WO1995022520A1 - Substituted biphenyl derivatives as phosphodiesterase inhibitors - Google Patents

Substituted biphenyl derivatives as phosphodiesterase inhibitors Download PDF

Info

Publication number
WO1995022520A1
WO1995022520A1 PCT/US1995/000996 US9500996W WO9522520A1 WO 1995022520 A1 WO1995022520 A1 WO 1995022520A1 US 9500996 W US9500996 W US 9500996W WO 9522520 A1 WO9522520 A1 WO 9522520A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
cycloalkyl
aryl
cyclopentyloxy
Prior art date
Application number
PCT/US1995/000996
Other languages
French (fr)
Inventor
Thomas Joseph Caggiano
Joseph Prol, Jr.
Original Assignee
American Home Products Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to EP95908671A priority Critical patent/EP0745063B1/en
Priority to AU16905/95A priority patent/AU692839B2/en
Priority to DE69508568T priority patent/DE69508568T2/en
Priority to MX9603414A priority patent/MX9603414A/en
Priority to JP7521806A priority patent/JPH09510191A/en
Priority to DK95908671T priority patent/DK0745063T3/en
Publication of WO1995022520A1 publication Critical patent/WO1995022520A1/en
Priority to KR1019960704462A priority patent/KR970701170A/en
Priority to FI963228A priority patent/FI963228A0/en
Priority to GR990401565T priority patent/GR3030490T3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/247—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C07C65/26—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to new methods of treating inflammatory diseases. More particularly, the present invention relates to new substituted biphenyl derivatives which are useful in the treatment of asthma, as well as other types of allergic and inflammatory diseases.
  • Asthmatic attacks are characterized by the narrowing of both large and small airways brought upoon by bronchial smooth muscle spasms, edema and inflammation of the bronchial mucose, and production of tenacious mucus.
  • the exact mechanisms involved in asthmatic bronchoconstriction are not completely understood, but an imbalance between beta adrenergic and cholinergic control of the airways has been indicated.
  • Such imbalances appear to be controlled by the cyclic 3',5'-adenosine monophosphate (cyclic AMP or cAMP)-cyclic 3',5'-guanosine monophosphate (cyclic GMP or cGMP) systems with various tissues, such as smooth muscle, mast cells and mucus secreting cells.
  • beta adrenergic agents which cause bronchial smooth muscle relaxation and modulate inhibition of mediator release.
  • beta adrenergic agents which cause bronchial smooth muscle relaxation and modulate inhibition of mediator release.
  • these agents include epinephrine, isoproterenol, ephedrine and beta2-adrenergic agents such as metaproterenol, terbutaline, isoetharine, albuterol, bitolterol and fenoterol (5-[l- Hydroxy-2-[[2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl-l,3-benzenediol).
  • Corticosteroids such as prednisone
  • prednisone have been useful in treating asthma as they inhibit attraction of polymorphonuclear leukocytes to the sites of allergic reactions, stimulate synthesis of beta2 receptors and block leukotriene synthesis.
  • Theophylline a methyxanthine
  • Anticholinergic agents such as atropine and its derivative ipratopium bromide, have been used to block cholinergic pathways that cause airway obstruction. Used for maintenance therapy alone, cromolyn sodium (disodium cromoglycate) appears to inhibit mediator release and reduce airway hyperactivity.
  • these CD4+ cells appear to be activated [Corrigan, CJ. and Kay, A.B., Am. Rev. Resp. Dis. Mi: 970-977 (1990)] by vi ⁇ ue of the increase in IL-2 receptor positive cells.
  • these cells are capable of producing cytokines (such as D -3, IL-5, and granulocyte macrophage colony stimulating factor) which can directly affect the differentiation, maturation and activation state of the eosinophils and other inflammatory cells.
  • cytokines such as D -3, IL-5, and granulocyte macrophage colony stimulating factor
  • Rapamycin a macrocyclic triene antibiotic produced by Streptomvces hvgroscopicus [U.S. Patent 3,929,992] has been shown to prevent the formation of humoral (IgE-like) antibodies in response to an albumin allergic challenge [Mattel, R., Can. J. Physiol. Pharm. 55: 48 (1977)], inhibit murine T-cell activation [Strauch, M., FASEB 3: 3411 (1989)].
  • This invention relates to compounds demonstrated to inhibit a specific phosphodiesterase (PDE), often called PDE IV, that selectively metabolizes cyclic adenosine 3':5'- monophosphate (cAMP) and that is insensitive to the modulatory effects of guanosine cyclic 3':5' monophosphate (cGMP) and calcium.
  • PDE phosphodiesterase
  • This PDE is found in both respiratory smooth muscle and inflammatory cells, and has been demonstrated to be a principle regulator of cAMP in these tissues [see Torphy and Cieslinski, Molecular Pharmacology. 37, 206 (1990), and Dent et al., British Journal of Pharmacology. 90, 163P (1990)].
  • the compounds named in this invention are both bronchodilatory and antiinflamatory, and are effective in animal models of allergic and nonallergic asthma.
  • the compounds named in this invention preferentially inhibit the PDE IV isozyme, they are expected to be more selective and safer anti-asthmatics than nonselective PDE inhibitors currently used for the treatment of asthma, such as theophylline.
  • These compounds are inhibitors of the enzyme 3', 5' cyclic AMP phosphodiester-ase. By virtue of this activity, the compounds act as bronchodilators as well as prevent the influx of leukocytes into the lung and pulmonary cavities of antigen sensitized and subsequently challenged laboratory animals. Thus these compounds are useful for the acute and chronic treatment of bronchial asthma and its associated pathology.
  • Ri alkyl, cycloalkyl, arylalkyl, aryl;
  • R2 cycloalkyl, aryl, C3-C10 alkyl;
  • X,Y O, S(O) n , NH;
  • R3, R4, R5, Re, R7 are each, independently, hydrogen, alkyl, aryl, aryalkyl, cycloalkyl, or fluoroalkyl; or a compound of Structure I, wherein:
  • R l alkyl, cycloalkyl, arylalkyl, or aryl;
  • R2 cycloalkyl, aryl, or alkyl;
  • X,Y CH 2 , O, S(O) n , or NH;
  • R3, R4, R5, R ⁇ , R7 hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, or fluoroalkyl;
  • R8 CO2R3, CONR2R3, or Rg and Z are concatenated such that
  • Rl C ⁇ -C 3 alkyl
  • R2 C3-C6 alkyl, C3-C7 cycloalkyl, or phenyl
  • R3, R4, R5, R ⁇ , R7 are each, independently, hydrogen, C1-C4 alkyl, aryl, arylalkyl, fluoroalkyl;
  • R 8 H or CO2R3; as well as pharmaceutically acceptable salts thereof.
  • ring A is attached to ring B in the meta or para position.
  • W O, NOH, NNH2, NOC(O)CH 3 , NNHC(O)CH3.
  • Ri C1-C3 alkyl
  • R2 C3-C7 cycloalkyl or C3-C6 alkyl
  • R3, R4, R5, R ⁇ , R7 are each, independently, H, C1-C4 alkyl, aryl, or trifluoromethyl; and
  • R 8 H or CO 2 R3; or pharmaceutically acceptable salts thereof.
  • these preferred compounds of the present invention may also include those in which ring B is described by structures in or IV, above, and is attached to ring A at the 5, 6 or 7 position.
  • R2 C4 alkyl, C5 cycloalkyl
  • R3, R4, R5, R* $ , R7 and R 8 are each, independently, hydrogen, methyl, phenyl, or trifluoromethyl; or pharmaceutically acceptable salts thereof.
  • R 8 and Z are CO2R3 or CONR4R5.
  • R 8 and Z are CO2R3 or CONR4R5.
  • the most preferred compounds of the present invention may be described by the formulas V and VI, below, or pharmaceutically acceptable salts of the compounds of formulas V and VI:
  • Also provided by the present invention is a method for treating allergic and inflammatory diseases, as well as asthma, both allergic and non-allergic.
  • a method for treating allergic and inflammatory diseases, as well as asthma, both allergic and non-allergic comprises administering to a mammal in need of such treatment an effective amount of one or more of the compounds listed herein and/or one or more of their phamaceutically acceptable salts.
  • Such a method is intended to include all treatments, administrations, or regimens related to such maladies including, but are not limited to, those which are prophylactic, therapeutic, progression inhibiting, remedial, maintenance, or other treatments regarding asthma and allergic and inflammatory disease states or conditions.
  • the effective dosages of the compounds presented herein will vary with the particular compound chosen and the form of administration. Furthermore, it will vary with the particular host under treatment. Generally, the compounds of this invention are administered at a concentration level that affords protective effects without any deleterious side effects. For example, the effective amount of compound can usually range from about 10 to about 250 mg/kg body weight per day administered once daily or divided into two to four administrations per week. The optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally with smaller doses being administered initially and thereafter increases in dosage are made to determine the most suitable dosage.
  • compositions comprising a mixture of one or more of the compounds disclosed herein, and/or one or more pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, which can be used according to the same methods of administration as the compounds, themselves. It is also contemplated that the compounds of the present invention may be used in a combined therapeutic regimen along with one or more additional medicinal agents.
  • the compounds of the present invention may form salts with suitable therapeutically acceptable inorganic and organic bases. These derived salts possess the same activity as their parent acid and are included within the scope of this invention.
  • Suitable inorganic bases to form these salts include, for example, the hydroxides, carbonates or bicarbonates of the therapeutically acceptable alkali metals or alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium and the like.
  • Suitable organic bases include primary and secondary amines such as methylamine, benzathine (NjN ⁇ -dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-l,3-propanediol) procaine, etc.
  • the quaternary salts for example, the tetraalkyl (e.g. tetramethyl), alkyl-alkanol (e.g. methyl-triethanol) and cyclic (e.g. N,N-dimethylmorpholine) ammonium salts. In principle, however, there can be used all the ammonium salts which are physiologically compatible.
  • Transformations to the corresponding salts are readily carried out by reacting the acid form of the compounds with an appropriate base, usually one equivalent, in a cosolvent.
  • the salt is isolated by concentration to dryness or by addition of a non- solvent.
  • a non- solvent for example, in the case of inorganic salts, it is preferred to dissolve the acid or the compound in water containing a hydroxide, carbonate or bicarbonate corresponding to the inorganic salt desired.
  • a water-miscible solvent of more moderate polarity for example, a lower alkanol such as butanol, or a lower alkanone such as ethyl methyl ketone, gives the solid inorganic salt.
  • Quaternary ammonium salts may be prepared by mixing the acid of the compound with a quaternary ammonium hydroxide in a water solution followed by evaporation of the water.
  • the compounds of the present invention may be clinically administered to mammals, including man, by either the oral or parenteral route.
  • Oral administration may be either alone or in combination with a solid or liquid pharmaceutically acceptable carrier or diluent such as starch, milk, sugar, certain types of clay, water, vegetable or mineral oils, and so forth to form tablets, capsules, powders, syrups, solutions, suspensions, and the like.
  • the active compounds may be used in combination with aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions prepared in this manner may be administered intravenously, intraperitoneally, subcutaneously or intramuscularly.
  • the compounds of this invention may also be administered in the form of suppositories.
  • the reaction was diluted with ethyl acetate (50 mL) and NaOH (0.5N, 50 mL).
  • the organic phase was separated and extracted with NaOH (0.5N, 2x50 mL).
  • the combined aqueous was acidified with HC1 (2.5N) until red to litmus.
  • the precipitate was extracted with ethyl acetate (3x50 mL).
  • the combined organic layers were washed with brine and dried (magnesium sulfate).
  • the organic layers were boiled with activated charcoal and filtered through a bed of silica atop a bed of celite. The resulting clear organic was concentrated to dryness. Recrystallization (ethyl acetate/ hexane) yielded 1.0 g of product (3.21 mmol, 75.4%): mp 231.5°C- 232.5°C.
  • the reaction was monitored by TLC (50% ethyl acetate in hexane), however, completion of the reaction was obvious when the catalyst turned black.
  • the reaction was diluted with ethyl acetate (50 mL).
  • the organic phase was separated and extracted with water (50 mL).
  • the organic phase was washed with brine and dried (magnesium sulfate).
  • the organic phase was boiled with activated charcoal and filtered through a bed of silica atop a bed of DCite.
  • the resulting clear organic phase was dried (magnesium sulfate), filtered, concentrated to dryness. Recrystallization, from ethyl acetate/ hexane, yielded 0.41 g (1.22 mmol, 38%) of product: mp 91°C- 92.5°C.
  • a solution of the diacid (120 mg, 0.33 mmol) prepared above is dissolved in ether (20 ml) and cooled to 0°C. To this was added an etherial solution of diazomethane until die yellow color persisted. The solution was stirred for 10 minutes and then glacial acetic acid was added to discharge the color. The solvent was removed in vacuo. The sample was chromatographed on silica gel with ethyl acetate in hexanes. This provided the product as an oil (118 mg, 93%).
  • the diacid prepared above (1.05 g, 2.94 mmol) was dissolved in acetic anhydride (10 ml) in a Carius tube. The tube was heated in a 140°C oil bath for 30 minutes, cooled and the solvent removed in vacuo. The crude anhydride was dissolved in dry dichloromethane (10 ml) and hydrazine hydrate was added (0.2 ml). The mixture was refluxed overnight with a Dean Stark trap. The sample was then diluted with IN NaOH and was extracted with ethyl acetate. The organic layer was discarded and the aqueous layer was acidifed with concentrated HCL. The resulting solid was filtered to give the product (1.02 g, 98%) as a dihydrate (mp > 255°C). IR (KBr) 1665 cm" 1
  • a solution containing PDE IV is prepared from canine tracheal muscle as follows: The dog is euthanized with an overdose of beuthanasia while under anesthesia induced by a 33 mg kg IV bolus of Nembutal. The trachealis muscle is removed, cleaned of connective tissue, and minced thoroughly. Three to four grams of tissue is then homogenized in Tris-HCl buffer (pH 7.8) using a Polytron. The homogenate is then centrifuged at 25,000 x g (4° C) for 30 minutes. The supernatant is decanted and filtered through four layers of gauze, and applied to a 40 cm x 2 cm DEAE-Sepharose column that is equilibrated with Tris-HCl buffer (pH 7.8).
  • PDE is eluted using 450 mL of Tris-HCl buffer containing a linear gradient of 0.0 - 1.0 M Na-acetate (80 mL/hr), and 7.5 mL fractions are collected. Each fraction is assayed for cAMP- and cGMP- metabolizing PDE activity. Fractions eluting at approximately 0.6 M Na- acetate, and containing cAMP but not cGMP metabolic activity are pooled and used as a PDE stock solution for assaying PDE IV inhibitory activity.
  • PDE IV activity is tested as described previously [see Thompson et al., Advances in Cyclic Nucleotide Research. JO. 69 (1979)] at 30° C in a reaction mixture containing: 10 mM Tris-HCl (pH 7.8), 5 mM MgCl2, 1 mM ⁇ -mercaptoethanol, 1 [_M ⁇ H-cAMP, 10 JJM CI-930, PDE IV stock solution, and die desired concentration of test compound.
  • CI-930 is included as an inhibitor of the cyclic GMP-sensitive, cyclic AMP-selective PDE (PDE III) that is also present in the PDE rv stock solution when prepared as described above.
  • test compound The ability of a test compound to inhibit PDE IV is determined by measuring the reduction in cAMP metabolism produced by the test compound and expressing it as a percentage of the reduction induced by 10 ⁇ M rolipram, a potent inhibitor of PDE r [see Beavo, Advances in Second Messenger and Phosphoprotein Research, 22, 1 (1988)]. IC50S are calculated for each test compound as the concentration of test compound that inhibits PDE IV by 50%.
  • Tracheal relaxation resulting from the inhibition of PDE-IV or PDE-III was assessed by a method similar to that employed by Harris et al. (1989). Tracheal rings were precontracted witii 1 ⁇ M carbachol until a stable level of tension was obtained (30 min). To explore the inhibition of PDE-IV, tracheal rings were then incubated (45 min) with CI-930 (10 ⁇ M), thus inhibiting PDE-III and sensitizing the ring to the relaxant effects of PDE-IV inhibitors. Conversely, the inhibition of tracheal PDE-III was explored using rings pretreated with rolipram (10 ⁇ M), and thereby sensitized to PDE- HI inhibitors (Harris et al., 1989).
  • the functional inhibition of PDE-IV or PDE-m was determined by adding a test compound to the tissue bath in cumulatively increasing concentrations and monitoring the degree of relaxation induced in the continued presence of CI-930 or rolipram (respectively). After adding the final concentration of test compound to the organ bath, tracheal rings were washed repeatedly with PSS, and allowed to relax to resting tension. Percent relaxations produced by each concentration of test compound were calculated as a percentage relaxation of tension maintained in the presence of the preincubating PDE inhibitor, relative to the final resting tension determined at die end of each experiment.
  • PDE IV inhibitory abilities of some of die compounds of the present invention The table below indicates die compounds tested and the results thereof. For each of Tests 1 and 2, die results are given as IC50S for the compound tested in M concentrations.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Liquid Crystal Substances (AREA)
  • Electroluminescent Light Sources (AREA)

