This invention is a method of treating cancer, including carcinomas and sarcomas through the administration of a pharmaceutical composition containing a pyridinylimidazole carbamate. The pyridinylimidazole carbamate is selected from the group consisting of:

A method of treating cancer, including carcinomas and sarcomas, with a pyridinylimidazole carbamate is provided. The pharmaceutical composition containing pyridinylimidazole carbamate is also claimed.
Cancers are a leading cause of death in animals and humans. The exact cause of cancer is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of cancers and tumors has been shown by a number of researchers.
Many types of chemotherapeutic agents have been shown to be effective against cancers and tumor cells, but not all types of cancers and tumors respond to these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism for the action of these chemotherapeutic agents are not always known.
Despite advances in the field of cancer treatment the leading therapies to date are surgery, radiation and chemotherapy. Chemotherapeutic approaches are said to fight cancers that are metastasized or ones that are particularly aggressive. Such cytocidal or cytostatic agents work best on cancers with large growth factors, i.e., ones whose cells are rapidly dividing. To date, hormones, in particular estrogen, progesterone and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti-metabolites form the bulk of therapies available to oncologists. Ideally cytotoxic agents that have specificity for cancer and tumor cells while not affecting normal cells would be extremely desirable. Unfortunately, none have been found and instead agents which target especially rapidly dividing cells (both tumor and normal) have been used.
The development of materials that would target tumor cells due to some unique specificity for them would be a breakthrough. Alternatively, materials that were cytotoxic to tumor cells while exerting mild effects on normal cells is also desirable.
Carbendazim, a benzimidazole carbamate, has been studied as a cancer treatment. See U.S. Pat. No. 5,767,138 issued Jun. 16, 1998 to J. B. Camden.
It has been found that pyridinylimidazole carbamates can be used to treat cancer. Alkyl pyridinylimidazole carbamate has been used as an anthelmintic (See GB 1,318,859 and U.S. Pat. No. 3,590,045.)
Claimed herein is a method of treating cancer, in particular, treating cancers in warm blooded animals and humans, comprising administering a therapeutically effective amount of a composition comprising one or more pyridinylimidazole carbamate compounds selected from the group consisting of:
wherein X is independently selected from the group consisting of halo, for example, bromo, fluoro, chloro, iodo; hydroxyl, alkyl of less than 8 carbon atoms or alkoxy of less than 8 carbon atoms; n is a positive integer less than 4; and R or R1 are independently selected from hydrogen or an alkyl group of from 1 to 8 carbons and its pharmaceutically acceptable salts and prodrugs thereof. Preferably R1 is an alkyl group of less than 3 carbon atoms, the preferred compounds are pyridinylimidazole carbamate wherein X is hydrogen, methyl or ethyl and R is methyl or hydrogen and R1 is methyl or ethyl.
Preferably the compound is imidazo [4,5-b]pyridine-2-carbamic acid, methyl ester which has the formula:
The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a pyridinylimidazole carbamate.
These compositions have been discovered to inhibit the growth of cancer or other tumors in humans or animals by administration of a therapeutically effective amount of the composition, preferably by administering pyridinylimidazole carbamate to the site of the cancer.
More specifically, this invention provides an anti-cancer composition comprising a pharmaceutical carrier and pyridinylimidazole carbamate as defined herein along with a method for treating such cancers. The composition can be used in conjunction with other chemotherapeutic agents and other cancer treatments.
A. Definitions:
As used herein, a xe2x80x9cpharmaceutically acceptablexe2x80x9d component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
As used herein, the term xe2x80x9csafe and effective amountxe2x80x9d refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. By xe2x80x9ctherapeutically effective amountxe2x80x9d is meant an amount of a compound of the present invention effective to yield the desired therapeutic response. For example, an amount effective to delay the growth of or to cause a cancer, either a sarcoma or lymphoma, or to shrink the cancer or prevent metastasis. The specific safe and effective amount or therapeutically effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal or animal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.
As used herein, a xe2x80x9cpharmaceutical saltxe2x80x9d is salt of the pyridinylimidazole carbamate which has been modified by making acid or base salts of the compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. Preferably the salts are made using an organic or inorganic acid. These preferred acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. The most preferred salt is the hydrochloride salt.
As used herein, a xe2x80x9cpharmaceutical carrierxe2x80x9d is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the pyridinylimidazole carbamate to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutical carrier.
As used herein, xe2x80x9ccancerxe2x80x9d refers to all types of cancer or neoplasm or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancers are cancer of the brain, breast, pancreas, cervix, colon, head and neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma.
The term xe2x80x9cleukemiaxe2x80x9d refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). The P388 leukemia model is widely accepted as being predictive of in vivo anti-leukemic activity. It is believed that compound that tests positive in the P388 assay will generally exhibit some level of anti-leukemic activity in vivo regardless of the type of leukemia being treated. Accordingly, the present invention includes a method of treating leukemia, and, preferably, a method of treating acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross"" leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling""s leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.
The term xe2x80x9csarcomaxe2x80x9d generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas which can be treated with pyridinylimidazole carbamate and optionally a potentiator and/or chemotherapeutic agent include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy""s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms"" tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing""s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin""s sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen""s sarcoma, Kaposi""s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.
The term xe2x80x9cmelanomaxe2x80x9d is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas which can be treated with pyridinylimidazole carbamate and optionally a potentiator and/or another chemotherapeutic agent include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman""s melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma.
The term xe2x80x9ccarcinomaxe2x80x9d refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas which can be treated with pyridinylimidazole carbamate and optionally a potentiator and/or a chemotherapeutic agent include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hxc3xcrthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher""s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.
Additional cancers which can be treated with pyridinylimidazole carbamate according to the invention include, for example, Hodgkin""s Disease, Non-Hodgkin""s Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, and prostate cancer.
As used herein, the xe2x80x9cpyridinylimidazole carbamatexe2x80x9d or xe2x80x9cpyridinylimidazole carbamate compoundxe2x80x9d are used interchangeably to mean those chemicals having the formula:
wherein X is independently selected from the group consisting of halo, for example, bromo, fluoro, chloro, iodo; hydroxyl, alkyl of less than 8 carbon atoms or alkoxy of less than 8 carbon atoms; n is a positive integer less than 4; and R and R1 are independently selected from hydrogen or an alkyl group of from 1 to 8 carbons and its pharmaceutically acceptable salts and prodrugs thereof. Preferably R is hydrogen and R1 is an alkyl group of less than 3 carbon atoms. More specific pyridinylimidazole carbamates are described in detail below.
By xe2x80x9calkylxe2x80x9d as used herein is meant a straight, branched or cyclic alkane derivatives. Preferably the alkyl is methyl or ethyl. While tert-butyl is a preferred alkyl, it is generally not present as more than one substituent due to its size.
As used herein xe2x80x9ccombination therapyxe2x80x9d or xe2x80x9cadjunct therapyxe2x80x9d means that the patient in need of the drug is treated or given another drug for the disease in conjunction with the pyridinylimidazole carbamate. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously.
B. The Pyridinylimidazole Carbamate
The compounds have the following structure:
