronic devices are particularly susceptible to performance variations due to the thermal sensitivity of certain components that operate within the devices. For example, increased temperatures or extreme operating environments can lead to component failures or improper sensor readings. As such, there is a need in the art for a cost efficient and robust device that address the above concerns.

Barrier device for an electrical connector


The substitution of the L-Pro at the 7-position of the peptide hormone bradykinin or other substituted analogs of bradykinin with a D-configuration hydroxyproline ether or thioether converts bradykinin agonists into bradykinin antagonists. The invention further includes the intermediate compounds and additional modifications at other positions within the novel 7-position modified bradykinin antagonists which increase enzyme resistance, antagonist potency, and/or specificity of the new bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of a mammal and human in which an excess of bradykinin or related kinins are produced or injected such as by insect bites.

1. Field of the Invention
This invention relates to compounds which are bradykinin receptor antagonists, pharmaceutical compositions and methods for using these compounds to antagonize the effects of bradykinin in mammals, including humans. More particularly, the invention relates to the substitution of the L-Pro at position 7 with D-hydroxyproline ether or thioether compounds and its intermediate product which convert bradykinin agonists into antagonists and also includes additional modifications at other positions within the 7-position modified bradykinin antagonist which confer increased antagonist potency, resistance to enzymatic degradation, and/or tissue specificity on the D-amino acid-containing bradykinin sequence.
2. Description of the Prior Art
Bradykinin (BK) is a nonapeptide generated as a result of the activity of kallikreins, a group of proteolytic enzymes present in most tissues and body fluids, on kininogens. Once released, kinins produce many physiological responses, including pain and hyperanalgesia by stimulating C- and A-fibers in the periphery. There is also considerable evidence that kinins contribute to the inflammatory response.
Bradykinin, and its physiologically important related peptides kallidin (Lys-bradykinin) and Met-Lys-bradykinin, exhibit physiological actions which qualify them as mediators of inflammatory reactions, hypotensive states, and pain. Bradykinin is overproduced in pathological conditions such as septic shock, anaphylaxis, rhinitis, asthma, inflammatory bowel disease, and certain other conditions including acute pancreatitis, post-gastrectomy dumping syndrome, carcinoid syndrome, migraine, and angioneurotic edema. The production of bradykinin from the plasma results in pain at the site of the pathological condition, and the overproduction intensifies the pain directly or via bradykinin-induced activation of the arachidonic acid pathway which produces prostaglandins and leukotrienes, the more distal and actual mediators of inflammation.
In addition to its analgesic and proinflammatory effects, bradykinin is a vasodilator. Because of its ability to lower blood pressure, bradykinin has been implicated in the pathogenesis of several shock syndromes, particularly septic or endotoxic shock. Bradykinin is also a potent bronchoconstrictor in animals and asthmatic subjects and it has been implicated as a contributor to the pathogenesis of airway inflammatory conditions such as allergic asthma and rhinitis.
Thus, a bradykinin inhibitor or bradykinin receptor antagonist is expected to possess a number of desirable biological effects in the treatment, for example, of inflammation, septic shock, asthma, burn pain, rhinitis, and allergy.
The search for understanding the mechanism of action of bradykinin, which is essential for the development of useful tools for diagnostic use, and for the development of therapeutic agents aimed at alleviating the intense pain caused by the production and overproduction of bradykinin, has been hindered by the lack of specific sequence-related competitive antagonists of bradykinin.
Several non-peptide, non-specific and non-selective antagonists of one or more of the biological activities of bradykinin have been described among compounds as diverse as analgesics and anti-inflammatory substances, which act via the prostaglandin system and not directly on bradykinin receptors. These are antihistamines; bradykinin-antibodies; benzodiazepine derivatives; high molecular weight ethylene oxide polymers; gallic acid esters; and serotonin inhibitors. None of these compounds or classes of compounds specifically inhibit the effects of bradykinin.
