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EP1001762A1 - Methode d'utilisation de carbamates et d'urees neurotrophiques - Google Patents

Methode d'utilisation de carbamates et d'urees neurotrophiques

Info

Publication number
EP1001762A1
EP1001762A1 EP98906647A EP98906647A EP1001762A1 EP 1001762 A1 EP1001762 A1 EP 1001762A1 EP 98906647 A EP98906647 A EP 98906647A EP 98906647 A EP98906647 A EP 98906647A EP 1001762 A1 EP1001762 A1 EP 1001762A1
Authority
EP
European Patent Office
Prior art keywords
straight
group
branched alkyl
neurological disorder
neurodegeneration
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98906647A
Other languages
German (de)
English (en)
Other versions
EP1001762A4 (fr
Inventor
Jia-He Li
Gregory S. Hamilton
Joseph P. Steiner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GPI Nil Holdings Inc
Eisai Corp of North America
Original Assignee
Guilford Pharmaceuticals Inc
GPI Nil Holdings Inc
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 Guilford Pharmaceuticals Inc, GPI Nil Holdings Inc filed Critical Guilford Pharmaceuticals Inc
Publication of EP1001762A1 publication Critical patent/EP1001762A1/fr
Publication of EP1001762A4 publication Critical patent/EP1001762A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a method of using neurotrophic low molecular weight, small molecule carbamates and ureas having an affinity for FKBP-tyne immunophilins, as inhibitors of the enzyme activity- associated with immunophilin proteins., particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
  • immunophilin refers to a number of proteins that serve as receptors for the principal imiminosuppressant drugs, cyclosporin A (CsA) , FK506 and rapamycin.
  • CsA cyclosporin A
  • FKBPs FKBPs .
  • Cyclosporin A binds to cyclophilin A while FK506 and rapamycin bind to FKBP12.
  • Immunophilins are known to have peptidyl-prolyl isomerase (PPIase) , or rotamase, enzyme activity. It has been determined that rotamase enzyme activity plays a role in the catalyzation of the interc ⁇ nversi ⁇ n of the c ⁇ 3 and trans isomers of peptide and protein substrates or the immunophilin proteins .
  • PPIase peptidyl-prolyl isomerase
  • Immunophilins were originally discovered and stu io in the immune tissue. It was initially postulated bv those skilled in the art that inhibition of immunophilins' rotamase activity leads to inhibition of T-cell proliferation, thereby causing che immunosuppressive activity exhibited by immunosuppressant drugs, such as cyclosporin A, FX506 and rapamycin. Further study has shown that the inhibition , of rotamase activity, in and of itself, does not result in immunosuppressive activity. Schreiber et al., Science, 1990, vol. 250, pp. 55S-559. Instead, immunosuppressicn appears to stem from the formulation of a complex of immunosuppressant drug and immunophilin.
  • immunosuppressant drugs such as cyclosporin A, FX506 and rapamycin.
  • immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al . , Cell , 1991, vol. SS, pp. 807-815.
  • the immunophilin-drug complexes bind to the enzyme calcineurin and inhibit the T-ceil receptor signalling which leads to T-cell proliferation.
  • the immunophilin-drug complex of FK3P-rapamycin interacts with the RAFTl/FRAP protein and inhibits the IL-2 receptor signalling.
  • Immunophilins have been found to be present at high concentrations in the central nervous system. Immunophilins are enriched 10-50 times more in central nervous system than in the immune system. Withi neural tissues, immunophilins appear to influence nitric oxide synthesis, neurotransmitter release and neuronal process extension.
  • neur ⁇ degenerative disorders such as Alzheimer' s disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) may occur due to the loss, ⁇ r decreased availability, of a neur ⁇ trophic substance specific for a particular population of neurons affected in the disorder.
  • ALS amyotrophic lateral sclerosis
  • neurotrophic factors affecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer' s disease results from a decrease ⁇ r loss of nerve growth factor (NGF) . It has thus been proposed to treat SDAT patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain derived growth factor, glial derived growth factor, ciliary neurotrophic factor and neurotro in-3 , to increase the survival of degenerating neuronal populations .
  • NGF nerve growth factor
  • immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailabiiity and specificity.