Abstract

A compound of structure (I), wherein, when R8 = H: R1 = alkyl, cycloalkyl, arylalkyl, aryl; R2 = cycloalkyl, aryl, C3-C10 alkyl; X, Y = O, S(O)n, NH; Z = CH2OH, NHSO2R3, CHO, CO2R3, CONHR4R5, CN, COR6, H, halo, NHCN, NHCONR4R5, CONR4OR5, CONR4NR5R6, 1-tetrazole, S(O)nOH, S(O)nNR3R4, C=NOH, C(=N(OH)NH2, OCONR7R6, P(O)(OR4)2, NH2, SH, OH, OS(O)2R3, C(O)CO2R3, C(O)CONR3R4, CH(OH)CO2R3, CHFCO2R3, CF2CO2R3, CH(OH)CONR3R4, CF2CONR3R4, C=NNH2, C(=NOC(=O)R3)R4, C(=NNHC(=O)R3)R4, C(=NOH)R3, C(=NNR3)R4, NHC(=O)R6 or C(O)CONH2; R3, R4, R5, R6, R7 = hydrogen, alkyl, aryl, aryalkyl, cycloalkyl, or fluoroalkyl; or a compound of Structure I, wherein: R1 = alkyl, cycloalkyl, aryalkyl, or aryl; R2 = cycloalkyl, aryl, or alkyl; X, Y = CH2, O, S(O)n), or NH; R3, R4, R5, R6, R7 are each, independently, hydrogen, alkyl, aryl, aryalkyl, cycloalkyl, or fluoroalkyl; R8 = CO2R3, CONR3, or R8 and Z are concatenated such that R8Z = C(O)NHNHC(O), (CH2)mC(=W), V(CH2)mC(=W), or VnCH=CH(CH2)nC(=W); where V = O, S(O)n, NH; W = O, NOH, NHNH2, NOC(O)CH3, or NNHC(O)CH3; halo = Cl, Br, or I; fluoroalkyl = CF3CHF2, CH2F, CH2CF3, C2F5; cycloalkyl = C3-C6 cycloalkyl; aryalkyl = C1-C4 aryl; aryl = phenyl, furanyl, thienyl, or pyridyl; n = 0-2; and m = 2-4 or pharmaceutically acceptable salts thereof, useful in the treatment of asthma, or allergic or inflammatory diseases, as well as methods of treatment and pharmaceutical compositions utilizing the same.

