Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications

Definitions

• the subject invention relates to novel N-phenyl-(substituted)-methyl-5,6-dihydro- imidazo[5,l-a]isoquinolin-3-amine compounds, pharmaceutical compositions containing them, and their therapeutic or preventative use in the areas of cardiovascular, oncology, infectious and inflammatory diseases.
• Rl is selected from alkyl, aryl, and heterocycle
• R2 if not nil, is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl and arylsulfonyl;
• R6, R7 and R8 are each independently selected from hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, sulfonamide, formyl (acyl), carboxy, and carboxamide; or R6 and R7 together are alkylene or heteroalkylene attached to adjacent carbons of the phenyl to which R6 and R7 are attached, and R8 is as specified in (f) above;
• R9 is selected from hydrogen, halo, alkyl, aryl, heterocycle, and carboxy and its alkyl and aryl esters and amides;
• RIO and R12, and Rll and R13 if not nil, are each independently selected from hydrogen, alkyl, and aryl; and an optical isomer, diestereomer or enantiomer thereof; a pharmaceutically acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.
• the subject invention also includes compositions comprising a subject compound and a pharmaceutically-acceptable excipient; and methods for treating or preventing diseases or disorders by administering to a human or lower animal in need thereof, a safe and effective amount of a subject compound.
• alkyl means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted.
• alkyl may be used alone or as part of another word where it may be shortened to "alk” (e.g., in alkoxy, alkylacyl).
• Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about ten carbon atoms, more preferably still from one to about six carbon atoms, still more preferably from one to about four carbon atoms; most preferred "" are methyl or ethyl.
• Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about ten carbon atoms, more preferably still from three to about seven carbon atoms, still more preferably from three to about five carbon atoms.
• Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused hydrocarbon rings.
• Preferred alkyl are unsaturated with from one to about three double or triple bonds, preferably double bonds; more preferably they are mono-unsaturated with one double bond. Still more preferred alkyl are saturated. Saturated alkyl are referred to herein as "alkanyl".
• alkyl unsaturated only with one or more double bonds (no triple bonds) are referred to herein as "alkenyl”.
• Preferred substituents of alkyl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted alkyl are preferred.
• heteroatom means a nitrogen, oxygen, or sulfur atom.
• alkylene means an alkyl which connects two other moieties, “heteroalkylene” means an alkylene having one or more heteroatoms in the connecting chain.
• aryl means an aromatic hydrocarbon ring (or fused rings) which is substituted or unsubstituted.
• aryl may be used alone or as part of another word (e.g., in aryloxy, arylacyl).
• Preferred aryl have from six to about fourteen, preferably to about ten, carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms.
• Preferred aryl is phenyl or naphthyl; most preferred is phenyl.
• Preferred substituents of aryl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted aryl are preferred.
• heterocycle means a saturated, unsaturated or aromatic cyclic hydrocarbon ring (or fused rings) with one or more heteroatoms in the hydrocarbon ring(s).
• Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms in the ring(s).
• Preferred heterocycles have from three to about fourteen, preferably to about ten, carbon plus heteroatoms in the ring(s), more preferably from three to about seven, more preferably still five or six, carbon plus heteroatoms in the rings(s); and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten, more preferably still five or six, carbon plus heteroatoms.
• Preferred heterocycles have one ring, but may have two, three, or more, fused rings. More preferred heterocycle rings include those which are one ring with 5 or 6 carbon plus heteroatoms in the ring with no more than three ring heteroatoms, no more than two of which are O and S. Still more preferred are such 5- or 6-ring atom heterocycles with one or two ring atoms being O or S and the others being C; or with one, two or three ring atoms being N and the others being C. Such preferred 5- or 6-ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic.
• Such preferred 5- or 6-ring atom heterocycles are preferably a single ring; or fused with a 3- to 6-ring atom hydrocarbon ring which is saturated, unsaturated with one double bond, or aromatic (phenyl); or fused with another such 5- or 6-ring atom heterocyclic ring.
• Heterocycles are unsubstituted or substituted.
• Preferred heterocycle substituents are the same as for alkyl.