Heptyl esters of various amino acid-containing substances, such as single basic amino acids, the dipeptide Phe-Gly, and analogs of C-terminal peptide fragments of bradykinin (i.e., Pro-Phe-Arg) have been reported as anti-bradykinin substances. When tested in bradykinin assay systems, they prove to be weak partial agonists/antagonists, depending on the dose, with little specificity for inhibiting bradykinin action.
Preparations of damaged vascular tissue have been reported to respond to bradykinin analogs which lack the C-terminal arginine residue, but not to bradykinin itself, and analogs of these des-Arg(9)-bradykinins have been developed as antagonists for the non-physiological activity of bradykinin. These antagonists have no significant bradykinin-like agonist effects, nor any antagonist effect on any of the physiologically significant kinin-responding systems. Furthermore, several bradykinin analogs containing the O-methyl ether of Tyr residues at positions 5 and/or 8 have been reported to produce mixed agonist/antagonist activity on isolated uteri of galactosemic rats, but not on normal rats.
Other changes in the bradykinin molecule have been additions of amino acids at the N-terminal end which affect the rate of enzymatic degradation of bradykinin in vivo.
It has been reported that the half life of bradykinin in the systemic circulation is less than 30 seconds. Bradykinin appears to be completely destroyed (98-99% destruction) on a single passage through the pulmonary circulation as determined in an anesthetized rat by measuring the depressor effects of an agonist following intra-aortic (IA) (bypassing the pulmonary circulation) and intravenous (IV) administration. Resistance of bradykinin agonists to pulmonary kininase destruction in vivo also appears promoted by addition of single (i.e., D-Arg-, D-Lys-, Lys-) and double (D-Lys-Lys-) basic amino acid residues to the N-terminal of the bradykinin sequence. The addition of the dipeptide Lysxe2x80x94Lys to the N-terminal of bradykinin agonists has been reported to confer complete resistance to in vivo destruction on initial passage through the pulmonary circulation.
Several research groups have prepared bradykinin receptor antagonists. Stewart and Vavrek in U.S. Pat. No. 4,801,613, (which reference is incorporated in its entirety herein) disclose a series of bradykinin antagonists wherein the L-Pro at the 7-position of the peptide hormone bradykinin or other substituted analogs of bradykinin is substituted with an aromatic amino acid of the D-configuration which converts bradykinin agonists into bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of a mammal and human in which an excess of bradykinin or related kinins are produced or injected as by insect bites into the body. The specific L-Pro substitutions are selected from the group consisting of D-Nal, D-PNF, D-Phe, D-Tyr, D-Pal, D-OMT, D-Thi, D-Ala, D-Trp, D-His, D-Homo-Phe, D-Phe, pCl-D-Phe (CDF), D-Phg, D-Val, D-Ile, D-Leu, and MDY.
In U.S. Pat. No. 4,693,993, also to Stewart and Vavrek, additional L-Pro substitution materials are disclosed.
Copending application Ser. No. 08/167,051, filed Dec. 16, 1993, which is a continuation of application Ser. No. 07/866,385 filed Apr. 14, 1992, which in turn was a continuation-in-part of Ser. No. 07/687,950 filed Apr. 19, 1991, discloses and claims additional L-Pro substitution materials with hydroxyproline ether and thioether compounds.
U.S. Pat. No. 4,242,329 to Claeson et al. disclose the formation of Bradykinin-inhibiting tripeptide derivatives. A process for producing said tripeptide derivatives by synthesis and purification methods which are known in the peptide chemistry is also disclosed as well as pharmaceutical preparations comprising the tripeptide derivative.
Published European Patent Applications No. 0 413 277 A1 and 0 370 453 AZ disclose bradykinin antagonists.
The present invention resides in the discovery that the novel compounds identified below, are potent bradykinin receptor antagonists. The compounds are useful in the treatment of various diseases including inflammatory disorders, asthma, septic shock, and burn pain. Included in the invention are pharmaceutical compositions containing the inventive compounds and methods of using the compounds as bradykinin receptor antagonists.