wherein X is independently selected from the group consisting of halo, for example, bromo, fluoro, chloro, iodo; hydroxyl, alkyl of less than 8 carbon atoms or alkoxy of less than 8 carbon atoms; n is a positive integer less than 4; and R and R1 are independently selected from the group of hydrogen or an alkyl group of from 1 to 8 carbons and pharmaceutically acceptable salts and prodrugs thereof. Preferably R1 is an alkyl group of less than 3 carbon atoms and R is hydrogen.
The pyridinylimidazole carbamate compounds also include prodrugs. xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug according to the formula of the pyridinylimidazole carbamate described above in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the pyridinylimidazole carbamate compound are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein amine or hydroxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free amino or hydroxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of amine or hydroxyl functional groups in the pyridinylimidazole carbamates; and the like. Aryl sulfonates, e.g. p-tolunesulfonates of hydroxyl which would hydrolyze to the free hydroxyl in the body.
The pharmaceutically acceptable salts of the pyridinylimidazole carbamate includes the conventional non-toxic salts or the quaternary ammonium salts of the pyridinylimidazole carbamate formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention are synthesized from the pyridinylimidazole carbamate which contain a basic moiety by conventional chemical methods. Generally, such salts are prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418.
Synthesis
The pyridinylimidazole carbamate is prepared in a number of ways well known to one skilled in the art of organic synthesis. They can be synthesized by starting with a substituted 2,3 -diaminopyridine. This compound is then converted to the pyridinylimidazole carbamate by cyclizing with isothiourea reagent. Isothiourea is prepared from 2-methyl-2-thiopseudourea sulfate and methyl chloroformate by reaction in a water-dichloromethane system under phase transfer conditions. This method is illustrated for the synthesis below.
The isothiourea reagent can be substituted to produce different substituent groups on the carbamate portion of the compound. The diaminopyridine can also be a substituted pyridine, for example, 3-methyl -1, 2-diaminopryidine.
See for example, the following references which describe methods of synthesis of pyridinylimidazole carbamates.
Berthold, et al, U.S. Pat. No. 3,590,045 (1971);
Boesch, GB 1,318,859 (1971)
One skilled in the art of organic synthesis can modify these reaction to make other compounds used herein.
C. Combination Therapy
In some embodiments, pyridinylimidazole carbamate is used in combination with one or more potentiators and/or chemotherapeutic agents for the treatment of cancer or tumors. These combinations can be administered together or sequentially.
An exemplary potentiator is triprolidine or its cis-isomer which are used in combination with chemotherapeutic agents and pyridinylimidazole carbamates. Triprolidine is described in U.S. Pat. No. 5,114,951 (1992). Another potentiator is procodazole, 1H-Benzimidazole carbamate-2-propanoic acid; [xcex2-(2-benzimidazole carbamate) propionic acid; 2-(2-carboxyethyl)benzimidazole carbamate; propazol]. Procodazole is a non-specific immunoprotective agent active against viral and bacterial infections that is used with the compositions claimed herein. It is effective with pyridinylimidazole carbamate in treating cancers, tumors or leukemia. Procodazole can also be combined with pyridinylimidazole carbamate and other chemotherapeutic agents to treat cancer, tumor or leukemia.
Other potentiators which can be used with pyridinylimidazole carbamate and optionally another chemotherapeutic agent to treat or inhibit the growth of cancer include monensin, an anti-sense inhibitor of the RAD51 gene, bromodeoxyuridine, dipyridamole, indomethacin, a monoclonal antibody, an anti-transferrin receptor immunotoxin, metoclopramide, 7-thia-8-oxoguanosine, N-solanesyl-N,Nxe2x80x2-bis(3,4-dimethoxybenzyl)ethylenediamine, leucovorin, heparin, N-[4-[(4-fluorphenyl)sulfonly]phenyl] acetamide, heparin sulfate, cimetidine, a radiosensitizer, a chemosensitizer, a hypoxic cell cytotoxic agent, muramyl dipeptide, vitamin A, 2xe2x80x2-deoxycoformycin, a bis-diketopiperazine derivative, and dimethyl sulfoxide.
The chemotherapeutic agents which can be used with pyridinylimidazole carbamate and an optional potentiator are generally grouped as DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents, Hormonal agents and others such as Asparaginase or hydroxyurea. Each of the groups of chemotherapeutic agents can be further divided by type of activity or compound. The chemotherapeutic agents used in combination with pyridinylimidazole carbamate includes members of all of these groups. For a detailed discussion of chemotherapeutic agents and their method of administration, see Dorr, et al, Cancer Chemotherapy Handbook, 2d edition, pages 15-34, Appleton and Lange (Connecticut, 1994).
DNA-Interactive Agents include the alkylating agents, e.g. Cisplatin, Cyclophosphamide, Altretamine; the DNA strand-breakage agents, such as Bleomycin; the intercalating topoisomerase II inhibitors, e.g., Dactinomycin and Doxorubicin); the nonintercalating topoisomerase II inhibitors such as, Etoposide and Teniposde; and the DNA minor groove binder Plicamydin.
The alkylating agents form covalent chemical adducts with cellular DNA, RNA, and protein molecules and with smaller amino acids, glutathione and similar chemicals. Generally, these alkylating agents react with a nucleophilic atom in a cellular constituent, such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione. The mechanism and the role of these alkylating agents in cancer therapy is not well understood. Typical alkylating agents include:
Nitrogen mustards, such as Chlorambucil, Cyclophosphamide, Isofamide, Mechlorethamine, Melphalan, Uracil mustard;
Aziridine such as Thiotepa;
methanesulphonate esters such as Busulfan;
nitroso ureas, such as Carmustine, Lomustine, Streptozocin;
platinum complexes, such as Cisplatin, Carboplatin;
bioreductive alkylator, such as Mitomycin, and Procarbazine, Dacarbazine and Altretamine.
DNA strand breaking agents include Bleomycin.
DNA topoisomerase II inhibitors include the following:
Intercalators, such as Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, and Mitoxantrone; and
nonintercalators, such as Etoposide and Teniposide.
The DNA minor groove binder is Plicamycin.
The antimetabolites interfere with the production of nucleic acids by one or the other of two major mechanisms. Some of the drugs inhibit production of the deoxyribonucleoside triphosphates that are the immediate precursors for DNA synthesis, thus inhibiting DNA replication. Some of the compounds are sufficiently like purines or pyrimidines to be able to substitute for them in the anabolic nucleotide pathways. These analogs can then be substituted into the DNA and RNA instead of their normal counterparts. The antimetabolites useful herein include:
folate antagonists such as Methotrexate and trimetrexate
pyrimidine antagonists, such as Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine and Floxuridine
purine antagonists such as Mercaptopurine, 6-Thioguanine, Pentostatin;
sugar modified analogs such as Cytarabine and Fludarabine; and
ribonucleotide reductase inhibitors such as hydroxyurea.
Tubulin Interactive agents act by binding to specific sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are critical cell structure units. When the interactive agents bind on the protein, the cell can not form microtubules Tubulin Interactive agents include colchicine, Vincristine and Vinblastine, both alkaloids and Paclitaxel and cytoxan.
Hormonal agents are also useful in the treatment of cancers and tumors. They are used in hormonally susceptible tumors and are usually derived from natural sources. These include:
estrogens, conjugated estrogens and Ethinyl Estradiol and Diethylstilbesterol, Chlortrianisen and Idenestrol;
progestins such as Hydroxyprogesterone caproate, Medroxyprogesterone, and Megestrol; and
androgens such as testosterone, testosterone propionate; fluoxymesterone, methyltestosterone.
Adrenal corticosteroids are derived from natural adrenal cortisol or hydrocortisone. They are used because of their anti inflammatory benefits as well as the ability of some to inhibit mitotic divisions and to halt DNA synthesis. These compounds include, Prednisone, Dexamethasone, Methylprednisolone, and Prednisolone.
Leutinizing hormone releasing hormone agents or gonadotropin-releasing hormone antagonists are used primarily the treatment of prostate cancer. These include leuprolide acetate and goserelin acetate. They prevent the biosynthesis of steroids in the testes.
Antihormonal antigens include:
antiestrogenic agents such as Tamoxifen,
antiandrogen agents such as Flutamide; and
antiadrenal agents such as Mitotane and Aminoglutethimide.
Hydroxyurea, which appears to act primarily through inhibition of the enzyme ribonucleotide reductase, can also be used in combination with pyridinylimidazole carbamates.
Asparaginase is an enzyme which converts asparagine to nonfunctional aspartic acid and thus blocks protein synthesis in the tumor. Asparaginase can also be used in combination with pyridinylimidazole carbamate to treat cancer.
D. Dosage
