A method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I), a key intermediate in the synthesis of atorvastatin calcium, is described.

A method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide, a key intermediate in the synthesis of atorvastatin calcium, is described.
5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I) is a key intermediate in the synthesis of atorvastatin calcium (Lipitor(copyright)), known also by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate. Atorvastatin calcium inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and thus is useful as a hypolipidemic and/or hypocholesterolemic agent.
A number of patents have issued disclosing atorvastatin, as well as processes and key intermediates for preparing atorvastatin. These include: U.S. Pat. Nos. 4,681,893, 5,273,995, 5,003,080; 5,097,045, 5,103,024, 5,124,482, 5,149,837, 5,155,251, 5,216,174, 5,245,047, 5,248,793, 5,280,126, 5,397,792, 5,342,952, 5,298,627, 5,446,054, 5,470,981, 5,489,690, 5,489,691, 5,510,488, 5,998,633, 6,087,511, 5,969,156, 6,121,461, 5,273,995 6,476,235, 5,969,156, and 6,121,461.
Existing approaches to the preparation of key intermediate (I) presented some shortcomings. For example, one approach relied on the use of a costly chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction.
Scheme 1 summarizes an alternative approach disclosed in U.S. Pat. No. 6,476,235. Hydrogenation of xcex2,xcex4 diketoacid 2 in the presence of a chiral ruthenium catalyst under acidic conditions proceeded to give diol 3 in moderate to good yields and 1:1 syn:anti diastereoselectivity with respect to the C-3 and C-5 chiral centers. A number of additional transformations are then necessary to reset the stereochemistry of the C-3 center in diol 3 to provide key intermediate (I). These steps include: (a) intramolecular cyclization of 3 to provide lactone 4; (b) elimination of water from lactone 4 to provide xcex1,xcex2 unsaturated lactone 5; (c) facial selective Michael addition of allyl or benzyl alcohol to xcex1,xcex2 unsaturated lactone 5 to provide saturated lactone 6; and removal of the allyl or benzyl moiety in lactone 6 via hydrogenolysis provided key intermediate (I).
As a preliminary matter, the asymmetric hydrogenation of ketones is a known transformation in organic synthesis. However, the complexity of the reaction increases in the case of 1,3,5-tricarbonyl systems, and poor yields and poor stereoselectivities often result. In fact, investigations by Saburi (Tetrahedron, 1997, 1993;49) and Carpentier (Eur. J. Org. Chem. 1999;3421) have independently demonstrated low to moderate diastereo- and/or enantio-selectivities for diketoester asymmetric hydrogenations.
Furthermore, the fact that the processes disclosed in the literature require high pressure hydrogenation and extended reaction times makes the procedures generally impractical and not amenable to large-scale manufacturing processes where safety, efficiency, and cost are critical considerations.
As a result, a need remains for an approach to the preparation of key intermediate (I) that is efficient, inexpensive, proceeds in a minimum of transformations, and occurs in good yield and high levels of diastereoselectivity.
These and other needs are met by the present invention which is directed to a process for the preparation of a compound of formula (I)
comprising:
(a) contacting in a solvent a compound of formula (II) with a transition metal catalyst, a hydrogen source, and a base to give a compound of formula (III):
wherein
R1 is defined as xe2x80x94XR, wherein X is O, S, or Se, or
xe2x80x83wherein R2 and R3 are independently alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R2 and R3 taken together are xe2x80x94(CH2)4xe2x80x94,
xe2x80x94(CH2)5xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)3xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)4xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)2xe2x80x94CH(R4))xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)3xe2x80x94CH(R4))xe2x80x94,
xe2x80x94CH2xe2x80x94CH2-A-CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2-A-CH2CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2-A-CH2xe2x80x94CH(R4)xe2x80x94, wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or NH or NR wherein R is defined as alkyl, aryl, arylalkyl, or heteroaryl;
(b) conversion of the compound of formula (III) wherein R1 is as defined above to a compound of formula (IV) using base;
and
(c) contacting in a solvent the compound of formula (IV) with an acid to afford a compound of Formula (I).
The invention also provides a process for the preparation of a compound of formula (I)
comprising:
(a) contacting in a solvent compound of formula (V) with a transition metal catalyst, a hydrogen source, and a base to give a compound of formula (VI):
wherein
Rxe2x80x3 is defined as Me, Et, or t-Bu;
(b) conversion of the compound of formula (VI) wherein Rxe2x80x3 is as defined above to a compound of formula (IV) using base;
and
(c) contacting in a solvent the compound of formula (IV) with an acid to afford a compound of Formula (I).