More particularly, the invention relates to the modification of the sequence of the mammalian peptide hormone bradykinin (Arg Pro Pro Gly Phe Ser Pro Phe Arg), SEQ ID NO 1, and pharmaceutically acceptable salts thereof, at the Pro residue at position 7 in a unique manner which produces sequence-related analogues that act as specific and competitive inhibitors of the biological activities of bradykinin. The invention specifically relates to the substitution of the L-Pro at position 7 with a material having the D-configuration (*) and the formula:
wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2; and pharmaceutically acceptable salts thereof.
More specifically, the invention relates to the formation of peptides having the formula:
N-A-B-C-D-E-F-G-H-I-J-Cn
wherein N is hydrogen;
A and B are independently selected from the group consisting of L-Arg, D-Arg, D-Gln, L-Gln, D-Asn, L-Asn, N-xcex5-acetyl-D-lysine, xcex5-acetyl-L-lysine, NG-p-tosyl-Arg, NG-nitro-Arg, Lysxe2x80x94Lys, acetyl-D-Arg, L-Citrulline, L-Lys, Sar, and D-Lys;
C and D are a direct bond or are independently selected from the group consisting of Pro, dehydroPro, 4Hyp, Tic, Aoc, L-azetidine-2-carboxylic acid, Eac, Gly, Thz, Oic, Ala, and Aib;
E is a direct bond or is selected from the group consisting of Gly, Ala, Thr, and Ser;
F is selected from the group consisting of Phe, Thi, Leu, Ile, Tic, Oic, homoPhe, phenylGly, xcex2-cyclohexylalanine, Nal, and Val;
G is a direct bond or is selected from the group consisting of Ser, Thr, 4Hyp, Gly, Val, and Ala;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Tic, L-indoline-2-carboxylic acid, octahydro-1H-isoindole-1-carboxylic acid, pipecolinic acid, Pro, 4Hyp, azetidine-2-carboxylic acid, Aib, Leu, Ile, Val, Thi, Phe, homoPhe, and compounds of the following formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula RNHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is selected from the group consisting of Arg, Orn, Asn, Gln, N-xcex5-acetyl-Lys, N-xcex4-acetyl-Orn, and Lys;
Cn is a hydroxyl group or a C-terminal extension is selected from the group consisting of amide, alkoxy group, an acidic, basic or neutral aliphatic, aromatic, cyclic amino acid residue of the D- or L-configuration, and a peptide extension composed of D- or L-amino acids; and pharmaceutically acceptable salts thereof.
A particularly preferred material is a peptide wherein:
N is hydrogen;
A and B are independently selected from the group consisting of L-Arg, D-Arg, Lysxe2x80x94Lys, Lys;
C and D are independently selected from the group consisting of Pro, dehydroPro, and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe, Thi, Leu, and xcex2-cyclohexylalanine;
G is a direct bond or is selected from the group consisting of Ser and Thr;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Pro, pipecolinic acid, Leu, Phe, Thi, Tic, and compounds of the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is selected from the group consisting of Arg and Lys;
Cn is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
Another preferred material is a peptide wherein:
N is hydrogen;
A is D-Arg;
B is Arg;
C is Pro;
D is selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe, Leu, and Thi;
G is a direct bond or is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, isobutyl, cyclohexylmethyl, allyl, methallyl, prenyl, benzyl, phenyl, nitrophenyl, napthal, chlorophenyl, 4-methylphenyl, 3-phenylpropyl, phenylpropyl, and methylbutyl, and where X is SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Tic, and compounds of the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, isobutyl, cyclohexylmethyl, allyl, methallyl, prenyl, benzyl, phenyl, 4-chlorophenyl, 4-methylphenyl, and phenylcarbamoyl and where X is either SOn or oxygen, and n=0, 1, or 2;
J is Arg;
Cn is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
The present invention also includes the intermediate compound having the D-trans formula:
Preferred peptides according to the invention include the following nonlimiting materials:
Hyp Pro Alkyl Ethers and Substituted Alkyl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-hydroxyproline cis methyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-hydroxyproline cis propyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline cis ethyl ether)-Oic Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Aoc-Arg
Proxe2x80x94Pro Alkyl Ethers
Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Aoc-Arg
Arylalkyl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans 3xe2x80x2-phenylpropyl ether)-Oic-Arg
