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WO1997014439A1 - Pharmaceutical composition containing a blood-brain barrier transport enhancer - Google Patents

Pharmaceutical composition containing a blood-brain barrier transport enhancer Download PDF

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Publication number
WO1997014439A1
WO1997014439A1 PCT/EP1996/004494 EP9604494W WO9714439A1 WO 1997014439 A1 WO1997014439 A1 WO 1997014439A1 EP 9604494 W EP9604494 W EP 9604494W WO 9714439 A1 WO9714439 A1 WO 9714439A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
raft
immunophilin
binds
calcineurin
Prior art date
Application number
PCT/EP1996/004494
Other languages
French (fr)
Inventor
Hendrikus Boddeke
Albert Enz
Esteban Pombo Villar
Original Assignee
Novartis Ag
Sandoz-Patent-Gmbh
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H
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.)
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Publication date
Application filed by Novartis Ag, Sandoz-Patent-Gmbh, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H filed Critical Novartis Ag
Priority to AU72938/96A priority Critical patent/AU7293896A/en
Publication of WO1997014439A1 publication Critical patent/WO1997014439A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to a novel means of therapy comprising co-administration of pharmaceutically active agents.
  • the invention more particularly relates to co-administration of (A) a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, and (B) a pharmaceutically acceptable blood-brain barrier transport enhancer.
  • Component (A) for use according to the invention may be any suitable component (A) for use according to the invention.
  • a calcineurin inhibitor which is either i) an immunophilin binding compound having calcineurin inhibiting activity, or ii) a non-immunophilin-binding calcineurin inhibitor; or
  • RAFT inhibitor which is either i) an immunophilin, particularly macrophilin binding compound having RAFT inhibiting activity, or ii) a non-immunophilin-binding RAFT inhibitor; or
  • an immunophilin binding compound particularly a non-immunosuppressive cyclophilin or macrophilin binding compound, which has no calcineurin or RAFT inhibiting activity.
  • Component (A) for use according to the invention is preferably a compound of class (a), i.e. a calcineurin inhibitor.
  • Calcineurin is a calcium/calmodulin-regulated protein phosphatase involved in intracellular signalling. It is a major soluble calmodulin-binding protein in brain extracts.
  • calcineurin see for example C. B. Klee et al., Calcineurin. Adv. Enzymol. 61 , 149 - 200 (1988) or Guerini et al., The biology and medicine of signal transduction, Raven Press ( 1990).
  • substrates which are specifically dephosphorylated by calcineurin in nervous tissue are DARPP-32 and GAP-43 [see for example Girault et al., Trends Neurosci. 13, 325 - 327 (1990) and Liu et al., J. Biol. Chem. 264, 12800 - 12804 (1989)].
  • Calcineurin inhibitors are substances which block calcineurin dephosphorylation e.g. of substrates as above.
  • the calcineurin inhibitor may be of group (i), i.e. immunophilin binding.
  • Immunophilin binding calcineurin inhibitors are compounds forming calcineurin inhibiting complexes with immunophilins, e.g. cyclophilin and macrophilin.
  • cyclophilin binding calcineurin inhibitors are cyclosporin derivatives and examples of macrophilin binding calcineurin inhibitors are ascomycins [see for example Liu et al., Cell 66, 807-815 (1991 )].
  • cyclosporins The class comprised by the cyclosporin derivatives (hereinafter cyclosporins) is known from the literature and consists in structurally distinct, cyclic, poly-N-methylated undecapeptides.
  • the first of the cyclosporins to be identified was the fungal metabolite Cyclosporin A, or Cyclosporin, and its structure is given in The Merck Index, 1 1th Edition; Merck & Co., Inc.; Rahway, New Jersey, USA (1989) under listing 2759.
  • cyclosporins to be identified include, for example, the naturally occurring cyclosporins B through Z [cf. Traber et al.; 1, Helv. Chim.
  • MeBmt residue 3'-O-atom of the N-methyl-(4R)-4-but-2E-en-l -yl-4-methyl-(L)-threonyl residue (MeBmt residue) is acylated or a further substituent is introduced at the ⁇ -carbon atom of the sarcosyl residue at the 3-position
  • cyclosporins in which the MeBmt residue is present in isomeric form e.g. in which the configuration across positions 6' and 7' of the MeBmt residue is cis rather than trans
  • variant amino acids are inco ⁇ orated at specific positions within the peptide sequence, e.g.
  • the class comprised by ascomycin derivatives is also known from the literature.
  • Ascomycin (FR 520) is a known macrolide antibiotic disclosed for example in US Patent No. 3,244,592 and in European Patent Publication No. 0 349 061. Ascomycin is obtainable by fermentation techniques employing, inter alia, actinomycetes of the genus Streptomycetes, e.g. S. hygroscopicus, or by total synthesis - see e.g. Yuki Gasei Kagaku Kyokaishi 50 (6), 522- 534.
  • ascomycin derivatives are known, which are either naturally occuring amongst fungal species or are obtainable by manipulation of fermentation procedures or by chemical derivatisation.
  • Such derivatives include notably the compound FK 506 (Tacrolimus), the structure of which correlates to that of ascomycin.
  • FK 506 is a macrolide immunosuppressant that is produced by Streptomyces tsukubaensis No 9993.
  • the structure of FK 506 is given in the appendix to the Merck Index, 1 1 h Ed., 1993, as item A5. Also a large number of related compounds which retain the basic structure and immunological properties of FK 506 are known.
  • the calcineurin inhibitor may also be of group (ii), i.e. non-immunophilin binding.