• the bond between the ⁇ carbon and the ⁇ nitrogen can be either a single bond, in which case R2 and the H attached to the ⁇ carbon exist, or a double bond, in which case R2 and that H do not exist (are nil).
• This C ⁇ -N ⁇ bond is preferably a single bond.
• the bond between carbons 5 and 6 can be either a single bond, in which case Rl l and R13 exist, or a double bond, in which case Rll and R13 do not exist (are nil).
• This C5- Cg bond is preferably a single bond.
• Rl is selected from alkyl, aryl, and heterocycle.
• Prefe ⁇ ed Rl include linear alkanyl having from 1 to about 10 carbon atoms, linear alkenyl having from 2 to about 10 carbon atoms, and branched and cyclic alkanyl and alkenyl having from 3 to about 10 carbon atoms, such alkenyl preferably having 1 double bond.
• Such preferred alkanyl and alkenyl are preferably unsubstituted, or substituted with phenyl, heterocycle having 5 or 6 ring atoms, carboxy and its C ⁇ - Cg alkyl and phenyl esters, or cyano. More preferably such alkanyl and alkenyl have up to about 7 carbon atoms, more preferably still up to 6 carbon atoms, still more preferably up to 4 carbon atoms. Most preferred Rl is unsubstituted methyl.
• R2 if it exists, is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl, and arylsulfonyl.
• Preferred R2 is selected from hydrogen; C1 -Cg alkyl, such alkyl being saturated or unsaturated with one double bond and unsubstituted or substituted with phenyl; Ci-Cg alkylacyl, the alkyl portion being saturated or unsaturated with one double bond; and phenylacyl. More preferred is the alkyl portions of the aforementioned moieties being C1-C4 and saturated. More preferred still is R2 being methyl. Most preferred R2 is hydrogen.
• R3, R4 and R5 are each independently selected from hydrogen, halo, alkyl, aryl, heterocycle, nitro and cyano; also from hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide which are unsubstituted or substituted, preferably with alkyl or aryl or heterocycle; or R3 and R4 together are alkylene or heteroalkylene attached to adjacent carbon atoms of the phenyl ring, thereby forming a cycloalkyl or aryl or heterocycle ring which is fused to the phenyl ring (phenyl of carbons l'-6'), and R5 is as defined above.
• R3, R4 and R5 are selected from hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl or aryl esters and amides; more preferably from hydrogen, halo, alkyl, alkoxy, phenoxy, thio, alkylthio, phenylthio, mono or dialkylamino, mono- or diphenylamino, alkylacyl, and phenylacyl.
• Alkyl portions of such substituents are preferably about Ci -C ⁇ , more preferably about C1 -C4, more preferably still methyl or ethyl.
• Alkyl and phenyl R3, R4 or R5 substituents or portions of such substituents are preferably unsubstituted or substituted with from 1 to about 3 fluoro, more preferably unsubstituted. More preferred is for from one to three of R3, R4, and R5 being halo, the other(s) being " hydrogen. Also more preferred is for from one to three of R3, R4 and R5 being methyl or ethyl, the other(s) being hydrogen.
• R3 being dialkylamino
• R4 and R5 being hydrogen, R3 preferably being attached to the 4' carbon. More preferred still is for from one to three of R3, R4 and R5 being independently selected from F, Cl and Br, the other(s) being hydrogen; still more preferred, when two or three of R3, R4 and R5 are F, Cl or Br, they are the same. Also more prefe ⁇ ed is from one to three of R3, R4 and R5 being unsubstituted methyl, the other(s) being hydrogen. Also more preferred is one or two of R3, R4 and R5 being trifluoromethyl, the other(s) being hydrogen or halo, and if halo, preferably fluoro. Also more preferred is one or two of R3, R4 and R5 being methoxy or trifluoromethoxy, the others being hydrogen or halo, and if halo, preferably fluoro.
• R3 and R4 which are attached to adjacent carbon atoms of the phenyl ring, together being a saturated or unsaturated alkylene or heteroalkylene having from 1 to about 6 carbon atoms and from 0 to about 3 heteroatoms, thus forming a ring fused to the phenyl, such ring having from about 5 to about 8 ring atoms.