As disclosed herein, we surprisingly and unexpectedly found that the diol esters of the present invention, (R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid esters, can be obtained directly from the corresponding 1,3,5-tricarbonyl precursors in a highly stereoselective manner via a mild and efficient ruthenium-catalyzed asymmetric transfer hydrogenation reaction utilizing transition metal catalysts with chiral non-racemic ligands. The reaction proceeds in good yields at ambient temperature and atmospheric pressure. The invention process is thus safer and more efficient in large scale than earlier approaches, because it avoids the need for specialized high pressure equipment and the use of hydrogen gas. Because the transfer hydrogenation reaction occurs with high levels of syn diastereoselectivity, additional transformations are not necessary to correct the stereochemistry of the C-3 center, as in previous approaches, and the overall number of steps needed to convert the compound of formula (II) to key intermediate (I) is minimized. Moreover, the invention process avoids the use of a costly, chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction, as was necessary in earlier approaches to the preparation of key intermediate (I).
Definitions
The term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d and xe2x80x9cthioalkoxyxe2x80x9d are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for xe2x80x9calkylxe2x80x9d.
The term xe2x80x9carylxe2x80x9d means an aromatic radical which is a phenyl group, a phenylalkyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano,
as defined above for alkyl, xe2x80x94(CH2)n2xe2x80x94N(alkyl)2 wherein n2 is an integer of from 1 to 5 and alkyl is as defined above and
as defined above for alkyl and n2.
The term xe2x80x9cheteroarylxe2x80x9d means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a benzene ring containing 1 to 3 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, or 2- or 5-thiadiazolyl and the like optionally substituted by a substituent selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano,
as defined above for alkyl, xe2x80x94(CH2)n2xe2x80x94N(alkyl)2 wherein n2 is an integer of 1 to 5, and alkyl is as defined above, and as
as defined above for alkyl and n2.
The term xe2x80x9carylalkylxe2x80x9d means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above for example, benzyl, phenylethyl, 3-phenylpropyl, (4-chlorophenyl)methyl, and the like.
Description of Invention Process
The invention process disclosed herein is depicted in Scheme 2 and commences in step (a) with transfer hydrogenation of a compound of formula (II) to form a compound of formula (III). In step (b), the
moiety (typically, an ester or an amide) in the compound of formula (III) is hydrolyzed to form the acid (IV). Finally, in step (c), lactonization of the acid (IV) provides key intermediate (I).
As a preliminary note, the carbonyl groups in the compound of formula (II) are shown in the keto form in Scheme 2. However, a compound of formula (II) can undergo xe2x80x9cketo-enolxe2x80x9d tautomerism and thus can exist in several tautomeric forms (II, II-a, II-b, II-c, and II-d), shown below, all of which are encompassed by the present invention.
Step (a)
The invention process commences with the transfer hydrogenation of a compound of formula (II) to provide a compound of formula (III). In one embodiment, R1 in a compound of formula (II) is defined as xe2x80x94XR,
wherein X is O, S, or Se, or
xe2x80x83wherein R2 and R3 are independently alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R2 and R3 taken together are xe2x80x94(CH2)4xe2x80x94,
xe2x80x94(CH2)5xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)3xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)4xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)2xe2x80x94CH(R4))xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)3xe2x80x94CH(R4))xe2x80x94,
xe2x80x94CH2xe2x80x94CH2-A-CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2-A-CH2CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2-A-CH2xe2x80x94CH(R4)xe2x80x94,
wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or NH or NR wherein R is defined as alkyl, aryl, arylalkyl, or heteroaryl.
In another embodiment of the present invention, R1 in a compound of formula (II) is OMe, OEt, or OtBu.
In step (a) of Scheme 2, the compound of formula (II) is contacted with a catalyst such as, for example, a transition metal catalyst with chiral non-racemic ligands in the presence of a hydrogen source and a base. xe2x80x9cContactingxe2x80x9d in step (a) comprises mixing the compound of formula II, formic acid, base, and a transition metal catalyst in a solvent to form a homogeneous or heterogeneous mixture.
The solvent in step (a) is typically an anhydrous or aqueous polar aprotic, polar protic, or nonpolar solvent, a ketone, toluene, benzene, or another aryl solvent available to the skilled artisan, or hexane. Thus, the solvent in step (a) is acetonitrile, ethyl acetate, tetrahydrofuran, dimethyl formamide, diethyl ether, methylene chloride, chloroform, methanol, ethanol, isopropanol, toluene, or the like, or mixtures or combinations thereof in the presence or absence of water as a cosolvent.
The concentration of the compound of formula (II) in the solvent in step (a) is generally about 0.2 Molar to about 0.6 Molar. Typically, the concentration is about 0.3 Molar to about 0.5 Molar, and preferably, about 0.35 Molar to about 0.45 Molar.
The transition metal catalyst in step (a) is typically a chiral, non-racemic transition metal catalyst. xe2x80x9cTransition metal catalystxe2x80x9d means a catalyst derived from one of the transition metal elements as provided in Rows 1B-8B of the periodic table of the elements. The chiral, non-racemic transition metal catalyst contemplated for use in the invention process include catalysts derived from the elements ruthenium, rhodium, iridium, or the like.
The chiral, non-racemic transition metal catalyst is prepared by reacting a catalyst precursor with a chiral, non-racemic ligand in a solvent such as, for example, methanol, ethanol, isopropanol, or the like, optionally in the presence of a co-solvent, for example, dichloromethane, tetrahydrofuran, toluene or the like, and a base such as triethylamine, according to methods available to the skilled artisan.
