Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
  • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the applicants have discovered a new class of phenylureido substituted phenoxy propionic acid compounds which can be administered orally to mammals to reduce total blood cholesterol levels and low density lipid-cholesterol levels without substantially affecting high density lipid- cholesterol levels.
• the compounds may also be utilized to modify the affinity of hemoglobin for oxygen or to prevent platelet aggregation.
• R 1 , R 2 , R 3 and R 4 may be the same or different and independently selected from the group consisting of hydrogen, halogen, straight and branched chain alkyl of from 1-6 carbon atoms, aryl, cycloalkyl of 4 to 7 carbon atoms; and alkoxy of
• R 5 and R 6 may be the same or different and are selected from the group consisting of hydrogen, halogen, straight and branched chain alkyl groups of from 1-6 carbon atoms, aralkyl groups wherein the alkyl portion has from 1-6 carbon atoms cycloalkyl of from 4-7 carbon atoms and aryl;
• R 7 is hydrogen or a straight or branched chain alkyl group of 1-6 carbon atoms and the pharmaceutically acceptable salts such as the sodium, potassium, ammonium, etc.
• the invention also includes pharmaceutical compositions that are based on a compound of Formula I and methods for the reduction of hyperlipidemia by the oral administration of a comoound of Formula I.
• FIG. 1 shows the effects of a compound of the invention on the oxygen dissociation of human hemoglobin solution.
• FIG. 2 shows the effects of a compound of the invention on the oxygen dissociation of intact human red blood cells.
• the nitrophenoxy acid is prepared according to the procedure described by P. Galimberti et al., Gazz. Chim. Ital. 77,431 (1947).
• the amino substituted compound is prepared by catalytic hydrogenation of the nitro compound according to the procedure of G.E. Wicks, Jr., J. Med. Chem. 15,436 (1972).
• the amino substituted compound is then reacted with an arylisocyanate to form the arylureido acid compound of the invention.
• the esters of the free acid are formed by reacting the appropriate alcohol with the free acid using conventional ester forming conditions.
• the pharmaceutically acceptable salts may be prepared by standard procedures using the appropriate metal or ammonium salt such as sodium hydroxide, sodium bicarbonate, potassium hydroxide and the like.
• the compounds of the invention may be administered to mammals including humans to reduce or prevent hyperlipidemia especially to reduce the levels of total serum cholesterol, low density lipoprotein-associated cholesterol and trigly- cerides.
• the compounds may be administered orally at a daily dosage of frdm about 1 to 200 mg per kilogram of body weight and more preferably at a level of about 10 to 50 mg per kilogram of body weight.
• the daily dosage is to be administered as a single dose, or in divided amounts three or four times a day. It is understood that the dose may be varied according to individual sensitivity and the type of hyperlipidemia being treated.
• the compounds may be administered parenterally or rectally. The parenteral dose will be 15-25% of the oral dosage and the rectal dosage may be adjusted to obtain the desired therapeutic affect.
• the compounds of the invention may be added to whole blood or packed cells in an amount of about 50mg to 2.0g per unit of blood (473ml) or unit of packed cells (235ml) and preferably from 250mg to 750mg per unit of blood or unit of packed cells in order to facilitate the dissociation of oxygen from hemoglobin and improve the oxygen delivery capability of blood.
• the hemoglobin in the blood tends to increase its affinity for oxygen by losin 2,3-diphosphoglycerides.
• the compounds of the invention are capable of reversing and/or preventing the functional abnormality of hemoglobin which is observed when whole blood or packed cells are stored.
• the compounds of the invention may be added to whole blood or red blood cell fractions in a closed system using an appropriate resevoir in which the compound is placed prior to storage or which is present in the anticoagulating solution in the blood collecting bag.
• the compounds may be administered to patients in whom the affinity of hemoglobin for oxygen is abnormally high (e.g. certain hemoglobinopathies), or when the availability of hemoglobin to tissues is decreased, (e.g. in ischemic conditions such as peripheral vascular disease, coronary occlusion or cerebral vascular accidents).
• the compounds may also be used to inhibit platelet aggregation and may be used for antithrombotic purposes.
• the dosage for the modification of the affinity of hemoglobin for oxygen may be based on the dosages set forth above for hyperlipidemia and these dosages may be adjusted for parenteral use to obtain the desired therapeutic result.