Pyridinylimidazole carbamate is preferably micronized or powdered so that it is more easily dispersed and solubilized by the body. Processes for grinding or pulverizing drugs are well known in the art. For example, a hammer mill or similar milling device are used. The preferred particle size is less than about 100xcexc and preferably less than 50 xcexc.
Dosage forms (compositions) suitable for internal administration contain from about 1.0 milligram to about 5000 milligrams of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Based on the body weight of the patient, the dosage may be administered in one or more doses several times per day or per week. Multiple dosage units may be required to achieve a therapeutically effective amount. For example, if the dosage form is 1000 mg, and the patient weighs 40 kg, one pill will provide a dose of 25 mg per kg for that patient. It will provide a dose of only 12.5 mg/kg for a 80 kg patient.
Pyridinylimidazole carbamate exhibites efficacy in vivo against cancers in mice at doses of about 1000 mg/kg, 2000 mg/kg and 4000 mg/kg. Generally, an effective dose in mice is about 12 times the expected effective dose in humans. By way of general guidance, for humans a dosage of as little as about 25 milligrams (mg) per kilogram (kg) of body weight and up to about 10000 mg per kg of body weight is suitable as a therapeutically effective dose. Preferably, from about 40 mg/kg to about 2500 mg/kg of body weight is used. Other preferred doses range between 100 mg/kg to about 3000 mg/kg of body weight. However, a dosage of between about 2 milligrams (mg) per kilogram (kg) of body weight to about 400 mg per kg of body weight is also suitable for treating some cancers.
Intravenously, the most preferred rates of administration may range from about 1 to about 1000 mg/kg/minute during a constant rate infusion. Pyridinylimidazole carbamate can be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Pyridinylimidazole carbamate is generally given in one or more doses on a daily basis or from one to three times a week.
Pyridinylimidazole carbamate is administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in combination with other therapeutic agents
The amount and identity of a chemotherapeutic agent that is used with pyridinylimidazole carbamate in treating cancer, tumor, leukemia, or other related diseases will vary according to patient response and physiology, type and severity of side effects, the disease being treated, the preferred dosing regimen, patient prognosis or other such factors.
When pyridinylimidazole carbamate is used in combination with other therapeutic agents, the ratio of pyridinylimidazole carbamate to the other therapeutic agent will be varied as needed according to the desired therapeutic effect, the observed side-effects of the combination, or other such considerations known to those of ordinary skill in the medical arts. Generally, the ratio of pyridinylimidazole carbamate to other therapeutic agent will range from about 0.5%: 99.5% to about 99.5%: 0.5% on a weight basis.
When pyridinylimidazole carbamate is administered before or after other therapeutic agents to treat cancer, tumors, or other diseases, the respective doses and the dosing regimen of pyridinylimidazole carbamate and the other therapeutic agent may vary. The adjunct or combination therapy can be sequential, that is the treatment with one agent first and then the second agent, or it can be concomitant treatment wherein two or more agents are administered substantially at the same time. The sequential therapy can be within a reasonable time after the completion of the first therapy before beginning the second therapy. The treatment with both agents at the same time can be in the same daily dose or in separate doses. For example treatment with one agent on day 1 and the other on day 2. The exact regimen will depend on the disease being treated, the severity of the disease and the response to the treatment.
For example, a full dosing regimen of pyridinylimidazole carbamate can be administered either before or after a full dosing regimen of the other therapeutic agent, or alternating doses of pyridinylimidazole carbamate and the other therapeutic agent may be administered. As a further example, pyridinylimidazole carbamate can be administered concomitantly with the other therapeutic agent.
The identity of the chemotherapeutic agent, the pharmaceutical carrier and the amount of compound administered will vary widely depending on the species and body weight of mammal and the type of cancer being treated. The dosage administered will vary depending upon known factors, such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
Pyridinylimidazole carbamates, the potentiator and/or the chemotherapeutic agent are administered together in a single dosage form or separately in two or more different dosage forms. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
Suitable pharmaceutical compositions and dosage forms will preferably comprise pyridinylimidazole carbamates, a potentiator and optionally a chemotherapeutic agent. The ratio of pyridinylimidazole carbamate to potentiator is generally in the range of about 1:0.01 to 10:1, and preferably 1:0.05 to 1:1 on a weight basis.
The dose and the range of chemotherapeutic agent will depend on the particular agent and the type of cancer being treated. One skilled in the art will be able to ascertain the appropriate dose.
E. Dosage Form
A dosage unit may comprise a single compound or mixtures thereof with other anti-cancer compounds, other cancer or tumor growth inhibiting compounds. Pyridinylimidazole carbamate can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Pyridinylimidazole carbamate may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
Pyridinylimidazole carbamate is typically administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration.
Pyridinylimidazole carbamate can be administered alone but is generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 to Robert, issued Sep. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modem Pharmaceutics, Chapters 9 and 10 (Banker and Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington""s Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers : Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).
Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
Pyridinylimidazole carbamate can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Pyridinylimidazole carbamate may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, pyridinylimidazole carbamate may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parentally, in sterile liquid dosage forms.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington""s Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Pyridinylimidazole carbamate may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
Useful pharmaceutical dosage forms for administration of pyridinylimidazole carbamates are illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 10 to 500 milligrams of powdered active ingredient, 5 to 150 milligrams of lactose, 5 to 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100-500 milligrams of the active ingredient. The capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit was 100-500 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 50-275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable Solution
A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Suspension
An aqueous suspension is prepared for oral administration so that each 5 ml contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin.
Kits
The present invention also includes pharmaceutical kits useful, for example, for the treatment of cancer, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of pyridinylimidazole carbamates. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit. It should be understood that although the specified materials and conditions are important in practicing the invention, unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.
The chemotherapeutic agents, pyridinylimidazole carbamate and, optionally, the potentiators are typically mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid and the type is generally chosen based on the type of administration being used. The active agent can be coadministered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid fonns include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
F. Method of Treatment
The method of treatment can be any suitable method which is effective in the treatment of the particular cancer or tumor type being treated. Treatment may be oral, rectal, topical, parenteral or intravenous administration or by injection into the tumor or cancer. The method of administering an effective amount also varies depending on the disorder or disease being treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of the pyridinylimidazole carbamates, formulated with an appropriate carrier, additional cancer inhibiting compound or compounds or diluent to facilitate application will be the preferred method of administering the compounds to warm blooded animals.
One skilled in the art will recognize that the efficacy of the pyridinylimidazole carbamates can be ascertained through routine screening using known cancer cell lines both in vitro and in vivo. Cell lines are available from American Tissue Type Culture or other laboratories.