  • Calcineurin inhibitors which do not bind to immunophilins are also known from the literature and include okadaic acid [see for example S. Nishiwaki et al., Carcinogenesis ⁇ , No. 10, 1837 - 1841 (1990)], Microcystin LR [e.g. from C. Mc Kintosh et al., FEBS Letters 264, No. 2, 187 - 192 (1990)] and Nodularin [e.g. from K.C. Rinehart et al., J. Amer. Chem. Soc. 1 10. 8557 (1988)]. These compounds inhibit calcineurin at relatively high concentrations only. When component (A) is a calcineurin inhibitor, this is preferably an ascomycin.
  • Preferred ascomycins for use in accordance with the invention comprise the compound 33-epi- chloro-33-deoxyascomycin, disclosed as Example 66a in EP 427 680, 32-hydroxymethyI- cyclopentyl-ascomycin, disclosed as Example 1 in EP 465 426, the compounds of Example 23 and 24 of same EP 465 426, the compounds of Examples 8, 24 and 32 of EP 626 385 and the benzoyl -protected FK 506 of Example 7 of EP 1 4 162.
  • the most preferred compound is 33-epi-chloro-33-deoxy ascomycin.
  • Calcineurin inhibitors e.g. as aforesaid have been shown to increase basal neurotransmission of synaptic transmission in vitro. See for example R. M. Mulkey et al., Nature 369 (6480), 486-488 (1994) and M. Funauchi et al., Neurosci. Res. 19(3), 269-278 (1994).
  • calcineurin inhibitors such as cyclosporins or ascomycins have been found to have only limited CNS effects. Indeed the above in vitro findings could not be confirmed in vivo with calcineurin inhibitors administered at non-toxic doses or at doses which do not cause unacceptable immunosuppression.
  • Component (A) for use in accordance with the invention may also be a compound of class (b), i.e. a RAFT inhibitor.
  • RAFT Japanese and FKBP 12 target proteins
  • FRAP Rapamycin associated protein
  • inhibitors include compounds of class (i), e.g. macrophilin binding compounds, e.g. compounds forming complexes with immunophilins of the FKBP type.
  • immunophilin binding compounds having RAFT inhibiting activity are especially rapamycin and derivatives thereof.
  • Rapamycin is a macrolide immunosuppressant that is produced by Streptomyces hygroscopicus and which has been found to be pharmaceutically useful in a variety of applications, particularly as an immunosuppressant for use in the treatment and prevention of organ transplant rejection and autoimmune diseases.
  • the structure of rapamycin is given in Kesseler, H., et al. Helv. Chim. Acta; 76: 1 17 (1993).
  • rapamycin large numbers of derivatives of rapamycin (herein: collectively with rapamycin “raparnycins”) have been synthesized, including for example certain acyl and aminoacyl-rapamycins (e.g., US patent 4316885, US patent 4650803, and US patent 5151413), 27-desmethyl-ra ⁇ amycin (WO 92/147327), 26- dihydro-rapamycin (US patent 5138051 ), certain pyrazole derivatives (US patent 5164399), certain alkoxyester derivatives (US patent 5233036), and 40-O-alkylated derivatives (WO 94/09010), the specifically exemplified product compounds of said patents / patent applications being inco ⁇ orated by reference.
  • certain acyl and aminoacyl-rapamycins e.g., US patent 4316885, US patent 4650803, and US patent 515141
  • 27-desmethyl-ra ⁇ amycin WO 92/147327
  • Preferred RAFT inhibitors for use according to the invention include rapamycin and its 40-O- alkylated derivatives as disclosed in WO 94/09010. especially 40-O-(2-hydroxy)ethyl- rapamycin (compound of Example 8).
  • component (A) for use in accordance with the invention may be a compound of class (c), i.e. an immunophilin binding compound which has no calcineurin or RAFT inhibiting activity, preferably a non-immunosuppressive cyclophilin or macrophilin binding compound.
  • a compound of class (c) i.e. an immunophilin binding compound which has no calcineurin or RAFT inhibiting activity, preferably a non-immunosuppressive cyclophilin or macrophilin binding compound.
  • Component (B) for use according to the invention is a blood-brain barrier transport enhancer, i.e. a compound which facilitates the entry of certain molecules into the central nervous system.
  • a blood-brain barrier transport enhancer i.e. a compound which facilitates the entry of certain molecules into the central nervous system.
  • Such compounds are also known as blood-brain barrier openers.
  • Such compounds are for example multidrug resistance (MDR) reversing agents, such as agents which inhibit P-glycoprotein (Pgp) in the blood-brain barrier and thus facilitate the accumulation of various substances in the brain.
  • MDR multidrug resistance
  • Pgp P-glycoprotein
  • MDR reversing agents are suitably non-immunosuppressive, since peripheral immunosuppression is generally not desired in the treatment of diseases of the central nervous system.
  • substantially non-immunosuppressive, MDR reversing Pgp inhibiting substances are the compounds disclosed in European Patent No 296 122 and in European Patent Publication No 360 760, the specifically exemplified product compounds therein being inco ⁇ orated by reference.
  • Pgp inhibitors known from the literature include Verapamil [J. Zacheri et al., Cancer Chemother. Pharmacol. 34, 125(1994)], Quinidine [L. J. Goldstein, Curr. Probl. Cancer 19(2), 65-124 (1995)] and the compounds of WO 96/18643, particularly 2-nitrophenylcarbamoyl- [(S)-propyl]-[(S)-3-(2-naphthyl)alanyl]-N-benzyl-N-methyl-amide disclosed as Example 1.
  • Component (B) for use according to the invention is preferably a Pgp inhibitor.