Description

SUBSTITUTED BIPHENYL DERIVATIVES AS PHOSPHODIESTERASE INHIBITORS
Background of the Tnvention
This invention relates to new methods of treating inflammatory diseases. More particularly, the present invention relates to new substituted biphenyl derivatives which are useful in the treatment of asthma, as well as other types of allergic and inflammatory diseases.
Asthmatic attacks are characterized by the narrowing of both large and small airways brought upoon by bronchial smooth muscle spasms, edema and inflammation of the bronchial mucose, and production of tenacious mucus. The exact mechanisms involved in asthmatic bronchoconstriction are not completely understood, but an imbalance between beta adrenergic and cholinergic control of the airways has been indicated. Such imbalances appear to be controlled by the cyclic 3',5'-adenosine monophosphate (cyclic AMP or cAMP)-cyclic 3',5'-guanosine monophosphate (cyclic GMP or cGMP) systems with various tissues, such as smooth muscle, mast cells and mucus secreting cells.
Several classes of drugs have been shown useful in the treatment of bronchial asthma. They include the beta adrenergic agents which cause bronchial smooth muscle relaxation and modulate inhibition of mediator release. Among these agents are epinephrine, isoproterenol, ephedrine and beta2-adrenergic agents such as metaproterenol, terbutaline, isoetharine, albuterol, bitolterol and fenoterol (5-[l- Hydroxy-2-[[2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl-l,3-benzenediol).
Corticosteroids, such as prednisone, have been useful in treating asthma as they inhibit attraction of polymorphonuclear leukocytes to the sites of allergic reactions, stimulate synthesis of beta2 receptors and block leukotriene synthesis. Theophylline, a methyxanthine, has also been used for its ability to relax bronchial smooth muscle and modulate mediator release. Anticholinergic agents, such as atropine and its derivative ipratopium bromide, have been used to block cholinergic pathways that cause airway obstruction. Used for maintenance therapy alone, cromolyn sodium (disodium cromoglycate) appears to inhibit mediator release and reduce airway hyperactivity.
In recent work, asthma has been recognized as being mediated by an inflammatory response in the respiratory tract [DeMonchy, J., Am. Rev. Resp. Dis. 131: 373-376 (1985)]. Recent findings suggest that human T-lymphocytes play a major role in regulating the airway inflammation associated with allergic asthma [Frew, A.J., J. Allergy Clin. Immunol. 85: 533-539 (1990)] and chronic obstructive pulmonary disease [O'Connor, G.T., Am. Rev. Resp. Dis. MO: 225-252 (1989)].
In addition to the infiltration of other inflammatory cells into the pulmonary system, human asthmatics and atopies who are dual responders (i.e., show both early and late phase reactions) show a small but significant infiltration of T-lymphocytes following antigen challenge [Frew, A.J. and Kay, A.B., J. Immunol. 141: 4158-4164 (1988)]. More importantly, these recruited T-lymphocytes are almost entirely of the CD4+ (T-helper) type, and there appears to be a direct correlation between the influx of CD4+ cells, the influx of eosinophils, and the IgE-related allergic response in these individuals [Frew, A.J. and Kay, A.B., J. Immunol. Hi: 4158-4164 (1988)]. In severe asthmatics, these CD4+ cells appear to be activated [Corrigan, CJ. and Kay, A.B., Am. Rev. Resp. Dis. Mi: 970-977 (1990)] by viπue of the increase in IL-2 receptor positive cells. Thus, these cells are capable of producing cytokines (such as D -3, IL-5, and granulocyte macrophage colony stimulating factor) which can directly affect the differentiation, maturation and activation state of the eosinophils and other inflammatory cells.
Rapamycin, a macrocyclic triene antibiotic produced by Streptomvces hvgroscopicus [U.S. Patent 3,929,992] has been shown to prevent the formation of humoral (IgE-like) antibodies in response to an albumin allergic challenge [Mattel, R., Can. J. Physiol. Pharm. 55: 48 (1977)], inhibit murine T-cell activation [Strauch, M., FASEB 3: 3411 (1989)].
Brief Description of the Present Invention
This invention relates to compounds demonstrated to inhibit a specific phosphodiesterase (PDE), often called PDE IV, that selectively metabolizes cyclic adenosine 3':5'- monophosphate (cAMP) and that is insensitive to the modulatory effects of guanosine cyclic 3':5' monophosphate (cGMP) and calcium. This PDE is found in both respiratory smooth muscle and inflammatory cells, and has been demonstrated to be a principle regulator of cAMP in these tissues [see Torphy and Cieslinski, Molecular Pharmacology. 37, 206 (1990), and Dent et al., British Journal of Pharmacology. 90, 163P (1990)]. Consequently, the compounds named in this invention are both bronchodilatory and antiinflamatory, and are effective in animal models of allergic and nonallergic asthma. However, because the compounds named in this invention preferentially inhibit the PDE IV isozyme, they are expected to be more selective and safer anti-asthmatics than nonselective PDE inhibitors currently used for the treatment of asthma, such as theophylline.
These compounds are inhibitors of the enzyme 3', 5' cyclic AMP phosphodiester-ase. By virtue of this activity, the compounds act as bronchodilators as well as prevent the influx of leukocytes into the lung and pulmonary cavities of antigen sensitized and subsequently challenged laboratory animals. Thus these compounds are useful for the acute and chronic treatment of bronchial asthma and its associated pathology.
This invention describes the composition and utility of novel biphenyls, and their pharmaceutically acceptable salts, of the general structure I:
Figure imgf000005_0001
I wherein, when R& = H: Ri = alkyl, cycloalkyl, arylalkyl, aryl;
R2 = cycloalkyl, aryl, C3-C10 alkyl; X,Y = O, S(O)n, NH; Z = CH2OH, NHSO2R3, CHO, CO2R3, CONHR4R5, CN, COR6, H, halo, NHCN, NHCONR4R5, CONR4OR5, CONR4NR5R6, 1-tetrazole, S(O)nOH, S(O)nNR3R4, C=NOH, C(=N(OH)NH2, OCONR7R6, P(O)(OR4)2, NH2, SH,OH, OS(O)2R3, C(O)CO2R3, C(O)CONR3R4, CH(OH)CO2R3, CHFCO2R3, CF2CO2R3, CH(OH)CONR3R4, CF2CONR3R4, C=NNH2,
C(=NOC(=O)R3)R4, C(=NNHC(=O)R3)R4, C(=NOH)R3, C(=NNR3)R4, NHC(=O)R6 or C(O)CONH2; R3, R4, R5, Re, R7 are each, independently, hydrogen, alkyl, aryl, aryalkyl, cycloalkyl, or fluoroalkyl; or a compound of Structure I, wherein:
Rl = alkyl, cycloalkyl, arylalkyl, or aryl; R2 = cycloalkyl, aryl, or alkyl; X,Y = CH2, O, S(O)n, or NH;
R3, R4, R5, Rό, R7 = hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, or fluoroalkyl; R8 = CO2R3, CONR2R3, or Rg and Z are concatenated such that
R8Z = C(O)NHNHC(O), (CH2)mC(=W), V(CH2)mC(=W), or VnCH=CH(CH2)nC(=W); where
V = O, S(O)n, NH; W = O, NOH, NHNH2, NOC(O)CH3, or NNHC(O)CH3; halo = CI, Br, or I; fluoroalkyl = CF3 CHF2, CH2F, CH2CF3, C2F5; cycloalkyl = C3-C6 cycloalkyl; arylalkyl = C1-C4 aryl; aryl = phenyl, furanyl, thienyl, or pyridyl; n = 0-2; and m = 2-4.
Preferred examples of the present invention may be described by the general structure II:
Figure imgf000007_0001
wherein:
Rl = Cι-C3 alkyl;
R2 = C3-C6 alkyl, C3-C7 cycloalkyl, or phenyl;
Z = CHO, CO2R3, CONHR4R5, CN, COR6, H, halo, NHCONR4R5, CONR4OR5, CONR4NR5R6, OCONR7R6, NH2, C=NOH, C=NNH2, C(=NOC(=O)R3)R4. C(=NNHC(=O)R3)R4, C(O)CO2R3, C(=NOH)R3, C(=NNR3)R4, NHC(=O)R6, or C(O)CONH2; and
R3, R4, R5, Rβ, R7 are each, independently, hydrogen, C1-C4 alkyl, aryl, arylalkyl, fluoroalkyl; and
R8 = H or CO2R3; as well as pharmaceutically acceptable salts thereof.
In these preferred compounds, it is further preferred that ring A is attached to ring B in the meta or para position.
In addition, preferred examples of this invention may be described by the formula II, above,wherein ring B is described by structures III or IV, seen below, and is attached to ring A at the 5, 6 or 7 position.
Figure imgf000008_0001
wherein W = O, NOH, NNH2, NOC(O)CH3, NNHC(O)CH3.
For the compounds listed, unless otherwise stipulated, alkyl = Ci-Cβ; halo =
CI, Br, or I; fluoroalkyl = CF3, CHF2, CH2F, CH2CF3 or C2F5; cycloalkyl = C3-C6 cycloalkyl; arylalkyl = C1-C4 substituted aryl; and aryl = phenyl, furanyl, thienyl or pyridyl.
Among the more preferred compounds of this invention are those having the general structure:
Figure imgf000008_0002
wherein:
Ri = C1-C3 alkyl;
R2 = C3-C7 cycloalkyl or C3-C6 alkyl; Z = CO2R3, CONHR4R5, CONR4NR5R6, H, halo, CHO, COR6, CN, NH2, NHCONR4R5, CONR4OR5, OCONR7R6, C(=NOH)R , C(=NNR3)R4, C(=NOC(=O)R3)R4, C(=NNHC(=O)R3)R4, or NHC(=O)R6; R3, R4, R5, Rβ, R7 are each, independently, H, C1-C4 alkyl, aryl, or trifluoromethyl; and
R8 = H or CO2R3; or pharmaceutically acceptable salts thereof.
It is also understood that these preferred compounds of the present invention may also include those in which ring B is described by structures in or IV, above, and is attached to ring A at the 5, 6 or 7 position.
The most preferred compounds of the present invention may be described by the formula:
Figure imgf000009_0001
wherein:
Rι = CH3;
R2 = C4 alkyl, C5 cycloalkyl;
Z = meta or para CHO, CO2R3, CONHR4R5, CN, CORβ, H, chloro, bromo, NHCONR4R5, CONR4OR5, CONR4NR5R6, OCONR6R7, NH2, C(=NOH)R3, C(=NNR3)R4, C(=NOC(=O)R3)R4,
C(=NNHC(=O)R3)R4; R3, R4, R5, R*$, R7 and R8 are each, independently, hydrogen, methyl, phenyl, or trifluoromethyl; or pharmaceutically acceptable salts thereof.
These most preferred compounds also include those in which R8 and Z are CO2R3 or CONR4R5. In addition, the most preferred compounds of the present invention may be described by the formulas V and VI, below, or pharmaceutically acceptable salts of the compounds of formulas V and VI:
Figure imgf000010_0001
wherein Ri, R2, and W are as described above.
These compounds show activity against PDE IV isolated from dog tracheal muscle with IC50S in the range of 10~6 to 10~9 M. These compounds also show activity in the functional PDE inhibitory test with IC50S in the range of 10"6 to 10"^ M. More information concerning these tests and their indications of the present compounds PDE IV inhibitory ability is set forth in Example 35, below.
Also provided by the present invention is a method for treating allergic and inflammatory diseases, as well as asthma, both allergic and non-allergic. Such a method comprises administering to a mammal in need of such treatment an effective amount of one or more of the compounds listed herein and/or one or more of their phamaceutically acceptable salts. Such a method is intended to include all treatments, administrations, or regimens related to such maladies including, but are not limited to, those which are prophylactic, therapeutic, progression inhibiting, remedial, maintenance, or other treatments regarding asthma and allergic and inflammatory disease states or conditions.
The effective dosages of the compounds presented herein will vary with the particular compound chosen and the form of administration. Furthermore, it will vary with the particular host under treatment. Generally, the compounds of this invention are administered at a concentration level that affords protective effects without any deleterious side effects. For example, the effective amount of compound can usually range from about 10 to about 250 mg/kg body weight per day administered once daily or divided into two to four administrations per week. The optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally with smaller doses being administered initially and thereafter increases in dosage are made to determine the most suitable dosage.
Further embraced by the present invention are pharmaceutical compositions. Among these are compositions comprising a mixture of one or more of the compounds disclosed herein, and/or one or more pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, which can be used according to the same methods of administration as the compounds, themselves. It is also contemplated that the compounds of the present invention may be used in a combined therapeutic regimen along with one or more additional medicinal agents.
