Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • 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
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/04—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to N-substituted cyclic aza compounds, pharmaceutical compositions comprising such compounds, and methods of their use for effecting neuronal activities .
• binding of the drugs to the immunophilins results in the formation of "activated complexes", which interact with downstream proteins to inhibit proliferation of T-lymphocytes .
• Schreiber, supra Rosen, et al . , supra .
• binding to FKBP results in a drug- protein complex which is a potent inhibitor of the calcium- calmodulin-dependent protein phosphatase, calcineurin.
• Analogues of FK506, rapamycin, and cyclosporin which bind to their respective immunophilins, but are devoid of immunosuppressive activity are known in the art.
• the FK506 analogue L-685,818 binds to FKBP but does not interact with calcineurin, and is therefore nonimmunosuppressive .
• Armistead et al also described several pipecolate FKBP12 inhibitors. X-ray structures of the complexes of these molecules with FKBP also demonstrated that the binding modes of these simple structures were related to that of FK506. Armistead, D.M., Badia, M.C., Deininger, D.D., Duffy, J.P., Saunders, J.O., Tung, R.D., Thomson, J.A. ; DeCenzo, M.T.; Futer, 0., Livingston, D.J., Murcko, M.A., Yamashita, M.M., Navia, M.A., Acta Crys t . (1995) D51:522-528.
• FKBP12 ligands lacking an effector element were inactive as immunosuppressant agents, failing to suppress lymphocyte proliferation both in vi tro and in vivo .
• FKBP12 ligands resulted in reduction in the decrease of axon number (25% and 5% reduction, respectively, compared to controls) and in the reduction of myelination levels (65% and 50% decrease compared to controls) . Similar results were subsequently reported by Gold et al . Gold, B.G., Zeleney-Pooley, M., Wang, M.S., Chaturvedi , P.; Armistead, D.M., Exp . Neurobiol . (1997) 147:269-278.
• Parkinson's Disease is a serious neurodegenerative disorder resulting from degeneration of this motor pathway. Lesioning of the nigral-striatal pathway in animals with
• MPTP showed a striking recovery of TH-stained striatal dopaminergic terminals, as compared with controls, suggesting that FKBP12 ligands may possess potent neuroprotective and neuro-regenerative effects on both peripheral as well as central neurons.
• FKBP12 ligands are not limited to dopaminergic neurons in the central nervous system.
• PCA para-chloro-amphetamine
• Subcutaneous administration of the FBKP12 ligand produced a four- fold sprouting of spared residual processes in the CAl, CA3 and dentate gyrus regions of the hippocampus, resulting in significant recovery of cholinergic innervation in all three regions as quantitated by choline acetyltransferase (ChAT) density.
• the ultimate mechanism of action and whether or not such compounds also possess other activity such as, for example, immunosuppressive activity, is not determinative of whether the compound is neurotrophic, promotes hair growth, regenerates vision, or improves memory for purposes of the invention, as long as the compound in question possesses the desired effect on nerve cells, hair follicles, eye tissues, or brain cells.
• immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity.
• immunosuppressants exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis (Kopp et al . , 1991, J " . Am. Soc . Nephrol . 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina such as non-localized headaches (De Groen et al . , 1987, N. Engl . J. Med. 317:861); and vascular hypertension with complications resulting therefrom (Kahan et al . , 1989 N. Engl . J. Med . 321 : 1725 ) .
• the present invention further relates to pharmaceutical compositions comprising such compounds in combination with a pharmaceutically acceptable carrier.
• the present invention also relates to methods of using such compounds to effect neuronal activity.
• Alkyl refers to a branched or unbranched saturated hydrocarbon chain comprising a designated number of carbon atoms.
• Ci-C 8 alkyl is a straight or branched hydrocarbon chain containing 1 to 9 carbon atoms, and includes but is not limited to substituents such as methyl, ethyl, propyl , iso-propyl, butyl, iso-butyl, tert-butyl, n- pentyl , n-hexyl, and the like, unless otherwise indicated.
• alkenyl refers to a branched or unbranched unsaturated hydrocarbon chain comprising a designated number of carbon atoms.