  • Preferred Pgp inhibitors for use in accordance with the invention include [3'-desoxy-3'-oxo- MeB t] '-Ciclosporin, P'-desoxy-S'-oxo-MeBmtl'-tVal -Ciclosporin, [3'-desoxy-3'-oxo- MeBmt]'-[Nva] -Ciclosporin, disclosed in EP 296 122 as cyclosporins 1.37, 1.38 and 1.39 respectively (compounds of Example H), as well as Cyclo-[Pec-MeVal-Val-MeAsp( ⁇ -O-t-Bu)- MeIle-MeIle-Gly-MeVal-Tyr(Me)-L-lact] and Cyclo-[Pec-MeVal-Val-MeAsp-MeIle-Me-Ile- Gly-MeVal-Tyr(Me)-D-Lact], disclosed in EP 360
  • the most preferred compound is [3'-desoxy-3'-oxo-MeBmt] 2 -[Val] 2 -Ciclosporin A of formula
  • PSC 833 is known e.g. from EP 296 122 (example H) or P.R. Twentyman, Eur. J. Cancer 27(12), 1639-42 (1991 ) and has been shown to inhibit Pgp activity.
  • component (A) inhibitors increase basal neurotransmission, enhance long term potentiation of synaptic transmission (LTP) and suppress neuroinflammatory processes, such as observed after injection of bacterial toxins (LPS), in vivo at non-toxic doses, if they are co-administered with component (B).
  • LPS bacterial toxins
  • combination of the invention The effects of the combination of component (A) with component (B) (hereinafter referred to as combination of the invention) on hippocampal LTP are determined in vivo in rats according to the following procedure:
  • the electrodes are implanted in the hippocampus at the following coordinates (calculated from bregma) A:-0.4 to -0.6; L: 1.5 to 2.5 and V: -2.5 to -3.5 mm.
  • the depth of the recording electrode is used to optimize the recorded evoked potential.
  • the recording electrodes are connected to conventional WPI amplifiers and the responses are monitored on an AST R PC.
  • the compounds are applied intraperitoneally.
  • combinations of the invention enhance LTP when component (A) is administered at about 0.05 to about 10 mg/kg i.p. and component (B) is administered at doses of about 0.5 to about 15 mg/kg i.p.
  • Rats are injected with 5 mg/kg LPS (bacterial lipopolysaccharides), via the tail vein.
  • the animals show first a decrease followed by an increase in body temperature.
  • 8 h after application of LPS a significant increase in both mRNA and protein of the cytokines ILl b and TNFalpha are observed in brain slices of LPS-treated rats.
  • the compounds are applied intravenously.
  • combinations of the invention strongly reduce expression of ILlb mRNA and protein as well as TNFalpha mRNA and protein when component (A) is administered at about 0.1 to about 20 mg/kg i.v. and component (B) at doses of about 1 to about 25 mg/kg i.v.
  • Activities of PPI and PP2A are determined by addition of okadaic acid, a selective PPI and PP2A inhibitor.
  • the dephosphorylative activity that remains after addition of both inhibitors is ascribed to non-specific phosphatases, e.g. alkaline phosphatase.
  • combinations of the invention increase the inhibition of calcineurin when component (A) is administered at about 0.1 to about 20 mg/kg i.v. and component (B) at doses of about 1 to about 25 mg/kg i.v.
  • combinations of the invention are indicated to be beneficial in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
  • Neurodegenerative diseases include Parkinson's disease and primary degenerative dementia, e.g. senile dementia, particularly senile dementia of the Alzheimer type, as well as senile mental decline, e.g. senile cognitive decline, and confusional conditions in the elderly.
  • Inflammatory nervous injury may result for example from encephalitis, traumatic processes and the above-mentioned neurodegenerative diseases.
  • Conditions involving a component of cerebral ischemia include ischemic damage to grey and white matter, stroke, subarachnoid haemorrhage, brain and spinal cord injury and trauma, high intracranial pressure, multi-infarct or vascular dementia, and any surgical procedure potentially associated with cerebral ischemia.
  • Preferred conditions for treatment with the combination of the invention include Parkinson's disease, Alzheimer's disease and stroke.
  • Preferred combinations of the invention include any combination of (a) a compound chosen from the above-indicated preferred ascomycins for use in accordance with the invention and the above-indicated preferred RAFT inhibitors for use according to the invention, with (b) a compound chosen from the above-indicated preferred Pgp inhibitors for use in accordance with the invention, particularly any combination of a compound chosen from said preferred ascomycins and RAFT inhibitors with PSC 833.
  • the present invention provides a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, for use in the preparation of a pharmaceutical composition for administration in association with a pharmaceutically acceptable blood-brain barrier transport enhancer, for use in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
  • the present invention also provides a pharmaceutically acceptable blood-brain barrier transport enhancer, for use in the preparation of a pharmaceutical composition for administration in association with a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, for use in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
  • the present invention provides the use of a pharmaceutically acceptable blood-brain barrier transport enhancer in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, involving administration of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT.
  • the present invention also provides the use of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, involving administration of a pharmaceutically acceptable blood-brain barrier transport enhancer.
  • the present invention provides a method for treating neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT and a pharmaceutically acceptable blood-brain barrier transport enhancer.
  • the present invention provides a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT and a pharmaceutically acceptable blood-brain barrier transport enhancer as a combined pharmaceutical preparation.
  • Components (A) and (B) may be administered concomitantly or separately. When administered separately, administration may take place substantially at the same time or at different times during the course of therapy. Administration at different times can be effected according to any sequence that may be appropriate for the treatment, depending e.g. on the disease to be treated or the mode of administration.
  • the present invention is to be understood as embracing concomitant as well as separate administration of the active components.
  • combined pharmaceutical preparation includes any pharmaceutical preparation suitable for concomitant or separate administration of the active components.
  • the combined pharmaceutical preparation may be a fixed pharmaceutical composition comprising both components (A) and (B).
