ZA200203037B - Phenyl- and pyridyl-tetrahydro-pyridines having TNF inhibiting activity. - Google Patents

Phenyl- and pyridyl-tetrahydro-pyridines having TNF inhibiting activity. Download PDF

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Publication number
ZA200203037B
ZA200203037B ZA200203037A ZA200203037A ZA200203037B ZA 200203037 B ZA200203037 B ZA 200203037B ZA 200203037 A ZA200203037 A ZA 200203037A ZA 200203037 A ZA200203037 A ZA 200203037A ZA 200203037 B ZA200203037 B ZA 200203037B
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group
formula
compound
hydrogen
halogen atom
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ZA200203037A
Inventor
Marco Baroni
Bernard Bourrie
Rosanna Cardamone
Pierre Casellas
Umberto Guzzi
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Sanofi Synthelabo
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    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • 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
    • C07D401/14—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 three or more hetero rings

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

PHENYL- AND PYRIDYL-TETRAHYDROPYRIDINES HAVING TNF-
INHIBITING ACTIVITY
The present invention relates to novel phenyl- and pyridyl-tetrahydropyridines, to pharmaceutical compositions containing them, to a process for preparing them and to synthetic intermediates in this process.
US 5 118 691 and US 5 620 988 disclose tetrahydropyridines substituted with a 3-quinolylalkyl radical, which show dopaminergic activity.
It has now been found that certain tetrahydropyridines substituted with a quinolinylalkyl or isoquinolylalkyl radical have powerful activity with respect to modulating TNF-alpha (tumour necrosis factor) .
TNF-alpha is a cytokine which has recently aroused interest as a mediator of immunity, of inflammation, of cell proliferation, of fibrosis, etc.
This mediator is present in abundance in inflamed synovial tissue and exerts an important role in the pathogenesis of autoimmunity (Annu. Rep. Med. Chem., 1997, 32:241-250).
Thus, according to one of its aspects, the present invention relates to tetrahydropyridines of formula (I): :
) _ Lo
X \ R, R,
R, 1, ty) in which
X represents N or CH;
R; represents a hydrogen or halogen atom or a CF; group;
R; and R; independently represent a hydrogen atom or a methyl group; n is 0 or 1;
A represents a group of formula (a) or (Db)
Don
R6 XN” 0-1
R
R,
R6 (a) (b) in which
Ry represents a hydrogen or halogen atom, a (C;-Cy)alkyl group, a CF; group, an amino group, a mono (C;-
C4)alkylamino group or a di (C;-
Cs) alkylamino group;
Rs represents a hydrogen or halogen atom, a (C;-C4q)alkoxy group, a (C;-
Cs) alkyl group or a CF; group;
x
Rg represents a hydrogen atom, a (C;-
Cs)alkyl group or a (C;-C4)alkoxy group; as well as the salts or solvates thereof.
In the present description, the term “(C;-
Cq)alkyl” denotes a monovalent radical of a saturated straight-chain or branched-chain C;-C; hydrocarbon.
In the present description, the term “halogen” denotes an atom chosen from chlorine, bromine, iodine and fluorine.
Preferred compounds are those in which n is
Zero.
Other preferred compounds are those in which
R; and R; are hydrogen.
Other preferred compounds are those in which
R; is a CF; group.
Other preferred compounds are those in which
R; is a fluorine atom.
Other preferred compounds are those in which
X is CH and R; is in position 2 or 3 of the benzene.
Other preferred compounds are those in which
X is CH and R; is a CF: group.
Other preferred compounds are those in which
X is a nitrogen atom and the pyridine is substituted in positions 2 and 6.
According to the present invention, the compounds of formula (I) can exist as N-oxide derivatives. As indicated in the above formula, the
. ) compounds of formula (I) can in particular bear the N- oxide group on the tetrahydropyridine or on the quinoline or the isoquinoline of the group A, or alternatively two N-oxide groups may be simultaneously present.