• C 2 -C 9 alkenyl is a straight or branched hydrocarbon chain containing 2 to 9 carbon atoms having at least one double bond, and includes but is not limited to substituents such as ethenyl, propenyl, iso-propenyl , butenyl , iso-butenyl, tert-butenyl , n-pentenyl, n-hexenyl, and the like, unless otherwise indicated.
• Alkoxy refers to the group -OR wherein R is alkyl as herein defined.
• R is a branched or unbranched saturated hydrocarbon chain containing 1 to 9 carbon atoms.
• Examples include cyclopropanyl , cyclobutyl, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene, cycloctene, benzene, naphthalene, anthracene, phenanthracene , biphenyl and pyrene .
• Heterocycle refers to a cyclic moiety having one or more closed rings that is/are alicyclic, aromatic, fused and/or bridged, with one or more heteroatoms (for example, sulfur, nitrogen or oxygen) in at least one of the rings.
• heteroatoms for example, sulfur, nitrogen or oxygen
• examples include, without limitation, pyrrolidine, pyrrole, thiazole, thiophene, piperidine, pyridine, isoxazolidine and isoxazole.
• Derivative refers to a substance produced from another substance either directly or by modification or partial substitution.
• Bioisosteres are isosteres which, in addition to their physical similarities, share some common biological properties. Typically, bioisosteres interact with the same recognition site or produce broadly similar biological effects .
• Carboxylic acid isosteres include without limitation direct derivatives such as hydroxamic acids, acyl- cyanamides and acylsulfonamides ; planar acidic heterocycles such as tetrazoles, mercaptoazoles , sulfinylazoles, s u 1 f ony 1 a z o 1 e s , isoxazoles, i s o t h i a z o 1 e s , hydroxythiadiazoles and hydroxychromes ; and nonplanar sulfur- or phosphorus-derived acidic functions such as phosphinates , phosphonates, phosphonamides, sulphonates, sulphonamides , and acylsulphonamides .
• Low molecular weight, small molecule compounds include, without limitation, molecules which are smaller in size, molecular weight, or both in relation to the compounds Rapamycin, Cyclosporin, and FK506.
• such compounds Preferably, such compounds have a molecular weight no more than about 800 daltons; more preferably, no more than about 650 daltons; and most preferably, no more than about 500 daltons .
• “Pharmaceutically acceptable carrier” refers to any carrier, diluent, excipient, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant , absorbent, preservative, surfactant, colorant, flavorant, or sweetener.
• the compounds of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal , and intracranial injection or infusion techniques.
• Enantiomers refer to a pair of stereoisomers that are non-superimposable mirror images of each other.
• R or “R m " , where m is an integer, designate various substituents.
• Each R group is independently selected at each instance it appears in a molecule.
• " - ( ⁇ - 3 ) 2 denotes two R 3 substituents, wherein each of said R 3 substituents may differ from the other; thus, R 3 may be a branched alkyl in one instance, and an aryl substituted with one or more substituents in the second instance.
• Alopecia refers to deficient hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness) , toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania.
• Alopecia results when the pilar cycle is disturbed. The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out.
• Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs.
• “Animal” refers to a living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Examples include, without limitation, an animal such as a member of the human, equine, porcine, bovine, murine, canine, or feline species. A preferred animal is mammal. In the case of a human, an "animal” may also be referred to as a "patient”.
• Disease refers to any deviation from or interruption of the normal structure or function of any part, organ, or system (or combinations) of the body that is manifested by a characteristic set of symptoms and signs and whose etiology, pathology, and prognosis may be known or unknown. Dorland' s Illustrated Medical Dictionary, (W.B.
• Memory impairment refers to a diminished mental registration, retention or recall of past experiences, knowledge, ideas, sensations, thoughts or impressions. Memory impairment may affect short and long-term information retention, facility with spatial relationships, memory (rehearsal) strategies, and verbal retrieval and production. Common causes of memory impairment are age, severe head trauma, brain anoxia or ischemia, alcoholic- nutritional diseases, drug intoxications and neurodegenerative diseases. For example, memory impairment is a common feature of neurodegenerative diseases such as Alzheimer's disease and senile dementia of the Alzheimer type.