  • Such compositions may be formulated in conventional manner, so as to be for example a solution or a tablet, and may be used for example in the treatment of neurodegenerative diseases.
  • the compositions of the invention may constitute a unit dosage form, whereby each unit dosage will comprise a predetermined amount of components (A) and (B).
  • the compositions of the invention may contain components (A) and (B) in admixture with suitable pharmaceutical diluents, carriers or other excipients suitably selected with respect to conventional pharmaceutical practice.
  • tablets may contain beside the active agents fillers, granulating agents, disintegrating agents, binding agents, lubricating agents, stabilizing agents, dyestuffs, sweetening and flavoring agents.
  • the invention moreover provides the use of a combined pharmaceutical preparation as defined above, for the manufacture of a pharmaceutical composition for treating neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of ischemia.
  • the invention provides a package containing a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, and a pharmaceutically acceptable blood-brain barrier transport enhancer, for use as a pharmaceutical.
  • such package is a pack or dispenser-device adapted for the concomitant or separate administration of the two active agents, wherein these agents are separately arranged.
  • Conveniently components (A) and (B) are contained in the pack or dispenser-device in separated unit dosage forms.
  • the pack or dispenser-device bears directions for the concomitant administration of a pre-determined amount of the active agents. The directions may for example be printed directly on the pack or device.
  • the appropriate dosage will of course vary depending upon, for example, the preparation employed, the host, the mode of administration and the nature and severity of the condition being treated.
  • satisfactory results are indicated to be obtained at daily dosages in the range utilized for the known indications of component (A), e.g. of about 1 to about 15 mg/kg animal body weight, and of about 1 to about 15 mg/kg animal body weight of the blood-brain barrier transport enhancer.
  • an indicated daily dosage is in the range from about 25 to about 1500 mg of component (A) and from about 25 to about 1500 mg of the blood-brain barrier transport enhancer, conveniently administered, for example, in divided doses two times a day.
  • an indicated daily dosage is from about 50 to about 1000 mg.
  • an indicated daily dosage is from about 50 to about 1000 mg.
  • a drink solution containing the ingredients indicated below and prepared by conventional techniques is useful in the treatment of Parkinson's disease or Alzheimer's disease at a dose of about 100 to 500 mg/day:
  • an injectable solution containing the ingredients indicated below and prepared by conventional techniques is useful in the treatment of stroke at a dose of about 25 to 100 mg/day.

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Abstract

A combined pharmaceutical preparation comprising a pharmaceutically acceptable compound which binds to immunophilin and/or inhibits calcineurin- or RAFT and a pharmaceutically acceptable blood-brain barrier transport enhancer is useful for the treatment of neurodegenerative diseases and inflammatory and traumatic nervous injury.

Description

PHARMACEUTICAL COMPOSITION CONTAINING A BLOOD-BRAIN BARRIER TRANSPORT ENHANCER
The present invention relates to a novel means of therapy comprising co-administration of pharmaceutically active agents.
The invention more particularly relates to co-administration of (A) a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, and (B) a pharmaceutically acceptable blood-brain barrier transport enhancer.
Component (A) for use according to the invention may be
a) *a calcineurin inhibitor, which is either i) an immunophilin binding compound having calcineurin inhibiting activity, or ii) a non-immunophilin-binding calcineurin inhibitor; or
b) a RAFT inhibitor, which is either i) an immunophilin, particularly macrophilin binding compound having RAFT inhibiting activity, or ii) a non-immunophilin-binding RAFT inhibitor; or
c) an immunophilin binding compound, particularly a non-immunosuppressive cyclophilin or macrophilin binding compound, which has no calcineurin or RAFT inhibiting activity.
Component (A) for use according to the invention is preferably a compound of class (a), i.e. a calcineurin inhibitor.
Calcineurin is a calcium/calmodulin-regulated protein phosphatase involved in intracellular signalling. It is a major soluble calmodulin-binding protein in brain extracts. For a review on calcineurin, see for example C. B. Klee et al., Calcineurin. Adv. Enzymol. 61 , 149 - 200 (1988) or Guerini et al., The biology and medicine of signal transduction, Raven Press ( 1990). Examples of substrates which are specifically dephosphorylated by calcineurin in nervous tissue are DARPP-32 and GAP-43 [see for example Girault et al., Trends Neurosci. 13, 325 - 327 (1990) and Liu et al., J. Biol. Chem. 264, 12800 - 12804 (1989)].
Calcineurin inhibitors are substances which block calcineurin dephosphorylation e.g. of substrates as above.
As indicated above, the calcineurin inhibitor may be of group (i), i.e. immunophilin binding.
Immunophilin binding calcineurin inhibitors are compounds forming calcineurin inhibiting complexes with immunophilins, e.g. cyclophilin and macrophilin.
Examples of cyclophilin binding calcineurin inhibitors are cyclosporin derivatives and examples of macrophilin binding calcineurin inhibitors are ascomycins [see for example Liu et al., Cell 66, 807-815 (1991 )].