The salts of the compounds of formula (I) according to the present invention comprise both the addition salts with pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulphonate 2-naphthalenesulphonate, etc., and the addition salts which allow a suitable separation or crystallization of the compounds of formula (I), such as the picrate or oxalate, or the addition salts with optically active acids, for example camphorsulphonic acids and mandelic acids or substituted mandelic acids.
The optically pure stereoisomers, and the mixtures of isomers of the compounds of formula (I), due to the asymmetric carbon, when either R; or R; is a methyl and the other is a hydrogen, in any proportion, form part of the present invention.
The compounds of formula (I) can be synthesized by a process which involves (a) reacting the compound of formula (II):
v
O
N—H
X
R, (Im) in which X and R; are defined as above, with a functional derivative of the acid of formula (III):
I \ :
HO Xo A — Nn ¢ (I) 5 in which R;, Ri, n and A are as defined above, (b) reducing the carbonyl group of the compound of formula (IV) thus obtained:
R, R, y 10
A
N——C n
X
R, Iv) (c) dehydrating the intermediate piperidinol of formula (V) thus obtained:
R, R; / Ma 74 N—CH, n
X
R
: V)
Tx (d) isolating the compound of formula (I) thus ! obtained and optionally converting it into a salt or solvate thereof or into the N-oxide derivatives thereof.
The reaction in step (a) can be suitably carried out in an organic solvent at a temperature of between -10°C and the reflux temperature of the reaction mixture.
It may be preferable to perform the reaction without heating when it is exothermic, such as in the case in which the chloride is used as functional derivative of the acid of formula (III).
Suitable functional derivatives of the acid of formula (III) which can be used are the free acid, optionally activated (for example with BOP = tris (dimethylamino)benzotriazol-l-yloxyphosphonium hexafluorophosphate), an anhydride, a mixed anhydride, an active ester or an acid halide, preferably the bromide. Among the active esters, the one which is particularly preferred is the p-nitrophenyl ester, but the methoxyphenyl, trityl and benzhydryl esters and the like are also suitable.
The reaction solvent preferably used is a halogenated solvent such as methylene chloride, dichloroethane, 1,1,1l-trichloroethane, chloroform and the like, but other organic solvents that are compatible with the reagents used, for example dioxane,
To tetrahydrofuran or a hydrocarbon such as hexane, can also be used.
The reaction may be carried out conveniently in the presence of a proton acceptor, for example an alkaline carbonate or a tertiary amine such as triethylamine.
The reduction in step (b) can be carried out conveniently using suitable reducing agents such as borane complexes, for example dimethyl sulphide/borane ([CH3]2S-BH3), aluminium hydrides or a lithium aluminium ) hydride complex in an inert organic solvent at a temperature of between 0°C and the reflux temperature of the reaction mixture, according to the usual techniques.
The expression “inert organic solvent” means a solvent which does not interfere with the reaction.
Such solvents are, for example, ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane or 1,2- dimethoxyethane.
According to one preferred procedure, the process is performed with the dimethyl sulphide/borane used in excess relative to the starting compound (II), at the reflux temperature, optionally under inert atmosphere. The reduction is normally complete after a few hours.
The dehydration in step {(c) is readily carried out, for example, using an acetic acid/sulphuric acid mixture, at a temperature of
’ § between room temperature and the reflux temperature of the solvent used.
According to a preferred method, the reaction in step (c) is carried out in an acetic acid/sulphuric acid mixture in a ratio of 3/1 by volume, by heating to a temperature of about 100°C for 1-3 hours.
The desired compound is isolated according to the conventional techniques in the form of free base or a salt thereof. The free base can be converted into one of its salts by simple salification in an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether such as 1,2-dimethoxyethane, ethyl acetate, acetone or a hydrocarbon such as hexane.
The compound of formula (I) obtained is isolated according to the usual techniques and optionally converted into a salt or solvate thereof or into the N-oxide derivatives thereof.
The compounds of formula (I) can also be prepared by a coupling/reduction reaction starting with a compound of formula (VI): >
N—H yy”
X
R, (VD) in which X and R; are as defined above, with an aldehyde of formula (VII):
: conn 11037 -® Boo ST .