  • immunosuppressant drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular . filtration and irreversible interstitial fibrosis (Kopp et al., J. Am. Soc. Nephral., 1991,
  • neurological deficits such as involuntary tremors, or non-specific cerebral angina, such as non- localized headaches (De Groen et al., N. ⁇ ngl. J. tied., 1987, 317:861) ; and vascular hypertension with complications resulting therefrom (Kahan et al., N. ⁇ ngl.
  • the present invention provides a method of using a non- immunosuppressive compound containing low molecular weight, small molecule carba ates and ureas to enhance neurite outgrowth, and to promote neuronal growth and regeneration in various neuropathol ⁇ gical situations where neuronal repair can be facilitated, including: peripheral nerve damage caused by physical injury or disease state such as diabetes ; physical damage to the central nervous system (spinal cord and brain) ; brain damage associated with stroke,- and neurological disorders relating to neurodegenerati ⁇ n, such as Parkinson's disease, SDAT (Alzheimer's disease) , and ayotrophic lateral sclerosis.
  • the present invention relates to a method of using a neur ⁇ trophic low molecular weight, small molecule carbamates and ureas having an affinity for FKBP-type immunophilins .
  • the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
  • a key feature of the neurotrophic compounds is that they do not exert any significant immunosuppressive activity.
  • the present invention relates to a method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotr ⁇ phically effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein : A is CH 2 , oxygen, NH or N-(C1-C 4 alkyl ) ; B and D are independently Ar, hydrogen, ( Cl-CS ) - straight or branched alkyl, (C2-CS) -straight or branched alkenyl or alkynyl, (C5-C7) -cycl ⁇ alkyl substituted ( C l - C 6) -straight or branched alkyl or (C3-C6 ) -straight or branched alkenyl or alkynyl, (C5-C7) -cycloalkenyl substituted ( Cl -CS ) -straight or branched alkyl or ( C3- C6) -straight or branched alkenyl
  • any one of the CH 2 groups of said alkyl chains may be optionally replaced by a heteroato selected from the group consisting of 0, S, SO, S0 2 , and NR, wherein R is selected from the group consisting of hydrogen, ( C1-C 4) - straight or branched alkyl, (C3-C4) -straight or branched alkenyl ⁇ r alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon acom 7 of said heteroat ⁇ m-containing chain to form a ring, and wherein said ring is optionally fused to an Ar 'group ;
  • J is selected from the group consisting of hydrogen, ( Cl-CS) -straight or branched alkyl, (C3-CS) -straight or branched alkenyl and -CH 2 Ar;
  • K is selected from the group consisting of (C1-C4) -straight or branched alkyl, -C.H j .Ar, and cyclohexylmethyl ; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of 0, s, SO and S0 2 ;
  • Z is 0 or S
  • Y is 0 or N, wherein when Y is 0, then j, is a lone pair and R 2 is selected from the group consisting of Ar, (Cl-CS) - straight or branched alkyl, and (C3-CS) -straight or branched alkenyl or alkynyl; and when Y is N, then Rj. and R 2 are independently selected from the group consisting of -Ar, (Cl-CS) - straight or branched alkyl, and (C3-C6) -straight or branched alkenyl or alkynyl; or Rj. and R 2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, i idazolidine, pyrazolidine, piperidine, and piperazine;
  • Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-na ⁇ hthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a 8 heterocyclic aromatic group selected from the grou t, consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxaz ⁇ lyl, thiazolyl, imidaz ⁇ lyl, pyrax ⁇ lyl, 2-pyrazolinyi, pyrazolidinyl , isoxazolyl, is ⁇ triazolyl, 1,2,3- oxadiazolyl, 1, 2, 3-triazolyl, 1,3 , 4-thiadiazolyi, pyridazinyl, pyrimidinyl, pyrazinyl,
  • Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, -S0 : H, trifluoromethyl, trifluoromethoxy, (Cl-CS) -straight or branched alkyl, (C2-CS) -straight or branched alkenyl, 0-
  • C (C1-C6) -straight ro branched alkyl] 0 [ (C3-C4) -.-traic t or branched alkenyl], O-benzyl, 0-phenyl., 1,1- methylenedioxy, -NR 3 R,, carboxyl, N- (C1-C5 -straight ⁇ r branched alkyl or C3-C5 -straight ⁇ r branched alkenyl) carboxamides, N,N-di- (C1-C5- straight or branched alkyl or
  • R j and R. are independently selected from the group consisting of ( Cl-CS ) -straight or branched alkyl, ( C3- CS ) -straight or branched alkenyl, hydrogen and benzyl ,-or
  • R and R, can be taken together to form a 5-6 membered heter ⁇ cylic ring;
  • X is selected from the group consisting of 4 - methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl , isoxazoyl, 2 - methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl; q is 0-2; and
  • ,n is 0 or l.