• Memory impairment also occurs with other kinds of dementia such as multi-infarct dementia, a senile dementia caused by cerebrovascular deficiency, and the Lewy-body variant of Alzheimer' s disease with or without association with Parkinson's disease.
• Creutzfeldt-Jakob disease is a rare dementia with which memory impairment is associated. It is a spongiform encephalopathy caused by the prion protein; it may be transmitted from other sufferers or may arise from gene mutations. Loss of memory is also a common feature of brain-damaged patients.
• Neopsic factors refers to compounds useful in treating vision loss, preventing vision degeneration, or promoting vision regeneration.
• Neurotrophic includes without limitation the ability to stimulate neuronal regeneration or growth, and/or the ability to prevent or treat neurodegeneration.
• neurotrophic compounds exhibit an MPTP Assay value which is greater than about 20% recovery of TH-stained dopaminergic neurons; more preferably, greater than about 35% recovery of TH-stained dopaminergic neurons; most preferably, greater than about 50% recovery of TH-stained dopaminergic neurons .
• Palm cycle refers to the life cycle of hair follicles, and includes three phases:
• “Promoting hair growth” refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair.
• “Promoting vision regeneration” refers to maintaining, improving, stimulating or accelerating recovery of, or revitalizing one or more components of the visual system in a manner which improves or enhances vision, either in the presence or absence of any ophthalmologic disorder, disease, or injury.
• Treating alopecia refers to:
• Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis.
• Vellus hair is fine, thin, non- pigmented short hair in which the hair bulb is located superficially in the dermis. As alopecia progresses, the hairs change from the terminal to the vellus type.
• “Treating memory impairment” refers to: (i) preventing memory impairment from occurring in an animal which may be predisposed to memory impairment but has not yet been diagnosed as having it;
• “Enhancing memory performance” refers to improving or increasing the mental faculty by which to register, retain or recall past experiences, knowledge, ideas, sensations, thoughts or impressions.
• Vision refers to the ability of humans and other animals to process images.
• Vision disorder refers to any disorder that affects or involves vision, including without limitation visual impairment, orbital disorders, disorders of the lacrimal apparatus, disorders of the eyelids, disorders of the conjunctiva, disorders of the cornea, cataracts, disorders of the uveal tract , disorders of the optic nerve or visual pathways, free radical induced eye disorders and diseases, immunologically-mediated eye disorders and diseases, eye injuries, and symptoms and complications of eye disease, eye disorder, or eye injury.
• Visual impairment refers to any dysfunction in vision including, without limitation, disturbances or diminution in vision (e.g., binocular, central, peripheral, scotopic) , visual acuity for objects near and for, visual field, ocular motility, color perception, adaptation to light and dark, accommodation, refraction, and lacrimation. See Physicians ' Desk Reference (PDR) for Ophthalmology, 16th Edi tion, 6:47 (1988) .
• PDR Physicians ' Desk Reference
• the present invention relates to an N-substituted cyclic aza compound.
• the compound may be polycyclic.
• the compound is low molecular weight, small molecule, neurotrophic and/or N,N' -disubstituted.
• the compound is nonimmunosuppressive, or otherwise does not exert any significant immunosuppressive activity.
• the compound has an affinity for (for example, binds to or otherwise interacts with) FKBP-type immunophilins, such as FKBP12; such binding or interaction may inhibit the prolyl-peptidyl cis- trans isomerase, or rotamase, activity of the binding protein.
• n 1 -3 ;
• R 2 and R 3 are independently hydrogen, alkyl, C 2 -C 9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle, wherein said alkyl, alkenyl, aryl heteroaryl, carbocycle or heterocycle is unsubstituted or substituted with one or more substituent (s) ; and X is O or S.
• R 3 may differ at each instance it appears in a molecule .
• the compound is an N-sulfonyl cyclic aza derivative compound having an affinity for an
• FKBP-type immunophilin or a pharmaceutically acceptable salt, ester or solvate thereof.