Abstract: wherein X is independently selected from the group consisting of halo, for example, bromo, fluoro, chloro, iodo; hydroxyl, alkyl of less than 8 carbon atoms or alkoxy of less than 8 carbon atoms; n is a positive integer less than 4; R is hydrogen or an alkyl group of from 1 to 8 carbons and its pharmaceutically acceptable salts and prodrugs thereof.


Apparatus and method for transporting a bicycle in a substantially upright orientation. The method includes positioning a bicycle in a carrier so that a wheel of the bicycle is located in a trap space of the carrier. The trap space is configured to maintain the bicycle in a substantially upright orientation when the wheel is located therein and the carrier is in a released configuration. This permits the operator to use both hands to secure the bicycle in the carrier. The wheel of the bicycle, and typically the front wheel, is fixed in the carrier by applying a squeeze force upon the wheel and thereby establishing a securing configuration of the carrier. Preferably, the squeeze force is imposed across a perimeter of the wheel and the actuators for imposing the squeeze force are positioned low enough to be within the typical user""s reach, also referred to as the reach zone, when the carrier is mounted on the roof-top of a carrying vehicle.

The present invention relates generally to load carriers, and more specifically to bicycle carriers designed to transport bicycle(s) in an upright orientation, preferably in a roof-mount configuration above a transporting vehicle.
Roof mounted load carriers are well known in the load carrier arts for carrying different types of cargo. In the case of sports equipment which is often too large to fit inside the carrying vehicle, specially configured carriers have been designed for transporting the bicycles in an upright configuration above the roof of the vehicle. Considering currently available designs, there are several deficiencies which can cause consumers to avoid their use. Most of these deficiencies stem from the location of roof-mounted carriers; by their nature, they are often difficult to reach by the average user because of the significant height above ground level at which they are positioned. In order to install a bicycle in such a roof-top carrier, the user must raise the bicycle at least to shoulder height, and oftentimes, overhead lifting is even required depending upon the user""s height.
Even though many bicycles are now of lightweight design, their remaining weight and bulk can be unwieldy and difficulty to control in this awkward lifting procedure that must be executed by the user. Still further, it should be appreciated that in order to position the bicycle above the vehicle and onto the roof-top carrier, it is usually required that the arms of the user be in an almost fully extended position, not only because of the height of the carrier, but also in order to move the bicycle, at the elevated height, from the side of the vehicle where the user is standing, to the load position over the vehicle""s roof surface.
In conventionally designed roof-top bicycle carriers, once a bicycle is located in the carrier above the roof, the user must maintain a grip on the bicycle to maintain its balance in the upright position while securement mechanisms are fastened thereto. This can present extreme hardship not only because of the awkward position at which the bicycle is positioned with respect to the user, but also because both hands are typically otherwise needed to manipulate the securing mechanisms. Requiring one hand to be utilized just to maintain the balance and orientation of the bicycle is a significant drawback to the user when these conventional roof-top carrier designs are considered.
In another aspect, conventionally designed roof-top bicycle carriers are asymmetrically constructed. That is to say, a particular carrier has been designed to be mounted on one side of the vehicle, and not the other. This stems from the fact that fastening actuators are positioned at the side of the carrier so that they are easier to reach from the position of the user beside the vehicle. The drawback of providing this convenience to the user, however, is that the utilization of the carrier is in turn limited. More particularly the carrier is not interchangeable with respect to the two sides of the vehicle; form either of which the user may desire to load a bicycle. Still further. many current designs for roof-top carriers place the actuating mechanisms high, at locations difficult to reach and manipulate by the user.
Because roof-top bicycle carriers typically have wheel trays in which a carried bicycle rests, securement is often accomplished by fasteners secured about the wheels and tray. This type of securement leaves the bicycle at risk of unauthorized removal. In most bicycle designs, quick releases are provided for removing at least the front wheel and can actually facilitate an authorized removal of the bicycle from such tray securement schemes.
In view of the above described deficiencies associated with the use of known methods and designs for roof-top, upright bicycle carriers, the present invention has been developed. These remedial aspects, as well as further enhancements and benefits are described in greater detail hereinbelow with respect to several alternative embodiments of the present invention.
The present invention in its several disclosed embodiments alleviates the drawbacks described above with respect to the conventionally designed roof-top, upright bicycle carriers, while at the same time providing several additionally beneficial features. Each of the deficient aspects of conventional designs described hereinabove are addressed by the present carrier. Initially, a trap space is utilized in the carrier and in which, once a bicycle is installed, its upright orientation is independently maintained. This accomplishes one of the most consumer influential benefits of the present carrier; that is, after the bicycle is installed, the user may release the bicycle altogether thereby freeing both hands so that the securement and locking procedures can be focused upon. No longer does the user have to perform a balancing act with respect to the bicycle while trying to fasten the securement and lock mechanisms.
The present carrier is designed to have a substantially symmetrical design. In this regard, actuating mechanisms are provided on both sides of the carrier so that the carrier can be located at either side of the vehicle""s roof. This also avoids the user having to reach across the carrier to execute securing and releasing procedures. As a further accommodation, the portions of the actuating mechanisms which must be grasped by the user are positioned in an easy xe2x80x9creach zone.xe2x80x9d That is, the actuating mechanisms are positioned low on the carrier, close to the roof-top surface of the vehicle enabling easy reach by the user. This reach zone is generally considered to be within one to eight inches of the roof rack members to which the carrier is mounted.
In another aspect, the design of the present invention maintains the wheel receiving tray of the carrier clear during the initial stages of installing the bicycle into the carrier so that the rolling capability of the bicycle can be capitalized upon in the loading process. An often complained about condition is that the tray of conventional roof-top bicycle carriers is obstructed during the loading process and therefore the bicycle cannot be rolled in the track into proper position for securement. Because the brace component of the current invention is configured for a conformance fit down into the wheel tray during initial load, the bicycle does not have to be positioned with exactness into its final resting position. In fact, the bicycle can be initially loaded at any location along the tray and rolled into proper position over the wheel engaging portion of the bracing arrangement and into the trap space for securement.