• Such ring fused to the phenyl preferably has from about 5 to about 6 ring atoms of which from 0 to 2, more preferably 0 or 1, are heteroatoms.
• Preferred fused rings include naphthyl, indolyl, benzimidazoyl, benzofuryl, benzopyranyl.
• R5 is preferably H.
• R6, R7 and R8 are each independently selected from hydrogen, halo, alkyl, aryl, heterocycle, cyano and nitro; also from hydroxy, thio, amino, amide, formyl (acyl), carboxy, carboxamide, and sulfonamide which are unsubstituted or substituted, preferably with alkyl or aryl or heterocycle; or R6 and R7 together are alkylene or heteroalkylene attached to adjacent carbon atoms of the phenyl ring, thereby forming a cycloalkyl or aryl or heterocycle ring which is fused to the phenyl ring (phenyl of carbons 7-10), and R8 is as defined above.
• R6, R7 and R8 are selected from hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, sulfonamide, alkylsulfonamide, arylsulfonamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides; more preferably from hydrogen, halo, hydroxy, C1 -C4 alkoxy, thio, C1 -C4 alkylthio, C1 -C4 alkyl esters and amides of carboxy, and heterocycle having 5 or 6 ring atoms.
• R6, R7 and R8 are selected such that at least one heteroatom is bonded directly to the phenyl ring.
• those heteroatoms may be connected by an alkylene moiety, the alkylene moiety preferably having from 1 to about 4, more preferably 1 or 2, carbon atoms.
• one or two of R6, R7 and R8 being non-hydrogen moieties bonded to the fused rings at carbons 8 and/or 9 (as in structure 2 below); more preferred is that two of them be non-hydrogen moieties bonded to carbons 8 and 9.
• R8 is hydrogen and that R6 and R7 are both alkoxy or both alkylthio bonded to carbons 8 and 9, respectively; preferably both R6 and R7 are the same.
• Prefe ⁇ ed alkyl portions of R6 and R7 have from 1 to about 4 carbon atoms, more preferably 1 or 2 carbon atoms; most preferred is methyl. Such alkyl portions are preferably unsubstituted. Such alkyl portions are preferably saturated. Most preferred is that both R6 and R7 are methoxy bonded to carbons 8 and 9, R8 being hydrogen.
• R6 and R7 which are attached to adjacent carbon atoms of the phenyl ring, together being a saturated or unsaturated alkylene or heteroalkylene having from 1 to about 6 carbon atoms and from 0 to about 3 heteroatoms, thus forming a ring fused to the phenyl, such ring having from about 5 to about 8 ring atoms.
• Such ring fused to the phenyl preferably has from about 5 to about 6 ring atoms of which from 0 to 2, more preferably 0 or 1, are heteroatoms.
• R6 and R7 Preferred rings formed by R6 and R7 include phenyl, furyl, pyrrolyl, dioxanyl, imidazoyl, pyridinyl, pyrrolidinyl, piperidinyl.
• R8 is preferably H.
• R9 is selected from hydrogen, halo, alkyl, aryl, heterocycle, carboxy and its alkyl esters and amides.
• Preferred R9 is selected from hydrogen, halo, C1 - C4 alkyl, phenyl. More preferred R9 is selected from hydrogen and unsubstituted and substituted phenyl; substituents on such phenyl are preferably selected from hydroxy, alkoxy, thio and alkylthio. Most preferred R9 is hydrogen.
• RIO and R12, and Rl 1 and R13 if they exist are each independently selected from hydrogen, alkyl and aryl.
• Preferred R10 and R12, and Rll and R13 if they exist are selected from hydrogen and alkyl having from 1 to about 4 carbon atoms, especially unsubstituted methyl or ethyl. Most preferred is for RIO and R12, and Rl 1 and R13 if they exist, to all be hydrogen.
• the subject invention includes optical isomers, diastereomers, and enantiomers of the compounds of structure I.
• the subject invention includes pharmaceutically-acceptable salts, hydrates, and biohydrolizable esters, amides and imides of such compounds.
• a “pharmaceutically-acceptable salt” is a cationic salt formed at any acidic group (e.g., carboxy group), or an anionic salt formed at any basic group (e.g., amino group) on a compound of structure 1.