The compounds of the present invention may form salts with suitable therapeutically acceptable inorganic and organic bases. These derived salts possess the same activity as their parent acid and are included within the scope of this invention. Suitable inorganic bases to form these salts include, for example, the hydroxides, carbonates or bicarbonates of the therapeutically acceptable alkali metals or alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium and the like. Suitable organic bases include primary and secondary amines such as methylamine, benzathine (NjNϊ-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-l,3-propanediol) procaine, etc. Furthermore, there may be mentioned the quaternary salts, for example, the tetraalkyl (e.g. tetramethyl), alkyl-alkanol (e.g. methyl-triethanol) and cyclic (e.g. N,N-dimethylmorpholine) ammonium salts. In principle, however, there can be used all the ammonium salts which are physiologically compatible.
Transformations to the corresponding salts are readily carried out by reacting the acid form of the compounds with an appropriate base, usually one equivalent, in a cosolvent. The salt is isolated by concentration to dryness or by addition of a non- solvent. For example, in the case of inorganic salts, it is preferred to dissolve the acid or the compound in water containing a hydroxide, carbonate or bicarbonate corresponding to the inorganic salt desired. Evaporation of the solution or addition of a water-miscible solvent of more moderate polarity, for example, a lower alkanol such as butanol, or a lower alkanone such as ethyl methyl ketone, gives the solid inorganic salt. In the case of an amine salt, it is preferred to use a cosolvent of moderate or low polarity such as ethanol, ethylacetate and benzene. Evaporation of the solvent or addition of a miscible diluent of lower polarity such as benzene or n-hexane gives the solid salt. Quaternary ammonium salts may be prepared by mixing the acid of the compound with a quaternary ammonium hydroxide in a water solution followed by evaporation of the water.
The compounds of the present invention may be clinically administered to mammals, including man, by either the oral or parenteral route. Oral administration may be either alone or in combination with a solid or liquid pharmaceutically acceptable carrier or diluent such as starch, milk, sugar, certain types of clay, water, vegetable or mineral oils, and so forth to form tablets, capsules, powders, syrups, solutions, suspensions, and the like. For parenteral administration, the active compounds may be used in combination with aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous solutions of water and soluble pharmaceutically acceptable salts of the compounds. The injectable solutions prepared in this manner may be administered intravenously, intraperitoneally, subcutaneously or intramuscularly. The compounds of this invention may also be administered in the form of suppositories.
Compounds of this invention may be prepared in the manner shown in the schemes below:
Figure imgf000012_0001
l)BuLi, THF (Ph3P)4Pd, Na2CO3
2) (MeO)3B then toluene, EtOH, H2O HCl/H2O 4-bromobenzoic acid
Figure imgf000012_0002
as a mixture of oligimers
Figure imgf000012_0003
Figure imgf000013_0001
Figure imgf000013_0002
X = Br, I, OTf, CI
Figure imgf000013_0003
Figure imgf000014_0001
Additional information regarding the synthesis and efficacy of the present invention's compounds is provided by the non-limiting examples below:
EXAMPLE 1
3-Cvclopentyloxy-4-methoxybromobenzene
Cyclopentyl bromide (37 mL, 0.345 mol) was added to a slurry of the phenol
(50 g, 0.246 mol) and potassium carbonate (17 g, 0.123 mol) in acetonitrile (500 mL) at reflux temperature. After two hours, cyclopentyl bromide (13.2 mL, 0.123 mol) and potassium carbonate (8.5 g, 0.062 mol) were added to complete the reaction (1 hour). Reaction pro gress was monitored by TLC (50% ethyl ether in hexane). The suspension was filtered. The filtered material was washed with ethyl acetate (2 x 100 mL). The filtrates were combined, concentrated and distilled under vacuum (0.1mm, 140°C- 145°C) to yield 65.62 g (0.242 mol,98%) of product.
3-Cvclopentyloxy-4-methoxyphenylboronic acid.
3-Cyclopentyloxy-4-methoxyphenylbromide (25 g, 0.0923 mol) was dissolved in dry THF (400 mL) in a flame dried flask under nitrogen. The solution was stirred and cooled (-78°C). n-Butyllithium (2.5M in THF, 42.44 mL, 0.106 mol) was added over 15 minutes with a raise in temperature to no hi gher than -50°C. The reaction was allowed to stir 2 hours at -78°C. Trimethylborate (28.76 mL, 0.277 mol) was added over 5 minutes. The reaction was allowed to warm toward ambient room temperature over two hours. HC1 (IN, 300 mL, 0.3 mol) was added and the reaction was stirred 18 hours. Reaction pro- gress was monitored by TLC (50% ethyl acetate in hexane). The product was extracted with ethyl ether (3 x 150 mL). The combined organic layers were washed with water (150 mL); brine(150 mL); and were dried (magnesium sulfate). The concentrated product is used crude. Yield was essentially "quantitative".
IR (KBr) 3420 cm-l;
NMR (DMSO/ D2O) δ 7.32 (d, 1H, J = 7.89) 7.28 (s,lH) 6.9 (d, 1H, J = 7.89) 4.72 (m, 1H) 3.70 (s,3H) 1.84-1.51 (m, 8H); MS (+FAB) m/z: 237 (M+H).
3 '-Cyclopentylox v-4'-methox v-biphen yl-4-carboxylic acid.
3-Cyclopentyloxy-4-methoxyphenylboronic acid (1 g, 4.25 mmol), 4- bromobenzoic acid (897mg, 4.46 mmol), sodium carbonate (1.5 g), toluene (30 mL), water (12 mL), and ethanol (6 mL) were added to a flask at room temperature and stirred. The reaction was flushed with nitrogen. The catalyst, tetrakistriphenylphospine palladium (0) (lOOmg) was added. The reaction was heated at reflux temperature sixteen hours. At that time the catalyst turned to a black suspension. The reaction was monitored by TLC (50% ethyl acetate in hexane) and was complete when the catalyst was dead. The reaction was diluted with ethyl acetate (50 mL) and NaOH (0.5N, 50 mL). The organic phase was separated and extracted with NaOH (0.5N, 2x50 mL). The combined aqueous was acidified with HC1 (2.5N) until red to litmus. The precipitate was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine and dried (magnesium sulfate). The organic layers were boiled with activated charcoal and filtered through a bed of silica atop a bed of celite. The resulting clear organic was concentrated to dryness. Recrystallization (ethyl acetate/ hexane) yielded 1.0 g of product (3.21 mmol, 75.4%): mp 231.5°C- 232.5°C.
IR (KBr) 2960, 1670 cm- 1;
NMR (DMSO) δ 12.89 (IH, s), 7.96 (2H, d, J = 8.5Hz), 7.74 (2H, d, J = 8.5Hz),
7.26 (IH, d, J = 8.2 Hz), 7.24 (IH, s), 7.04 (IH, d, J = 8.2 Hz), 4.93 (IH, m), 3.78
(3H, s), 2.0-1.5 (8H, m);
MS m/z: 312 (M+), 244 (100);
Elemental analysis for: C19H20O4 Calc'd: C, 73.06; H, 6.45
Found: C, 72.73; H, 6.45
EXAMPLE 2
3'-Cvclonentvloxv-4'-methoxv-hinhenvl-4-carhoxvlic acid amide
Following the procedure of Example 1, 4-bromobenzoic acid amide yielded 21% of the title compound a white solid.
IR (KBr) 3400, 3180, 1670, 1640 cm"l;
NMR (CDCI3) δ 7.88 (2H, d, J = 8.4Hz), 7.62 (2H, d, J = 8.4Hz), 7.17 (IH, d, J = 8.30Hz), 7.13 (IH, d, J = 2.1Hz), 6.95 (IH, d, J = 8.3Hz), 4.33 (IH, m), 3.89 (3H, s), 2.0 - 1.6 (8 H, m); MS m z: 311 (M+);
Elemental analysis for: Ci9H2iNO3»H2O Calc'd: C, 69.3; H, 6.38; N, 4.25 Found: C, 70.79; H, 6.40; N 3.12 EXAMPLE 3
3'-Cvclonentvloxv-4'-niethoxv-hinhenvl-4-carhoxvlic acid hvdrazide
Following the procedure of Example 1, 4-bromobenzoic acid hydrazide yielded
81% of the title compound as colorless crystals: mp 167-168.5°C.
IR (KBr) 3300, 1600 cm"1;
NMR (DMSO) δ 9.78 (IH, s), 7,86(2H, d, J = 8.4Hz), 7.69 (2H, d, J = 8.4Hz), 7.24 (IH, d, J = 8.1Hz), 7.22 (IH, d, J = 8.1 Hz), 7.02 (IH, d, J = 8.1Hz), 4.93 (IH, m), 4.49 (2H, s), 3.77 (3H, s), 2.0-1.5 (8H, m); MS m/z 277 (M+H), 294 (100);
Elemental analysis for: C19H22N2O3 Calc'd: C, 69.92: H, 6.79; N,8.58
Found: C, 69.62;H, 6.82; N, 8.55
EXAMPLE 4
3'-CvclθDentvloxv-4'-τnethoxv-hinhenvl-3-carhoxvlic acid hvdrazide
Following the procedure of Example 1, 3-bromobenzoic acid hydrazide yielded 25% of the title compound as colorless crystals: mp 167-168.5°C.
IR (KBr) 3310, 3390, 1645 cm" 1 ;
NMR (DMSO) δ 9.87 (IH, s), 8.01 (IH, s), 7.75 (2H, m), 7.49 (IH, t, J = 8.6Hz), 7.25 (2H, m) 7.04 (IH, d, J = 8.9Hz), 4.94 (IH, m), 4.51 (IH, s), 3.78 (3H, s), 2.0 - 1.5 (8 H, m);
MS m z: 326 (M+), 227 (100).
Elemental analysis for: C 19H22N2O3C, 69.92 Calc'd: C, 69.92:H, 6.79; N, 8.58 Found: C, 69.16; H, 6.75; N, 8.21 EXAMPLE 5
3'-Cγclgpentvl Y-4'-mgthoχγ-biphenγl-3-carboχγlic acid
Following the procedure of Example 1, 3-bromobenzoic acid yielded 37% of the title compound as colorless crystals from ether: mp 153-154°C .
IR (KBr) 3420, 3100-2500 (br) cm"1;
NMR DMSO δ 13.03 (IH, s), 8.11 (IH, m) 7.87 (2H, m), 7.55 (2H, t, J = 8 Hz), 7.21 (1 H, m), 7.19 (IH, s), 7.05 (IH, d, J = 7.9 Hz), 4.93 (IH, m), 3.78 (3 H, s), 2.0 - 1.5 (8H, m); MS m z: 313 (M+H), 245 (100).
Elemental analysis for: C19H20O4 Calc'd: C, 73.06: H, 6.45
Found: C, 72.23: H, 6.42
EXAMPLE 6
4-Ch1oro.3'-Cvclonentvloxv-4'-methoxv-hinhenvl
Following the procedure of Example 1, 4-chloro-phenylboronic acid and 3- cyclopentyloxy-4-methoxybromobenzene yielded 92% of the title compound as white needles: mp 94-95°C.
IR (KBr) 2950 cm'1;
NMR (CDCI3) δ 7.45 (2H, d, J = 8.5Hz), 7.36 (2H, d, J = 8.5Hz), 7.07 (IH, dd, J = 8.1Hz), 7.05 (IH, s), 6.91 (IH, d, J = 8.1Hz), 4.83 (IH, m), 3.87 (3H, s), 1.98 - 1.55 (8 H, m); MS m/z: 303 (M+), 235 (100 ).
Elemental analysis for: Cι8Hi9Clθ2 Calc'd: C, 71.40; H, 6.32 Found: C, 71.24; H, 6.41 EXAMPLE 7
3-CyglPpentYlQχγ-4-metho7_y-p.phgnγl
Following the procedure of Example 1, phenylboronic acid and 3- cyclopentyloxy-4-methoxybromobenzene yielded 46% of the title compound as white needles: mp 62-64°C.
IR (KBr ) 2960 cm"1; NMR (CDC1 ) δ 7.53 (2H, d, J = 7.06Hz), 7.40 (2H, t, J = 7.5Hz), 7.29 (IH, t, J = 7.5Hz), 7.10 (2 H, m), 6.92 (IH, d, J = 7.5Hz), 4.85 (IH, m), 3.87 (3H,s), 1.98 - 1.52 (8 H,m); MS m/z: 268 (M+), 200 (100).
Elemental analysis for: Ci8H2oO2 Calc'd: C, 80.58; H, 7.51 Found: C, 79.86; H, 7.49
EXAMPLE 8
3,-Cvclopentvloxv-4,-methoxv-hiDhenvl-3-carhaldehvde
Following the procedure of Example 1, 3-bromobenzaldehyde yielded 40% of the title compound as an amorphous solid.
IR (KBr) 1720, 1690 cm"1;
NMR (CDCI3) δ 10.08 (IH, s), 8.04 (IH, t, J = 1.5Hz), 7.82 (IH, d, J = 7.6Hz), 7.81 (IH, d, J = 7.4Hz), 7.58 (IH, t, J = 7.7Hz), 7.18 (IH, dd, J = 2.2, 8.2Hz), 7.14 (IH, d, J = 2.2Hz), 6.96 (IH, d, J = 8.2Hz), 4.88 (IH, m), 3.90 (3H, s), 2.02 1.56 (8H, m);
MS m/z: 296 (M+), 228 (100) .
Elemental analysis for: C19H20O3 Calc'd: C, 77.00; H, 6.80 Found: C, 76.85; H, 6.91 EXAMPLE 9
3,-Cvclopentvloxv-4'-methoxv-hiphenvl-4-carhaldehvde
Following the procedure of Example 1, 4-bromobenzaldehyde yielded 28% of the title compound as a crystalline solid: mp 86.5 - 87.5°C.
IR (KBr) 1705 cm"1; NMR δ 10.04 (IH, s), 7.93 (2H, d, J = 8.5Hz), 7.70 (2H, d, J = 8.5Hz), 7.20 (IH, dd, J = 2.1,8.4 Hz), 7.17 (IH, d, J = 2.1Hz), 6.96 (IH, d, J = 8.4Hz), 4.87 (IH, m), 3.90 (3H, s), 2.06 - 1.6 (8 H,m); MS m/z: 296 (M+), 228 (100).
Elemental analysis for: C19H20O3 Calc'd: C, 77.00; H, 6.80 Found: C, 76.84; H, 6.76
EXAMPLE 10
3'-CvcloDentvloxv-4'-methoxv-hiphenvl-2-carhaldehvde
Following the procedure of Example 1, 2-bromobenzaldehyde yielded 59% of the tide compound as a yellow oil.
IR (film) 1695 cm"1;
NMR DMSO δ 9.91 (IH, s), 7.87 (IH, d, J = 7.6Hz), 7.71 (IH, dt, J = 7.7 , 1.5 Hz), 7.53 (2H, m), 7.07 (IH, d, J = 8.3Hz), 6.98 (IH, d, J = 2.1Hz), 6.91 (IH, dd, J = 8.3, 2.1Hz), 4.85 (IH, m) 3.80 (3H, s) 1.93 - 1.5 (8H m); MS m/z: 296 (M+), 228 (100, M - C5H9).
Elemental analysis for: C19H22O3 Calc'd: C, 77.00; H, 6.80 Found: C, 75.89; H, 6.86 EX AMPLE 11