Catalyst precursors contemplated for use in the invention process include [dichloro-(1,5-cycloocta-diene)]ruthenium (II) oligomer, [RuCl2benzene]2, [RuCl2p-cymene]2, [RuCl2 mesitylene]2, [dibromo-(1,5-cyclooctadiene)]ruthenium (II) dimer, [bis-(2-methallyl)cycloocta-1,5-diene]ruthenium (II) complex, pentamethylcyclopenta-dienyl iridium (III)chloride dimer, and pentamethylcyclopentadienyl rhodium (III)chloride dimer.
Chiral, non racemic ligands contemplated for use in the invention process include chiral, non-racemic diphosphine ligands as well as chiral diamine ligands. Such ligands are disclosed, for instance, by Noyori, Ryoji; Hashiguchi, and Shohei in Acc. Chem. Res. (1997), 30(2), 97-102; or by Palmer, Matthew J. and Wills, Martin in Tetrahedron: Asymmetry (1999), 10(11), 2045-2061. For example, chiral diamine ligands, chiral amino alcohol ligands can be used to prepare the chiral, non-racemic transition metal catalyst. Chiral diamine ligands include compounds 7 and 8. Chiral alcohol amine ligands include norephedrine and the like.
However, any rhodium, iridium, or ruthenium (II) precursor/diphosphine or /diamine ligand combination may be employed in the transfer hydrogenation reaction of step (a).
Once prepared, the chiral, non-racemic transition metal catalyst is added to a mixture comprising the compound of formula (II), the hydrogen source, base, and solvent. The hydrogen source contemplated for use in the invention process is selected from isopropanol, formic acid, or ammonium formate. If isopropanol is selected as the hydrogen source, it is typically present in large excess and is used with NaOH as the base. If formic acid is selected as the hydrogen source, an amine is selected as the base. If ammonium formate is selected as the hydrogen transfer agent, an excess of ammonia may be used, or just 2 equivalents of a base as described herein may be used. Typically, the hydrogen source employed in step (a) in the invention process is formic acid.
As indicated previously, when formic acid is selected as the hydrogen source, an amine is typically selected as the base for the transfer hydrogenation reaction of step (a). The amine base is typically selected from triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU), lutidine, collidine, 4-dimethyl aminomethyl pyridine, diisopropyl amine, piperidine, pyrrolidine, tri-n-butyl amine, 4-methylmorpholine, and the like. Typically, however, the amine base is triethylamine.
In step (a) of the invention process, the molar equivalents of the compound of formula (II), of the hydrogen source, the base, and the transition metal catalyst respectively are generally about 1 equivalent of the compound of formula (II); about 2.0 to about 2.5 equivalents of hydrogen source; about 4 to about 5 equivalents of amine base; and about 0.05 to about 2 mol percent of the transition metal catalyst.
Typically, in step (a) of the invention process, the molar equivalents of the compound of formula (II), of the hydrogen source, the base, and the transition metal catalyst, respectively, are about 1 equivalent of the compound of formula (II); about 2.1 equivalents of hydrogen source; about 4.1 equivalents of amine base; and about 1 mol percent of the transition metal catalyst.
The step (a) mixture comprising the compound of formula (II), chiral, non-racemic transition metal catalyst, hydrogen source, base, and solvent is agitated, for example by employing a mechanical stirrer, magnetic stirrer, or other agitating means available to the skilled artisan, at a temperature of about 0 to about 50xc2x0 C. Typically, the temperature is about 10 to about 40xc2x0 C. Preferably, the temperature is about 20 to about 30xc2x0 C.
The pressure in step (a) is generally atmospheric pressure, or about 0.9 to about 1.1 atmospheres. Typically, the pressure is about 0.95 to about 1.05 atmospheres. Preferably, the pressure is about 0.99 to about 1.02 atmospheres.
The step (a) mixture is typically stirred or otherwise agitated at the temperature and pressure provided above until the reaction is complete by thin layer chromatography, or any other appropriate monitoring method available to the skilled artisan. Generally reaction times range from about 6 to about 24 hours. Typically, the reaction time for step (a) is from about 12 to about 18 hours.
When the step (a) reaction is complete, the solvent is removed by distillation at atmospheric or reduced pressure, to leave the compound of formula (III) as a residue, which can be used without further purification in subsequent reactions, or can be purified by column chromatography, or by other appropriate means known to the skilled artisan.
Step (b)
Step (b) of the invention process is disclosed in U.S. Pat. No. 6,476,235. In step (b), the ester or amide moiety in the compound of formula (III) is converted in a solvent to an acid moiety in compound (IV) under basic conditions. Thus, for example, the ester is dissolved in aqueous methanol tetrahydrofuran, or the like, and is treated with KOH. Alternatively, the ester can be dissolved in aqueous THF or a non water miscible solvent such as dichloromethane and phase transfer catalyst. Such methods and conditions are known and readily available to the skilled artisan.
Step (c)
Step (c) of the invention process is disclosed in U.S. Pat. No. 6,476,235 and provides 1, which is a convenient precursor to atorvastatin. Lactonization of compound (IV) in step (c) of the invention process occurs in the presence of aqueous acid to provide key intermediate (I). Thus, for example, the acid is stirred in toluene in the presence of a catalytic amount of HCl.