The class comprised by the cyclosporin derivatives (hereinafter cyclosporins) is known from the literature and consists in structurally distinct, cyclic, poly-N-methylated undecapeptides. The first of the cyclosporins to be identified was the fungal metabolite Cyclosporin A, or Cyclosporin, and its structure is given in The Merck Index, 1 1th Edition; Merck & Co., Inc.; Rahway, New Jersey, USA (1989) under listing 2759. Later cyclosporins to be identified include, for example, the naturally occurring cyclosporins B through Z [cf. Traber et al.; 1, Helv. Chim. Acta, 60, 1247 - 1255 (1977); Traber et al.; 2, Helv. Chim. Acta, 6.5, 1655 - 1667 (1982); Kobel et al., Europ. J. Applied Microbiology and Biotechnology, \4, 273 - 240 (1982); and von Wartburg et al., Progress in Allergy, 38, 28 - 45, (1986)], as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins including dihydro-cyclosporins; derivatised cyclosporins (e.g. in which the 3'-O-atom of the N-methyl-(4R)-4-but-2E-en-l -yl-4-methyl-(L)-threonyl residue (MeBmt residue) is acylated or a further substituent is introduced at the α-carbon atom of the sarcosyl residue at the 3-position); cyclosporins in which the MeBmt residue is present in isomeric form (e.g. in which the configuration across positions 6' and 7' of the MeBmt residue is cis rather than trans); and cyclosporins in which variant amino acids are incoφorated at specific positions within the peptide sequence, e.g. employing the total synthetic method for the production of cyclosporins developed by R. Wenger - see e.g. Traber et al., 1 , Traber et al., 2 and Kobel et al., loc. cit.; US Patents Nos. 4,108,985, 4,220,641 , 4,288,431 , 4,554,351, 4,396,542 and 4,798,823; European Patent Publications Nos. 34,567 A, 56,782A, 300/784A, 300 85A and 414,632A; Intemational Patent Publication No. WO 86/02080 and UK Patent Publications Nos. 2,206,1 19 and 2,207,678, the specifically exemplified product compounds of these patents / patent publications being incoφorated by reference; Wenger 1 , Transpl. Proc, J_5 Suppl. 1 :2230 (1983); Wenger 2., Angew. Chem. Int. Ed. 24, 77 (1985) and Wenger 3., Progress in the Chemistry of Organic Natural Products, 50, 123 (1986).
The class comprised by ascomycin derivatives is also known from the literature.
Ascomycin (FR 520) is a known macrolide antibiotic disclosed for example in US Patent No. 3,244,592 and in European Patent Publication No. 0 349 061. Ascomycin is obtainable by fermentation techniques employing, inter alia, actinomycetes of the genus Streptomycetes, e.g. S. hygroscopicus, or by total synthesis - see e.g. Yuki Gasei Kagaku Kyokaishi 50 (6), 522- 534.
A wide range of ascomycin derivatives (herein: with ascomycin collectively "ascomycins") are known, which are either naturally occuring amongst fungal species or are obtainable by manipulation of fermentation procedures or by chemical derivatisation. Such derivatives include notably the compound FK 506 (Tacrolimus), the structure of which correlates to that of ascomycin.
FK 506 is a macrolide immunosuppressant that is produced by Streptomyces tsukubaensis No 9993. The structure of FK 506 is given in the appendix to the Merck Index, 1 1 h Ed., 1993, as item A5. Also a large number of related compounds which retain the basic structure and immunological properties of FK 506 are known. These compounds are described in a large number of publications, for example EP 184162, EP 315973, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/13889, WO 91/19495, EP 484936, EP 532088, EP 532089, EP 626385, WO 93/5059 and the like, the specifically exemplified product compounds of which are incoφorated by reference.
The calcineurin inhibitor may also be of group (ii), i.e. non-immunophilin binding.
Calcineurin inhibitors which do not bind to immunophilins are also known from the literature and include okadaic acid [see for example S. Nishiwaki et al., Carcinogenesis ϋ, No. 10, 1837 - 1841 (1990)], Microcystin LR [e.g. from C. Mc Kintosh et al., FEBS Letters 264, No. 2, 187 - 192 (1990)] and Nodularin [e.g. from K.C. Rinehart et al., J. Amer. Chem. Soc. 1 10. 8557 (1988)]. These compounds inhibit calcineurin at relatively high concentrations only. When component (A) is a calcineurin inhibitor, this is preferably an ascomycin.
Preferred ascomycins for use in accordance with the invention comprise the compound 33-epi- chloro-33-deoxyascomycin, disclosed as Example 66a in EP 427 680, 32-hydroxymethyI- cyclopentyl-ascomycin, disclosed as Example 1 in EP 465 426, the compounds of Example 23 and 24 of same EP 465 426, the compounds of Examples 8, 24 and 32 of EP 626 385 and the benzoyl -protected FK 506 of Example 7 of EP 1 4 162. The most preferred compound is 33-epi-chloro-33-deoxy ascomycin.
Calcineurin inhibitors, e.g. as aforesaid, have been shown to increase basal neurotransmission of synaptic transmission in vitro. See for example R. M. Mulkey et al., Nature 369 (6480), 486-488 (1994) and M. Funauchi et al., Neurosci. Res. 19(3), 269-278 (1994).
After systemic administration, however, calcineurin inhibitors such as cyclosporins or ascomycins have been found to have only limited CNS effects. Indeed the above in vitro findings could not be confirmed in vivo with calcineurin inhibitors administered at non-toxic doses or at doses which do not cause unacceptable immunosuppression.
Component (A) for use in accordance with the invention may also be a compound of class (b), i.e. a RAFT inhibitor.
RAFT (Rapamycin and FKBP 12 target proteins) [or FRAP (FKBP and Rapamycin associated protein)] inhibitors include compounds of class (i), e.g. macrophilin binding compounds, e.g. compounds forming complexes with immunophilins of the FKBP type.
Examples of immunophilin binding compounds having RAFT inhibiting activity are especially rapamycin and derivatives thereof.