In yet another aspect, lock mechanisms are provided not only for securing the carrier to the rack system of the carrying vehicle, but cable locks are also provided so that a securement cable can be snaked or looped through the bicycle and then locked to the load carrier. In a preferred embodiment, these functions are combined at a single flip-handle component. At a minimum, however, if more than one lock assembly is utilized, the several lock cylinders are commonly keyed so that the user only needs a single key for unlocking both the bicycle securement and the carrier securement arrangements.
Hereinbelow, several illustrative embodiments and preferred aspects of the present invention are described. Individually and collectively, each should be considered in their exemplary capacity, and not as requirements outside of those expressly required in the claims appended herewith.
In at least one embodiment, the present invention takes the form of a method for transporting a bicycle in a substantially upright orientation. The method includes positioning a bicycle in a carrier so that a wheel of the bicycle is located in a trap space of the carrier. In this regard, it should be appreciated that bicycle wheels are predominantly referenced herein with respect to the invention; it should be understood that usually full wheel assemblies are intended by this terminology, including a pneumatic tire. The trap space is configured to maintain the bicycle in a substantially upright orientation when the wheel is located therein and the carrier is still in a released configuration. This permits the operator to use both hands to secure the bicycle in the carrier. The wheel of the bicycle, most typically the front wheel of the bicycle, is fixed in the carrier by applying a squeeze force upon the wheel which establishes a securing configuration of the carrier. Preferably, the squeeze force is imposed across a perimeter of the wheel and the actuators for imposing the squeeze force are located low enough to be within the typical user""s reach. The suitable area in which the actuators may be located is referred to as the reach zone. In general terms, the reach zone is defined as a vertical distance between one and eight inches above a load bars of the vehicle""s rack system to which the carrier is mounted.
Preferably, a pair of actuators are provided, one each on opposite lateral sides of the carrier and each is capable of independently imposing a proper squeeze force on the wheel of the bicycle. In this way, installation of the carrier is accommodated at either side of the carrying vehicle and the user is prevented from having to reach across the carrier for actuation purposes, regardless of the side of the vehicle upon which the carrier is mounted.
The squeeze force is imposed so that a predominant component of the squeeze force is vertically oriented and downwardly directed in the securing configuration. In this manner, the support of the tray in which the trapped wheel rests is advantageously utilized in establishing the trap space.
The trap space is defined, at least partially, underneath a trap arrangement that is configured to be manipulated between released and securing configurations. The trap arrangement includes a closed-top portion that is arranged for pressing engagement upon the wheel. As illustrated, the closed-top portion is substantially formed as an inverted U-shaped assembly.
A telescoping function is provided in the trap arrangement thereby facilitating extension and retraction of a bite portion of the closed-top portion for transitioning the trap arrangement between the released and securing configurations. As shown, an extension member is telescopically positioned within a sleeve and an actuator is utilized to translate the extension member within the sleeve for transitioning the trap arrangement between the released and securing configurations.
Telescopic action of the extension member is driven by pivotal movement of the actuator. The sleeve is provided with an access slot therethrough for accommodating extension of the actuator across the sleeve to the extension member. The extension member is spring biased within the sleeve for assuring proper relative positioning between the extension member and the sleeve to for initial engagement of the actuator with the extension member. An insert pin is provided on the actuator and is configured to extend across the access slot and be insertibly engaged in a receiving aperture in the extension member. The spring bias function is tuned to assure proper alignment between the access slot and the receiving aperture for acceptance of the insert pin.
To optimize user operation of the actuator, an indicator is utilized showing an intended area of application of a user""s hand grip upon the actuator. Preferably, the indicator is configured like a bicycle handlebar-style grip. An end cap portion of the indicator fixedly connects to a wheel engaging portion of a bracing arrangement of the carrier and pivotally connects to a support portion of the bracing arrangement. These connections facilitate transition between the released, the securing and a non-bicycle-transporting, folded-down configuration of the carrier.
The trap arrangement includes a macro-adjustment arrangement adapted to be variously configured for accommodating entrapment of differently sized bicycle wheels. A macro-adjustment member of the arrangement is configured for sliding movement within the trap arrangement between a plurality of indicated discreet locations, each of such locations being arranged to accommodate application of a substantially uniform squeeze force upon differently sized bicycle wheel. A stop arrangement is provided at the macro-adjustment member for relatively fixing the member with respect to the trap arrangement. The adjustment may be continuously variable, but is preferably limited to discreet and selectable locations. In the instance of discreet locations, a pin-in-selected-aperture mechanism may be advantageously utilized.
The trap space is at least partially defined adjacent to a bracing arrangement that is also configured to be manipulated between released and securing configurations. A brace force is imposed on the bicycle wheel having a first component that is vertically oriented and directed upwardly. A second component is horizontally oriented and directed toward the trap arrangement. The bracing arrangement has a wheel engaging portion that is arranged for pressing engagement upon the wheel. In a preferred embodiment, the wheel engaging portion is formed from a band having sufficient width to avoid becoming embedded in the wheel""s tire tread.
The actuator is arranged between the bracing arrangement and the trap arrangement and is configured to transition both the bracing arrangement and the trap arrangement between released and securing configurations. The bracing arrangement is controlled utilizing a ratchet mechanism that is configured to fix the bracing arrangement in the securing configuration under a biasing action imposed by the squeezed wheel. This biasing action is derived from the reaction or spring-back force of the wheel and tire responsive to the squeeze force being exerted thereupon by the trap and bracing arrangements.
The bracing arrangement is configured so that in a bicycle receiving configuration, at least a portion of the arrangement fits substantially flush within the wheel receiving tray thereby permitting rolling access of the wheel into and out of the trap space during initial load and final unload stages.
A lock arrangement is provided that secures the carrier to a load bar of a carrying vehicle and anchors a securing cable connectable through the bicycle. If one locking mechanism is utilized, then of course only one key is required for operation of the lock. If more than one lock mechanism is utilized, however, the several lock arrangements are commonly keyed so that still, only one key is required for performing all unlocking functions of the total lock arrangement.
The beneficial aspects described above apply generally to the exemplary devices and methods disclosed herein regarding the upright bicycle carrier. The specific structures and steps through which these benefits are delivered will be described hereinbelow.