Process for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide


A disposable dispensing capsule for a plant injectable liquid composition includes a flexible cap hermetically sealed to a receptacle. The capsule is pressurized when the cap is forcibly flexed inwardly. In one embodiment flexure and thereby pressurization are maintained by an interference fit between a spindle in the receptacle and a socket depending downwardly from the cap central portion. In another embodiment flexure is maintained by engagement of hook-shaped posts in the receptacle with a lip in a collar depending downwardly from the cap central portion.

1. Field of the Invention
The invention relates to devices for injecting plants, principally trees, with therapeutic liquid compositions such as pest control agents and nutrients. More particularly, it relates to devices providing for safe handling of toxic liquids in economical disposable containers within which a slight super-atmospheric pressure can be developed by the user which forces the liquid contents out of the container and into a feeder tube inserted into a tree trunk or other plant stem.
2. Description of the Related Art
The treatment of plants, especially trees, through injection of pest control agents and liquid nutrients has been known for some time. U.S. Pat. No. 3,286,401 to J. J. Mauget (xe2x80x9c""401xe2x80x9d) discloses an apparatus and method for such treatment wherein a container including two mutually slidable cups with spaced interlocks is used in combination with a feeder tube which at one end penetrates a frangible diaphragm sealing a container aperture; the other end is driven into the plant stem. The telescopically compressible cups provide a container with a variable interior volume partially filled with a liquid composition; the remainder of the volume is occupied by a gaseous substance such as air. Sealing of the liquid contents is effected by means of interference fits between the concentric, smooth walls of the cups. This arrangement does not always provide a reliable seal. Small variations in the concentricities and dimensions of the cups and/or in atmospheric pressure, as well as imperfections due to interior surface scratches can permit discharge between the mutually slidable walls of at least a portion of the contents during shipment or storage. Such leakage is especially likely to occur if the liquid has a high affinity for forming a capillary film. Since liquid compositions such as insecticides and fungicides used to treat plants may be toxic or otherwise harmful to humans, it is important that the possibility of leakage under shipment, storage and operational conditions be eliminated.
U.S. Pat. No. 4,365,440 (xe2x80x9c""440xe2x80x9d) to D. D. Lenardson discloses a similar telescopically compressible container with improved sealing. The container includes a pair of cup-like body portions having interfitting and mutually slidable sidewalls which telescopically engage through open ends of the portions. The upper portion (or closure) has a base and a depending cylindrical sidewall. The lower portion (or receptacle) has a base and outer and inner concentric, spaced cylindrical sidewalls determining an annular socket for slidably receiving the closure sidewall. The distance between two parallel rings projecting from the outer surface of the closure sidewall determines the extent of axial travel of the compressed container. The inner surface of the receptacle outer wall has a groove for successively receiving the rings. A ratchet-like ring configuration impedes reversible disengagement of the closure from the receptacle while permitting forward, telescopically compressible relative movement of the receptacle and closure. Compression of the internal volume of the container pressurizes the fluid contents, forcing liquid into a connected feeder tube. Although the seal provided by the ring-and-groove combination minimizes leakage, it is not totally hermetic.
U.S. Pat. No. 5,249,391 to J. A. Rodgers discloses a telescopically compressible binary container including an integrated liquid discharge tube. The container is intended to be non-disposable, in contrast to the ""401 and ""440 containers. The tube, which is slidably carried by a guide tube, resists being pulled from the guide tube when it is withdrawn from a tree upon completion of an injection operation. A resiliently deformable latch on one container section and a latch surface and cam means on the other container section engageable with the latch combine to provide locking in the compressed position. The container sections may be divided into separate volumes for storing dissimilar liquid and liquid or solid compositions. When a seal is ruptured by piercing means carried by the latch, the several compositions are mixed prior to entering the discharge tube.
Other devices for injecting plants which do not utilize the technique of self-pressurizing a compressible binary container are known. For example, U.S. Pat. No. 6,032,411 to V. K. Foust and U.S. Pat. No. 5,239,773 to G. D. Doolittle, Jr. disclose a two-piece syringe, U.S. Pat. No. 4,989,366 to T. A. DeVlieger discloses a device including a plunger and funnel, and U.S. Pat. No. 4,144,673 to D. H. Quast et al. discloses a gravity-fed multi-injector system.
It is a primary object of the present invention to provide a hermetically sealed, disposable capsule for injecting a plant with a liquid composition which will not leak during shipment, storage or during an injection operation.
Another object of the invention is to provide a telescopically compressible capsule which will remain locked when in a pressurized state.
Yet another object of the invention is to provide a capsule which is inexpensive to fabricate and suitable for mass production using thermoplastic injection molding.
Other objects of the invention will become evident when the following description is considered with the accompanying drawing figures. In the figures and description, numerals indicate the various features of the invention, like numerals referring to like features throughout both the drawings and description.
These and other objects are achieved by the present invention which in one aspect provides a plant injection dispensing capsule including a receptacle containing a therapeutic liquid composition and having a floor and a wall, orthogonal to the floor, terminating in a rim. The capsule further includes a cap having a central portion, a flexible portion symmetric about the central portion, and a circumferential edge hermetically sealed to the rim. The capsule further includes means for maintaining inward flexure of the flexible portion, thereby keeping the capsule pressurized.
In another aspect the invention provides a plant injection dispensing capsule including a receptacle containing a therapeutic liquid composition and having a planar floor and a cylindrical wall, orthogonal to the floor, terminating in a circular rim. The wall has an aperture proximate to the floor sealed by a dislodgeable membrane, and the floor has a channel proximate to the aperture. The capsule further includes a cap having a rigid central portion circumscribed by a living hinge including concentric annuluses bridged by stepped ridges orthogonal to the annuluses, and a circular edge hermetically sealed to the rim. The living hinge flexes inwardly when a downward force is applied to the cap central portion. The receptacle further includes an upwardly tapering spindle depending upwardly from the floor and having an outer surface. The cap further includes a polygonal-shaped socket, depending downwardly from its central portion, having a polygonal bore determined by a plurality of planar surfaces. The spindle is forcibly received within the bore when the living hinge is forcibly flexed inwardly, thereby pressurizing the capsule and creating an interference fit between the spindle outer surface and the socket bore surfaces which maintains the inward flexure.
In still another aspect the invention provides a plant injection dispensing capsule including a receptacle containing a therapeutic liquid composition and having a planar floor and a cylindrical wall, orthogonal to the floor, terminating in a circular rim. The wall has an aperture proximate to the floor sealed by a dislodgeable membrane, and the floor has a channel proximate to the aperture. The capsule further includes a cap having a rigid central portion circumscribed by concentric annuluses bridged by stepped ridges orthogonal to the annuluses, and a circular edge hermetically sealed to the rim. The cap flexes inwardly when a downward force is applied to its central portion. The receptacle further includes three posts depending upwardly from the floor. Each post has a hook-shaped upper portion with a planar lower surface, and a lower portion orthogonal to the floor. The cap further includes a cylindrical collar, depending downwardly from its central portion, having a distally tapering end portion with a circumferential groove determining an annular lip having a generally planar upper surface. The lower surface of each post upper portion engages the lip upper surface when the cap is forcibly flexed inwardly, thereby maintaining the inward flexure to keep the capsule pressurized.
A more complete understanding of the present invention and other objects, aspects and advantages thereof will be gained from a consideration of the following description of the preferred embodiments read in conjunction with the accompanying drawings provided herein.