Rapamycin is a macrolide immunosuppressant that is produced by Streptomyces hygroscopicus and which has been found to be pharmaceutically useful in a variety of applications, particularly as an immunosuppressant for use in the treatment and prevention of organ transplant rejection and autoimmune diseases. The structure of rapamycin is given in Kesseler, H., et al. Helv. Chim. Acta; 76: 1 17 (1993). Large numbers of derivatives of rapamycin (herein: collectively with rapamycin "raparnycins") have been synthesized, including for example certain acyl and aminoacyl-rapamycins (e.g., US patent 4316885, US patent 4650803, and US patent 5151413), 27-desmethyl-raρamycin (WO 92/147327), 26- dihydro-rapamycin (US patent 5138051 ), certain pyrazole derivatives (US patent 5164399), certain alkoxyester derivatives (US patent 5233036), and 40-O-alkylated derivatives (WO 94/09010), the specifically exemplified product compounds of said patents / patent applications being incoφorated by reference.
Preferred RAFT inhibitors for use according to the invention include rapamycin and its 40-O- alkylated derivatives as disclosed in WO 94/09010. especially 40-O-(2-hydroxy)ethyl- rapamycin (compound of Example 8).
Finally, component (A) for use in accordance with the invention may be a compound of class (c), i.e. an immunophilin binding compound which has no calcineurin or RAFT inhibiting activity, preferably a non-immunosuppressive cyclophilin or macrophilin binding compound.
Examples of such compounds are disclosed in J. Rotonda et al., J. Biol. Chem. 268. 7607 (1993) and in B.E. Bierer et al., Science 250, 556 (1990).
Component (B) for use according to the invention is a blood-brain barrier transport enhancer, i.e. a compound which facilitates the entry of certain molecules into the central nervous system. Such compounds are also known as blood-brain barrier openers.
Such compounds are for example multidrug resistance (MDR) reversing agents, such as agents which inhibit P-glycoprotein (Pgp) in the blood-brain barrier and thus facilitate the accumulation of various substances in the brain.
These MDR reversing agents are suitably non-immunosuppressive, since peripheral immunosuppression is generally not desired in the treatment of diseases of the central nervous system.
Examples of substantially non-immunosuppressive, MDR reversing Pgp inhibiting substances are the compounds disclosed in European Patent No 296 122 and in European Patent Publication No 360 760, the specifically exemplified product compounds therein being incoφorated by reference.
Further Pgp inhibitors known from the literature include Verapamil [J. Zacheri et al., Cancer Chemother. Pharmacol. 34, 125(1994)], Quinidine [L. J. Goldstein, Curr. Probl. Cancer 19(2), 65-124 (1995)] and the compounds of WO 96/18643, particularly 2-nitrophenylcarbamoyl- [(S)-propyl]-[(S)-3-(2-naphthyl)alanyl]-N-benzyl-N-methyl-amide disclosed as Example 1.
Component (B) for use according to the invention is preferably a Pgp inhibitor.
Preferred Pgp inhibitors for use in accordance with the invention include [3'-desoxy-3'-oxo- MeB t] '-Ciclosporin, P'-desoxy-S'-oxo-MeBmtl'-tVal -Ciclosporin, [3'-desoxy-3'-oxo- MeBmt]'-[Nva] -Ciclosporin, disclosed in EP 296 122 as cyclosporins 1.37, 1.38 and 1.39 respectively (compounds of Example H), as well as Cyclo-[Pec-MeVal-Val-MeAsp(β-O-t-Bu)- MeIle-MeIle-Gly-MeVal-Tyr(Me)-L-lact] and Cyclo-[Pec-MeVal-Val-MeAsp-MeIle-Me-Ile- Gly-MeVal-Tyr(Me)-D-Lact], disclosed in EP 360 760 as Examples 52 and 1 (first compound) respectively.
The most preferred compound is [3'-desoxy-3'-oxo-MeBmt]2-[Val]2-Ciclosporin A of formula
""X-Val -Sar-MeLeu-Val -MeLeu-Ala- ( D ) Ala-MeLeu-MeLeu-MeVa-T"
1 2 3 10 11
wherein X is the residue of formula
Figure imgf000008_0001
hereinafter referred to as PSC 833, is known e.g. from EP 296 122 (example H) or P.R. Twentyman, Eur. J. Cancer 27(12), 1639-42 (1991 ) and has been shown to inhibit Pgp activity.
It has now suφrisingly been found that component (A) inhibitors increase basal neurotransmission, enhance long term potentiation of synaptic transmission (LTP) and suppress neuroinflammatory processes, such as observed after injection of bacterial toxins (LPS), in vivo at non-toxic doses, if they are co-administered with component (B).
The effects of the combination of component (A) with component (B) (hereinafter referred to as combination of the invention) on hippocampal LTP are determined in vivo in rats according to the following procedure:
Experiments are performed on male Sprague Dawley rats (250-300 g). The animals are anaesthetized with 1.5% halothane/oxygen mixture throughout the experiment. Body temperature is kept at 38°C by means of a heating table. The rats are placed in a stereotaxic apparatus with the mouthbar positioned 5 mm above the earbar. Conventional NaCl-filled glass electrodes with resistances of 1 -3 MΩ are used for recording. Stimulating electrodes are constructed from electrolytically shaφened tungsten wire insulated with varnish. The electrodes are implanted in the hippocampus at the following coordinates (calculated from bregma) A:-0.4 to -0.6; L: 1.5 to 2.5 and V: -2.5 to -3.5 mm. The depth of the recording electrode is used to optimize the recorded evoked potential. The recording electrodes are connected to conventional WPI amplifiers and the responses are monitored on an ASTR PC. The compounds are applied intraperitoneally.
In this test, combinations of the invention enhance LTP when component (A) is administered at about 0.05 to about 10 mg/kg i.p. and component (B) is administered at doses of about 0.5 to about 15 mg/kg i.p.