  • the present invention also relates to a method of effecting a neuronal activity in an animal, comprising : administering to the animal a neurotrophically effec t ive amount of a compound of formula II or III :
  • the present invention further relates to a method of effecting a neuronal activity in an animal, comprisinc : administering to the animal a neurotrophicaliy effective amount of a compound of formula III or IV :
  • Y, Rj. and R 2 are as defined in claim 1
  • Ar is as defined in claim 4
  • J is hydrogen, (Cl-CS) -straight or branched alkyl or (C3-CS) -straight or branched alkenyl
  • w is 1 or 2.
  • Alkyl means a branched or unbrancned saturated hydrocarbon chain containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, and the like, unless otherwise indicated.
  • Hydrocarbon means fluoro, chloro, bro o, or iodo, unless otherwise indicated.
  • “Pharmaceutically acceptable salt” refers to salts of the subject compounds which possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable.
  • the salts can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camp orsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate , ethanesulf ⁇ nate , fu arate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate, hydrochioride hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, ⁇ xalate, thio
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salt with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen- containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl , ⁇ lstyl ⁇ g chloride , bromide and iodides , aralkyl halides U ,.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl, lauryl , ⁇ lstyl ⁇ g chloride , bromid
  • benzyl and phenethyl bro ⁇ des and others , water or c ⁇ i - soluble or dispersible products are thereby obtained'" ⁇ P ⁇ yl.
  • Treatment covers any treatment of a d isease and/or condition in an animal, particularly a human, and includes :
  • This activity is useful in the stimulation of damaged neurons , the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathies .
  • the present invention relates to a method of effecting a neuronal activity in an animal , comprising: administering to the animal a neurotrophically effective amount of a compound of formula I :
  • A is CH 2 , oxygen, NH or N- (C1-C4 alkyl) ;
  • B and D are independently Ar, hydrogen, (Cl-CS) - straight or branched alkyl , (C2 -CS) -straight or branched alkenyl or alkynyl , (C5-C7) -cycloalkyl substituted (Cl- CS) -straight or branched alkyl ⁇ r (C3 -CS) -straight or branched alkenyl or alkynyl , (C5-C7) -cycloalkenyl substituted (Cl-CS) -straight or branched alkyl or (C3 - CS ) -straight or branched alkenyl or alkynyl, Ar- substituted ( Cl-CS ) -straight or branched alkyl, Ar- substituted (C3-CS ) -straight or branched alkyl, Ar- substitute
  • any one of the CH 2 groups of said alkyl chains may be optionally replaced by a heteroatom selected from the group consisting of 0, S, SO, S0 2 , and NR, wherein R is selected from the group consisting of hydrogen, ( C1-C4 ) - straight or branched alkyl, (C3-C4) -straight or branched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group ;
  • J is selected from the group consisting of hydrogen, ( Cl-CS ) -straight or branched alkyl, (C3-CS ) -straight ⁇ r branched alkenyl and -CH 2 Ar;
  • K is selected from the group consisting of ( C1-C4 ) -straight or branched alkyl, -CH 2 Ar, and cyclohexylmethyl ; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of 0, S, SO and S0 2 ;
  • Z is 0 or S
  • Y is 0 or N, wherein when Y is 0, then Rj. is a lone pair and R 2 is selected from the group consisting of Ar, ( Cl-CS ) - straight or branched alkyl, and (C3-CS ) -straight or 7882
  • R , _ and R 2 are independently selected from the group consisting of Ar, (Cl-CS ) - straight or branched alkyl, and (C3-CS) -straight or branched alkenyl or alkynyl; or Rj.
  • R 2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine
  • Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrax ⁇ lyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3- oxadiazolyl,
  • R 3 and R are independently selected from the group consisting of ( Cl-CS) -straight or branched alkyl, (C 3- CS) -straight or branched alkenyl, hydrogen and benzyl ; or R 3 and R, can be taken together to form a 5- 6 membered heter ⁇ cylic ring;
  • X is selected from the group consisting of 4 - methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3 , 5-dimethylisoxazoyl, isoxazoyl, 2- methylthiaz ⁇ yl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl; q is 0-2; and n is o or l. /37882
  • J and K are taken together to form a 5-7 membered ring.
