Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/10—Expectorants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/14—Antitussive agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• This invention is directed to pharmaceutical compositions comprising an elastase inhibitor and an (F)-actin shortening protein such as gelsolin or vitamin D binding protein (DBP), for use in the treatment of Cystic Fibrosis and related diseases.
• an elastase inhibitor and an (F)-actin shortening protein such as gelsolin or vitamin D binding protein (DBP), for use in the treatment of Cystic Fibrosis and related diseases.
• this invention is directed to pharmaceutical compositions comprising elastase inhibitors of Formula I
• proteases from granulocytes and macrophages have been reported to be responsible for the chronic tissue destruction mechanisms associated with inflammation, including rheumatoid arthritis and emphysema. Accordingly, specific and selective inhibitors of these proteases are candidates for potent anti-inflammatory agents useful in the treatment of inflammatory conditions resulting in connective tissue destruction, e.g., rheumatoid arthritis, emphysema, bronchial inflammation, chronic bronchitis, glomerulonephritis, osteoarthritis, spondylitis, lupus, psoriasis, atherosclerosis, sepsis, septicemia, shock, myocardial infarction, reperfusion injury, periodontitis, cystic fibrosis and acute respiratory distress syndrome.
• the role of proteases from granulocytes, leukocytes or macrophages are related to a rapid series of events which occurs during the progression of an inflammatory condition:
• lymphoid cells especially macrophages and polymorphonuclear leukocytes (PMN). It has been known that a variety of proteases are released from the macrophages and PMN, further indicating that the proteases do play an important role in inflammation.
• proteases are an important family of enzymes within the peptide bond cleaving enzymes whose members are essential to a variety of normal biological activities, such as digestion, formation and dissolution of blood clots, the formation of active forms of hormones, the immune reaction to foreign cells and organisms, etc., and in pathological conditions such as the degradation of structural proteins at the articular cartilage/pannus junction in rheumatoid arthritis etc.
• Elastase is one of the proteases. It is an enzyme capable of hydrolyzing the connective tissue component elastin, a property not contained by the bulk of the proteases present in mammals. It acts on a protein's nonterminal bonds which are adjacent to an aliphatic amino acid.
• Neutrophil elastase is of particular interest because it has the broadest spectrum of activity against natural connective tissue substrates.
• the elastase of the granulocyte is important because, as described above, granulocytes participate in acute inflammation and in acute exacerbation of chronic forms of inflammation which characterize many clinically important inflammatory diseases.
• Proteases may be inactivated by inhibitors which block the active site of the enzyme by binding tightly thereto.
• Naturally occurring protease inhibitors form part of the control or defense mechanisms that are crucial to the well-being of an organism. Without these control mechanisms, the proteases would destroy any protein within reach.
• the naturally occurring enzyme inhibitors have been shown to have appropriate configurations which allow them to bind tightly to the enzyme. This configuration is part of the reason that inhibitors bind to the enzyme so tightly (see Stroud, "A Family of Protein-Cutting Proteins" Sci. Am., July 1974, pp. 74-88).
• i-Antitrypsin is a glycoprotein contained in human serum that has a wide inhibitory spectrum covering, among other enzymes, elastase both from the pancreas and the PMN. This inhibitor is hydrolyzed by the proteases to form a stable acyl enzyme in which the active site is no longer available. Marked reduction in serum ⁇ i-antitrypsin, either genetic or due to oxidants, has been associated with pulmonary emphysema which is a disease characterized by a progressive loss of lung elasticity and resulting respiratory difficulty.
• Rheumatoid arthritis is characterized by a progressive destruction of articular cartilage both on the free surface bordering the joint space and at the erosion front built up by synovial tissue toward the cartilage. This destruction process, in turn, is attributed to the protein-cutting enzyme elastase which is a neutral protease present in human granulocytes. This conclusion has been supported by the following observations:
• (F)-actin shortening proteins including gelsolin, plasma gelsolin (brevin), vitamin D binding protein (DBP), villin, fragmin, and severin, and their use in shortening (F)-actin and treating (F)-actin mediated diseases is described in U.S. 5,260,224, issued to Stossel et al, on November 9, 1993, which patent is hereby incorporated by reference.