• Preferred cationic salts include the alkali metal salts, such as sodium and potassium, alkaline earth metal salts, such as magnesium and calcium, and organic salts, such as ammonium.
• Preferred anionic salts include halides, sulfonates, carboxolates, phosphates, and the like. Salts of addition may provide an optical center where once there was none.
• the compounds of the subject invention, and salts thereof, may have one or more chiral centers.
• the invention includes all optical isomers of the compounds of structure 1 and salts thereof, including diastereomers and enanteomers
• the subject invention includes and contemplates each optical isomer, diastereomer or enanteomer thereof, in purified form, substantially purified form, and mixtures, including racemic mixtures.
• the ⁇ carbon is stereogenic.
• those having the R stereoscopic configuration are generally preferred over those having the S configuration.
• Preferred compounds of the subject invention include those having structure 2:
• Rl, R6, and R7 are as described hereinabove, and Y is the combinations of R3, R4 and R5 described hereinabove.
• Rl is preferably selected from linear alkanyl having from one to four carbon atoms, linear alkenyl having one double bond and from two to four carbon atoms, branched and cyclic alkanyl having from three to five carbon atoms, and branched and cyclic alkenyl having one double bond and from three to five carbon atoms.
• Such preferred Rl are unsubstituted or substituted with one phenyl, more preferably are unsubstituted.
• Rl is selected from methyl, ethyl, ethenyl, n-propyl, i-propyl, n-propenyl, i- propenyl, s-butyl, cyclopropyl, cyclobutyl, and cyclopentyl. More preferred still Rl is selected from methyl, ethyl, ethenyl, i-propyl, and n-propenyl. Most preferred Rl is methyl.
• R6 and R7 are preferably alkylthio or more preferably alkoxy with alkanyl having from one to four carbon atoms. If one of R6 and R7 is not alkylthio or alkoxy, it is preferably hydrogen. More preferred is both R6 and R7 being methoxy or ethoxy; most preferred is both R6 and R7 being methoxy.
• Y is preferably selected from all hydrogen; mono-, di-, or trihalo, preferably selected from fluoro, chloro and bromo, preferably in one or more of the 2', 3', 4' and 5' positions; mono- di-, and trimethyl, preferably in one or more of the 2', 3', 4' and 6' positions; and mono- or di-trifluoromethyl, preferably in one or both of the 3' and 5' positions.
• Y being diakylamino, preferably in the 4' position, the two alkyls preferably being the same and preferably having from 1 to 4 carbon atoms.
• More preferred Y is selected from 4'-fluoro, 4'-chloro, 4'-bromo, 2',4'-difluoro, 2',4'-dichloro, 2',4'-dibromo, 2',4',5'-trifluoro, 2',4',5'-trichloro, 3',4'-difluoro, 3',4'-dichloro, 3', 4'- dibromo, 4'-methyl, 2',4'-dimethyl, 2 ',4 ',6 '-trimethyl, 3 '-trifluoromethyl, 3',5'-di- trifluoromethyl, and 4'-dibutylamino.
• Y is selected from 2',4'-dihalo and 3',4'-dihalo, where one halo is selected from fluoro, chloro, and bromo, and the other halo is a different one of those three; more preferably one of such halo is fluoro. Most preferred Y is selected from 4'-cholor, 4'-bromo, and 2',4'-dichloro.
• Non-limiting examples of compounds of the subject invention include those of structure 2 wherein R6 and R7 are both methoxy, and Rl and Y are as indicated in the following table:
• the order of synthetic steps may be varied to increase yield of desired product.
• the skilled artisan will recognize that the judicious choice of reactants, solvents, and temperatures is important in successful synthesis.
• the starting materials used in preparing the subject compounds are known, made by known methods, or are commercially available.
• Benzyl-imine B Method 1: A mixture of compound A (808 mg, 3.3 mmol) and 4-F-benzaldehyde (10 mmol) in 35 mL of absolute EtOH is reflux ed for 14 h. (For substituted benzaldehydes that are not reactive enough, molecular sieves can be added to drive the reaction by removing H O.) Evaporation of the solvent and chromatography of the resultant residue provides purified imine B.