• the compound has a structure of formula II
• n is 1-3;
• R- L is -CR 3 , -COOR 3 , -COR 3 or a carboxylic acid isostere, wherein said carboxylic acid isostere is unsubstituted or substituted with one or more substituent (s) , wherein R x is preferably not -CON(R 3 ) 2 ; and R 2 and R 3 are independently hydrogen, alkyl, C 2 -C 9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle, wherein said alkyl, alkenyl, aryl heteroaryl, carbocycle or heterocycle is unsubstituted or substituted with one or more substituent (s) .
• the compound is tertiary N- aminocarbonyl cyclic aza compound having an affinity for an FKBP-type immunophilin.
• the tertiary N- aminocarbonyl cyclic aza compound has a structure of formula III
• n is l-3;
• R- L is -CR 3 , -COOR 3 , -COR 3 or a carboxylic acid isostere, wherein said carboxylic acid isostere is unsubstituted or substituted with one or more substituent (s) ;
• R and R 2 are independently C- ⁇ Cg alkyl, C 2 -C 9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle, wherein said alkyl, alkenyl, aryl heteroaryl, carbocycle or heterocycle is unsubstituted or substituted with one or more substituent (s) ,* and
• R 3 is hydrogen alkyl, C 2 -C 9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle, wherein said alkyl, alkenyl, aryl heteroaryl, carbocycle or heterocycle is unsubstituted or substituted with one or more substituent (s) .
• the compound is a secondary N- aminocarbonyl cyclic aza compound having an affinity to FKBP-type immunophilins.
• the secondary N- aminocarbonyl cyclic aza compound has a structure of formula IV
• R 3 is hydrogen, C x -C 9 alkyl, C 2 -C 9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle, wherein said alkyl, alkenyl, aryl heteroaryl, carbocycle or heterocycle is unsubstituted or substituted with one or more substituent (s) .
• the carboxylic acid isostere is -COOH, - COSR 3 , -CSSR 3 , -CSOR 3 , -S0 3 H, -S0 2 HNR 3 , -CN, -P0 2 (R 3 ) 2 , - P0 3 (R 3 ) 2 , -0R 3 , -SR 3 , -NHCOR 3 , -N(R 3 ) 2 , -CON(R 3 ) 2 , -CSN(R 3 ) 2 , - CONH(0)R 3 , -CONHNHS0 2 R 3 , -COHNS0 2 R 3 , -CONR 3 CN, or any of the following structures:
• any of said ring structures may be optionally substituted at one or more position (s) with one or more substituent (s) .
• Possible substituents of said alkyl, alkenyl, aryl, heteroaryl, carbocycle and heterocycle include, without limitation, C x -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C x -C 9 alkoxy, C 2 -C 9 alkenyloxy, phenoxy, benzyloxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl , hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, nitroso, nitrilo, isonitrilo, imino, azo, diazo, sulfonyl, sulfoxy, thio, thiocarbonyl , thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoro
• the compounds of this invention possess at least one asymmetric center and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers .
• the individual enantiomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving a compound of the present invention. It is understood that the individual R- and S- stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers are encompassed by this invention.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising:
• the compound is present in an effective amount for effecting a neuronal activity.
• the present invention further relates to a method for effecting a neuronal activity in a mammal, comprising administering to said mammal an effective amount of a compound of the present invention, as defined above.
• the neuronal activity that is effected by the inventive method may be selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of a neurological disorder.
• neurological disorders examples include without limitation: trigeminal neuralgia; glossopharyngeal neuralgia; Bell's Palsy; myasthenia gravis; muscular dystrophy; amyotrophic lateral sclerosis; progressive muscular atrophy; progressive bulbar inherited muscular atrophy; herniated, ruptured or prolapsed invertebrate disk syndromes; cervical spondylosis; plexus disorders; thoracic outlet destruction syndromes; peripheral neuropathies such as those caused by lead, dapsone, ticks, porphyria, or Guillain-Barre syndrome; Alzheimer's disease; Huntington's disease; and Parkinson's disease.