l -(3,-Cvclonentvloxv-4'-nιethoxv.hiphenvl-3-vn-ethanone
Following the procedure of Example 1, 3-bromoacetophenone yielded 53% of the title compound as a viscous yellow oil.
IR (film) 1680 cm"1;
NMR (DMSO) δ 8.10 (IH, t, J = 1.6), 7.89 (2H, m), 7.57 (IH, t, J = 7.7), 7.23 (2H, m), 7.05 (IH, d, J = 8.1 Hz), 4.93 (IH, m), 3.78 (3H, s), 2.64 (3H, s), 1.95 - 2.5 (8H, m); MS m/z: 310 (M+), 242 (100).
Elemental analysis for: C20H22O3 Calc'd: C, 77.35; H, 7.14
Found: C, 74.99; H, 7.19
EXAMPLE 12
1 -(3'-Cvclonentvloxv-4'-methoxv-hiphenvl-4-vn-ethanone
Following the procedure of Example 1, 4-bromoacetophenone yielded 42% of the title compound as a crystalline solid: mp 117-118°C.
IR (KBr) 1670 cm"1;
NMR (DMSO) δ 7.99 (2H, d, J = 8.5 Hz), 7.77 (2H, d, J = 8.5Hz), 7.28 (IH, dd, J = 8.3, 2 Hz), 7.25 (IH, d, J = 2.4Hz), 4.94 (IH, m), 3.79 (3H, s) 2.59 (3H, s), 2.0 - 1.5 (8 H, m); MS m/z: 310 (M+), 242 (100).
Elemental analysis for: C22H22O3 Calc'd: C, 77.39; H, 7.14 Found: C, 74.99; H, 7.19 EXAMPLE 13
(3'-Cvclonentvloxv-4'-methoxv-hinhenvl-4-vn-Dhenvlmethanone
Following the procedure of Example 1 , 4-bromobenzophenone yielded 37% of the title compound as a viscous oil in 38% yield.
IR (film) 1650 cm"1;
NMR (DMSO) δ 7.8 (6H, m), 7.68 (IH, t, J = 1.2 Hz), 7.58 (2H, t, J = 7 Hz), 7.3 (2H, m), 7.08 (IH, d, J = 8.3 Hz), 4.95 (IH, m), 3.80 (3H, s); MS m/z: 372 (M+), 304 (100).
Elemental analysis for: C25H24O3 Calc'd: C, 80.62; H, 6.50 Found: C, 79.53; H, 6.79
EXAMPLE 14
3,-Cvclonentvloxv-4'-methoxv-hinhenvl-3-carhonitrile
Following the procedure of Example 1, 3-bromobenzonitrile yielded 25% of the title compound as an amorphous solid.
IR (KBr) 2220 cm"1; NMR (DMSO) δ 8.1 (IH, s), 7.98 (IH, d, J = 8.1Hz), 7.75 (IH, d, J = 7.7Hz), 7.61(1H, t, J = 7.7Hz), 7.28 (2H, m), 7.04 (IH, d, J = 8.5Hz), 4.97 (IH, m), 3.8 (3H, s); MS m/z: 293 (M+), 225 (100).
Elemental analysis for: Ci8Hi9NO2
Calc'd: C, 76.84; H, 6.81; N, 4.98 Found: C, 77.62; H 6.51; N, 4.54 EXAMPLE 15
3'-Cvclnnentvloxv-4'-metlioxv-hinhenvl-4-carhonitrile
Following the procedure of Example 1 , 4-bromobenzonitrile yielded 56% of the title compound as a crystalline solid, mp 97-98.5.
IR (KBr) 2200 cm-1;
NMR (CDC13) δ 7.69 (2H, d, J = 8.7Hz), 7.62 (2H, d, J = 8.7),7.13 (IH, dd J = 8.3 2.2Hz), 7.08 (IH, d, J = 2.2Hz), 6.95 (IH, d, J = 8.3Hz), 4.85 (IH, m), 3.89 (IH, s), 2.05 - 1.58 (8H, m); MS m/z: 294 (M+, 100).
Elemental analysis for: C19H19NO2 Calc'd: C, 77.79; H, 6.53; N, 4.77
Found: C, 78.08; H, 6.59; N, 4.82
EXAMPLE M
S'-Cvclopentvloxv^'-methoxvhinhenvl^-vlamine
Following the procedure of Example 1, 4-bromoaniline yielded 55% of the title compound as a crystalline solid, mp 94-95°C.
IR (KBr) 3460, 3380 cm"1;
NMR (DMSO) δ 7.43 (2H, d, J = 8.6Hz), 7.05 4H, m), 6.90 (2H, d, J = 8.6Hz), 4.84 (IH, m), 3.87 (3H, m), 2.0-1.5 (8H, m); MS m/z: 283 (M+), 215 (100).
Elemental analysis for: Ci8H2iNO2
Calc'd: C, 76.30: H, 7.47; N, 4.94 Found: C, 76.03; H, 7.45; N, 4.64 EXAMPLE 17
3'-Cvclopentyloxy-4'-methoxy-biphenyl-4-carboxyIic acid sodium salt
3'-Cyclopentyloxy-4'-methoxybiphenyl-4-carboxylic acid (0.5 g, 1.6 mmol) was suspended in H2O (5 mL). A solution of sodium hydroxide (1.6 mL, 1M, 1.6 mmol) was added and the reaction was heated to ca 90°C for 30 seconds. Product was concentrated to dryness, dissolved in hot methanol (25 mL) precipetated from solution with ethyl ether and filtered. The filter cake was washed with ether and hexane then pumped under high vacuum to constant weight. This provided 0.354 g (1.06 mmol, 66%) of product .
IR (KBr) 3400 cm"1;
NMR (DMSO) δ 7.89 (2H, d, J = 8.5Hz), 7.49 (2H, d, J = 8.5Hz), 7.18 (IH, d, J = 8.92 Hz), 7.18 (2H, m), 7.01 (IH, d, J = 8.92 Hz), 4.91 (IH, m), 3.77 (3H, s), 2.0- 1.5 (8H, m); MS [-FAB] m/z: 311 (M-Na)--
Elemental analysis for: C 19H 19θ4Na Calc'd: C, 68.26; H, 5.73
Found: C, 63.32; H, 5.61
EXAMPLE 18
3'.Cvclopentvloxv-4'-methoxv-biphenvl-3-carhoxvlic acid methvl ester
3'-Cyclopentyloxy-4'-methoxy-biphenyl-3-carboxylic acid (0.2 g, 0.64 mmol) in THF/ MeOH (1;1, 10 mL) was cooled to 0°C. To this was added a solution of trimethylsilyldiazomethane in hexane until TLC (1:1 ethyl acetate/hexane) showed no more starting material. The solvents were removed and the product was purified using radial chromatography (lOOOμm silica, 30% ethyl acetate in hexane as eluant). This yielded 150 mg (79%) of the tide product as a crystalline solid, mp 85-87°C.
IR (KBr) 3420, 1710 cm"1; NMR δ 8.22 (IH, t, J = 1.6Hz), 7.97 (IH, dt, J = 7.6, 1.5Hz), 7.39, (IH, dt, J = 7.6, 1.5Hz), 7.48 (IH, t, J = 7.9Hz), 7.16 (IH, dd, J = 8.2, 2.1Hz), 7.13 (IH, d, J = 2.1Hz), 4.87 (IH, m), 3.95 (3H, s), 3.89 (3H, s), 2.20 - 1.6 (8H,m); MS m/z: 326 (M+), 258 (100 ).
Elemental analysis for: C20H22O4
Calc'd: C, 73.60; H, 6.79
Found: C, 73.53; H, 6.80
EXAMPLE 19
3'-Cvclopentvloxv-4'.methoxv-biphenvl-4-carboxvlic acid methvl ester
Following the method described in Example 18, 3'-cyclopentyloxy-4'-methoxy- biphenyl-4-carboxylic acid yielded the title compound in 71% yield as a crystalline solid: mp 128-131°C.
IR (KBr) 1720 cm"1;
NMR (CDCI3) δ 8.04 (2H, d, J = 8.6Hz), 7.61 (2H, d,J = 8.6Hz), 7.17 (IH, dd J = 8.32, 3Hz), 7.15 (IH, d, J = 2.3Hz), 6.95 (IH, d, J = 8.3Hz), 4.87 (IH, m), 3.93 (3H, s), 3.90 (3H, s), 2.05-1.55 (8H, m); MS m/z: 326 (M+), 258 (100).
Elemental analysis for: C20H22O4 Calc'd: C, 73.60; H, 6.79
Found: C, 73.46; H. 6.83
EXAMPLE 20
6-(3-Cvclonentvloxv-4-methoxv-nhenvn-3.4-dihvdro-2H-nanhthalen-1 - one
3-Cyclopentyloxy-4-methoxyphenylboronic acid (0.76 g, 3.23 mmol), 6- trifluoromethanesulfonate-3,4,-dihydro-2H-naphthalen-l-one (0.95 g, 3.23 mmol), sodium carbonate (1.0 g), toluene (30 mL), water (12 mL), and ethanol (6 mL) were added to a flask at room temperature and stirred. The reaction was flushed with nitrogen. The catalyst, tetrakistriphenylphospine palladium(O) (lOOmg) was added. The reaction was heated at reflux temperature sixteen hours. At that time the catalyst turned to a black suspension. The reaction was monitored by TLC (50% ethyl acetate in hexane), however, completion of the reaction was obvious when the catalyst turned black. The reaction was diluted with ethyl acetate (50 mL). The organic phase was separated and extracted with water (50 mL). The organic phase was washed with brine and dried (magnesium sulfate). The organic phase was boiled with activated charcoal and filtered through a bed of silica atop a bed of ceiite. The resulting clear organic phase was dried (magnesium sulfate), filtered, concentrated to dryness. Recrystallization, from ethyl acetate/ hexane, yielded 0.41 g (1.22 mmol, 38%) of product: mp 91°C- 92.5°C.
IR (KBr) 1670 cm"1;
NMR (DMSO) δ 7.90 (IH, d, J = 8.9Hz), 7.60 (2H, m), 7.25 (2H, m), 7.05 (IH, d, J = 8.9Hz), 4.94 (IH, m), 3.79 (3H, s), 3.0 (2H, t, J = 6Hz), 2.60 (2H, t, J = 6 Hz), 2.05 (2H, m), 2.0 - 1.5 (8H, m); MS m/z: 337 (M + H), 269 (100, M - C5H9).
Elemental analysis for: C22H24O3 Calc'd: C, 78.54; H, 7.19 Found: C, 78.38; H, 7.22
EXAMPLE 21
rE)-6-(3-Cvclonentvloxv-4-methoxv-phenvn-3.4-dihvdro-2H- nanhthalen-1-one oxime
6-(3-Cyclopentyloxy-4-methoxy-phenyl)-3,4-dihydro-2H-naphthalen-l-one
(0.17 g, 0.51 mmol), hydroxylamine hydrochloride (0.175 g, 2.51 mmol), and pyridine (1.0 mL) were added to a flask at room temperature and stirred sixteen hours. The reaction was dissolved in dichloromethane and concentrated to dryness. Ethyl acetate(25 mL) was added and the resulting solution was washed with water (25 mL), brine (25 mL), dried (magnesium sulfate), filtered, concentrated to dryness and recrystallized from ethyl acetate/ hexane. Yield of product (0.1 g, 0.285 mmol, mp 151°- 152°C); 56%.
IR (KBr) 3250 cm"1; NMR (DMSO) δ 11.06 (IH, s), 7.88 (IH, d, J = 8.1Hz), 7.44 (IH, d, J = 7.9Hz), 7.43 (IH, s) 7.19, (IH, d, J = 7.9Hz), 7.18 (IH, s), 7.01 (IH, d, J = 8.1Hz), 4.92 (IH, m), 3.77 (3H, s), 2.77 (2H, t, J = 3.5Hz), 2.66 (2H, t, J = 6.3Hz); MS m/z: 351 (M+), 283 (100).
Elemental analysis for: C22H25NO3
Calc'd: C, 75.18; H, 7.17; N, 3.98 Found: C, 74.84; H, 7.13; N, 3.96
EXAMPLE 22
S'-Cvclonentvloxv^'-methoxv-hinhenvl^-carhaldehvde oxime
Following the procedure in Example 21, one 3'-cyclopentyloxy-4'-methoxy- biphenyl-4-carbaldehyde yielded the title compound in 26% as a crystalline solid: mp 153-153°C.
IR (KBr) 3450, 3300 cm"1;
NMR (DMSO) δ 11.2 (IH, s), 8.15 (IH, s), 7.65 (4H, m), 7.21 (IH, d, J = 8.7Hz) 7.20 (IH, s), 7.02 (IH, d, J = 8.7Hz), 4.92 (IH, m), 3.77 (3H, s), 2.0 - 1.5 (8H, m);
MS m/z: 311 (M+), 225 (100).
Elemental analysis for: C19H21NO
Calc'd: C, 73.29; H, 6.80; N, 4.50 Found: C, 72.60; H, 6.66; N, 4.35 EXAMPLE 23
3'-Cvclonentvloxv-4,-methoxv-hinhenvl-3-carhaldehvde oxime
Following the procedure in Example 21, 3'-cyclopentyloxy-4'-methoxy- biphenyl-3-carbaldehyde yielded the title compound in 45% as a crystalline solid mp 87-9 l°c.
IR (KBr) 3420, 3300 cm"1; NMR (DMSO) δ 8.20 (IH, s), 7.74 (IH, s), 7.57 (IH, dt, J = 7.9, 2.6Hz), 7.52 (IH, dt, J = 7.9, 2.6Hz), 7.44 (IH, d, J = 8.6Hz), 7.38 (IH, s), 7.14 (IH, d, J = 2.2Hz),
7.12 (IH, d, J = 2.2Hz), 6.94 (IH, d, J = 8.6Hz), 4.86 (IH, m), 3.89 (3H, s), 2.0 -
1.58 (8H, m);
MS m/z: 311 (M+), 243 (100 ).
Elemental analysis for: C19H21NO3
Calc'd: C 3.29; H,6.80; N, 4.50 Found: C, 73.14; H, 6.78; N, 4.47
EXAMPLE 24
3'-Cvclopentvloxv-4'-methoxv-hinhenvl-2-carbaldehvde oxime
Following the procedure in Example 21, 3'-cyclopentyloxy-4'-methoxy- biphenyl-2-carbaldehyde yielded the tide compound in 45% as a low melting (< 50°C) white solid.
IR (KBr) 3440 cm"1
NMR (DMSO) δ 11.2 (IH, s), 7.94 (IH, s), 7.83 (IH, d, J = 8.7Hz), 7.20 (3H, m), 7.04 (IH, d, J = 8.1 Hz), 6.81 (2H, m), 4.80 (IH, m), 3.79 (3H, s), 1.9-1.5 (8 H, m)
MS m/z: 311 (M+), 226 (100)
Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 72.40; H, 6.89;
N, 4.52. EXAMPLE 25
E-6-(3-CyclopentyIoxy-4-methoxy-phenyl)-3,4-dihydro-2H-naphthalen-
1-one oxime acetate
E-6-(3-Cyclopentyloxy-4-methoxy-phenyl)-3,4-dihydro-2H-naphthalen-l-one oxime (0.08 g, 0.228 mmol), acetic anhydride (2 mL), potassium carbonate and dichloromethane (25 mL) were added to a flask and heated to reflux for 0.5 hours. The reaction was cooled and was washed with water (25 mL), brine (25 mL), dried (magnesium sulfate), filtered, concentrated to dryness and recrystallized from ethyl acetate/hexane. This yielded 0.053 g (0.134 mmol, 59%) of product : mp 100°- 102°C.
IR (KBr) 3400, 1750 cm"1;
NMR (DMSO) δ 7.99 (IH, d, J = 1.4Hz), 7.54 (IH, d, J = 7.5Hz), 7.53 (IH, s), 7.25 (IH, d, J = 7.5Hz), 7.22 (IH, s), 7.03 (IH, d, J = 8.3Hz), 4.93 (IH, m) 3.78 (3H, s), 2.83 (2H, t, J = 3.7Hz); MS m/z: 393 (M+), 283 (100).
Elemental analysis for: C24H28 NO4 Calc'd: C, 73.07; H, 7.15; N, 3.55
Found: C, 72.62; H, 7.01; N, 3.57
EXAMPLE 2
(3'-Cvclopentvloxv-4'-methoxv-biphenvl-4-vn-ιιrea
3'-Cyclopentyloxy-4'-methoxybiphenyl-4-ylamine(0.283 g, 1.0 mmol) was dissolved in acetic acid (4.8 mL). A solution of sodium isocyanate in water (9 mL) was added. The precipitate formed was dissolved in dichloromethane (25 mL) washed saturated sodium bicarbonate(25 mL) with water (25 mL), brine (25 mL), dried (magnesium sulfate), filtered, and concentrated. Precipitation from dichloromethane. yielded 0.155 g (0.475 mmol, 61.2%) of product as an amorphous solid.
IR (KBr) 3420, 1657 cm"1; NMR (DMSO) δ 8.56 (IH, s), 7.45 (4H, dd, J = 6.6, 5.1Hz), 7.0 (2H, m), 6.96 (IH, d, J = 8.9Hz), 5.83 (2H, s), 4.88 (IH, m), 3.74 (3H, s); MS m/z: 327 (M+H), 257 (100).
Elemental analysis for: C19H22N2O3
Calc'd: C, 69.92; H, 6.79; N, 8.58 Found: C, 68.53; H, 7.09; N, 7.91
EXAMPLE 27
(3'-Cvclonentvloxv-4'-methoxv-hiphenvl-3-vn-urea
Following the procedure in Example 26, 3'-cyclopentyloxy-4'-methoxy- biphenyl-3-yl amine yielded the title compound in 79% yield as a crystalline solid (CH2C12). mp 174-175°C.
IR (KBr) 3390, 1700 cm"1;
NMR (DMSO) δ 8.56 (IH, s), 7.59 (IH, t, J = 1.9) 7.32 (IH, d, J = 7.90Hz), 7.24 (IH, t, J = 7.8Hz), 7.1 (2H, m), 7.01 (IH, d, J = 9 Hz), 5.85 (IH, s), 4.86 (IH, m), 3.76 (3H, s);