• the compounds should not be administered to patients with sickle cell disease to avoid the possibility of excessive oxygen loss which may precipitate a sickle cell crisis.
• halogen is used to include bromo, chloro, fluoro and iodo
• alkyl includes straight and branched chain hydrocarbon groups of 1-6 carbon atoms such as methyl, ethyl, n-propyl, n-pentyl and the like
• aryl includes phenyl and naphthyl
• cycloalkyl includes cycloaliphatic groups of 4 to 7 carbon atoms such a cyclobutyl, cyclopentyl, cyclohexyl and the like
• alkoxy is used to include R 8 OH groups wherein R 8 is alkyl of 1 to 6 carbon atoms
• aralkyl is used to include phenalkyl groups wherein the alkyl portion is an alkylene moiety of 1-6 carbons such as benzyl, phenethyl, phenpropyl and the like.
• pharmaceutically acceptable diluent is used to include liquid and solid materials conventionally utilized to prepare injectable dosage forms and solid dosage forms such as tablets and capsules.
• Water may be used for the preparation of injectable compositions which may also include conventional buffers and agents to render the injectable composition isotonic
• the solid diluents and excipients include lactose, starch, conventional disintegrating agents, coatings and the like.
• UK patent 1,535,683 which is incorporated by reference, gives several embodiments of formulation that may be utilized in the preparation of tablets and capsules.
• nitrophenoxy 2-methyl propionic acid intermediate was prepared by the reaction of chlorofrom with 4-nitrophenol and sodium hydroxide in dry acetone as described by P. Galimberti and A. Defranceschi, Gazz. Chim. Ital. 77, 431, (1947). The yield was 54%. mp 121-123°. (recrystallized from CCl 4 ).
• the amino phenoxy hydrochloride compound was prepared by catalytic hydrogenation of the nitro compound as described by H. Z. Sommer and G. E. Wicks, Jr., J. Med. Chem. 15, 436 (1972).
• the free base required for the synthesis of phenylureido derivatives was obtained by alkalinization of the hydrochloride with IN NaOH followed by the addition of concentrated acetic acid to precipitate the free acid as a crystalline compound, mp 214-216°.
• FIG. 1 illustrates the oxygen dissociation curves produced by a 50 uM solution of normal human hemoglobin tested at pH 7.2 using TRIS as the buffer in a Hemox analyzer. In this test, percent oxygen saturation (on the vertical axis) is plotted against the partial pressure of oxygen (pO 2 in the horizontal axis).
• Curve #1 shows the normal oxygen dissociation curve in the absence of any modifying agent.
• Curve #2 shows a shift to the right when 5mM Bezafibrate that was solubilized with an equimolar amount of sodium bicarbonate is added.
• Curve #3 shows the right shift caused by 1mM concentration of the compound of Example 3 that was solubilized with an equimolar amount of sodium bicarbonate and curve #4 shows the shift affected by the presence of 0.5mM of the compound of Example 3.
• Fig. 2 illustrates the same effects when the intact human RBCs are treated with the same compounds.
• 50 uL washed human RBCs were suspended in 4ml of HEPES buffer (pH 7.4) and oxygen dissociation curves were obtained.
• Curve #1 shows the oxyge dissociation curve produced by Hb in untreated RBCs.
• Curve #2 illustrates the right shift caused by the presence of 5mM Bezafibrate.
• This example describes the cholesterol and lipoprotein reducing activities of the compounds of the invention.
• Animals in Group one received normal rat diet.
• Nath's diet is composed of 49% sucrose, 24% coconut oil, 18% casein, vitamin mixture 2%, Maize oil 1%, Mineral salts 4%, cholic acid 1%, and cholesterol 1%.
• Animals in Group two received no medications and served as hyperlipemic controls.
• Animals in Group 3 received 30 mg/kg/day of the compound of Example 3 mixed with their food. At the end of fifteen days all the animals were sacrificed and their blood cholesterol and lipids were measured. The results are as follows:

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• 1988
  • 1988-06-15 WO PCT/US1988/002092 patent/WO1988010113A1/en not_active Application Discontinuation
  • 1988-06-15 EP EP19880906435 patent/EP0358724A4/de not_active Withdrawn
  • 1988-06-15 AU AU19986/88A patent/AU616674B2/en not_active Ceased
  • 1988-06-15 JP JP63505967A patent/JPH02503797A/ja active Pending

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