• Gelsolin's primary function in the plasma is to sever actin filaments. If gelsolin is present in excess of actin, only gelsolin-actin complexes result; if actin is in excess, there are free actin oligomers and gelsolin-actin complexes. The actin severing occurs by way of a non- proteolytic cleavage of the noncovalent bond between adjacent actin molecules.
• Efficacious levels of actin-binding compounds may be administered so as to provide therapeutic benefits against the secondary toxic effects of excessive extracellular actin.
• efficacious levels of actin-binding compounds is meant levels in which the toxic effects of free extracellular actin are, at a minimum, ameliorated.
• excessive extracellular actin is meant an amount of extracellular actin which exceeds the ability of the plasma proteins to bind and clear the actin from extracellular fluids without secondary tissue damage or toxic effects.
• secondary tissue damage or toxic effects is meant the tissue damage or toxic effects which occur to otherwise healthy tissues, organs, and the cells therein, due to the presence of excessive extracellular actin in the plasma, usually as a result of a "primary" tissue injury elsewhere in the body.
• This invention relates to pharmaceutical compositions and methods for the treatment of lung disease, and in particular Cystic Fibrosis comprising the a non-toxic effective amount of an elastase inhibitor such as the compounds of Formula (I),
• a non-toxic effective amount of a (F)-actin shortening protein such as gelsolin, and a pharmaceutically acceptable carrier.
• This invention relates to pharmaceutical compositions and methods for the treatment of lung disease, and in particular Cystic Fibrosis comprising the a non-toxic effective amount of an elastase inhibitor such as the compounds of Formula (I),
• a non-toxic effective amount of a (F)-actin shortening protein such as gelsolin, and a pharmaceutically acceptable carrier.
• R is Cl-6alkyl
• R 1 is Ci-6alkyl or Cl-6alkoxy-Ci-6alkyl; M is
• R2 and R3 are each independently
• R2 and R3 may be joined together to form a methylenedi ⁇ xy group or a ftiran ring
• R 4 is (a) Q- ?C-Y-N , or
• R5 and R6 are each individually Cl-3alkyl or hydrogen
• Rl2 is hydrogen or Cl-3alkyl; R7 and R are each individually
• 10 includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, (m) carboxy Cl-6alkyl, (n) carbo Cl-6alkoxy C 1-3 alkyl,
• Ci-6alkyl (u) aminocarbonyl wherein the amino is optionally mono or di substituted with Cl-6alkyl, (v) aminocarbonyloxyC2-6alkyl wherein the
• 25 amino is optionally mono or di substituted with
• Ci-6alkyl (w) azabicyclo of 7 to 12 atoms, (x) di Cl-3alkylamino C2-6alkyl wherein the
• Ci-6alkyl (y) bicycloalkyl of 7 to 12 atoms, (z) C3-l ⁇ cycloalkyl optionally substituted with
• Cl-6alkyl (aa) pyrazolidinyl, (bb) substituted piperidinyl or prrolidinyl wherein the substituent is hydrogen, Cl-3alkyl, hydroxyCl-3alkylbenzyl, carboxamido or amino wherein the amino is optionally mono or di substituted with Cl-6alkyl,
• R7 and R8 are joined together to form mono or di substituted ring of 4, 5, 6, or 7 atoms or 7 to 12 atoms such as
• alkyl such as in Cl-6alkyl, includes, methyl, ethyl, propyl, butyl, pentyl, and hexyl, and where appropriate, branched chained forms including isopropyl and tert-butyl.
• the (-CRl2-)n spacer in definition Y may, in the alternative be placed to the right of CRioRl 1.