The effects of the combination of the invention upon LPS-induced brain inflammatory processes are determined n vivo in rats according to the following procedure:
Rats are injected with 5 mg/kg LPS (bacterial lipopolysaccharides), via the tail vein. The animals show first a decrease followed by an increase in body temperature. 8 h after application of LPS a significant increase in both mRNA and protein of the cytokines ILl b and TNFalpha are observed in brain slices of LPS-treated rats. The compounds are applied intravenously. In this test, combinations of the invention strongly reduce expression of ILlb mRNA and protein as well as TNFalpha mRNA and protein when component (A) is administered at about 0.1 to about 20 mg/kg i.v. and component (B) at doses of about 1 to about 25 mg/kg i.v.
These activities are confirmed ex vivo in the rat, according to a procedure where inhibition of calcineurin is determined in several brain areas.
After peripheral administration of the compounds to Sprague-Dawley rats, the animals are sacrified, decapitated and their brains stored on ice. After dissection, brain regions are homogenised at 0° and the total phosphatase activity remaining is determined by HPLC assay [A. Enz et al., Analytical Biochemistry 216. 147-153 (1994)] by monitoring the dephosphorylation of a 19-amino acid phosphopeptide, a partial sequence of the regulatory subunit of cAMP-dependent protein kinase [D.K. Blumenthal et al., J. Biol. Chem. 261. 8140- 45 (1986)]. Specific calcineurin activity is determined as that inhibitable with added cyclosporin A. Activities of PPI and PP2A are determined by addition of okadaic acid, a selective PPI and PP2A inhibitor. The dephosphorylative activity that remains after addition of both inhibitors is ascribed to non-specific phosphatases, e.g. alkaline phosphatase.
In this test, combinations of the invention increase the inhibition of calcineurin when component (A) is administered at about 0.1 to about 20 mg/kg i.v. and component (B) at doses of about 1 to about 25 mg/kg i.v.
For example 2 hours after administration of 33-epi-chloro-33-deoxyascomycin at the non-toxic dose of 0.3 mg/kg i.v. and PSC 833 at the non-toxic dose of 10 mg/kg i.v., a significant inhibition of calcineurin in several brain regions (cerebellum, pons medulla and hippocampus) is observed whereas no calcineurin inhibition is observed with said ascomycin alone at the same dose.
In view of these activities, combinations of the invention are indicated to be beneficial in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
Neurodegenerative diseases include Parkinson's disease and primary degenerative dementia, e.g. senile dementia, particularly senile dementia of the Alzheimer type, as well as senile mental decline, e.g. senile cognitive decline, and confusional conditions in the elderly. Inflammatory nervous injury may result for example from encephalitis, traumatic processes and the above-mentioned neurodegenerative diseases.
Conditions involving a component of cerebral ischemia include ischemic damage to grey and white matter, stroke, subarachnoid haemorrhage, brain and spinal cord injury and trauma, high intracranial pressure, multi-infarct or vascular dementia, and any surgical procedure potentially associated with cerebral ischemia.
Preferred conditions for treatment with the combination of the invention include Parkinson's disease, Alzheimer's disease and stroke.
Preferred combinations of the invention include any combination of (a) a compound chosen from the above-indicated preferred ascomycins for use in accordance with the invention and the above-indicated preferred RAFT inhibitors for use according to the invention, with (b) a compound chosen from the above-indicated preferred Pgp inhibitors for use in accordance with the invention, particularly any combination of a compound chosen from said preferred ascomycins and RAFT inhibitors with PSC 833.
According to the foregoing, the present invention provides a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, for use in the preparation of a pharmaceutical composition for administration in association with a pharmaceutically acceptable blood-brain barrier transport enhancer, for use in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
The present invention also provides a pharmaceutically acceptable blood-brain barrier transport enhancer, for use in the preparation of a pharmaceutical composition for administration in association with a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, for use in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
In a further aspect, the present invention provides the use of a pharmaceutically acceptable blood-brain barrier transport enhancer in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, involving administration of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT.
The present invention also provides the use of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, involving administration of a pharmaceutically acceptable blood-brain barrier transport enhancer.
In yet a further aspect, the present invention provides a method for treating neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT and a pharmaceutically acceptable blood-brain barrier transport enhancer.
In still a further aspect the present invention provides a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT and a pharmaceutically acceptable blood-brain barrier transport enhancer as a combined pharmaceutical preparation.
Components (A) and (B) may be administered concomitantly or separately. When administered separately, administration may take place substantially at the same time or at different times during the course of therapy. Administration at different times can be effected according to any sequence that may be appropriate for the treatment, depending e.g. on the disease to be treated or the mode of administration.
Accordingly the present invention is to be understood as embracing concomitant as well as separate administration of the active components. Similarly the term "combined pharmaceutical preparation" includes any pharmaceutical preparation suitable for concomitant or separate administration of the active components.
Thus the combined pharmaceutical preparation may be a fixed pharmaceutical composition comprising both components (A) and (B). Such compositions may be formulated in conventional manner, so as to be for example a solution or a tablet, and may be used for example in the treatment of neurodegenerative diseases. The compositions of the invention may constitute a unit dosage form, whereby each unit dosage will comprise a predetermined amount of components (A) and (B). The compositions of the invention may contain components (A) and (B) in admixture with suitable pharmaceutical diluents, carriers or other excipients suitably selected with respect to conventional pharmaceutical practice. For example, tablets may contain beside the active agents fillers, granulating agents, disintegrating agents, binding agents, lubricating agents, stabilizing agents, dyestuffs, sweetening and flavoring agents.
The invention moreover provides the use of a combined pharmaceutical preparation as defined above, for the manufacture of a pharmaceutical composition for treating neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of ischemia.
In yet a further aspect the invention provides a package containing a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, and a pharmaceutically acceptable blood-brain barrier transport enhancer, for use as a pharmaceutical.