Dispensing capsule for injecting plants with pesticides and nutrients


A double-acting hydraulic actuator with an axial locking device has a cylinder chamber defined by two coaxial cylindrical walls of different diameters interconnected by a frustoconical wall. A guide piston sliding in the smaller-diameter cylindrical wall is fixed to an end of an actuator rod. The actuator rod has an annular protuberance of diameter equal to the diameter of the cylindrical wall. An annular stepped piston providing sealing between the two cylinder chambers is slidably mounted in a middle portion of the actuator rod to slide between the piston and the annular protuberance. When the actuator is extended, a narrowed end of the annular piston bears against conical surfaces of two half-rings and urges them outwards. When the half-rings are pushed outwards and the narrowed end of the annular piston becomes interposed between them and the middle portion of the actuator rod.

The invention relates to a double-acting hydraulic actuator comprising a cylinder body closed at one end by an end wall and at the other end by a cylinder head, a guide piston slidably mounted in the cylinder body, an actuator rod secured to the guide piston and passing in leaktight manner through the cylinder head, hydraulic means for actuating the actuator rod, and mechanical locking means for locking the actuator rod in a predetermined extended position.
In numerous applications, actuators are used for moving parts or tools, and said parts or tools need to be held in a fixed position throughout the duration of an operation.
This applies in particular when the parts in question are elements of a multi-part mold used for injection-molding pieces out of plastics material. In general, each mold element is fixed to the end of an actuator rod and actuating the actuator rod causes the element to move in translation. To prevent the actuator rod from retracting while the plastics material is being injected under high pressure, the moving element is prevented from moving relative to a fixed structure by means of a pin received in a bore formed in the element and in the structure, the bore extending in a direction perpendicular to the axis of the actuator rod. The pin is also handled by a second double-acting actuator. Thus, in order to position and fix a mold element relative to the structure, two double-acting actuators are used having rods that form a right angle, one of the actuators serving to displace the mold element while the other actuator serves to displace the fixing pin. The stresses due to pressure forces during molding are then taken up by the fixing pin.
That technique thus requires a bore to be made in each mold element and it requires two double-acting actuators to be available for each mold element. Above all, it presents the drawback of requiring considerable time both to put the mold into place and to perform unmolding, since the two actuators must be actuated consecutively. When the mold is being put into place, the actuator rod connected to the element is actuated first, and then once the element is in position, the actuator rod connected to the pin is actuated. For unmolding the injected part, the reverse procedure is performed.
DE 12 57 583 discloses a hydropneumatic actuator in which:
a) the cylinder body presents two coaxial cylindrical walls of different inside diameters and interconnected by a frustoconical annular section, the larger-diameter cylindrical wall being placed beside the cylinder head and the smaller-diameter cylindrical wall serving to guide the guide piston;
b) the actuator rod presents an annular protuberance between the guide piston and the cylinder head, the diameter of the protuberance being not more than the diameter of the smaller-diameter cylindrical wall, said protuberance being disposed in register with the larger-diameter cylindrical wall when the actuator rod is in the predetermined extended position;
c) the guide piston has means putting both sides of said guide piston into fluid communication;
d) an annular piston is placed on the portion of the actuator rod that is situated between the guide piston and the annular protuberance, the annular piston being capable of sliding in leaktight manner against the smaller-diameter cylindrical wall and being capable of sliding in leaktight manner against said portion of the actuator rod under drive of pressure agent between a position in which the actuator rod is released in which it bears against the guide piston, and a locked position in which it bears against the annular protuberance, said annular piston presenting a narrowed end section adjacent to the annular protuberance; and
e) the locking means have locking members and means for urging said locking members to move radially, which locking members, in the released position of the actuator rod, are received axially between a radial face of the protuberance and the annular piston and are housed radially between the portion of the actuator rod and the smaller-diameter cylindrical wall, and in the locked position, are received radially between the larger-diameter cylindrical wall and the narrowed end section of the annular piston and are housed axially between said radial face of the protuberance and the frustoconical section of the cylinder body.
In that document, the narrowed end of the annular piston is frustoconical and it terminates in a plane front face. The means for moving the locking members radially comprise chamfered pins passing axially through the annular protuberance and having chamfers disposed between the locking members to move them apart when the pins come to press against the head of the cylinder in the maximally extended position of the actuator rod. In the locked position, locking members bear against the frustoconical annular section of the cylinder body and against the frustoconical narrowed end of the annular piston. That is why that document provides for a spring between the annular piston and the guide piston.
The spring needs to exert considerable force in order to prevent total or partial unlocking of the actuator while the actuator rod is withstanding forces during an injection-molding operation. In addition, the chamfered pins are of a given length, which prevents subsequent modification of the length of the larger-diameter cylindrical wall in order to adjust the extended position of the actuator rod during injection-molding. In addition, the pressure of the fluid must be sufficient to compensate for the forces delivered by the spring.
An object of the invention is to propose a double-acting actuator which makes it possible to position a mold element in an accurate position and to withstand external compression forces exerted on the actuator rod during a molding operation, e.g. an injection-molding operation.
Another object of the invention is to provide a double-acting actuator in which the piston rod can be held stationary mechanically and with precision in a predetermined extended position.
Starting from the above state of the art, the hydraulic actuator of the present invention is characterized by the fact that the narrowed end section of the annular piston is cylindrical and is terminated by a conical surface for co-operating with a conical surface of the locking members so as to urge them radially outwards when the pressure agent acts on said annular piston in the direction for extending the actuator rod.
Thus, in the locked position, when the actuator rod is withstanding forces tending to cause it to retract, the locking members bear against the frustoconical annular section of the actuator body and exert radial forces only on the cylindrical narrowed section of the annular piston. The prior art spring is thus unnecessary and small pressures suffice for moving the actuator rod. The chamfered pins of the prior art are also eliminated.
Because the locking members in the locked position are spaced apart outwards and co-operate with the frustoconical section of the cylinder body, the bearing surfaces may be large in area, and the compression forces exerted axially on the head of the actuator rod can be taken up by the locking members alone, without any help from the pressure agent.
In order to increase considerably the area of the bearing surfaces, the locking members have conical surfaces facing radially outwards, which surfaces, in the locked position, co-operate with the frustoconical section of the cylinder body.
Preferably, the locking members are constituted by two half-rings.
In order to facilitate maintenance of the actuator in the event of the actuator rod buckling, the actuator rod is made up of two separable cylindrical parts connected together by screw-fastening, one of the parts having the annular protuberance and the portion of the piston rod on which the annular piston is mounted, and the other part sliding in the cylinder head.
Thus, in the event of the actuator rod buckling, the integrity of the internal portion of the actuator is ensured, and it suffices to use a spare part to replace the portion which slides in the cylinder head.
In order to enable the locked position to be adjusted accurately, the cylinder body is constituted by two coaxial portions, of which an outer portion includes the cylinder head, means for fixing to a structure, couplings for coupling to a fluid source, and a cylindrical outer wall having inside tapping, and an inner other portion comprises the end wall of the cylinder body and the body of the cylinder chamber, and presents an outside thread for co-operating with said inside tapping so as to enable the predetermined extended position to be adjusted relative to the structure, internal ducts being provided in said two portions between the couplings and the ends of the cylinder chamber.
This disposition presents an additional advantage. Because the couplings are disposed on the external portion fixed to the structure, the external ducts for hydraulic fluid delivery and exhaust are not subjected to any modification during adjustment. They can be constituted by rigid metal ducts instead of using flexible hoses.