• R7 may also be oxidized to the corresponding oxide -N N — O
• R 1 is Ci-6alkyl or Ci-6alkoxy-Ci-6alkyl; Mis
• R5 and R6 are each individually Cl-3alkyl or hydrogen or a covalent bond
• Ci-6alkyl (r) di Cl-3alkylamino Cl-6alkyl wherein the amino is optionally mono or di substituted with
• Ci-6alkyl (s) pyrazolidinyl,
• n 1, 2, 3, 4 or 5;
• R9 is selected from hydrogen, Ci-4 alkyl, and Cl-3alkoxyCi -3alkyl;
• RlO and Rl l are each independently selected from hydrogen, Ci-4alkyl, and Cl-3alkoxy Ci-3alkyl; or
• R7 and R8 are joined together to form mono or di substituted ring of 4, 5, 6, or 7 atoms such as
• R8 and R9 are joined together to form a saturated ring of 5 to 7 atoms and having two hetero atoms;
• R9 and RlO are joined together to form a saturated ring of 5 to 7 atoms and having one hetero atom; or wherein R9 and R12 are joined together to form a ring of 5, 6, or 7 . atoms, said ring being saturated; or wherein Rio and Rl2 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein R and Rl l are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated and having one hetero atom.
• the invention concerns compounds of
• n 1, 2 or 3
• R9, RlO and Rl l are each independently selected from hydrogen, Cl-4alkyl, and Ci-3alkoxy Cl-3alkyl; or R7 and R8 are joined together to form a substituted ring selected from
• R8 and R9 are joined together to form a ring of 6 to 7 atoms and having two hetero atoms;
• R9 and Rio are joined together to form a saturated ring of 5 to 7 atoms and having one hetero atom; or wherein R9 and R12 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein Rio and Rl2 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein R8 and Rl l are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated and having one hetero atom.
• Q is a covalent bond
• R is methyl or ethyl
• Rl is methyl or ethyl
• M is
• R2 and R are joined together to form a furan or dioxacyclopentane ring; n is 1 or 2;
• R9 and RlO are each independently selected from
• R7 and R8 are joined together to form a substituted ring selected from
• (F)-actin shortening proteins are effective in reducing the viscosity of sputum, particularly cystic Fibrosis sputum.
• liquefaction is not instantaneous. However, once a sufficient degree of viscosity reduction is achieved, a patient can more easily expectorate or otherwise rid himself of excess sputum.
• the compounds of Formula I are surprisingly, highly active in viscous sputum as well as liquified sputum.
• treatment with applicants composition is capable of returning a patent with lung disease to substantially normal lung function, as measured, for example, by FEVl (forced expiration volume).
• FEVl forced expiration volume
• treatment with applicants composition is capable of returning a patent with lung disease to at least 60-75% of normal lung function, as measured, for example, by FEVl .
• treatment with applicants composition is capable of returning a patent with lung disease to 75-90% of normal lung function or greater, as measured, for example, by FEVl .
• the invention encompasses a method of treating a patient with a lung disease, comprising: administration to a patient in need of sputum viscosity reduction, a therapeutically effective non-toxic amount of an (F)-actin shortening protein and a therapeutically effective non-toxic amount of compound of Formula I as described herein.
• the invention encompasses a method of treating a patient with a lung disease, comprising: administration to a patient in need of sputum viscosity reduction, a therapeutically effective non-toxic amount of an (F)-actin shortening protein and a therapeutically effective non-toxic amount of compound of Formula I as described herein, said amounts effective to return the lung function of said patients to at least 60-75% of normal as measured by FEVl .
• the invention encompasses a method of treating a patient with a lung disease, comprising: administration to a patient in need of sputum viscosity reduction, a therapeutically effective non-toxic amount of an (F)-actin shortening protein and a therapeutically effective non-toxic amount of compound of Formula I as described herein, said amounts effective to return the lung function of said patients to 75 to 90% of normal as measured by FEVl .
• the compounds of the invention are prepared by known methods or are prepared among other methods by the following representative schemes. For example, methods for making such compounds are disclosed in EP O 337 549, published October 18, 1989, which is hereby incorporated by reference.
• This invention also relates to a method of treating inflammation in patients using a compound of Formula (I), particularly a preferred compound as the active constituent.
• the solid was first dissolved in 10.0 ml DMSO. Buffer at pH 7.5 was then added to a final volume of 100 ml.
• the elastase activity in the crude PMN extract may vary from one preparation to another. A control of each new batch is run, and the volume added in the assay procedure is adjusted according to activity.
• This invention also relates to a method of treating inflammation in patients using a compound of Formula (I), particularly a preferred compound as the active constituent.