For example such package is a pack or dispenser-device adapted for the concomitant or separate administration of the two active agents, wherein these agents are separately arranged. Conveniently components (A) and (B) are contained in the pack or dispenser-device in separated unit dosage forms. Preferably the pack or dispenser-device bears directions for the concomitant administration of a pre-determined amount of the active agents. The directions may for example be printed directly on the pack or device.
For the above mentioned indications, the appropriate dosage will of course vary depending upon, for example, the preparation employed, the host, the mode of administration and the nature and severity of the condition being treated. However, satisfactory results are indicated to be obtained at daily dosages in the range utilized for the known indications of component (A), e.g. of about 1 to about 15 mg/kg animal body weight, and of about 1 to about 15 mg/kg animal body weight of the blood-brain barrier transport enhancer. In larger mammals, for example humans, an indicated daily dosage is in the range from about 25 to about 1500 mg of component (A) and from about 25 to about 1500 mg of the blood-brain barrier transport enhancer, conveniently administered, for example, in divided doses two times a day.
For ascomycins and cyclosporins, for example, an indicated daily dosage is from about 50 to about 1000 mg. For PSC 833, for example, an indicated daily dosage is from about 50 to about 1000 mg.
For example
a) a drink solution containing the ingredients indicated below and prepared by conventional techniques is useful in the treatment of Parkinson's disease or Alzheimer's disease at a dose of about 100 to 500 mg/day:
Ingredients Weight (mg)
Cyclosporin A 100
PSC 833 100
Labrafil M 1944 CS 300
Ethanol 100
Olive oil 320
b) an injectable solution containing the ingredients indicated below and prepared by conventional techniques is useful in the treatment of stroke at a dose of about 25 to 100 mg/day.
Ingredients Weight (mg)
33-epi-chloro-33- deoxy ascomycin 50
PSC 833 50
Ethanol 40
Miglyol up to 1 ml

Claims

1. A pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, for use in the preparation of a pharmaceutica] composition for administration in combination with a pharmaceutically acceptable blood-brain barrier transport enhancer, for use in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
2. A pharmaceutically acceptable blood-brain barrier transport enhancer, for use in the preparation of a pharmaceutical composition for administration in combination with a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, for use in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
3. The use of a pharmaceutically acceptable blood-brain barrier transport enhancer in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, involving administration of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT.
4. The use of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, involving administration of a pharmaceutically acceptable blood-brain barrier transport enhancer.
5. A method for treating neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, and a pharmaceutically acceptable blood-brain barrier enhancer.
6. A pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, and a pharmaceutically acceptable blood-brain barrier transport enhancer, as a combined pharmaceutical preparation.
7. A pharmaceutical preparation according to claim 6, wherein the pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT is an immunophilin binding compound having calcineurin inhibiting activity.
8. A pharmaceutical preparation according to claim 6, wherein the pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT is an immunosuppressant cyclosporin or ascomycin derivative.
9. A pharmaceutical preparation according to claim 6, wherein the pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT is a non-immunophilin binding calcineurin inhibitor.
10. A pharmaceutical preparation according to claim 6, wherein the pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT is a macrophilin binding compound having RAFT inhibiting activity.
1 1. A pharmaceutical preparation according to claim 6, wherein the pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT is a non-immunophilin binding RAFT inhibitor.
12. A pharmaceutical preparation according to claim 4, wherein the pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT is a non-immunosuppressive cyclophilin or macrophilin binding compound which has no calcineurin or RAFT inhibiting activity.
13. A pharmaceutical preparation according to claim 6 wherein the pharmaceutically acceptable blood-brain barrier transport enhancer is a P-glycoprotein inhibitor.
14. A pharmaceutical preparation according to claim 6 wherein the pharmaceutically acceptable blood-brain barrier transport enhancer is PSC 833.
15. A pharmaceutical preparation according to claim 6, which is a fixed pharmaceutical composition.
16. The use of a pharmaceutical preparation according to claim 15, in the treatment of neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
17. The use of a pharmaceutical preparation according to claim 15, for the manufacture of a pharmaceutical composition for treating neurodegenerative diseases, inflammatory nervous injury and conditions involving a component of cerebral ischemia.
18. A package containing unit dosages of a pharmaceutically acceptable compound which binds to an immunophilin and/or inhibits calcineurin or RAFT, and unit dosages of a pharmaceutically acceptable blood-brain barrier transport enhancer, for use as a pharmaceutical.
PCT/EP1996/004494 1995-10-17 1996-10-16 Pharmaceutical composition containing a blood-brain barrier transport enhancer WO1997014439A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
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US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
US6544987B2 (en) 1999-12-01 2003-04-08 Pfizer Inc. Compounds, compositions, and methods for stimulating neuronal growth and elongation
FR2806626A1 (en) * 2000-03-22 2001-09-28 Centre Nat Rech Scient USE OF MODULATING SUBSTANCES FOR THE EXPRESSION OR FUNCTION OF A PROTEIN INVOLVED IN THE CELL CYCLE FOR THE TREATMENT OR PREVENTION OF ACUTE NEURAL INJURIES
WO2001070231A3 (en) * 2000-03-22 2002-06-20 Centre Nat Rech Scient Use of substances modulating the expression or the function of a protein involved in the cell cycle for treating or preventing acute neural injuries
EP2292240A1 (en) * 2001-07-19 2011-03-09 ISIS Innovation Limited Use of rapamycin for treatment or prevention of Alzheimer's Disease
US7259170B2 (en) 2001-10-23 2007-08-21 Novartis Ag Macrolides containing pharmaceutical compositions
AU2008200714B2 (en) * 2002-07-16 2011-02-03 Biotica Technology Limited Production of polyketides

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