• the inventive method is particularly useful for treating a neurological disorder selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to spinal cord, stroke associated with brain damage, demyelinating disease and neurological disorder relating to neurodegeneratio .
• the present invention further relates to a method for treating alopecia in a mammal, comprising administering to the mammal an effective amount of a compound of the present invention, as defined above.
• the present invention further relates to a method for treating a vision disorder, promoting vision regeneration or improving vision in a mammal, comprising administering to the mammal an effective amount of a compound of the present invention, as defined above.
• the present further relates to a method for treating memory impairment or enhancing memory performance in a mammal, comprising administering to the mammal an effective amount of a compound of the present invention, as defined above .
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal , intracranial , intracerebral , intraosseous, infusion, transdermal, transpulmonary routes.
• the compounds should readily penetrate the blood-brain barrier when peripherally administered. Compounds which cannot penetrate the blood-brain barrier can be effectively administered by an intraventricular route .
• the compounds and compositions of the present invention may be administered by a single dose, multiple discrete doses or continuous infusion.
• the compounds are well suited to continuous infusion.
• Pump means, particularly subcutaneous pump means, are preferred for continuous infusion. Dose levels on the order of about 0.1 mg to about
• 10,000 mg of the active ingredient compound, but less than 40 mg/kg where the compound is Suramin, are useful in the treatment of the above conditions, with preferred levels being about 0.1 mg to about 1,000 mg.
• the specific dose level for any particular patient will vary depending upon a variety of factors, including the activity and the possible toxicity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration.
• vi tro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful .
• the considerations for determining the proper dose levels are well known in the art .
• any administration regimen well known to an ordinarily skilled artisan for regulating the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment .
• Such regimen may include pretreatment and/or co-administration with additional therapeutic agents.
• compositions of the present invention may be used alone or in combination with one or more additional agent (s) for simultaneous, separate or sequential use.
• the additional agent (s) may be any therapeutic agent (s) known to an ordinarily skilled artisan, including without limitation: one or more compound (s) of the present invention; and one or more neurotrophic factor (s) selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neutrophic factor, insulin growth factor, acidic fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factor, neurotropin-3 , neurotropin- 4 and neurotropin-5 ; one or more neopsic factors.
• EXAMPLE 12 K. Test Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of the inventive compounds can be evaluated by known methods described in the literature (Harding et al . , Na ture, 1989, 341:758-760; Holt et al . J " . Am. Chem . Soc , 115:9923-9938) . These values are obtained as apparent Ki's and are presented for representative compounds in Table IV.
• the cis- trans isomerization of an alanine-proline bond in a model substrate, ⁇ -succinyl-Ala-Ala-Pro-Phe-p- nitroanilide is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para- nitroanilide from the trans form of the substrate.
• the inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent K t values .
• a plastic cuvette In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM ⁇ aCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM ⁇ aCl, 1 mM dithiothreitol) , 25 mL of chymotrypsin (50 mg/ml in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide.
• the reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe- para-nitroanilide, 5 mg/mL in 2.35 mM LiCl in trifluoroethanol) .
• the neurotrophic and neuroregenerative effects of the inventive compounds were demonstrated in an animal model of neurodegenerative disease.
• MPTP lesioning of dopaminergic neurons in mice was used as an animal model of Parkinson's Disease.
• Four week old male CD1 white mice were dosed i.p. with 30 mg/kg of MPTP for 5 days.
• Test compounds (4 or 10 mg/kg) or vehicle, were administered s.c. along with the MPTP for 5 days, as well as for an additional 5 days following cessation of MPTP treatment .
• the animals were sacrificed and the striata were dissected and homogenized.
• a patient is suffering from a disease, disorder or condition described above.
• the patient may then be administered an effective amount of a compound of the present invention. It is expected that after such treatment, the patient would not suffer any significant injury due to, would be protected from further injury due to, or would recover from the disease, disorder or condition.

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  • 2000-08-28 WO PCT/US2000/023603 patent/WO2001036388A1/en not_active Ceased
  • 2000-08-28 HK HK03100396.7A patent/HK1048312A1/zh unknown

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