MS m/z: 326 (M+), 241 (100).
Elemental analysis for: Ci9H22N2θ3#H2θ Calc'd: C, 66.33; H, 7.03; N, 8.14 Found: C, 66.17; H, 6.45; N, 8.06
EXAMPLE 2ft
N-^'-Cvclonentvloxv^'-methoxv-biphenvl^-vn-acetamide
3'-Cyclopentyloxy-4'-methoxybiphenyl-4-ylamine (0.220 g, 0.78 mmol), pyridine (0.189 mL, 2.33 mmol), and acetic anhydride were dissolved in dichloromethane (25 mL). 4-pyrrolidinopyridine (lmg) was added and the reaction was stirred 2 hours. The reaction was washed with saturated sodium bicarbonate (25 mL), water (25 mL), brine (25 mL), dried (magnesium sulfate), filtered, and concentrated to dryness. Product was recrystallized from ethyl acetate/ hexane. Yield of product (0.170 g, 0.523 mmol); 67% as an amorphous solid.
IR (KBr) 3300, 1620 cm"1;
NMR (DMSO) δ 7.54 (2H, d, J = 8.3Hz), 7.49 (2H, d, J = 8.3Hz), 7.26 (IH, s),
7.10 (IH, d, J = 8.9Hz), 7.08 (IH, s), 6.92 (IH, d, J = 8.9Hz), 4.84 (IH, m), 3.88
(3H, s), 2.20 (3H, s);
MS m/z: 325 (M+), 257 (100).
Elemental analysis for: C20H23NO3
Calc'd: C, 73.82; H, 7.12; N, 4.30 Found: C, 73.23; H; 7.07; N, 4.10
EXAMPLE 29
N-(3,-Cγtl pgntγl9χγ-4'-metiιoχγ-t?ipl gpγJ-3-γ|)-acgtanιitfg
Following the procedure of Example28, 3'-cyclopentyloxy-4'-methoxy- biphenyl-3-yl amine yielded the title compound in 82% as a crystalline solid: mp 112- I I40C.
IR (KBr) 3290, 1660 cm"1;
NMR (CDCI3) δ 7.67 (IH, s), 7.46 (IH, d, J = 7.4Hz), 7.36 (IH, t, J = 7.8Hz), 7.25 (2H, m), 7.10 (2H, m), 6.92 (IH, d, J = 8.8Hz), 4.85 (IH, m), 3.88 (3H, s), 2.20 (3H, s); MS m/z: 325 (M+), 257 (100).
Elemental analysis for: C20H23NO3 Calc'd: C, 73.82; H, 7.12; N, 4.30
Found: C, 73.78; H; 7.13; N, 4.19 EXAMPLE 30
3,-Cvclonentvlnxv-4,-methoxv-hinhenvI-3-carhoxvlic acid amide
A solution of 3-bromobenzoyl chloride in toluene (30 mL) is treated witii concentrated ammonium hydroxide (2 mL) at room temperature for ten minutes. This mixture is then treated with 3-cyclopentylox-4-methoxy-phenyl boronic acid (0.5 g, 2.12 mmol), sodium carbonate (1 g), ethanol (10 mL) and tetrakis- (triphenylphosphine) palladium (25 mg). The reaction was warmed at reflux overnight under a nitrogen blanket. This provided the title compound in 34% as a crystalline solid (ethyl acetate/hexane): mp 133-135°C.
IR (KBr) 3300, 3150, 1660 cm"1;
NMR (DMSO) δ 8.07 (2H, m), 7.79 (IH, d, J = 7.8Hz), 7.75 (IH, d, J = 7.8Hz), 7.49 (IH, t, J = 7.6Hz), 7.41 (IH, br s), 7.24 (2H, m), 7.04 (IH, d, J = 9.2Hz), 4.94 (IH, m), 3.78 (3H, s), 2.0 - 1.5 (8H, m); MS m/z: 311 (M+), 243 (100).
Elemental analysis for: C19H21NO3 Calc'd: C, 73.29; H, 6.80; N, 4.50
Found: C, 72.64; H, 6.94; N, 4.34
EXAMPLE 31
3'-Cvclonentvloxv-4,-methoxv-hiphenvl-4-carhoxvlic acid hvdroxvlamide
A solution of 3'-cyclopentyloxy-4'-methoxy-biphenyl-4-carboxylic acid (0.5 g, 1.602 mmol) in toluene (30 mL) was treated with a 2M solution of oxalyl chloride (0.840 mL, 1.68 mmol) in dichloromethane and 1 drop of dimethyl formamide was added. This mixture was heated to reflux for ten minutes, cooled and concentrated in vacuo to an oil. This oil is dissolved in dichloromethane and added dropwise to a mixture of hydroxylamine hydrochloride (0.139 g, 1.25 eq) and triethylamine (0.405 g, 2.5eq) in dichloromethane (10 mL). After about thirty minutes the reaction the reaction appears to go no further, some of the starting acid remains (by tic). The reaction is washed with water dried and concentrated. The material is purified via reversed phase HPLC, using a Dynamax-60A Phenyl column wand 70% acetonitrile/water as carrier. This provided the title compound in 9% yield as a crystalline solid (CH2CI2). mp 181-183°C.
IR (KBr) 3225, 1620 cm-1;
NMR (DMSO) δl l.24 (lH,s), 9.01 (lH,s), 7.80 (2H,d, J = 8.5Hz), 7.70 (2H, d, J = 8.5Hz), 7.24 (IH, d, J = 8.3Hz), 7.22 (IH, s), 7.04 (IH, d, J = 8.3Hz), 4.94 (IH, m), 3.78 (3H, s); MS m/z: 327 (M+), 227 (100).
Elemental analysis for: C19 H21NO4
Calc'd: C, 69.71; H, 6.47; N, 4.28 Found: C, 69.54; H, 6.44; N, 3.81
Example 32
3'-Cvclonentvloxv-4,-meHιoxv-hinhenvl-3.4-dicarhoxvlic acid
Following the procedure of Example 1, 4-bromophthalic acid yielded 25% of the title compound a white powder, mp 143-146" C
IR (KBr) 3500-2500(br), 1720, 1680 cm-l
NMR (DMSO) δl3 (IH, br s), 7.83 (IH, s), 7.80 (H, d, J = 1.8Hz), 7.76 (IH, d, J = 8.1Hz), 7.26 (IH, d, J = 6.0 Hz), 7.25 (IH, s), 7.05 (IH, d, J = 8.5 Hz), 4.96 (IH, m), 3.79 (3H, s), 1.9 (2H, m), 1.74 (4H, m), 1.58 (2H, m) MS (FAB) 357 (M+H)+
Elemental analysis for: C20H20O6 Calc'd: C, 67.41; H, 5.66
Found: C, 65.79; H, 6.00 Example 33
3,-Cvclopentvloxv-4'-methoxv-biphenvl-3.4-dicarboxvlic acid dimethyl ester
A solution of the diacid (120 mg, 0.33 mmol) prepared above is dissolved in ether (20 ml) and cooled to 0°C. To this was added an etherial solution of diazomethane until die yellow color persisted. The solution was stirred for 10 minutes and then glacial acetic acid was added to discharge the color. The solvent was removed in vacuo. The sample was chromatographed on silica gel with ethyl acetate in hexanes. This provided the product as an oil (118 mg, 93%).
IR (film) 1725 cm-l
NMR (DMSO) δ7.91 (IH, d, J=4.8Hz), 7.90 (IH, s), 7.82 (IH, d, J=4.5Hz), 7.30 (IH, d, J=2.1Hz), 7.28 (IH, s), 7.06 (IH, d, J=8.1Hz), 4.96 (IH, m), 3.84, (3H, s), 3.83 (3H, s), 3.70 (3H, s), 1.89 (2H, m), 1.72 (4H, m), 1.57 (2H , m) MS (CI) 385 (M+H)+
Elemental analysis for: C22H24O6 Calc'd: C, 68.74; H, 6.29
Found: C, 68.18; H, 6.49
Example 34
6-(3^Cvclopentvloxv-4^methoxvnhenvn-2.3-dihvdronhthalizine-1 -4- joji≤
The diacid prepared above (1.05 g, 2.94 mmol) was dissolved in acetic anhydride (10 ml) in a Carius tube. The tube was heated in a 140°C oil bath for 30 minutes, cooled and the solvent removed in vacuo. The crude anhydride was dissolved in dry dichloromethane (10 ml) and hydrazine hydrate was added (0.2 ml). The mixture was refluxed overnight with a Dean Stark trap. The sample was then diluted with IN NaOH and was extracted with ethyl acetate. The organic layer was discarded and the aqueous layer was acidifed with concentrated HCL. The resulting solid was filtered to give the product (1.02 g, 98%) as a dihydrate (mp > 255°C). IR (KBr) 1665 cm"1
NMR (DMSO δ8.23 (IH, s), 8.09 (2H, s), 7.30 (2H, m), 7.08 (IH, d, J=8.3Hz), 4.95 (IH, m), 3.80 (3H, s), 1.90 (2H, m), 1.75 (4H, m), 1.60 (2H, m) MS (El) 352 (M+)
Elemental analysis for: C2θH2θN2θ4»2H2θ Calc'd: C, 61.84; H, 6.23; N, 7.21 Found: C, 61.86; H, 5.22; N, 7.07
EXAMPLE 35
The following standard tests are employed to assess the abilities of compounds to inhibit PDE IV in vitro.
Test Procedure No. 1
A solution containing PDE IV is prepared from canine tracheal muscle as follows: The dog is euthanized with an overdose of beuthanasia while under anesthesia induced by a 33 mg kg IV bolus of Nembutal. The trachealis muscle is removed, cleaned of connective tissue, and minced thoroughly. Three to four grams of tissue is then homogenized in Tris-HCl buffer (pH 7.8) using a Polytron. The homogenate is then centrifuged at 25,000 x g (4° C) for 30 minutes. The supernatant is decanted and filtered through four layers of gauze, and applied to a 40 cm x 2 cm DEAE-Sepharose column that is equilibrated with Tris-HCl buffer (pH 7.8). The column is then washed with an additional 240 mL of buffer to remove unbound proteins. PDE is eluted using 450 mL of Tris-HCl buffer containing a linear gradient of 0.0 - 1.0 M Na-acetate (80 mL/hr), and 7.5 mL fractions are collected. Each fraction is assayed for cAMP- and cGMP- metabolizing PDE activity. Fractions eluting at approximately 0.6 M Na- acetate, and containing cAMP but not cGMP metabolic activity are pooled and used as a PDE stock solution for assaying PDE IV inhibitory activity.
PDE IV activity is tested as described previously [see Thompson et al., Advances in Cyclic Nucleotide Research. JO. 69 (1979)] at 30° C in a reaction mixture containing: 10 mM Tris-HCl (pH 7.8), 5 mM MgCl2, 1 mM β-mercaptoethanol, 1 [_M ^H-cAMP, 10 JJM CI-930, PDE IV stock solution, and die desired concentration of test compound. CI-930 is included as an inhibitor of the cyclic GMP-sensitive, cyclic AMP-selective PDE (PDE III) that is also present in the PDE rv stock solution when prepared as described above. The ability of a test compound to inhibit PDE IV is determined by measuring the reduction in cAMP metabolism produced by the test compound and expressing it as a percentage of the reduction induced by 10 μM rolipram, a potent inhibitor of PDE r [see Beavo, Advances in Second Messenger and Phosphoprotein Research, 22, 1 (1988)]. IC50S are calculated for each test compound as the concentration of test compound that inhibits PDE IV by 50%.
Test Procedure No, 2
The following standard test is also employed to assess the abilities of compounds to inhibit PDE r functionally.
Male Hartley guinea pigs (500-550 g, Charles River) were euthanized by a blow to the head, and the tracheas were removed and placed in aerated physiological salt solution (PSS) containing NaCl (118 mM), KH2PO4 (1.18mM), KC1 (4.74 mM), CaCl2 (2.5 mM), MgSO4.7H2O (1.19 mM), NaHCO3 (25 mM), dextrose (11.1 mM), cocaine and hydrocortisone (3 μM and 10 μM, respectively, to block intraneural and extraneural uptake mechanisms), propranolol and phentolamine (1 μM and 10 μM, respectively, to block adrenoceptors), indomethacin (2.8 μM; to block spontaneous tension generation), and calcium disodium EDTA (26 μM, as an antioxidant). Tracheal rings were prepared and mounted in 10 ml organ baths for the measurement of isometric tension generation as previously described (Heaslip et al., 1986).
Tracheal relaxation resulting from the inhibition of PDE-IV or PDE-III was assessed by a method similar to that employed by Harris et al. (1989). Tracheal rings were precontracted witii 1 μM carbachol until a stable level of tension was obtained (30 min). To explore the inhibition of PDE-IV, tracheal rings were then incubated (45 min) with CI-930 (10 μM), thus inhibiting PDE-III and sensitizing the ring to the relaxant effects of PDE-IV inhibitors. Conversely, the inhibition of tracheal PDE-III was explored using rings pretreated with rolipram (10 μM), and thereby sensitized to PDE- HI inhibitors (Harris et al., 1989). The functional inhibition of PDE-IV or PDE-m was determined by adding a test compound to the tissue bath in cumulatively increasing concentrations and monitoring the degree of relaxation induced in the continued presence of CI-930 or rolipram (respectively). After adding the final concentration of test compound to the organ bath, tracheal rings were washed repeatedly with PSS, and allowed to relax to resting tension. Percent relaxations produced by each concentration of test compound were calculated as a percentage relaxation of tension maintained in the presence of the preincubating PDE inhibitor, relative to the final resting tension determined at die end of each experiment.
The two abovementioned PDE IV inhibition tests were used to determine the
PDE IV inhibitory abilities of some of die compounds of the present invention. The table below indicates die compounds tested and the results thereof. For each of Tests 1 and 2, die results are given as IC50S for the compound tested in M concentrations.
TABLE
Compound of Example # Test No. 1 Test No. 2
1 24.5 x 10-8 nt
2 6.0 x 10-8 16 x 10-8
3 5.8 x 10-8 6.6 x 10-8
4 10 x 10-8 nt
5 2.3 x 10-8 6.1 x 10-8
6 10 x 10-8 1200 x lO"8
7 nt nt
8 3.4 x 10-8 33 x 10-8
9 2.0 x lO"8 2.3 x 10-8
10 10 x lO"8 nt
11 0.43 x 10-8 nt
12 8.6 x 10-8 nt
13 61 x 10-8 nt
14 8.4 x 10-8 nt
15 nt nt
16 33 x 10-8 nt TABLE (Cont'd)
Compound of Example # Test No.1 Test No.2
17 11x10-8 nt
18 3.1 x 10-8 23 x 10-8
19 58 x lO"8 nt
20 5.9 x 10-8 nt
21 29 x 10-8 nt
22 3.6 x 10-8 14 x 10-8
23 3.9 x lO"8 190 X 10-8
24 nt nt
25 73 x 10-8 nt
26 27 x 10-8 nt
27 55 x 10-8 nt
28 100 x 10-8 nt
29 47 x 10-8 nt
30 1.6x10-8 nt
31 10 x 10-8 nt
32 1,000x10-8 nt
33 110 10-8 nt
34 4.9 x lO"8 nt
(nt=not tested)