Method and apparatus for providing a roof-mounted upright bicycle carrier


A prosthesis (18) comprising stents (7,8) sutured to a graft (5) comprising a tube of biocompatible material. The stents are attached to the inside surface of the tube and there is at least one fenestration (10) in the tube corresponding to an intersecting artery opening. A further stent (1) extends proximally and may have caudally facing barbs (2). Each fenestration includes one or more radiopaque markers (11) defining a periphery of the fenestration. A release mechanism for the prosthesis includes trigger wires (15,17) stitched into a fold (16) on the material to retain the prosthesis in a partially compressed state during deployment. A delivery device (20) has a sheath (26) to hold the compressed prosthesis during insertion and a top cap (24) to retain the top stent (1).

The present invention relates generally to the field of the treatment of aortic disease and in particular to endoluminal aortic stents and a method of deployment of such stents which allows accurate placement of a covered stent in the aorta. In particular it is capable of being deployed and positioned accurately above the renal arteries in the treatment of infra-renal aortic aneurysmal disease.
According to the prior art, aortic disease is often treated by surgical techniques involving the use of stents and grafts. For example, it is well known in the art to interpose, within the stenotic portion of an artery, a stent, whether made of stainless steel or other materials, capable of being balloon-expandable for strengthening the walls of a stenotic or occluded artery. In addition, it is well known in the prior art to use a graft to repair highly damaged portions of, for example, the aorta or other arteries thereby ensuring blood flow and reducing the risk of aneurisms or ruptures. The grafts, hollow tubes comprised of material such as dacron, are normally inserted within the walls of a damaged artery and can be sewn into position or expanded through the use of a stented balloon catheter.
A more severe problem occurs when it is necessary to use a graft at or around the intersection of a major artery (e.g. the aorta) with intersecting arteries (e.g. the renal arteries, carotid or brachycephalic artery). While the graft is clearly required to strengthen and ensure the flow of blood through, for example, the aorta, the use of a graft effectively seals or blocks off the blood flow to the kidneys or cerebral circulation. Accordingly, it is often impossible or impractical to use a graft to treat aortic disease at or around the intersection of the aorta and other arteries. Instead a surgeon must attempt to repair the weakened walls of such artery using other surgical techniques having high failure rates and limited success. For example, although several centers around the world have been routinely deploying endoluminal grafts for the treatment of infra-renal aortic aneurisms, as many as 30% of abdominal aortic aneurisms are unsuitable for this method of treatment due to an insufficient length of aneurysmal-free infra-renal aorta to firmly anchor the graft or stent.
The present invention solves the problem in the prior art by utilizing the supra-renal aorta to provide adequate anchorage for an aortic graft whilst at the same time employing extremely accurate placement of a fenestrated covered stent which corresponds to the exact sites of origin of the intersecting arteries.
The present invention in general relates to a fenestrated endoluminal aortic stent which is a single component device comprising two or more stainless steel or nitinol stents such as Z stents which may have caudally facing barbs sutured to a variable length of a bio-compatible material tube in which the stents are attached to the inside surface of the bio-compatible material tube and, depending on the geometry of the intersecting arteries to be covered, customized fenestrations accurately placed in the bio-compatible material tube corresponding to the intersecting artery openings.
In one form, therefore, the invention may be said to reside in a prosthesis comprising two or more stents sutured to a graft comprising a bio-compatible material tube, wherein the two or more stents are attached to the inside surface of the bio-compatible material tube and at least one fenestration in the bio-compatible material tube corresponding to an intersecting artery opening.
Preferably there are more than two stents attached to the bio-compatible material tube.
There may be a further stent fastened to the bio-compatible material tube and extending proximally from the bio-compatible material tube.
At least one of the stents may have caudally facing barbs thereon to assist with accurate retention of the prosthesis when completely inserted.
The proximally extending stent may be the stent which has the caudally facing barbs thereon.
The bio-compatible material tube may in one embodiment be a DACRON material tube.
There may be two or more fenestrations according to the number of intersecting arteries.
The or each fenestration may include one or more radiopaque markers defining a periphery of the fenestration.
The distal most of the stents may include a loop extending distally of the graft.
The prosthesis may further include a release mechanism for the prosthesis including one or more trigger wires wherein a portion of the bio-compatible material tube is folded longitudinally with the one or more trigger wires respectively threaded longitudinally through the bio-compatible material tube at the fold to retain the prosthesis in a partially compressed state.
At least one of the stents may include one or more shortened loops to enable location of the fenestrations as required.
Accurate siting of the branches of the aorta may be achieved from Computerised Axial Tomograms (CT) and angiography and the invention is customised to each patient in relation to the sites corresponding with the CT. The fenestrations are marked with radiopaque beads to facilitate their positioning under X-ray control before deployment.
In an alternative form the invention may be said to reside in a method for treating arterial disease at an intersection of two arteries, including the steps of:
X-raying arteries to be treated so as to accurately determine the position of the intersection of the arteries, customizing one or more fenestrations to a prosthesis comprising a selected length of a bio-compatible material tube, attaching radiopaque markers around the or each fenestrations, placing two or more stents into the bio-compatible material tube, bends in the stents being shortened if necessary in such a way so as not to cover the fenestrations, manually gathering a top stent, covering the top stent with a top cap and holding the stent in place in the top cap with a trigger wire, stitching the trigger wire or another trigger wire through a longitudinal fold in the bio-compatible material tube to narrow the diameter of said prosthesis thereby providing a customised fenestrated covered graft to be inserted into an artery to be treated.
The method may further include the step of sewing a further stent to the top ring of the bio-compatible material tube, such that the further stent extends proximally from the bio-compatible material tube.
There may be more than two stents attached to the bio-compatible material tube and two or more than two fenestrations according to the number of intersecting arteries.
The process of insertion of the graft may include the steps of; compressing the graft and placing it into a sheath which fits snugly around the top cap, the prosthesis, the stents and an obturator, inserting through a femoral artery in a groin the prosthesis using a delivery device which includes the top cap, the sheath, the obturator and guide wires, withdrawing the sheath to reveal the graft in semi-deployed position, positioning the prosthesis, partially withdrawing the sheath and obturator to enable insertion of angiography catheters and guide wires, inserting the angiography catheters and guide wires through a contralateral groin into the artery to be treated to provide maneuverability, and accurate positioning of the graft by positioning right and left angiography catheters and guide wires through the fenestrations into the intersecting arteries, releasing the trigger wire to provide full deployment of the the graft, withdrawing said angiography catheters and pushing up the sheath and obturator through the stent and docking with the top cap and fully withdrawing the delivery device, whereby the said fully deployed stent ensures the flow of blood at the intersection of the arteries to be treated.
The method by which the prosthesis of the present invention may be maneuvered into place prior to full deployment is by way of the right and left angiography catheters and guide wires.
The radiopaque markers may be gold or any other bio-compatible material which enables the marker to be visualized by X-ray or other methods.
This generally describes the invention but to assist with understanding of the invention reference will now be made to preferred embodiments of the invention with the assistance of the following drawings.


A method of inspecting a pipe, by pushing a video camera through the pipe on a cable, with a wire helical coil disposed between the video camera and a stop on the cable, the wire helical coil being long enough to permit passage of the video camera around a first bend. As the video camera is pushed into the pipe and moves around the first bend, a cable stiffener is placed on the cable to stiffen the cable in the first straight section while permitting the cable to move through the cable stiffener. The video camera is then pushed down a second straight section and around a second bend to view a third straight section. The cable stiffener comprises a rod having first and second ends, a straight slot running along the rod from the first end to the second end for receiving a cable, and the rod having an enlarged portion along part of the rod forming a centralizer.

This invention relates to a device and method for inspecting pipes.
Pipes used for example-in heaters and heat exchangers tend to have many bends, many of which are tight U-turns. It is desirable to be able to inspect deeply into the pipes, using a video camera, but the bends make it hard to get the video camera far into the pipe. The first straight section can usually be inspected, and also the second straight section, but it is difficult to inspect the third straight section.
Pipe inspection devices are known which have a video camera head at the end of a cable. A wire helical coil (spring or snake) is disposed between a stop on the cable and the video camera head. The cable may pass through the wire helical coil. When such a device is used to inspect a pipe with bends in it, the wire helical coil can be easily pushed around the first bend and the video camera used to inspect the second straight section. However, as the video camera head passes into the second bend, binding at the first bend and first straight section due to friction of the cable as it winds through the first bend prevents the video camera head from being pushed around the second bend.
It is an object of this invention to provide a pipe inspection device and method for inspecting past the second bend in a pipe having many bends.
There is therefore providing in accordance with an aspect of the invention, a method of inspecting a pipe having a first, second and third straight sections and first and second bends, the method comprising the steps of:
pushing a video camera through the pipe on a cable, with a wire helical coil disposed between the video camera and a stop on the cable, the wire helical coil being long enough to permit passage of the video camera around the first bend;
as the video camera is pushed into the pipe and moves around the first bend, placing a cable stiffener on the cable to stiffen the cable in the first straight section while permitting the cable to move through the cable stiffener; and
pushing the video camera down the second straight section and around the second bend to view the third straight section.
In a further aspect of the invention, there is provided a pipe inspection device, comprising a video camera head, a cable having a stop, a wire helical coil between the video camera head and the stop and a cable stiffener lining the cable on the other side of the stop from the wire helical coil.
In a further aspect of the invention, there is provided a cable stiffener, comprising:
a rod having first and second ends;
a straight slot running along the rod from the first end to the second end for receiving a cable; and
the rod having an enlarged portion along part of the rod forming a centralizer.
Preferably, multiple cable stiffeners are placed on the cable and each cable stiffener is placed on the cable such that the straight slots of adjacent cable stiffeners are rotationally offset from one another. The cable stiffener preferably has a centralizer at one end and the cable stiffener is urged into the pipe with the centralizer forward.
In a further aspect of the invention, the first and second ends of the cable stiffeners are configured for mating with respective second and first ends of adjacent cable stiffeners, and are preferably threaded.
In a further aspect of the invention, the enlarged portion is disposed at one of the ends of the rod, and is tapered towards the second end of the rod.
These and other aspects of the invention are described in the detailed description of the invention and claimed in the claims that follow.