Thioalkyl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiomethylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thioethylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiopropylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiomethylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thioethylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiopropylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiomethylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thioethylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiopropylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiomethylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thioethylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiopropylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiomethylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thioethylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiopropylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiomethylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thioethylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiopropylproline)-Aoc-Arg
Thioaryl Ethers and Substituted Aryl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiophenylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiophenylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiophenylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiophenylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiophenylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiophenylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans 4xe2x80x2-nitrophenyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans napthal thioether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline cis phenyl thioether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans 2xe2x80x2-nitrophenyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-hydroxyproline trans phenyl thioether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans p-chlorophenyl thioether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans p-methylphenyl thioether)-Oic-Arg
Allyl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans allyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans allyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans allyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans allyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans allyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans allyl ether)-Aoc-Arg
Hydroxyproline Ethers Hydroxyproline Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline trans methyl ether)-Arg
Another embodiment of the invention involves a pharmaceutical composition useful as a bradykinin receptor antagonist comprising a pharmaceutical carrier and an effective amount of the novel bradykinin-type peptide. The invention also involves a process for antagonizing bradykinin receptor activity in mammals which comprises: administering to a subject an effective amount of the novel compound to antagonize bradykinin receptor activity.
A further embodiment involves a pharmaceutical preparation for treating local pain and inflammation from burns, wounds, cuts, rashes and other such trauma, and pathological conditions caused by the production of bradykinin or related kinins by an animal which comprises administering an effective amount of the novel peptide sufficient to antagonize bradykinin with a suitable pharmaceutical carrier. Another aspect of this invention involves a process for treating local pain and inflammation which comprises administering an effective amount of the pharmaceutical preparation to an animal in need thereof.
The present compounds which are bradykinin receptor antagonists have the following formula:
N-A-B-C-D-E-F-G-H-I-J-Cn
wherein N is hydrogen;
A and B are independently selected from the group consisting of L-Arg, D-Arg, D-Gln, L-Gln, D-Asn, L-Asn, Nxcex5E-acetyl-D-lysine, xcex5-acetyl-L-lysine, NG-p-tosyl-Arg, NG-nitro-Arg, Lysxe2x80x94Lys, acetyl-D-Arg, L-Citrulline, L-Lys, Sar, and D-Lys;
C and D are a direct bond or are independently selected from the group consisting of Pro, dehydroPro, 4Hyp, Tic, Aoc, Ala, L-azetidine-2-carboxylic acid, Eac, Gly, Thz, Oic, and Aib;
E is a direct bond or is selected from the group consisting of Gly, Ala, Thr, and Ser;
F is selected from the group consisting of Phe, Thi, Leu, Ile, Tic, Oic, homoPhe, phenylGly, xcex2-cyclohexylalanine Nal, and Val;
G is a direct bond or is selected from the group consisting of Ser, Thr, 4Hyp, Gly, Val, and Ala;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Tic, L-indoline-2-carboxylic acid, octahydro-1H-isoindole-1-carboxylic acid, pipecolinic acid, Pro, 4Hyp, azetidine-2-carboxylic acid, Aib, Leu, Ile, Val, Thi, Phe, homoPhe, and compounds of the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is selected from the group consisting of Arg, Orn, Asn, Gln, N-xcex5-acetyl-Lys, N-xcex4-acetyl-Orn, and Lys;
Cn is a hydroxyl group a C-terminal extension selected from the group consisting of amide, alkoxy group, an acidic, basic or neutral aliphatic aromatic, and cyclic amino acid residue of the D- or L-configuration, and a peptide extension composed of D- or L-amino acids; and pharmaceutically acceptable salts thereof.