• the compounds of Formula (I) can be used to reduce inflammation and/or relieve pain in diseases such as emphysema, rheumatoid arthritis, osteoarthritis, gout, bronchial inflammation, chronic or acute bronchitis, cystic fibrosis, adult respiratory distress syndrome, atherosclerosis, sepsis, septicemia, shock, periodontitis, glomerular nephritis or nephosis, myocardial infarction, reperfusion injury, infectious arthritis, rheumatic fever and the like, and may reduce hemorrhage in acute promyelocytic leukemia and the like.
• diseases such as emphysema, rheumatoid arthritis, osteoarthritis, gout, bronchial inflammation, chronic or acute bronchitis, cystic fibrosis, adult respiratory distress syndrome, atherosclerosis, sepsis, septicemia, shock, periodontitis, glomerular ne
• the compounds of Formula (I) and (F)-actin shortening proteins may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit Formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
• the compounds of the invention are effective in the treatment of humans.
• compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene
• the said aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxy- benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
• a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
• the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example, olive oil or arachis oils, or a mineral oil, for example, liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth, naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the pharmaceutical compositions may be in the form of a sterile mjectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
• Suitable vehicles and solvents that may be employed are water, Ringer's solution glucose in water and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• compositions of this invention may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials are cocoa butter and polyethylene glycols.
• creams, ointments, jellies, solutions or suspensions, etc., containing the anti-inflammatory agents are employed.
• the amount of active ingredient(s) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a formulation intended for the oral administration of humans may contain from 5 mg to 2000 mg or 5000 mg of each active agent(s) compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
• this broad dosage range is specifically intended to include, but is not limited to, range of 5 mg to 2000 mg; 25 mg to 2000 mg; 5 mg to 1000 mg; 25 mg to 1000 mg; 5 mg to 500 mg; and 25 mg to 500 mg.
• Dosage unit forms will generally contain between from about 25 mg to about 500 mg of active ingredient(s).
• most effective treatment may warrant administration of an initial dosage of one range (e.g., 1-5 mg of active agent per kg of patient weight) followed by administration of a second range (e.g., 0.1 to 1 mg of active agent per kg of patient weight).
• one range e.g., 1-5 mg of active agent per kg of patient weight
• a second range e.g., 0.1 to 1 mg of active agent per kg of patient weight
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drag combination and the severity of the particular disease undergoing therapy.
• the dosage can be calculated in the following manner.
• the normal blood gelsolin concentration is 2.4 ⁇ M (2.4 ⁇ mol/L), and the normal blood DBP concentration is 5 ⁇ M (5 ⁇ mol/L).
• the total blood actin-binding capacity (ABC) is approximately 7.5 ⁇ mol/L.
• the blood volume if 6% of the body weight, hence a 70 Kg person has 4.2 liters of blood and thus (4.2 L x 7.5 ⁇ mol/L) 31.5 ⁇ mols ABC. Since DBP and gelsolin are distributed throughout the extracellular space (which is 10% of the body weight, the body contains (7.5 x 7) 52.5 ⁇ mols ABC.
• actin binding an actin binding compound (herein actin shortening) compound (or 0.46 ⁇ mol/kg body weight) to cover total complexing or depletion of endogenous ABC. Since 0.425 mg of actin is equal to 1 ⁇ mol, and since there is 4.86 mg actin per gram of skeletal muscle, each gram of muscle contains 11.3 ⁇ mol actin or 4.6 grams of muscle destruction could neutralize total body ABC.
• actin permeates an organ faster than binding proteins neutralize it
• a theoretically minimum dose will have to be adjusted upward in order to achieve kinetically favorable therapeutic effects.
• the kinetic effect can be important, for example, since hemolysis of about half of erythron, which should liberate only 4.2 ⁇ mol of actin, reduces the plasmia gelsolin concentration by half acutely (Smith, et al., Blood 72:214-2181 (1988)), suggesting slow equilibration between extravascular and blood compartments.
• a therapeutically effective state capable of breaking up local deposits of actin, may be achievable only by a transient pulse of a high concentration of actin-binding molecules.
• the compounds of the invention can be administered in any appropriate pharmacological carrier for administration. They can be administered in any form that effects prophylactic, palliative, preventative or curing conditions of tissue injury in humans and animals.
• compounds may be produced and used in the form of pharmaceutically acceptable salts.