This invention relates to a (1.fwdarw.3, 1.fwdarw.4)-.beta.-glucanase (glucanase EII endohydrolase) enzyme, whose amino acid sequence has been modified in order to provide an enzyme whose three-dimensional structure confers improved thermostability and/or pH stability. Specific modifications are based upon a comparison between the three-dimensional structure (1.fwdarw.3, 1.fwdarw.4)-.beta.-glucanase and that of (1.fwdarw.3)-.beta.-glucanase. The (1.fwdarw.3, 1.fwdarw.4)-.beta.-glucanase gene has been modified by site-directed mutagenesis, and modified enzymes have been expressed in E. coli. Modified sequences, DNA molecules encoding them, plasmids, expression vectors and transgenic plants are disclosed.

Barley quality encompasses a range of physical and chemical attributes, depending on whether the grain is to be used in the preparation of malt for brewing purposes, in the formulation of stockfeed, or as a component of human foods. Currently, specifications or barley quality are tailored primarily for the malting and brewing industries, in which germinated barley (malt) is the principal raw material. The quality specifications include such parameters as grain size, dormancy, malt extract, grain protein content, development of enzymes for starch degradation in malt and (1.fwdarw.3,1.fwdarw.4)-.beta.-glucan content. Malt extract is a widely-used quality indicator. It is an estimate of the percentage of malted grain that can be extracted with hot water. Barley breeders and growers strive to produce grain with high malt extract values, because greater extract percentages provide higher levels of materials for subsequent fermentative growth by yeast during brewing. Malt extract values are influenced both by the composition of the ungerminated barley and by the speed and extent of endosperm modification during malting. Given the central role of cell walls as a potential barrier against the free diffusion of starch- and protein-degrading enzymes from the scutellum or from the aleurone to their substrates in cells of the starchy endosperm, it is not surprising that wall composition and the ability of the grain to rapidly produce enzymes that hydrolyse wall constituents are important determinants of malt extract values.
The major constituents of endosperm cell walls of barley are the (1.fwdarw.3,1.fwdarw.4,-.beta.-glucans, which account for approximately 70% by weight of the walls (Fincher, 1975). In the germinating grain (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanases function to depolymerise (1.fwdarw.3,1.fwdarw.4)-.beta.-glucans of cell walls during endosperm mobilisation.
Total (1.fwdarw.3,1.fwdarw.4)-.beta.-glucan in ungerminated barley grain is not highly correlated with malt extract (Henry 1986; Stuart et al, 1988). However, the residual (1.fwdarw.3,1.fwdarw.4)-.beta.-glucan in malted barley is highly correlated, in a negative sense, with malt extract (Bourne et al, 1982; Henry 1986; Stuart et al, 1988), and this residual polysaccharide reflects a combination of the initial (1.fwdarw.3,1.fwdarw.4)-.beta.-glucan levels in the barley and, more importantly, the capacity of the grain to rapidly produce high levels of (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase during malting (Stuart et al, 1988). The (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase potential of barley cultivars is also dependent on both genotype and environment, although environmental conditions during grain maturation appear to be particularly important in the development of the enzymes (Stuart et al, 1988). Monoclonal antibodies specific for barley (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanases have been used in enzyme-linked immunoadsorbent assays (ELISA) that may be useful for the quantitation of (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase levels in large numbers of barley lines generated in breeding programs (H.o slashed.j et al, 1990). Furthermore, mutant barleys with altered (1.fwdarw.3,1.fwdarw.4)-.beta.-glucan content (Aastrup 1983; Molina-Cona et al, 1989) or (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase potential will be useful in future studies on the effects of these components on malting quality and may be valuable in breeding programmes.
The ability of the (1.fwdarw.3;1.fwdarw.4)-.beta.-glucanases [E. C. 188.8.131.52] to retain enzymatic activity at elevated temperatures (thermostability) is of extreme importance during the utilization of barley in the malting and brewing industries. Malt quality, as measured by the `malt extract` index, is highly dependent on the ability of the grain to rapidly synthesize high levels of the enzyme during germination (Stuart et al, 1988). High levels of (1.fwdarw.3;1.fwdarw.4)-.beta.-glucanases are also desirable in the brewing process, where residual (1.fwdarw.3;1.fwdarw.4)-.beta.-glucans in malt extracts can adversely effect wort and beer filtration due to their propensity to form aqueous solutions of high viscosity. These residuals can also contribute to the formation of certain hazes or precipitates at elevated ethanol concentrations or low temperatures in the final beer (Woodward and Fincher, 1983). The elevated temperatures used during commercial malting and brewing lead to rapid and extensive inactivation of these enzymes. The high temperatures (up to 85.degree.) of commercial kilning processes destroy greater than 60% of the enzyme activity and much of the remaining enzyme is inactivated by the hot water used for malt extraction (Brunswick et al, 1987), Loi et al, 1987). It is therefore highly desirable to develop commercial strains of barley that express a thermostable (1.fwdarw.3;1.fwdarw.4)-.beta.-glucanase enzyme, or to produce the (1.fwdarw.3;1.fwdarw.4)-.beta.-glucanase enzyme exogenously as an additive to be used in the brewing process.
Barley (1.fwdarw.3;1.fwdarw.4)-.beta.-glucans also pose problems in the stockfeed industry. In poultry formulations prepared from cereal grains, (1.fwdarw.3;1.fwdarw.4)-.beta.-glucans significantly raise the viscosity of the gut contents of chickens. This impairs digestion and slows growth rates, and results in sticky faecal droppings that make hygienic handling of eggs and carcases difficult (Fincher and Stone, 1986). This application would require the enzyme to be stable at a range of pHs, particularly in the pH region of the foregut. It would also be an advantage for the enzyme to be sufficiently thermostable to withstand the steam pelleting processes widely used in stockfeed manufacture.
Thus it is envisaged that (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase of amino acid sequence modified so as to provide enhanced thermostability and/or pH stability will have a variety of industrial uses, either by means of barley expressing the modified enzyme, or by addition of the modified enzyme to barley being processed.
There has been considerable interest in inserting (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase genes into brewing yeasts, in the expectation that low level, constitutive expression would lead to the secretion of active enzyme and the depolymerisation of residual (1.fwdarw.3,1.fwdarw.4)-.beta.-glucan during fermentation (Hinchliffe, 1988). A barley (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase cDNA (Fincher et al, 1986) fused with a mouse .alpha.-amylase signal peptide is expressed and secreted from yeast under the direction of the yeast alcohol dehydrogenase I gene promoter (Jackson et al, 1986). Although the gene for isoenzyme EII has not yet been isolated, the availability of almost full length cDNA for use as a probe means that such isolation can readily be carried out using conventional methods.
We have now determined the three dimensional structure of (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase isoenzyme EII and (1.fwdarw.3,1.fwdarw.4)-.beta.-glucanase isoenzyme GII (E.C.184.108.40.206), and have identified regions of the structures of these enzymes which are candidates for modification in order to provide enhanced thermal and pH stability, as well as suitable point mutations for achieving such stabilisation. We have found that the 3-dimensional structures of these two enzymes, which share only 50% sequence homology, are remarkably similar in their structural framework, and that their active sites are also surprisingly similar, despite the difference in substrate specificity.