Claims

What is Claimed;
1. A compound of the following structure:
Figure imgf000039_0001
wherein, when R% = H:
Rl = alkyl, cycloalkyl, arylalkyl, aryl; R2 = cycloalkyl, aryl, C3-C10 alkyl;
X,Y = O, S(O)n, NH;
Z = CH2OH, NHSO2R3, CHO, CO2R3, CONHR4R5, CN, COR6, H, halo, NHCN, NHCONR4R5. CONR4OR5, CONR4NR5R6, 1-tetrazole, S(O)nOH, S(O)nNR R4, C=NOH, C(=N(OH)NH2, OCONR7R6, P(O)(OR4)2, NH2, SH,OH, OS(O)2R3, C(O)CO2R3, C(O)CONR R4, CH(OH)CO2R3.
CHFCO2R3, CF2CO2R3, CH(OH)CONR3R4, CF2CONR3R4, C=NNH2, C(=NOC(=O)R3)R4, C(=NNHC(=O)R )R4, C(=NOH)R , C(=NNR3)R4, NHC(=O)R6 or C(O)CONH2; R3, R4, R5, R6, R7 are each, independently, hydrogen, alkyl, aryl, aryalkyl, cycloalkyl, or fluoroalkyl; or a compound of Structure I, wherein:
Rl = alkyl, cycloalkyl, arylalkyl, or aryl; R2 = cycloalkyl, aryl, or alkyl; X,Y = CH2, O, S(O)n, or NH; R3, R4, R5, R6, R7 = hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, or fluoroalkyl;
R8 = CO2R3, CONR2R3, or R8 and Z are concatenated such tiiat R8Z = C(O)NHNHC(O), (CH2)mC(=W), V(CH2)mC(=W), or VnCH=CH(CH2)nC(=W); where V = O, S(O)n, NH;
W = O, NOH, NHNH , NOC(O)CH3, or NNHC(O)CH ; halo = CI, Br, or I; fluoroalkyl = CF CHF , CH2F, CH2CF3, C2F5; cycloalkyl = C3-C6 cycloalkyl; arylalkyl = C1-C4 aryl; aryl = phenyl, furanyl, thienyl, or pyridyl; n = 0-2; and m = 2-4 or pharmaceutically acceptable salts thereof.
2. The compound of Claim 1 wherein ring B further comprises structure HI or structure IV:
Figure imgf000040_0001
wherein W = O, NOH, NNH , NOC(O)CH3, or NNHC(O)CH and further wherein ring B is attached to ring A at the 5, 6, or 7 position, or pharmaceutically acceptable salts thereof.
3. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-4- carboxylic acid amide.
4. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-4- carboxylic acid hydrazide.
5. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-3- carboxylic acid.
6. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-3- carbaldehyde.
7. A compound of Claim 1 which is l-(3'-Cyclopentyloxy-4'-methoxy-biphenyl- 3-yl)-ethanone.
8. A compound of Claim 1 which is (3'-Cyclopentyloxy-4'-methoxy-biphenyl-4- yl)-phenylmethanone.
9. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-3- carbonitrile.
10. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-4- carbonitrile.
11. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-3- carboxylic acid metiiyl ester.
12. A compound of Claim 1 which is 6-(3-Cyclopentyloxy-4-methoxy-phenyl)-3,4- dihydro-2H-naphthalen- 1 -one.
13. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-4- carbaldehyde oxime.
14. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-3- carbaldehyde oxime.
15. A compound of Claim 1 which is 3'-Cyclopentyloxy-4'-methoxy-biphenyl-3- carboxylic acid amide.
16. A compound having the general structure:
Figure imgf000042_0001
wherein:
Rl = C1-C3 alkyl;
R2 = C3-C6 alkyl, C3-C7 cycloalkyl, or phenyl; Z = CHO, CO2R3, CONHR4R5, CN, COR6, H, halo, NHCONR4R5, CONR4OR5, CONR4NR5R6, OCONR6R7, NH2, C=NOH, C=NNH2, C(=NOC(=O)R3)R4, C(=NNHC(=O)R3)R4,
C(O)CO2R3, C(=NOH)R3, C(=NNR3)R4, NHC(=O)R6, or C(O)CONH2; and
R3, R4, R5, R , R7 are each, independently, hydrogen, C1-C4 alkyl, aryl, arylalkyl, fluoroalkyl; and R8 = H, CONR4R5 or CO2R3; and pharmaceutically acceptable salts thereof.
17. The compound of Claim 16 wherein ring A is attached to ring B in die meta or para position, or pharmaceutically acceptable salts thereof.
18. The compound of Claim 16 wherein ring B further comprises structure IH or structure IV:
Figure imgf000043_0001
wherein W = O, NOH, NNH2, NOC(O)CH , or NNHC(O)CH3 and further wherein ring B is attached to ring A at the 5, 6, or 7 position, or pharmaceutically acceptable salts thereof.
19. The compound of Claim 16 wherein:
Rl = C1-C3 alkyl;
R2 = C3-C7 cycloalkyl or C3-C6 alkyl; Z = CO2R3, CONHR4R5, CONR4NR5R6, H, halo, CHO, CORό, CN, NH2,
NHCONR4R5, CONR4OR5, OCONR7R6, C(=NOH)R3, C(=NNR )R4, C(=NOC(=O)R3)R4, C(=NNHC(=O)R3)R4, or NHC(=O)R6; R3, R4, R5, R6, R7 = H, C1-C4 alkyl, aryl, or trifluoromethyl; and R8 = H or CO2R3; or pharmaceutically acceptable salts thereof.
20. The compound of Claim 16 wherein:
Ri = CH3;
R2 = C4 alkyl, C5 cycloalkyl;
Z = meta or para CHO, CO2R3, CONHR4R5, CN, CORό, H, chloro, bromo,
NHCONR4R5, CONR4OR5, CONR4NR5R6, OCONR7R6, NH2,
C(=NOH)R3, C(=NNR3)R4, C(=NOC(=O)R3)R4,
C(=NNHC(=O)R3)R4; R3, R4, R5, Rό, and R7 = hydrogen, methyl, phenyl, or trifluoromethyl; and R8 = hydrogen; or pharmaceutically acceptable salts thereof.
21. A method of treating asthma or allergic or inflammatory diseases in a mammal in need tiiereof, the method comprising administering to said mammal an effective amount of a compound as claimed in any of Claims 1 to 20.
22. A pharmaceutical composition for use in treating astiima or allergic or inflammatory diseases in a mammal in need tiiereof, the composition comprising an effective amount of a compound as claimed in any of Claims 1 to 20.
PCT/US1995/000996 1994-02-17 1995-01-25 Substituted biphenyl derivatives as phosphodiesterase inhibitors WO1995022520A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP95908671A EP0745063B1 (en) 1994-02-17 1995-01-25 Substituted biphenyl derivatives as phosphodiesterase inhibitors
AU16905/95A AU692839B2 (en) 1994-02-17 1995-01-25 Substituted biphenyl derivatives as phosphodiesterase inhibitors
DE69508568T DE69508568T2 (en) 1994-02-17 1995-01-25 SUBSTITUTED BIPHENYL DERIVATIVES WITH PHOSPHODIESTERASE INHIBITING EFFECT
MX9603414A MX9603414A (en) 1994-02-17 1995-01-25 Substituted biphenyl derivatives as phosphodiesterase inhibitors.
JP7521806A JPH09510191A (en) 1994-02-17 1995-01-25 Substituted biphenyl derivatives as phosphodiesterase inhibitors
DK95908671T DK0745063T3 (en) 1994-02-17 1995-01-25 Substituted biphenyl derivatives with phosphodiesterase inhibitory effect
KR1019960704462A KR970701170A (en) 1994-02-17 1996-08-16 Substituted biphenyl derivatives as phosphodiesterase inhibitors
FI963228A FI963228A0 (en) 1994-02-17 1996-08-16 Substituted biphenyl derivatives as phosphodiesterase inhibitors
GR990401565T GR3030490T3 (en) 1994-02-17 1999-06-10 Substituted biphenyl derivatives as phosphodiesterase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19803194A 1994-02-17 1994-02-17
US08/198,031 1994-02-17

Publications (1)

Publication Number Publication Date
WO1995022520A1 true WO1995022520A1 (en) 1995-08-24

Family

ID=22731725

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/000996 WO1995022520A1 (en) 1994-02-17 1995-01-25 Substituted biphenyl derivatives as phosphodiesterase inhibitors

Country Status (19)

Country Link
US (1) US5650444A (en)
EP (1) EP0745063B1 (en)
JP (1) JPH09510191A (en)
KR (1) KR970701170A (en)
AT (1) ATE178046T1 (en)
AU (1) AU692839B2 (en)
CA (1) CA2182792A1 (en)
DE (1) DE69508568T2 (en)
DK (1) DK0745063T3 (en)
ES (1) ES2130597T3 (en)
FI (1) FI963228A0 (en)
GR (1) GR3030490T3 (en)
HU (1) HUT74611A (en)
IL (1) IL112538A (en)
MX (1) MX9603414A (en)
NZ (1) NZ279689A (en)
SG (1) SG47624A1 (en)
TW (1) TW394757B (en)
WO (1) WO1995022520A1 (en)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998009961A1 (en) * 1996-09-04 1998-03-12 Pfizer Inc. Indazole derivatives and their use as inhibitors of phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnf)
EP0934933A1 (en) * 1998-02-06 1999-08-11 Byk Gulden Lomberg Chemische Fabrik GmbH Phthalazinones
WO2001098245A2 (en) * 2000-06-21 2001-12-27 Sunesis Pharmaceuticals, Inc. Triphenyl compounds as interleukin-4 antagonists
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
WO2007009083A2 (en) * 2005-07-12 2007-01-18 Acadia Pharmaceuticals Inc. Compounds with activity at retinoic acid receptors
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
US7652062B2 (en) 2005-07-29 2010-01-26 Wyeth Llc Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
EP2193808A1 (en) 1999-08-21 2010-06-09 Nycomed GmbH Synergistic combination
EP2223920A2 (en) 1996-06-19 2010-09-01 Aventis Pharma Limited Substituted azabicyclic compounds
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2011134468A1 (en) 2010-04-28 2011-11-03 Leo Pharma A/S Biaryl phosphodiesterase inhibitors
WO2012118972A2 (en) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Process of preparing guanylate cyclase c agonists
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
WO2014131024A2 (en) 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015021358A2 (en) 2013-08-09 2015-02-12 Dominique Charmot Compounds and methods for inhibiting phosphate transport
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
WO2020237096A1 (en) 2019-05-21 2020-11-26 Ardelyx, Inc. Combination for lowering serum phosphate in a patient