Double acting hydraulic cylinder with axial locking device


A predictive model specifies a workload to be applied to a hierarchy of caches having multiple levels of caches. The predictive model defines a configuration for the hierarchy of caches by specifying cache characteristics of each level of the hierarchy of caches and the underlying storage pool and applies the workload to the configuration. For each level of the configuration, the predictive model computes a performance metric based on a portion of the workload satisfied at the level and the cache characteristics of the level. The predictive model computes resource allocation metrics based on the performance metric for the levels and a cost associated with the configuration. Based on the workload, the configuration, performance metrics, and resource allocation metrics, the predictive model creates a design time recommendation for the hierarchy of caches, a configuration time recommendation and run time recommendation for the hierarchy of caches.

The rapid expansion of information service and data processing industries has resulted in a need for computer systems to manage and store large amounts of data. As an example, financial service industry businesses such as banks, mutual fund companies or the like often operate large and complex data processing systems that require access to many hundreds of gigabytes or even terabytes of data. Data storage system developers have responded to these types of data storage requirements by integrating large capacity data storage systems, data communications devices and computer systems into networks called "storage networks" or "storage area networks" (SANs). A storage area network is a collection of data storage systems that are networked with a number of host computer systems that operate as servers to access data stored in the data storage systems.
SANs are large, complex environments that include various elements such as storage arrays, switches, hosts and databases all inter-networked. These elements occur in several hundreds in such environments. These elements in turn may consist of several hundred thousands of manageable elements such as storage devices, storage and switch ports, database instances, caches, host devices and file systems, and the like.
By storing frequently used data in caches placed throughout the SAN, requests for the frequently used data can be satisfied without incurring time costs associated with accessing the data at slower storage mediums. Hence, the efficiency and effectiveness of the SAN can be greatly improved by choosing a configuration of caches to be included in the SAN in light of the requests the SAN handles.

This patent is subject to a terminal disclaimer.

Predicting and optimizing I/O performance characteristics in a multi-level caching system


A chewing gum comprising at least one active pharmaceutical ingredient (API) with a core onto which is applied at least one inner polymer film coating and thereafter onto which is applied at least one outer hard coating. A preferred API is nicotine. Flavoring agents may be incorporated in the core, in the at least one inner polymer film coating and/or in the at least one outer hard coating. The gums formed exhibit a long lasting effect of flavoring agent(s) and result in the domination of flavoring agents in the coating(s) over flavoring agent(s) in the core, thereby (a) avoiding problems of chemical or pharmaceutical incompatibility between an API in the core and flavoring agent(s) in the coating(s) and (b) achieving an increased control of the release of the API and of non-active excipients.