  • At least one of B and D is independently represented by the formula - ( CH 2 ) r -(X) -(CH 2 ),-Ar, wherein: r is 1-4; S is 0-1;
  • Ar is as defined in claim 1; and each X is independently selected from the group consisting of CH 2 , 0, S, SO, S0 2 , and NR, wherein R is selected from the group consisting of hydrogen, (C1-C4)- straight ⁇ r branched alkyl, (C3-C4) -straight ⁇ r branched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen atom and the Ar group .
  • Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, is ⁇ ind ⁇ lyl, quinoiinyl, isoquin ⁇ linyl , 1,2,3, 4-tetrahydroisoquinolinyl, and 1,2,3, 4-tetrahydroquinolinyl, wherein said Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, hydroxyl, nitro, trifluoromethyl, (Cl-CS) -straight or branched alkyl, 0- C (Cl-CS) -straight or branched alkyl], halogen, S0 3 H, and NR 3 R 4 ; and *.
  • « ⁇ R. are independently selected from the -,» consisting of ⁇ C 1 -C S , -straight or branched alkyl; « ) -straigh t or branched alkenyl, hydrogen and benzyl - o- «. «d *. can be taken together heterocyclic ring .
  • the p resen t invention also relates t o a metho d 0 - effecting a neuronal activity in an animal, comprising - a d ministering to the animal a neurotrophically effective amoun t of a compound of formula II or m :
  • the present invention further relates to a method of effecting a neuronal activity in an animal, comprising : administering to the animal a neurotrophically effective amount of a compound of formula III or IV :
  • te is a . defined in claim , . , is hydrogen , (C1 _ M) .
  • the neuronal activity that is effected by the -thods of the present invention m y be selected from the sro p consisting of : stimulation of damaged neurons Promotion of neuronal regeneration, prevention of neurodegeneration an d treatment of a neurologica l d i sorder.
  • H a.ples of a neurological disorder that is "eatable by the methods of the present invention include «"hout limitation: Crig ⁇ ninal ⁇ ⁇ Slossopnaryngeal neuralgia,- BelLs Palsy,- asthenia *rv_s, ⁇ Bcul ⁇ r dystrophy; a yotrophic lateral sclerosxs,- progressive .uscular atrophy,- progressive fculbar inherited .u oular atrophy; hemiated, 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-Barr syndrome; Alzheimer's disease ; and Parkinson's disease.
  • the methods of the present invention are particularly useful for treating a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and a neurological disorder relating to neurodegenerati ⁇ n.
  • a neurological disorder relating to neurodegeneration include Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.
  • the neurotrophic compound 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 phar aceutically-acceptable carriers, ad j uvan t s and vehicles .
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneally, intrathecally, intraventricularly, intrasternal and intracranial injection ⁇ r infusion techniques . 98/37882
  • the neurotrophic 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 neurotrophic compounds may also be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or .oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparations may also be sterile injectable solutions or suspensions in non-t ⁇ xic parenterally-acceptable diluents or solvents, for example, as solutions in 1, 3-butanediol .
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as solvents or suspending mediums.
  • any bland fixed oil such as a synthetic mono- or di-glyceride may be employed.
  • Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their poly ⁇ xyethylated versions, are useful in the preparation of injectables.
  • These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersant s .
  • Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate.
  • Capsules may contain diluents including lactose and dried com starch.
  • Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient .
  • the oral dosage forms may further contain sweetening and/or flavoring and/or coloring agents .
  • the neurotrophic compounds may further be administered rectally in the form of suppositories .
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols .
  • the neurotrophic compounds may be administered topically, especially when the conditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin, ⁇ r the lower intestinal tract. Suitable topical formulations can be readily prepared for each of these areas . 7882
  • the compounds can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as a solution in isotonic, pH adjus t ed sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the compounds may be formulated into ointments, such as petrolatum, for ophthalmic use.
  • the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, p ⁇ lysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Topical application to the lower intestinal tract can be effected in a rectal suppository formulations (see above) ⁇ r in suitable enema formulations.