Formula 2
Preferred compounds are those in which:
N is hydrogen;
A and B are independently selected from the group consisting of L-Arg, D-Arg, Lysxe2x80x94Lys, Lys;
C and D are independently selected from the group consisting of Pro, dehydroPro, and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe, Thi, Leu, and xcex2-cyclohexylalanine;
G is a direct bond or is selected from the group consisting of Ser and Thr;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Pro, pipecolinic acid, Leu, Phe, Thi, Tic, and compounds of the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is selected from the group consisting of Arg and Lys;
Cn is hydroxyl;
and pharmaceutically acceptably salts thereof.
Formula 3
Most preferred are compounds wherein:
N is hydrogen;
A is D-Arg;
B is Arg;
C is Pro;
D is selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe, Leu, and Thi; G is a direct bond or is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, isobutyl, cyclohexylmethyl, allyl, methallyl, prenyl, benzyl, phenyl, nitrophenyl, napthal, chlorophenyl, methylphenyl, phenylpropyl, and methylbutyl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Tic, and compounds of the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, isobutyl, cyclohexylmethyl, allyl, methallyl, prenyl, benzyl, phenyl, and phenylcarbamoyl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is Arg;
Cn is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
Formula 4
The inventive compositions also include the following preferred formulations:
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Tic, Aoc, and Oic;
J is Arg;
CN is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
Formula 5
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe and Thi;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is Oic;
J is Arg;
CN is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
Formula 6
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, phenyl, chlorophenyl, naphthyl, methylphenyl, and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 7
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, 3-phenylpropyl, methylbutyl, and phenyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 8
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe and Thi;
G is a direct bond or is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, chlorophenyl, methylphenyl, phenylpropyl, and phenyl and X is sulfur or oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 9
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is methyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 10
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is ethyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 11
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is propyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 12
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is phenyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 13
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is allyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 14
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is 3-methylbutyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 15
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is 3-phenylpropyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 16
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is methyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 17
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is ethyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 18
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is propyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 19
A is D-Arg;
B is Arg;;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is phenyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 20
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is p-chlorophenyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 21
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is p-methylphenyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 22
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, allyl, methallyl, benzyl, phenyl, nitrophenyl, napthal, chlorophenyl, methylphenyl, phenylpropyl, methylbutyl and phenyl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is a compound of the formula:
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, allyl, methallyl, benzyl, methylphenyl, chlorophenyl, phenylpropyl, and phenyl and where X is either SOn or oxygen, and n=0, 1, or 2;
J is Arg;
and pharmaceutically acceptable salt thereof.
The invention also contemplates the preparation of an intermediate chemical entity as well as its use to prepare a bradykinin antagonist peptide. The intermediate is in the D-configuration, either the cis or trans structure, preferably trans has formula:
wherein R is-selected from the group consisting of, hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C8 alkenyl, an aryl group, and an arylalkyl group;
R3 is H or a suitable amine protecting group; provided that when R is hydrogen, R2 is a C1-C6 alkyl group.
As used in the specification and claims, xe2x80x9calkylxe2x80x9d is a paraffinic hydrocarbon group which may be derived from an alkane by dropping one hydrogen from the formula, such as methyl, ethyl, propyl, isopropyl, butyl, and so forth; xe2x80x9csubstituted C1-C6 alkylxe2x80x9d is a branched alkyl, such as methyl butyl; xe2x80x9carylxe2x80x9d is an aromatic ring compound such as benzene, phenyl, naphthyl; xe2x80x9csubstituted arylxe2x80x9d is a substituted aromatic ring, such as nitro substitution, or halogen substitution; and xe2x80x9caralkylxe2x80x9d is an aryl being attached through an alkyl chain, straight or branched, containing from one through six carbons, such as a phenylpropyl group. A xe2x80x9cdirect bondxe2x80x9d is a bond which replaces a particular amino acid compound between adjacent amino acids and which amino acid may also be indicated to be absent by the term xe2x80x9cnullxe2x80x9d. The phrase xe2x80x9ca suitable amine protecting groupxe2x80x9d is a group, such as BOC (t-butyloxy-carbonyl-) protecting group which protects the amine moiety from reaction and which can be removed under mild conditions so as not to affect the rest of the molecule.