• Method 2 can be used to obtain good yield with benzaldehydes having variety of substituents of different electronic and steric properties. Method 1 often does not work well when the benzaldehydes have electron donating substituent groups.
• N-bromosuccinimide (NBS) solid (98 mg, 0.55 mmol) is added to a solution of compound B (0.5 mmol) in 15 mL of CCI4. Radical initiator benzoyl peroxide (2 mol%) is subsequently added. The flask is placed onto a 90°C oil bath. After 10 min stirring, TLC (CHCl3/MeOH 9:0.3) indicates the reaction is complete. Filtration of the mixture through a celite pad, and evaporation of the filtrate gives a residue. Purification by chromatography affords purified product D.
• the filtrate is concentrated on a high vacuum rotovapor apparatus.
• the residual is partitioned in 1:1 CH 2 Cl 2 /brine, extracted with CH 2 C1 2 , dried over Na SO4, and filtered over Na 2 SO4.
• the filtrate is concentrated in vacuo to yield crude product, and chromatography (silica gel) with 2.5:7.5 ethyl acetate/hexane yields F as an orange solid.
• the aqueous layer is extracted- with CH 2 C1 2 .
• the extracts are washed with 5% aqueous NaHCO3 and brine, and are dried over Na 2 SO4.
• the crude residue after evaporation is purified by chromatography to provide product G.
• compositions of the invention comprises: a) a safe and effective amount of a compound of the invention; and b) a pharmaceutically-acceptable excipient.
• a composition of the subject invention comprises several excipients. It may also optionally comprise other active compounds which do not substantially interfere with the activity of the subject invention compound.
• compositions of the subject invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical or parenteral administration.
• Compositions of the subject invention are preferably provided in unit dosage form.
• a "unit dosage form” is a composition containing an amount of a subject compound that is suitable for administration to a human or lower animal subject, in a single dose, according to good medical practice.
• a "safe and effective amount" of a subject compound is an amount large enough to significantly induce a positive modification in the symptoms and/or condition to be treated in a host, but small enough to avoid serious adverse side effects in the host (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio.
• the safe and effective amount will vary with such factors as the particular condition being treated, the age and physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, and the dosage regimen employed.
• pharmaceutically-acceptable excipient includes physiologically inert, pharmacologically inactive substances which are compatible with the physical and chemical characteristics of the subject invention compound used, and which are of sufficiently high purity and sufficiently low toxicity to be suitable for administration to a human or lower animal.
• compatible means that the excipients of the subject composition are capable of being commingled with the subject invention compound, and with each other in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the compound, under ordinary use situations.
• Excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, and dyes or pigments.
• the amount of excipients employed in conjunction with the subject compound is sufficient to provide a practical quantity of material for administration per unit dose of the subject compound.
• substances which can serve as pharinaceutically-acceptable excipients are sugars, such as lactose, dextrose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylcellulose and cellulose acetate; polymers, such as povidone and carbomers; powdered tragacanth; gums, such as xanthan, guar and acacia; malt; solid lubricants, such as stearic acid, magnesium stearate, and talc; inorganic fillers, such as calcium phosphates and calcium sulfate; disintigrants, such as sodium starch glycolate, crospovidone, croscarmelose sodium, and microcrystalline cellulose; encapsulating and coating materials, such as gelatins, waxes, and cellulose derivatives; vegetable oils, such as peanut oil, cottonseed oil,
• compositions of the subject invention are oral dosage forms.
• oral dosage form means any pharmaceutical composition intended to be systemically administered to an individual by delivering the composition via the mouth to the gastrointestinal tract of an individual.
• oral unit dosage forms such as tablets, coated or non-coated, and capsules, hard or soft gel.
• Subject oral unit dosage form compositions comprise preferably at least about 4 mg, more preferably at least about 20 mg, more preferably still at least about 100 mg, and preferably at most about 1000 mg, more preferably at most about 500 mg, more preferably still at most about 250 mg, of a subject compound.
• Subject oral dosage form compositions comprise preferably at least about 1%, more preferably at least about 10%, and preferably at most about 70%, more preferably at most about 40%, of a subject compound; and comprise preferably at least about 30%, more preferably at least about 60%, and preferably at most about 99%, more preferably at most about 90%, pharmaceutically-acceptable excipients.