(1.fwdarw.3, 1.fwdarw.4)--.beta.-glucanase of enhanced stability


The present invention relates to a heterojunction bipolar transistor structure having a device mesa 401 with a collector region 402, a base region 403 and an emitter region 404. An emitter metal layer 405 is connected to a ballast resistor 406 which in turn is connected to an emitter bump 407 by way of the air bridge 408. The thermal bump 409 is connected to the emitter metallization by way of a layer of heat dissipation material 410, preferably silicon nitride. The present structure enables dissipation of heat at the emitter contact as well as a ballast resistor connected to the emitter by way of metallization 405. This arrangement enables the dissipation of joule heat to avoid higher temperature of operation which results increased current at the collector which increases the temperature thereby further increasing the current, as well as provides a ballast resistor to reduce the collector current back to an acceptable value to avoid thermal runaway. The present invention effects the desired result without the creation of a natural resonator by separating the thermal and electrical paths.

The present invention relates to a technique and apparatus, therefore, for improving heterojunction bipolar transistor stability.
Bipolar semi-conductor devices are inherently thermally unstable, especially when biased with a low impedance bias circuit as is normally required for power amplifier applications. This is a self-feeding problem, wherein the higher temperatures of operation result in an increased current at the collector which in turn increases the temperature thereby further increasing the current. The relationship of pn junction diode current and temperature is well known, and clearly the increase in temperature results in an increase in current which in turn results in an increase in temperature. A solution to the problem of collector current run-away is to place a small but finite resistance in the emitter of the transistor. Then, as the collector current increases, the emitter voltage increases, decreasing the emitter-base voltage drop, thereby reducing the collector current back to an acceptable value. This type of negative feedback with a ballast resistor is well known in the field of bipolar junction transistors.
In most applications, the ballast resistor is optimally distributed over the emitter fingers so that the feedback can be more effectively utilized to control runaway current in an individual or small group of fingers. Often times, a thin film or implanted resistor is placed at the end of each emitter finger or pair of fingers. This technique is advantageous in that one can readily modify the resistance value by modifying the geometry of the resistor without changing the resistor process. An alternative technique is to grow or implant a lightly doped semi-conductor region above the device emitter to provide the ballasting resistance. This technique is less advantageous than the first mentioned technique because the emitter area is defined by the fabrication transistor process and often one can not change the resistor value without modifying the transistor growth and/or fabrication process. Additionally, it is often difficult to actually control the resistance of lightly doped semi-conductor materials. Accordingly, the off-finger resistance technique is often used.
While it is true that the placement of off-finger resistance will serve to reduce the current and thereby to a great extent reduce the ill-effects of joule heating, there is clearly heat generated through the operation of the device which may be detrimental to device performance. Accordingly, it is necessary to have means to dissipate the heat from the device, preferably at the emitter where the heat is generated. There are basically two methods to reduce the thermal impedance of the device. The first technique extracts the heat generated through the semi-conductor material. To optimize this structure, the material below the heat generating active area must generally be very thin on the order of microns. This low yield process hence not practical for production. An alternative method is to extract the heat generated from the top of the device through the contact metals and place these contact metals on a large heat sink. This is most readily achieved by turning the device upside-down on the heat sink. Accordingly, this process is well known in the art as flip-chip technology. In most cases, the interface between the device contacts in the heat sink is a relatively thick region of metal. This region of metal is deposited in many ways but is usually referred to as a "bump" hence flip-chip heat dissipation is often referred to as "bumping". To attach the bump to the heat sink, solders are often used and often therefore this process is known as solder bumping.
Flip-chip mounting of an HBT requires the mounting bump to be placed directly over the emitter fingers as this is where the heat is generated and therefore must be extracted. In conventional flip-chip mounting in GaAs devices, the bump would provide the path to thermal ground and the path also to the electrical ground, resulting in a low-thermal resistance device while maintaining a low ground inductance, which is important for high gain power devices. This configuration, however, does not allow one to place an off-finger ballast resistor between the emitter fingers and the ground because the ground bump must lie directly over the emitter fingers to maintain low-thermal resistance.
Turning to FIG. 1, one possible solution is shown for the extraction of heat through the heat sink as well as the necessary connection for the off-finger resistor. To this end, the mesa type structure HBT 101 having the emitter (102) base (103) and collector 104, is electrically connected to the resistor 105 off the emitter (102) by way of the metallization (106). A layer of silicon nitride or other suitable material (107) for heat dissipation is connected to the top of the metallization at the emitter as well as to the resistor (105). The metal layer (108) serves as the electrical and thermal path in this arrangement. FIG. 2 shows a top view of the schematic for the electrical contacts of the device shown in FIG. 1. This arrangement as shown in FIG. 1 runs the electrical path from the emitter fingers off to a resistor and then back through a bump which is electrically but not thermally isolated from the emitter fingers by way of the layer of heat sink material such as Si.sub.3 N.sub.4. Unfortunately, this arrangement creates a natural inductor in through the metallization from the emitter to the resistor and then back to the bump and a natural capacitor between the emitter fingers and the metallization. This extra ground inductance causes many problems including a reduced gain, and instability problems such as when the inductance resonates with the dielectric spacer capacitance to create an unstability.
Turning to FIG. 3, an alternative arrangement is shown which reduces the ill-effects of the natural inductance. The structure as shown in FIG. 3 is not practical for the following reasons. The emitter structure 301 has a well defined area which is predetermined by the area of the mask. This area is well defined as the transistor characteristices, such as frequency and power are determined by the area of the emitter mesa as is well known to one of ordinary skill in the art. Accordingly, the electrical performance of the device which is dependent upon these characteristics is also well defined by the predesignation of the emitter mesa area. The resistor 302 is fabricated through an epitaxial growth of a suitable epitaxial material, having a well defined area again defined by the mask layer. Because the area of this epitaxial material is well defined, the resistance is well defined as well. Accordingly, effecting a change in the resistance is difficult, as there are basically two techniques in which this can be carried out. The first technique would be to change the area of the resistor 302 through a change in the mask layer. However, changing the mask layer will also change the emitter mesa area and in the process would thereby change the device characteristics which are defined by the emitter mesa area as is described above. The alternative approach would be to change the epitaxial material used to change the resistance while maintaining the area constant. Unfortunately, this is also an unattractive option as a change in the epitaxial material would be prohibitively expensive. Accordingly, the device structure as shown in FIG. 3 is unattractive as it would require a significant alteration in the processing steps or a significant increase in the cost due to the differing epitaxial material used for the resistance.
Accordingly, what is needed is a device which will enable the dissipation of joule heat as well as provide the required ballast resistors without the creation of the resonator that results in the conventional technique described above. Furthermore, what is required is a technique for fabricating the HBT having the thermal dissipation characteristics as well as ballast resistors in off-finger sight which is within the standard techniques of fabrication of the HBT. Such a technique will offer both the required end product as well as the advantage of standard processing steps.

Separation of thermal and electrical paths in flip chip ballasted power heterojunction bipolar transistors