S
R, R,
Ba»
O— C n (VID in which R;, R3;, n and A are as defined above, isolation of the compound of formula (I) and optional conversion into a salt or solvate thereof or into the N-oxide derivatives thereof.
The coupling/reduction reaction is carried out by mixing the starting compounds (VI) and (VII) in an organic solvent such as an alcohol such as for example, methanol, in acidic medium, in the presence of a reducing agent such as sodium cyanoborohydride, according to the conventional methods.
The starting compounds of formulae (II), (ITT) and (VI) are known or else can be prepared in an analogous manner to that of the known compounds. Such products are described, for example, in WO 97/01536;
J. Am. Chem. Soc., 1948, 70:2843-2847; J. Med. Chem., 1997, 40 (7):1049.
The compounds of formulae (IV), (V) and (VII) are novel compounds and constitute a further aspect of the present invention.
The compounds of formula (VII) can be prepared by heating the trifluoromethylsulphonyl derivative (also known as “triflate”) of a suitable hydroxy (iso)quinoline with N,N-dialkylethanolamine
To vinyl ether in the presence of a palladium catalyst and a strong base such as, for example, triethylamine, and by reacting the intermediate thus obtained with concentrated sulphuric acid, according to the usual procedures. Examples of such a process are reported in the experimental section. Alternatively, the compounds of formula (VII) can be prepared by reducing the corresponding acids of formula (III) according to the well-known methods.
The compounds of formula (I) bearing an N- oxide group on the nitrogen atom of the quinoline or of the isoquinoline can be prepared from the N-oxide derivatives of the compounds of formula (III) or (VII).
Examples of such syntheses are given in the experimental section.
The compounds of formula (I) bearing an N- oxide group on the nitrogen atom of the tetrahydropyridine can be prepared by oxidation of the corresponding compounds of formula (I). In this case, the compound of formula (I) as obtained by the above syntheses is subjected to an oxidation reaction according to the conventional methods, for example to a reaction with m-chloroperbenzoic acid in a suitable solvent, and isolated according to the usual techniques that are well known to those skilled in the art.
The compounds of the invention have advantageous properties with respect to the inhibition of TNF-C.
Tov
These properties were demonstrated with the aid of a test aimed at measuring the effect of molecules on the synthesis of TNF-a induced in Balb/c mice by lipopolysaccharide (LPS) from Escherichia Coli (055:B5, Sigma, St. Louis, Mo).
The test products are administered orally to groups of 5 female 7- to 8-week old Balb/c mice (Charles River, France). One hour later, the LPS is administered intravenously (10 pg/mouse). The blood of each animal is taken 1.5 hours after the administration of the LPS. The samples are centrifuged and the plasma is recovered and frozen at -80°C. The TNF-O is measured using commercial kits (R and D, Abingdon, UK).
In this test, representative compounds of the invention were found to be very active, by inhibiting the synthesis of TNF-0 even at very low doses.
By virtue of this activity and their low toxicity, the compounds of formula (I) and the salts or solvates thereof can be used in the treatment of diseases associated with immune and inflammatory disorders or as analgesics. In particular, the compounds of formula (I) can be used for treating atherosclerosis, autoimmune diseases, diseases entailing demyelinization of the neurons (such as multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases, pulmonary idiopathic fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorbtion, osteoporosis, Paget's disease, multiple myeloma, uveoretinitis, septic shock, septicaemia, endotoxic shock, graft-versus-host reaction, graft rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, disseminated lupus erythematosus, haemodynamic shock, ischaemic pathologies (myocardial infarction, myocardial ischaemia, coronary vasospasm, angina pectoris, cardiac insufficiency, heart attack), post- ischaemic reinfusion attacks, malaria, mycobacterial infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpesvirus), opportunistic infections associated with AIDS, tuberculosis, psoriasis, atopic dermatitis and contact dermatitis, diabetes, cachexia, cancer and radiation-mediated damage.
The compounds of formula (I) and the pharmaceutically acceptable salts and solvates thereof are preferably administered orally.