The present invention is useful for any active pharmaceutical ingredient (API), which may be administered with a chewing gum. A preferred API is nicotine. The following background mainly concerns nicotine as the API.
Tobacco dependence and reduction thereof is an important field. In recent years, with the recognition of the harmful effects of tobacco smoking, there have been numerous campaigns and programs by governmental agencies and various health groups and other interested organisations to disseminate information about the adverse health effects resulting from tobacco smoking. Moreover, and as a result of this recognition of the harmful effects, there have been many programs directed to attempts in reducing smoking incidence.
Nicotine is an organic compound and is the principal alkaloid of tobacco. Nicotine is the chief addictive ingredient in the tobacco used in cigarettes, cigars, snuff and the like. Nicotine is also an addictive drug, though, and smokers characteristically display a strong tendency to relapse after having successfully stopped smoking for a time. Nicotine is the worlds second most used drug, after caffeine from coffee and tea.
The main problem with tobacco smoking is its enormous implications on health. It is estimated that smoking related diseases cause some 3-4 million deaths per year. According to Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 1995, MMWR 1997; 46:1217-1220, around 500,000 persons in the USA die each year as a result of tobacco use. In fact, excessive smoking is now recognised as one of the major health problems throughout the world. This grim consequence of tobacco smoking has urged many medical associations and health authorities to take very strong actions against the use of tobacco.
Even though tobacco smoking is decreasing in many developed countries today it is hard to see how the societies could get rid of the world's second most used drug.
The most advantageous thing a heavy smoker can do is to reduce or preferably even stop smoking completely. Experience shows, however, that most smokers find this extremely difficult since, mostly, tobacco smoking results in a dependence disorder or craving. The WHO has in its International Classification of Disorders a diagnosis called Tobacco Dependence. Others like the American Psychiatric Association call the addiction Nicotine Dependence. It is generally accepted that these difficulties to stop smoking result from the fact those heavy smokers are dependent on nicotine. The most important risk factors are, however, substances that are formed during the combustion of tobacco, such as carbon monoxide, tar products, aldehydes, and hydrocyanic acid.
The effects of nicotine must be considered. The administration of nicotine can give satisfaction and the usual method is by smoking, either by smoking e.g. a cigarette, a cigar or a pipe. However, smoking has health hazards and it is therefore desirable to formulate an alternative way of administering nicotine in a pleasurable manner that can be used to facilitate withdrawal from smoking and/or used as a replacement for smoking.
When smoking a cigarette, nicotine is quickly absorbed into the smoker's blood and reaches the brain within around ten seconds after inhalation. The quick uptake of nicotine gives the consumer a rapid satisfaction or kick. The satisfaction, then, lasts during the smoking time of the cigarette and for a period of time thereafter. The poisonous, toxic, carcinogenic, and addictive nature of smoking has provided efforts for methods, compositions and devices, which help in breaking the habit of smoking cigarettes.
Nicotine is an addictive poisonous alkaloid C5H4NC4H7NCH3, derived from the tobacco plant. Nicotine is also used as an insecticide. Approximately 40 milligrams of nicotine is able to kill an adult (Merck Index).
Nicotine replacement products are important in the reduction of smoking. One way to reduce smoking is to provide nicotine in a form or manner other than by smoking and some products have been developed to fulfill this need. Nicotine containing formulations are currently the dominating treatments for tobacco dependence.
The successes in achieving reduction in the incidence of smoking have been relatively poor using presently known products. The present state of the art involves both behavioral approaches and pharmacological approaches. More than 80% of the tobacco smokers who initially quit smoking after using some behavioral or pharmacological approach. These persons who singly reduce smoking incidence generally relapse and return to the habit of smoking at their former rate of smoking within about a one year's period of time.
As an aid for those who are willing to stop smoking there are several ways and forms of nicotine replacement products available on the market; such as nicotine chewing gum. Several methods and means have been described for diminishing the desire of a subject to use tobacco, which comprises the step of administering to the subject nicotine or a derivative thereof as described in e.g., U.S. Pat. No. 5,810,018 (oral nicotine spray), U.S. Pat. No. 5,939,100 (nicotine containing microspheres) and U.S. Pat. No. 4,967,773 (nicotine containing lozenge).
Nicotine-containing nose drops have been reported (Russell et al., British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al., Brit. J. of Addiction, Vol. 82, p. 983 (1987)). Nose drops, however, are difficult to administer and are not convenient for use at work or in other public situations. Ways of administrating nicotine by way of delivering nicotine directly into the nasal cavity by spraying is known from U.S. Pat. No. 4,579,858; DE 32 41 437; and WO 93/127 64. There may, however, be local nasal irritation with use of nasal nicotine formulations. The difficulty in administration also results in unpredictability of the dose of nicotine administered.
The use of skin patches for transdermal administration of nicotine has been reported (Rose, in Pharmacologic Treatment of Tobacco Dependence, (1986) pp. 158-166, Harvard Univ. Press). Nicotine-containing skin patches that are in wide use today can cause local irritation and the absorption of nicotine is slow and affected by cutaneous blood flow.
Also, inhaling devices resembling a cigarette are known for uptake of nicotine vapours as suggested in U.S. Pat. No. 5,167,242. Said means and methods address the problems associated with addiction to nicotine.
Nicotine chewing gum is an important approach. One of the most successful approaches to date in reducing the incidence of smoking relies upon nicotine containing chewing gum that is designed to reduce smoking withdrawal symptoms. The reported success rate is approximately twice that of placebo.
Various approaches have been discussed for smoking reduction and/or cessation. One successful product that is used as a smoking substitute and/or as a smoking cessation aid and which is based on nicotine is the chewing gum Nicorette®. This product was one of the first nicotine replacement forms that was approved by the Food and Drug Administration (FDA) and is still one of the most used nicotine replacement products. Nicorette® chewing gum has been on the market in many countries for several years. In this chewing gum the nicotine is present in the form of a complex with an insoluble cation-exchanger (polacrilex) that is dispersed in a gum base. The nicotine is slowly released from the gum due to chewing and will reach similar plasma levels as when smoking a cigarette after about 30 minutes depending on the chewing technique, i.e., slow or active. Patents related to this product are, e.g., U.S. Pat. Nos. 3,877,468; 3,901,248; and 3,845,217.
WO 98/23165 discloses a chewing gum wherein nicotine may be in the coating. This concept may provide rapid release of the nicotine from the coated chewing gum, but not a sufficiently rapid buccal uptake of the nicotine. The fraction of the released nicotine that is not immediately absorbed will be flushed down in the gastrointestinal (G.I.) tract by the saliva, thereby possibly causing hiccups and other G.I. side effects. Once absorbed by the G.I. route, this swallowed nicotine will be subjected to first pass metabolism.
WO 00/13662 discloses a chewing gum for systemic, oral administration of an active whereby said active is administered by the chewing gum composition in a bi-phasic manner. The bi-phasic delivery is obtained by the gum matrix as such, not from any coating.
WO 00/19977 discloses a substantially moisture-free and possibly coated chewing gum for delivery of an active. The possible coating is not described as being buffered.
U.S. Pat. No. 5,433,960, assigned to William Wrigley Jr. Company, discloses a stick-shaped chewing gum being coated with an edible film, which comprises at least one active chewing gum agent such as sweetener, flavor, softener, slip agent, flavor enhancer, antioxidant and/or color. The coating may comprise a first layer as an edible film and a second layer comprising e.g. wax, fat, oil and/or a lipid derivative. It is not disclosed that the stick-shaped chewing gum with its coating may comprise any other drug than said active chewing gum agent.
WO 02/102357, assigned to Pharmacia AB, discloses a nicotine-containing chewing gum product comprising at least one coating, which coating is buffered.
U.S. Pat. No. 5,135,761, assigned to the Wrigley Company, discloses a coated chewing gum comprising a center, an emulsifier coating covering the center, and a hard panned coating covering the emulsifier coating. The emulsifier coating does not contain a polymer.
EP 302024A, assigned to Warner-Lambert, discloses a chewing gum comprising a first portion containing an L-aspartic acid derived sweetener, a second portion containing at least one flavoring agent, and a protective barrier film between the first and the second portions.
U.S. Pat. No. 4,828,845, assigned to Warner-Lambert, discloses a process for producing a coated chewing gum, whereby at least three coating solutions are applied one after the other by spraying on to a chewing gum core.
ZA 8702849, assigned to Warner-Lambert, discloses a chewing gum with a core and at least two coating solutions, both solutions comprising sorbitol and film-forming agents, such as hydroxypropylmethyl cellulose ("HPMC").
U.S. Pat. No. 4,933,190, assigned to Warner-Lambert, discloses a chewing gum capable of releasing increased amounts of sweetness, which has a first inner coating comprising polyvinyl acetate and a second outer coating comprising a hydrophilic polymer.
None of the above references disclose any solution to the combined problems of obtaining a long lasting effect of flavoring agent(s), domination of flavoring agents in the coating(s) over flavoring agent(s) in the core, avoiding problems of chemical or pharmaceutical incompatibility between a drug in the core and flavoring agent(s) in the coating(s), and/or increasing the control of the release of the drug.