Exemplary Boc protected amino acids include the following nonlimiting materials:
N-Boc-L-cis-4-methoxyproline;
N-Boc-L-cis-4-(n-propoxy)proline;
N-Boc-L-trans-4-methoxyproline;
N-Boc-L-trans-4-(n-propoxy)proline;
N-Boc-L-trans-4-ethoxyproline;
N-Boc-D-trans-4-phenylthioproline;
N-Boc-D-trans-4-methoxyproline;
N-Boc-L-trans-4-cyclohexylmethoxyproline;
N-Boc-D-trans-4-(3-methylbutoxy)proline;
N-Boc-D-trans-4-(3-phenylpropoxy)proline;
N-Boc-D-trans-4-(p-chlorophenylthio)proline;
N-Boc-D-trans-4-(2-naphthalenethio)proline;
N-Boc-D-trans-4-hydroxyproline methyl ester;
N-Boc-D-trans-4-(n-propoxy)proline;
N-Boc-D-trans-4-ethoxyproline;
N-Boc-L-trans-4-phenylthioproline;
N-Boc-L-trans-4-phenoxyproline;
N-Boc-D-trans-4-(2-nitrophenoxy)proline;
N-Boc-D-cis-4-phenylthioproline;
N-Boc-D-trans-4-(4-nitrophenoxy)proline.
N-Boc-L-trans-4-ethoxyproline
N-Boc-D-trans-4-(p-methylphenylthio)proline
N-Boc-L-cis-4-ethoxyproline
N-Boc-L-trans-4-O-phenylcarbamoylproline
Definitions of the amino acid abbreviations used herein are as follows:
Arg is arginine; Ala is alanine; Aib is 2-aminoisobutyric acid; Aoc is (S,S,S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid; Asn is asparagine; Eac is xcex5-aminocaproic acid; Gln is glutamine; Gly is glycine; Ile is isoleucine; Leu is leucine; Lys is lysine; Met is methionine; Nal is beta-2-naphthylalanine; Orn is ornithine; Pro is proline; dehydroPro is 3,4-dehydroproline; homoPhe is homophenylalanine; 4Hyp is 4-hydroxyproline; Ser is serine; Sar is sarcosine; Thi is beta-2-thienylalanine; Thr is threonine; Thz is thiazolidine-4-carboxylic acid; Phe is phenylalanine; phenylGly is 2-phenylglycine; Tic is tetrahydroisoquinoline-3-carboxylic acid; Oic is (2S, 3aS, 7aS)-octahydro-1H-indole-2-carboxylic acid; Val is valine. Further more, prenyl is a 3-methyl-2-butenyl radical.
Aoc can be prepared by the method of V. Teetz, R. Geiger and H. Gaul, Tetrahedron Lett. (1984), 4479. Tic can be prepared by the method of K. Hayashi, Y. Ozaki, K. Nunami and N. Yoneda, Chem. Pharm. Bull. (1983) 31, 312.
All amino acids residues, except Gly, and Sar, described in the specification are preferably of the L-configuration unless otherwise specified. It would be recognized, however, that the 7 position must always be the D-configuration whereas the hydroxyproline ethers and thioethers of position 8 may be either in the D- or L-configuration. The symbols and abbreviations used for amino acids, their derivatives and protecting groups, and peptides and their salts are those customarily used in peptide chemistry. (See Biochem. J. (1972), 126, 773), which Journal reference is hereby incorporated by reference).
Table I shows the general location of the amino acid groups as used herein.
The synthesis of the peptides of this invention including derivation, activation, and coupling of protected amino acid residues, and their purification, and the analytical methods for determining identity and purity are included in the general body of knowledge of peptide chemistry, as described in Houben Weyl Methoden der Organischen Chemie, (1974), Vol. 16, parts I and II for solution-phase synthesis, and in Solid Phase Peptide Synthesis, (1984), by Stewart and Young for synthesis by the solid-phase method of Merrifield.
Any chemist skilled in the art of peptide synthesis can synthesize the peptides of this invention by standard solution methods or by manual or automated solid phase methods.