• Parenteral dosage forms are also preferred subject invention compositions.
• parenteral dosage form means any pharmaceutical composition intended to be systemically administered to a human or lower animal via delivery of a solution or emulsion containing the active ingredient, by puncturing the skin of the individual, in order to deliver the solution or emulsion to the circulatory system of the individual either by intravenous, intramuscular, intraperitoneal or subcutaneous injection.
• Subject parenteral unit dosage form compositions comprise preferably at least about 1 mg, more preferably at least about 6 mg, more preferably still at least about 30 mg, and preferably at most about 400 mg, more preferably at most about 100 mg, more preferably still at most about 40 mg, of a subject compound.
• Subject parenteral dosage form compositions comprise preferably at least about 1%, more preferably at least about 5%, and preferably at most about 20%, more preferably at most about 10%, of a subject compound; and comprises preferably at least about 80%, more preferably at least about 90%, and preferably at most about 99%, more preferably at most about 95%, pharmaceutically-acceptable excipients.
• dosages for injection may be prepared in dried or lyophilized form. Such forms can be reconstituted with water, saline solution, or a buffer solution, depending on the preparation of the dosage form. Such forms may be packaged as individual dosages or multiple dosages for easier handling. Where lyophilized or dried dosages are used, the reconstituted dosage form is preferably isotonic, and at a physiologically compatible pH, and comprises the subject compound and excipients in the amounts and percentages indicated previously in this paragraph.
• Subject invention compounds have demonstrated pharmacological activity in processes known to be associated with one or more of cardiovascular activity, inflammatory mechanisms, oncology, and regulation of protein transport from cells.
• the subject invention includes methods of using the above compounds of the subject invention for therapeutic or preventative treatment of one or more of the following diseases or disorders: congestive heart failure, arrhythmia, hypotension, cardiac reperfusion injury, arteriosclerosis, restenosis, vascular tone, bacterial infection, cancer, Kaposi's sarcoma, psoriasis, migraine, nasal congestion, allergic responses, rheumatoid arthritis, and osteoporosis.
• Such methods comprise administering to a human or lower animal in need of such treatment or prevention a safe and effective amount of a subject invention compound.
• a subject invention compound preferably at least about 0.1 mg/kg, more preferably at least about 0.5 mg/kg, more preferably still at least about 2 mg/kg, and preferably at most" about 20 mg/kg, more preferably at most about 5 mg/kg, more preferably still at most about 2 mg/kg, of a subject compound is administered to a human or lower animal, preferably at least about 1 time, more preferably at least about 2 times, and preferably at most about 4 times, more preferably at most about 2 times, daily.
• Treatment duration using such oral daily dosages is dependent on the disease or disorder being treated; it is preferably at least about 1 day, more preferably at least about 3 days, more preferably still at least 7 days, and preferably at most about 5 years, more preferably at most about 60 days, more preferably still at most about 15 days.
• a subject compound is administered to a human or lower animal, preferably at least about 1 time, more preferably at least about 2 times, and preferably at most about 4 times, more preferably at most about 2 times, daily.
• Treatment duration using such parenteral daily dosages is dependent on the disease or disorder being treated; it is preferably at least about 1 day, more preferably at least about 3 days, more preferably still at least 7 days, and preferably at most about 60 days, more preferably at most about 20 days, more preferably still at most about 5 days.

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• 1999
  • 1999-10-06 EP EP99950181A patent/EP1121359A1/en not_active Withdrawn
  • 1999-10-06 JP JP2000575867A patent/JP2002527440A/ja not_active Withdrawn
  • 1999-10-06 IL IL14227899A patent/IL142278A0/xx unknown
  • 1999-10-06 AU AU62893/99A patent/AU748699B2/en not_active Ceased
  • 1999-10-06 WO PCT/US1999/023152 patent/WO2000021961A1/en active IP Right Grant
  • 1999-10-06 CA CA002346414A patent/CA2346414A1/en not_active Abandoned
• 2001
  • 2001-04-11 NO NO20011859A patent/NO20011859L/no not_active Application Discontinuation

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