  • 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about _,000 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a specific dose level for any particular patient will ⁇ depend upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex, and diet of the patient ; the time . of administration ; the rate of excretion,- drug combination,- the severity of the particular disease being treated ; an d the form of administration.
  • the compounds can be administered with other neurotrophic agents such as neurotrophic growth factor ( N G F ) , glial derived growth factor, brain derived grow t h factor, ciliary neurotrophic factor, and neurotropin- 3 .
  • neurotrophic growth factor N G F
  • glial derived growth factor glial derived growth factor
  • brain derived grow t h factor brain derived grow t h factor
  • ciliary neurotrophic factor ciliary neurotrophic factor
  • neurotropin- 3 neurotropin- 3
  • the compounds used in the methods of the present invention may be readily prepared by standard techni ⁇ ues of organic chemistry, utilizing the general synthetic pathway depicted below.
  • cyclic amino acids 1 protected by suitable blocking groups P on the amino acid nitrogen may be reacted with alcohols ROE to generate esters 2.
  • the free amine 3 may be reacted with.a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively.
  • reaction of 1 with amines provides the corresponding amide compounds .
  • Isocyanates ( l NCO ) or isothiocyanates (R l NCS) 4 may be conveniently prepared from the corresponding readily 2S available amines by reaction with phosgene or thiophosgene, as depicted in Scheme II.
  • the reaction mixture was diluted with methylene chlor i de ( 5 0 m ) and water (l O O mL ) , and the layers were separated.
  • the organic phase was washed with water (3 x ⁇ oo ⁇ , dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting 8/37882
  • the carbamates and ureas used in the methods of the present invention have an affinity for the FK5Q6 binding protein, particularly FKBP12.
  • the inhibition of the prolyl peptidyl cis- trans isomerase activity of FKBP may be measured as an indicator of this affinity.
  • a plastic cuvette In a plastic cuvette are added 950.mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl) , 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol) , 25 mL of chymotrypsin (50 mg/ml in 1 mM
  • the absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.
  • the neurotrophic effects of the carbamates and ureas used in the methods of the present invention can be demonstrated in cellular biological experiments in vitro, as described below .
  • Dorsal root ganglia were dissected from chick embryos of ten day gestation . Whale ganglion explants were cultured on thin layer Matrigel -coated 12 well plates with Lieb ⁇ vitz L15 plus high . glucose media supplemented with 2 mM glutamine and 1 0% fetal calf serum, and also containing 10 ⁇ M cytosine ⁇ -D arabinofuranoside (Ara C) at 37°C in an environmen t containing 5% C0 2 . Twenty- four hours later, the D R G s were treated with various immunophilin ligands .
  • the ganglia w ere visualize d under phase contrast or Hoffman M o d ulation contrast with a Zeiss Axiovert inver t ed microscope .
  • P hotomicrographs of the explants were made , and neurite outgrowth was quant itated.
  • Neurites lon g er than t he D RG d iameter were counted as positive , with to t al number of neurites quantitated per each experimental condition.
  • T hree to four DRGs are cultured per well , an d each treatment was performed in duplicate .
  • the remarkable neurotrophic and neuroregenerative effects of the present inventive compounds were f urthe . ' demonstrated in an animal model of neurodegenerative disease , MPT lesioning of dopaminergic neurons in mice w s used as an animal model of Parkinson's Disease.
  • Four week old male CD1 white mice were dosed i.p. with 3Q g/kg of MPTP for 5 days.
  • Test compounds (4 mg/kg ) , or vehicle, were administered s.c. along with'-the MPTP for S days, as well as for an additional 5 days following cessation of MPTP treatment.
  • the animals were sacrificed and the striata were dissected and perfusion-fixed.

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Abstract

Selon cette invention, un ensemble de verrous orthodontiques à ligature autonome comprend un verrou comportant une fente transversale pour arc dentaire. Une première surface antérieure du verrou, orientée vers l'un des côtés de la fente, se termine sur l'un des côtés de la surface de la fente. Elle est exempte de toute protubérance antérieure, qui pourrait occulter l'orifice pour la fente de l'arc dentaire lors de l'installation ou du réglage du verrou. Une deuxième surface antérieure se termine sur l'autre côté de la surface de la fente. Un curseur de ligature est guidé à l'intérieur de deux glissières possédant des fentes de guidage orientées vers l'intérieur et disposées sur le deuxième côté de la fente pour arc dentaire. Le curseur de ligature peut être déplacé entre une position rentrée et une position en saillie au-dessus de la fente pour arc dentaire. Le curseur de ligature a une couleur différente de celle du verrou orthodontique. Plusieurs ergots, qui sont intégrés au curseur de ligature ou se trouvent à l'extérieur de celui-ci et sont enfoncés à l'intérieur du verrou orthodontique, sont utilisés pour bloquer le curseur dans la position désirée par rapport à la structure du verrou servant de support.