• the basic compounds may be used in the form of a hydrochloride or mesylate or other acceptable salt. See Preformulation in Remington's Pharmaceutical Sciences, Mack Publishing, Easton PA.
• glycolic acid derivatives described herein can be prepared according to the following scheme.
• the starting acid (as carboxy late anion) may be alkylated (Ex IA) with a suitably protected ⁇ -halo acetic acid derivative to give the glycolate ester 4 which can be deprotected (Ex IB) to the glycolic acid ester 5.
• a condensing agent such as dicyclohexylcarbodumide or carbomyldiinidazole (Ex 2) affords the deserved amide 6.
• the starting acid 1 may be converted to its acid chloride 2 (Ex 3A) and treated with a suitably protected ⁇ -hydroxyalkanoic acid (Ex 3B) in the presence of base to give the protected ester 7.
• Example 4 The acid (.250 gm) from Example 4 is treated with oxalyl chloride according to the procedure of Example 3A and the corresponding acid chloride is obtained. This material is dissolved in 5 ml methylene chloride and 0.4 ml of diethylamine added. After 1 hour the reaction mixture is concentrated in vacuo and the residue taken in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer is dried through sodium sulfate, concentrated and the residue chromatographed on silica gel. Elution with 5% of ethyl acetate in methylene chloride gives Compound 12. Analysis: C33H45N3O6 Calc: C, 68.37; H, 7.82, N, 7.25
• the diamines used to prepare the amino amides described herein were commercially available or prepared according to the following routes
• a mixture of 0.900 gm N-benzyl-N,N'-dimethylethyl- enediamine, 1.10 gm powdered sodium carbonate and 0.75 ml of 2- phenylethylbromide is refluxed for 5 hours. An additional 0.25 ml of bromide is added during this time.
• the reaction mixture is then cooled and filtered.
• the filterate is concentrated in vacuo and the residue chromatographed on silica gel using an eluent of CH2CI2/CH3OH/- NH4OH (97/3/0.3) to yield 0.875 gm of N-benzyl-N,N'-dimethyl-N'-(2- phenylethyl)ethylenediamine.
• Step A [S-R*,S*)]-2-[4-[[(4-(t-Butoxycarbonyl))piperazin-l - yl]carbonyl]phenoxy]-((3,3-diethyl-N-[l-(4-methyl- phenyDbutyll -4-oxo- 1 -azetidinecarboxamide
• Step B [S-R*,S*)]-2-[4-[(Piperazin-l -yl)carbonyl]phenoxy]- ((3,3-diethyl-N-[l-(4-methyl ⁇ henyl)butyl-4-oxo-l- azetidine-carboxamide
• Step A [S-R*,S*)]-2-[4-[[(4-Benzyloxycarbonyl) Piperazin-1- yl]carbonyl]phenoxy]-((3,3-diethyl-N-[ 1 -3,4-methylene- dioxyphen vDbutyll -4-oxo-l -azetidinecarboxamide
• Step B [S-R*,S*)]-2-[4-[(Piperazin-l-yl)carbonyl]phenoxy]-((3,3- diethyl-N-[l -(3,4-methylenedioxyphenyl)butyl-4-oxo-l - azetidinecarboxamide

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Pulmonology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Marine Sciences & Fisheries (AREA)
• Zoology (AREA)
• Oncology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Vascular Medicine (AREA)
• Tropical Medicine & Parasitology (AREA)
• Communicable Diseases (AREA)
• Gastroenterology & Hepatology (AREA)
• Immunology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Urology & Nephrology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=22790936

Family Applications (1)

Country Status (5)

Families Citing this family (5)

Citations (1)

Family Cites Families (3)

• 1995
  • 1995-03-07 WO PCT/US1995/002938 patent/WO1995024207A1/en not_active Application Discontinuation
  • 1995-03-07 JP JP7523641A patent/JPH09510212A/ja active Pending
  • 1995-03-07 AU AU20994/95A patent/AU686780B2/en not_active Ceased
  • 1995-03-07 CA CA002184385A patent/CA2184385A1/en not_active Abandoned
  • 1995-03-07 EP EP95913618A patent/EP0755262A4/de not_active Withdrawn

Patent Citations (1)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events