The appropriate hydroxyproline substituents used in the 7-position are prepared by the process described in the Examples and depicted in the sequences shown below. The starting materials are commercially available and can be prepared by known procedures. Both the cis and trans stereoisomers can be prepared by these means and are within the scope of the present invention.
In Scheme II M represents sodium, potassium and other useable salts such as alkaline earth metals and alkali metals and X is oxygen or sulfur.
Alternately, they also can be prepared by the method of Scheme II from commercially available starting materials.
The preparation of compounds for administration in pharmaceutical preparations may be performed in a variety of methods well known to those skilled in the art. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid; and organic acids such as tartaric acid, fumaric acid, lactic acid, oxalic acid, ethylsulfonic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the hydrochloride, sulfate, phosphate, nitrate, methanesulfonate, tartrate, benzenesulfonate, p-toluensulfonate, and the like, salt, respectively.
The compounds of the invention may contain an asymmetric carbon atom. Thus, the invention includes the individual stereoisomers, and the mixtures thereof. The individual isomers may be prepared or isolated by methods known in the art.
Therapeutic applications of the novel bradykinin antagonists include not only treatment for the production of bradykinin or related kinins by the animal but also the injection of bradykinin related peptides into an animal as a result of bites and stings. Topical application alone or in combination with subcutaneous utilization of the bradykinin antagonists of the invention can be employed to treat the effects of bradykinin-related peptides causing pain, inflammation and swelling.
The therapeutic use of bradykinin antagonists of this invention for other traumatic inflammatory or pathological conditions which are known to be mediated by bradykinin or exacerbated by an overproduction of bradykinin can also be achieved. These conditions include local trauma such as wounds, burns and rashes, angina, arthritis, asthma, allergies, rhinitis, shock, inflammatory bowel disease, low blood pressure, and systemic treatment of pain and inflammation.
In parenteral administration of the novel compounds and compositions of the invention the compounds may be formulated in aqueous injection solutions which may contain antioxidants, buffers, bacteriostats, etc. Extemporaneous injection solutions may be prepared from sterile pills, granules or tablets which may contain diluents, dispersing and surface active agents, binders and lubricants which materials are all well known to the ordinary skilled artisan.
In the case of oral administration, fine powders or granules of the compound may be formulated with diluents and dispersing and surface active agents, and may be prepared in water or in a syrup, in capsules or cachets in the dry state or in a non-aqueous suspension, where a suspending agent may be included. The compounds may also be administered in tablet form along with optional binders and lubricants, or in a suspension in water or syrup or an oil or in a water/oil emulsion and may include flavoring, preserving, suspending, thickening, and emulsifying agents. The granules or tablets for oral administration may be coated and other pharmaceutically acceptable agents and formulations may be utilized which are all known to those skilled in the pharmaceutical art.
Solid or liquid carriers can also be used. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Ointments and creams are prepared using various well known hydrophilic and hydrophobic bases. Topical reservoirs suitably are prepared using known polymeric materials such as various acrylic-based polymers selected to provide desired release characteristics. Suppositories are prepared from standard bases such as polyethylene glycol and cocoa butter.
The method of treatment according to this invention comprises administering internally or topically to a subject an effective amount of the active compound. Doses of active compounds in the inventive method and pharmaceutical compositions containing same are an efficacious, nontoxic quantity selected from the range of 0.01 to 100 mg/kg of active compound, preferably 0.1 to 50 mg/kg. Persons skilled in the art using routine clinical testing are able to determine optimum doses for the particular ailment being treated. The desired dose is administered to a subject from 1 to 6 or more times daily, orally, rectally, parenterally, topically, or by inhalation.
The efficacy of the inventive compounds of this invention as bradykinin receptor antagonists can be determined using the bradykinin binding and tissue assays described herein. The results of these assays demonstrate that the novel compounds are potent, selective bradykinin receptor antagonists.
The following examples are illustrative of preferred embodiments of methods of preparation and compounds of the invention and are not to be construed as limiting the invention thereto.