In the pharmaceutical compositions of the present invention for oral use, the active principle can be administered in unit administration forms, as a mixture with conventional pharmaceutical supports, to animals and human beings for the treatment of the abovementioned complaints. The appropriate unit administration forms comprise, for example, tablets,
EE which may be splittable, gel capsules, powders, granules and oral solutions or suspensions.
When a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or alternatively they can be treated such that they have sustained or delayed activity and such that they release a predetermined amount of active principle continuously.
A preparation in the form of gel capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gel capsules.
A preparation in the form of syrup or elixir can contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propyl paraben as antiseptic agents, as well as a flavouring and a suitable colorant.
The water-dispersible powders or granules can contain the active ingredient as a mixture with dispersants or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavour enhancers.
The active principle can also be formulated in the form of microcapsules, optionally with one or more supports or additives.
In the pharmaceutical compositions according to the present invention, the active principle can also be in the form of an inclusion complex in cyclodextrins, or ethers or esters thereof.
The amount of active principle to be administered depends, as always, on the degree of progress of the disease as well as the age and weight of the patient. Nevertheless, the unit doses generally comprise from 0.001 mg to 100 mg, better still from 0.01 mg to 50 mg and preferably from 0.1 mg to 20 mg, of active principle, advantageously from 0.5 mg to 10 mg.
According to another of its aspects, the present invention relates to a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and at least one compound chosen from immunosuppressants, such as interferon beta-1b; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; interleukin-1 inhibitors.
More particularly, the invention relates to a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one compound chosen from roquinimex (1, 2- dihydro-4-hydroxy-N, 1-dimethyl-2-oxo-3- quinolinecarboxanilide), myloran (product from the company Autoimmune containing bovine myelin), antegren (monoclonal human antibody from the companies

Claims (22)

1. Compound of formula (I): ~N 4 N nA 7 \ R, [O] 0-1 @D in which X represents N or CH; Rr; represents a hydrogen or halogen atom or a CFs; group; R; and Rz independently represent a hydrogen atom or a methyl group; n is 0 or 1; A represents a group of formula (a) or (Db) 0 Yon Na 0] R6 N [ 0-1 R, R, R6 (a) ® in which Ry represents a hydrogen or halogen atom, a (C;-Cy)alkyl group, a CF; group, an amino group, a mono (Ci- Cs)alkylamino group or a di (C;- Cs)alkylamino group;
Rs represents a hydrogen or halogen atom, a (C;-C4)alkoxy group, a (C;- Cs) alkyl group or a CF; group; Rg represents a hydrogen atom, a {(Ci- Cs) alkyl group or a (C;-C4)alkoxy group; : as well as the salts or solvates thereof.
2. Compound according to Claim 1, in which n is zero.
3. Compound according to Claim 1 or 2, in which R; and R; are hydrogen. :
4, Compound according to any one of Claims 1 to 3, in which R; is a CFs group.
5. Compound according to any one of Claims 1 to 3, in which R; is a fluorine atom.
6. Compound according to any one of Claims 1 to 3, in which X is CH and R; is in position 3 of the benzene.
7. Compound according to any one of Claims 1 to 3, in which X is CH and R; is in position 2 of the benzene.
8. Compound according to any one of Claims 1 to 3, in which X is a nitrogen atom and the pyridine is substituted in positions 2 and 6. }
9. Compound according to any one of Claims 1 to 8, chosen from the mono-N-oxide and bis-N-oxide derivatives thereof.
10. Compound according to Claim 1, chosen from 7-(2-(4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydro-l-pyridyl)ethyl)isoquinoline, the mono-N- AMENDED SHEET 2003 -05- 22 oxide and bis-N-oxide derivatives thereof and the salts and solvates thereof.
11. Process for preparing the compound of Claim 1, characterized in that a coupling/reduction reaction is carried out on a compound of formula (VI): J / N——=H X R1 (VD in which X and R; are as defined in Claim 1, with an aldehyde of formula (VII): H R, R, PEW O—~cC n (VID) in which R;, Ri, n and A are as defined in Claim 1, and the compound of formula (I) is isolated and optionally converted into a salt or solvate thereof or an N-oxide thereof.