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981549A (en) * 1997-02-14 1999-11-09 Synapse Pharmaceutical International Method for controlling or alleviating the symptoms of respiratory disease and allergies
ES2248107T3 (en) 1999-08-31 2006-03-16 Incyte San Diego Incorporated BENCILIDEN-TIAZOLIDINDIONAS AND ANALOGS AND ITS USE IN THE TREATMENT OF DIABETES.
AU2002252227A1 (en) 2001-03-07 2002-09-24 Maxia Pharmaceuticals, Inc. Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
CA2473156A1 (en) * 2001-03-08 2002-09-19 Incyte San Diego, Inc. Rxr activating molecules
CA2340824A1 (en) * 2001-03-14 2002-09-14 Ibm Canada Limited-Ibm Canada Limitee Method and system for application behavior analysis
EP1421061A4 (en) * 2001-08-17 2004-12-22 Incyte San Diego Inc Oxime derivatives for the treatment of dyslipidemia and hypercholesteremia
JP2005513026A (en) * 2001-11-15 2005-05-12 インサイト サン ディエゴ インコーポレイテッド Hypercholesterolemia, dyslipidemia and other metabolic disorders; N-substituted heterocycles to treat cancer and other diseases
US7196108B2 (en) * 2002-03-08 2007-03-27 Incyte San Diego Inc. Bicyclic heterocycles for the treatment of diabetes and other diseases
US7102000B2 (en) * 2002-03-08 2006-09-05 Incyte San Diego Inc. Heterocyclic amide derivatives for the treatment of diabetes and other diseases
US6706895B1 (en) * 2002-11-14 2004-03-16 Uniroyal Chemical Company, Inc. 4-methoxybiphenyl hydrazone derivatives
US20050014767A1 (en) * 2003-01-29 2005-01-20 Magnus Pfahl Benzoxazole, benzothiazole, and benzimidazole derivatives for the treatment of cancer and other diseases
MXPA05011242A (en) * 2003-04-18 2006-07-06 Incyte San Diego Inc Substituted isochroman compounds for the treatment of metabolic disorders, cancer and other diseases.
US7279600B2 (en) * 2003-05-02 2007-10-09 Wyeth Hydroxy-biphenyl-carbaldehyde oxime derivatives and their use as estrogenic agents

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015451A1 (en) * 1990-04-05 1991-10-17 Smithkline Beecham Pharma Gmbh Novel derivatives of phenyl-cycloalkanes and -cycloalkenes
WO1992006963A1 (en) * 1990-10-16 1992-04-30 Byk Gulden Lomberg Chemische Fabrik Gmbh Arylpyridazinones
WO1993007111A1 (en) * 1991-10-02 1993-04-15 Smithkline Beecham Corporation Cyclopentane and cyclopentene derivatives with antiallergic antiinflammatory and tumor necrosis factor inhibiting activity
WO1994010118A1 (en) * 1992-10-23 1994-05-11 Celltech Limited Tri-substituted phenyl derivatives and processes for their preparation
WO1994012461A1 (en) * 1992-12-02 1994-06-09 Pfizer Inc. Catechol diethers as selective pdeiv inhibitors

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2759964A (en) * 1953-07-09 1956-08-21 Dow Chemical Co Dialkylaminoalkyl esters of phenyl substituted dihydroxybenzoic acids
US2716663A (en) * 1953-07-09 1955-08-30 Dow Chemical Co Hydrazides of phenyl substituted dihydroxybenzoic acids
US2921939A (en) * 1955-11-28 1960-01-19 Metal & Thermit Corp Process for preparing alpha-substituted acetic acids
US3043746A (en) * 1959-11-02 1962-07-10 Vismara Francesco Spa 2-(4-biphenylyl)-delta-hexenoic acid and derivatives as anticholesterinemic agents
US3120551A (en) * 1961-03-20 1964-02-04 Warner Lambert Pharmaceutical 5-(4-biphenylyl)-3-methylvaleric acid and functional derivatives thereof
US3624142A (en) * 1964-09-10 1971-11-30 Merck & Co Inc Substituted biphenyl acetic acid derivatives
US3457300A (en) * 1965-06-11 1969-07-22 Merck & Co Inc Acetic acid type compounds
US3681445A (en) * 1968-01-19 1972-08-01 Merck & Co Inc Substituted phenyl benzoic acid compounds
US3671580A (en) * 1969-12-22 1972-06-20 Merck & Co Inc Substituted biphenyl acetic acids and ester derivatives thereof
GB1433130A (en) * 1972-11-09 1976-04-22 Secr Defence Substituted biphenyl and polyphenyl compounds and liquid crystal materials and devices containing them
GB1459084A (en) * 1973-05-24 1976-12-22 Boots Co Ltd Preparation of arylalkanoic acid
JPS5387340A (en) * 1977-01-10 1978-08-01 Seiko Epson Corp Method of synthesis
US4916145A (en) * 1987-07-10 1990-04-10 Hoffmann-La Roche Inc. Substituted n-[(pyridyl)alkyl]aryl-carboxamide
DE3903989A1 (en) * 1989-02-10 1990-09-20 Basf Ag DIPHENYLHETEROALKYL DERIVATIVES, THEIR PREPARATION, AND MEDICAMENTS AND COSMETICS THEREOF
DE3903988A1 (en) * 1989-02-10 1990-08-30 Basf Ag OXIDIZED DIPHENYLHETEROALKANES, THEIR PREPARATION AND USE
CA2044533A1 (en) * 1990-06-29 1991-12-30 Philippe Guerry Substituted aminoalkylbiphenyl derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015451A1 (en) * 1990-04-05 1991-10-17 Smithkline Beecham Pharma Gmbh Novel derivatives of phenyl-cycloalkanes and -cycloalkenes
WO1992006963A1 (en) * 1990-10-16 1992-04-30 Byk Gulden Lomberg Chemische Fabrik Gmbh Arylpyridazinones
WO1993007111A1 (en) * 1991-10-02 1993-04-15 Smithkline Beecham Corporation Cyclopentane and cyclopentene derivatives with antiallergic antiinflammatory and tumor necrosis factor inhibiting activity
WO1994010118A1 (en) * 1992-10-23 1994-05-11 Celltech Limited Tri-substituted phenyl derivatives and processes for their preparation
WO1994012461A1 (en) * 1992-12-02 1994-06-09 Pfizer Inc. Catechol diethers as selective pdeiv inhibitors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 56, no. 4, 19 February 1962, Columbus, Ohio, US; abstract no. 3392b, V. BELIAH, M. UMA: "Isomerization of 4-biphenylylarenesulfonates" *
CHEMICAL ABSTRACTS, vol. 76, no. 11, 13 March 1972, Columbus, Ohio, US; abstract no. 59106, R. M. SCHISLA: "Synthesis of ten new diphenoxybiphenyls" page 426; *
J. CHEM. ENG. DATA, vol. 17, no. 1, 1972, pages 112 - 115 *
J. ORG. CHEM., vol. 26, 1961, pages 3027 - 3028 *

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2223920A2 (en) 1996-06-19 2010-09-01 Aventis Pharma Limited Substituted azabicyclic compounds
WO1998009961A1 (en) * 1996-09-04 1998-03-12 Pfizer Inc. Indazole derivatives and their use as inhibitors of phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnf)
US6262040B1 (en) 1996-09-04 2001-07-17 Pfizer Inc Indazole derivatives and their use as inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF)
EP0934933A1 (en) * 1998-02-06 1999-08-11 Byk Gulden Lomberg Chemische Fabrik GmbH Phthalazinones
EP2193808A1 (en) 1999-08-21 2010-06-09 Nycomed GmbH Synergistic combination
WO2001098245A2 (en) * 2000-06-21 2001-12-27 Sunesis Pharmaceuticals, Inc. Triphenyl compounds as interleukin-4 antagonists
WO2001098245A3 (en) * 2000-06-21 2003-01-23 Sunesis Pharmaceuticals Inc Triphenyl compounds as interleukin-4 antagonists
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2007009083A2 (en) * 2005-07-12 2007-01-18 Acadia Pharmaceuticals Inc. Compounds with activity at retinoic acid receptors
WO2007009083A3 (en) * 2005-07-12 2007-07-19 Acadia Pharm Inc Compounds with activity at retinoic acid receptors
US7652062B2 (en) 2005-07-29 2010-01-26 Wyeth Llc Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
EP2923706A1 (en) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2011134468A1 (en) 2010-04-28 2011-11-03 Leo Pharma A/S Biaryl phosphodiesterase inhibitors
US9051290B2 (en) 2010-04-28 2015-06-09 Leo Pharma A/S Biaryl phosphodiesterase inhibitors
WO2012118972A2 (en) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Process of preparing guanylate cyclase c agonists
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
EP4309673A2 (en) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
EP3708179A1 (en) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
EP3718557A2 (en) 2013-02-25 2020-10-07 Bausch Health Ireland Limited Guanylate cyclase receptor agonist sp-333 for use in colonic cleansing
WO2014131024A2 (en) 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
EP4424697A2 (en) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015021358A2 (en) 2013-08-09 2015-02-12 Dominique Charmot Compounds and methods for inhibiting phosphate transport
EP3492106A1 (en) 2013-08-09 2019-06-05 Ardelyx, Inc. Compounds and methods for inhibiting phosphate transport
EP3884935A1 (en) 2013-08-09 2021-09-29 Ardelyx, Inc. Compounds and methods for inhibiting phosphate transport
WO2020237096A1 (en) 2019-05-21 2020-11-26 Ardelyx, Inc. Combination for lowering serum phosphate in a patient

Also Published As

Publication number Publication date
DK0745063T3 (en) 1999-10-11
FI963228A (en) 1996-08-16
SG47624A1 (en) 1998-04-17
KR970701170A (en) 1997-03-17
HU9602267D0 (en) 1996-10-28
FI963228A0 (en) 1996-08-16
IL112538A0 (en) 1995-05-26
AU692839B2 (en) 1998-06-18
CA2182792A1 (en) 1995-08-24
TW394757B (en) 2000-06-21
EP0745063A1 (en) 1996-12-04
DE69508568T2 (en) 1999-10-21
JPH09510191A (en) 1997-10-14
GR3030490T3 (en) 1999-10-29
IL112538A (en) 1999-09-22
MX9603414A (en) 1997-03-29
EP0745063B1 (en) 1999-03-24
DE69508568D1 (en) 1999-04-29
AU1690595A (en) 1995-09-04
ES2130597T3 (en) 1999-07-01
HUT74611A (en) 1997-01-28
US5650444A (en) 1997-07-22
NZ279689A (en) 1997-08-22
ATE178046T1 (en) 1999-04-15

Similar Documents

Publication Publication Date Title
EP0745063B1 (en) Substituted biphenyl derivatives as phosphodiesterase inhibitors
US5691376A (en) Substituted biphenyl derivatives
US7186870B2 (en) Process for the preparation of 1,3-substituted indenes and aryl-fused azapolycyclic compounds
JP5036648B2 (en) Acetylene derivatives having MGLUR5 antagonist activity
JPH08134073A (en) Method of suppressing formation of tumor necrosis factor in mammal
PL174610B1 (en) Novel heterocyclic compounds for use as pharmaceuticals
EP2040703B1 (en) Derivatives of 2-benzoyl-imidazopyridines, preparation method thereof and use of same in therapeutics
EP0576357A1 (en) Pyrazole derivatives, process for their preparation and pharmaceutical compositions containing them
CA2668196A1 (en) Substituted 2,5-dfflydro-3h-pyrazolo[4,3-c]pyridazin-3-one derivatives, preparation thereof and use of same as cannabinoid cb1 receptor ligands
WO2005000817A2 (en) Diphenylpyridine derivatives, preparation and therapeutic application thereof
JP2796876B2 (en) Substituted pyrrolidine compounds and pharmaceutical compositions
EP2040705A2 (en) Use of 2-benzoyl-imidazopyridines in therapeutics
JP3825636B2 (en) 2-aminopyridine containing fused ring substituents
CA2193468C (en) 3-[(5-substituted benzyl)amino]-2-phenylpiperidines as substance p antagonists
JPH05194350A (en) Substituted 3,4-dihydronaphthalene, medicine containing this compound, and process for producing this compound and this medicine
FR2849849A1 (en) NOVEL CARBOXYLIC ACIDS AND DERIVATIVES FOR THE TREATMENT AND PREVENTION OF DIABETES AND DYSLIPEMICS
Rakowitz et al. Synthesis of novel phenylacetic acid derivatives with halogenated benzyl subunit and evaluation as aldose reductase inhibitors
JPH0283376A (en) Benzoxazolone derivative and antiallergic or anti-inflammatory composition
JPH0629264B2 (en) 2-amino-5-hydroxy-4-pyrimidone
NZ205466A (en) 1-pyridyloxy-3-indolylalkylamino-2-propanol derivatives and pharmaceutical compositions
US5602167A (en) 4-arylcyclohepta[c] pyrrole analgesics
JP3172461B2 (en) 3-[(5-Substituted benzyl) amino] -2-phenylpiperidines as substance P antagonists
JPH0521898B2 (en)
IE980421A1 (en) Compounds
JPH06321776A (en) Antiinflammatory agent

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AU BB BG BR BY CA CN CZ EE FI GE HU JP KG KP KR KZ LK LR LT LV MD MG MN MX NO NZ PL RO RU SD SI SK TJ TT UA UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i

Free format text: PAT.BUL.36/95 UNDER INID (51) "IPC" ADD "A61K 31/275, 31/11, 31/12, 31/215"

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 279689

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1995908671

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2182792

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 963228

Country of ref document: FI

WWP Wipo information: published in national office

Ref document number: 1995908671

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1995908671

Country of ref document: EP