EP98906647A 1997-02-27 1998-02-26 Methode d'utilisation de carbamates et d'urees neurotrophiques Withdrawn EP1001762A4 (fr)

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US805646 1985-12-06
US80564697A 1997-02-27 1997-02-27
PCT/US1998/003485 WO1998037882A1 (fr) 1997-02-27 1998-02-26 Verrou orthodontique a ligature autonome

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US6218424B1 (en) * 1996-09-25 2001-04-17 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
US6242468B1 (en) * 1997-02-27 2001-06-05 Jia-He Li Carbamate and urea compositions and neurotrophic uses
HUP0200637A3 (en) 1998-07-17 2003-05-28 Agouron Pharmaceuticals Inc La Compounds, compositions, and their use for stimulating neuronal growth and elongation
US7338976B1 (en) * 1998-08-14 2008-03-04 Gpi Nil Holdings, Inc. Heterocyclic esters or amides for vision and memory disorders
US6395758B1 (en) * 1998-08-14 2002-05-28 Gpi Nil Holdings, Inc. Small molecule carbamates or ureas for vision and memory disorders
US6376517B1 (en) * 1998-08-14 2002-04-23 Gpi Nil Holdings, Inc. Pipecolic acid derivatives for vision and memory disorders
US6544976B1 (en) 1999-07-09 2003-04-08 Ortho-Mcneil Pharmaceutical, Inc. Neurotrophic 2-azetidinecarboxylic acid derivatives, and related compositions and methods
BR0012327A (pt) * 1999-07-09 2002-07-02 Ortho Mcneil Pharm Inc Pirrolidinas e piperidinas neurotróficas, e composições e métodos relacionados
AU5606400A (en) 1999-07-09 2001-01-30 Ortho-Mcneil Pharmaceutical, Inc. Neurotrophic tetrahydroisoquinolines and tetrahydrothienopyridines, and related compositions and methods
WO2001017953A1 (fr) * 1999-09-08 2001-03-15 Guilford Pharmaceuticals Inc. Composes non-peptidiques de liaison cyclophiline et leur utilisation
CO5261615A1 (es) 1999-12-01 2003-03-31 Agouron Pharma Compuestos, composiciones y metodos para estimular el crecimiento y elongacion de neuronas
AU2002225767A1 (en) * 2000-11-28 2002-06-11 Guilford Pharmaceuticals Inc. Bisubstituted carbocyclic cyclophilin binding compounds and theirus
JP2004532187A (ja) * 2001-01-25 2004-10-21 ギルフォード ファーマシュウティカルズ インコーポレイテッド 三置換カルボサイクリックサイクロフィリン結合化合物とその用途
EP1402888A1 (fr) * 2002-09-18 2004-03-31 Jerini AG Utilisation des composés carbocycliques substitués comme inhibiteurs de Rotamases

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US5620971A (en) * 1991-05-09 1997-04-15 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
US5744485A (en) * 1994-03-25 1998-04-28 Vertex Pharmaceuticals Incorporated Carbamates and ureas as modifiers of multi-drug resistance
US5859031A (en) * 1995-06-07 1999-01-12 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
US6037370A (en) * 1995-06-08 2000-03-14 Vertex Pharmaceuticals Incorporated Methods and compositions for stimulating neurite growth
US5780484A (en) * 1996-11-13 1998-07-14 Vertex Pharmaceuticals Incorporated Methods for stimulating neurite growth with piperidine compounds

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ZA98825B (en) 1998-10-19
PE46599A1 (es) 1999-05-12
WO1998037882A1 (fr) 1998-09-03
PA8447901A1 (es) 2000-05-24
AU6181698A (en) 1998-09-18
AR011869A1 (es) 2000-09-13
EP1001762A4 (fr) 2002-05-08
CA2281096A1 (fr) 1998-09-03

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