12. Process for preparing the compound of Claim 1, characterized in that (a) the compound of formula (II): O v; N—H X Ri (Im in which X and R; are defined as in Claim 1, is reacted with a functional derivative of the acid of formula (III): R, R; I Xo A in which R;, R3, n and A are as defined in Claim 1, (b) the carbonyl group of the compound of formula (IV) thus obtained: R, Ry 0 140 A N—~C n X R, (IV) is reduced, (c) the intermediate piperidinol of formula (V) thus obtained: R, R, (6) Mpa 74 N CH, n X R, v) is dehydrated, (d) the compound of formula (I) thus obtained is isolated and is optionally
. “ny 3037 @& Fx» V5 i converted into a salt or solvate thereof or into the N-oxide derivatives thereof.
13. Compound of formula (V) R,, R; / Xa J N— CH, n X R ! V) in which X represents N or CH; R; represents a hydrogen or halogen atom or a CF3 group; R; and Ri; independently represent a hydrogen atom or a methyl group; n is 0 or 1; A represents a group of formula (a) or (b) 0)
¥ 0.1 Ns [0] R6 NT 0] R; R, R6 (a) (b) in which Ry represents a hydrogen or halogen atom, a (C;-Cy)alkyl group, a CF; group, an amino group, a mono (C;-
34a Cs)alkylamino or a di(C4-Cy)alkylamino group; Rs represents a hydrogen or halogen atom, a (C-C,) alkoxy group, a (C4-C,) alkyl group or a CF; group; R6 represents a hydrogen atom, a (C,-C,) alkyl group or a (C4-C,) alkoxyl group; As well as the salts or solvates thereof.
14. Compound of the formula (IV)
-
_
R, R, 0 13 A N—-C n X Ri av) in which X represents N or CH; R; represents a hydrogen or halogen atom or a CF; group; R; and R; independently represent a hydrogen atom or a methyl group; n is 0 or 1; A represents a group of formula (a) or (b) AMENDED SHEET
It 0-1 R6 N70 Rs R, R6 (a) (b) in which Ry represents a hydrogen or halogen atom, a (C;-C4)alkyl group, a CF; : group, an amino group, a mono (C;- Cq4)alkylamino group or a di(C;- C;)alkylamino group; Rs represents a hydrogen or halogen atom, a (C;-C4)alkoxy group, a (C;- Cq)alkyl group or a CF; group; Rg represents a hydrogen atom, a (C;- Cy) alkyl group or a (C;-C4)alkoxy group; as well as the salts or solvates thereof.
15. Pharmaceutical composition containing, as active principle, a compound of formula (I) according to any one of Claims 1 to 10 or a pharmaceutically acceptable salt or solvate thereof.
16. Composition according to Claim 15, characterized in that it contains from 0.001 mg to 100 mg of active principle. - AMENDED SHEET 2003 -05- 2 2
17. Use of a compound of formula (I) according to any one of Claims 1 to 10, or of a pharmaceutically acceptable salt or solvate thereof, for the preparation of analgesic medicinal products, and/or which are intended for the treatment of diseases associated with immune and inflammatory disorders.
18. A compound of Claim 1, other than the compounds of Claim 10, as specifically described herein.
19. A process of Claim 11, substantially as herein described with reference to any one of the illustrative Examples.
20. A process of Claim 12, substantially as herein described with reference to any one of the illustrative Examples.
21. A compound of Claim 13, as specifically described herein.
22. A compound of claim 14, as specifically described herein. AMENDED SHEET 2003 -05- 22
ZA200203037A 1999-10-22 2002-04-17 Phenyl- and pyridyl-tetrahydro-pyridines having TNF inhibiting activity. ZA200203037B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5118691A (en) * 1990-09-20 1992-06-02 Warner-Lambert Co. Substituted tetrahydropyridines as central nervous system agents

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FR2800071A1 (en) 2001-04-27

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