Flavoring of drug-containing chewing gums


A method of using oligocarbonates having terminal groups containing iodine to prepare molded articles (e.g., toys and medical equipment) having high X-ray contrast is described. The oligocarbonates contain more thaan one diol unit, and have a weight average molecular weight (Mw) of less than 3000.

The present patent application claims the right of priority under 35 U.S.C. 119 and 35 U.S.C. 365 of International Application No. PCT/EP99/09557, filed Dec. 7, 1999, which was published in German as International Patent Publication No. WO 00/37530 on Jun. 29, 2000, which is entitled to the right of priority of German Patent Application No. 198 58 774.0, filed Dec. 18, 1998.
This invention relates to the use of oligocarbonates having terminal groups containing iodine for moulded articles having high X-ray contrast, in particular for toys and medical accessories.
Materials which have as high a transparency as possible and good mechanical properties and can be detected in the body in X-ray examinations are sought for the field of medicine and for children""s toys. Unlike metallic articles, as a rule articles made of plastic are not, or only with difficulty, detectable in the X-ray image, particularly behind bones. X-ray contrast can be imparted to such moulding compositions by means of suitable additives.
Transparent plastics moulding compositions made from polycarbonates having terminal groups containing iodine are described in U.S. Pat. No. 3,469,704 and DE-A 17 20 812.
However, the expense of synthesis, especially in the case of polymers having a high molecular weight, can be extremely high and the iodine content attained in the moulding is in some cases low.
In commercially available iodine-containing compounds, problems can arise in connection with the compatibility, the colour fastness and the migration of molecules.
In prior art there is thus to date still no plastics composition available having an adequate X-ray contrast for use as transparent plastics articles, particularly toys and medical accessories.
Owing to its excellent mechanical properties, polycarbonate has long been used in particular for parts of toys which are transparent and subjected to high mechanical stress. It is now intended to develop a type of plastic which can be detected in a conventional X-ray image, with unaltered high transparency and as far as possible only slightly impaired mechanical properties. The layer thickness at which the plastic is still detectable should be as small as possible, but at most 1.2 mm.
The object was to develop moulding compositions which possess an adequate contrast in X-ray examinations, while having good mechanical properties and transparency. The addition of heavy metals was excluded on toxicological grounds, as materials for children""s toys were being sought.
The present application accordingly provides the use of oligocarbonates having terminal groups containing iodine for moulded articles having high X-ray contrast, wherein the oligocarbonates contain more than one diol unit and have a weight average molecular weight Mw of less than 3,000.
Mixtures of the iodine-containing compounds specified above with one another and with other iodine-containing substances are possible.
Particularly suitable oligocarbonates are those containing iodinated phenols, such as 2-iodophenol, 3-iodophenol, 4-iodophenol, 2,3-diiodophenol, 2,4-diiodophenol, 2,5-diiodophenol, 2,6-diiodophenol, 3,4-diiodophenol, 3,5-diiodophenol, 2,3,4-triiodophenol, 2,3,5-triiodophenol, 2,3,6-triiodophenol, 2,4,5-triiodophenol, 2,4,6-triiodophenol, 3,4,5-triiodophenol, as well as their alkyl-substituted compounds, as terminal groups. 2,4,6-triiodophenol is a particularly preferred terminal group. All diols mentioned in the present patent for use in polycarbonate are suitable as a diol unit for the iodinated oligocarbonates; 2,2-bis(4-hydroxyphenyl)propane is preferred.
The moulded articles, in particular toys and medical equipment, contain the oligomeric iodine compound in quantities such that the iodine content is from 0.2 to 19.9 wt. %, preferably 0.3 to 15 wt. %, particularly preferably 0.4 to 10 wt. %.
The oligocarbonates having terminal groups containing iodine are generally used in transparent plastics.
The transparent plastics used are preferably transparent thermoplastics, particularly preferably the polymers of ethylenically unsaturated monomers and/or polycondensates of bifunctional reactive compounds.
Particularly suitable plastics are polycarbonates or copolycarbonates based on diphenols. The oligomers according to the invention may also be used, however, with poly- or copolyacrylates and poly- or copolymethacrylates such as, for example, poly- or copolymethyl methacrylate, and also as copolymers with styrene such as, for example, transparent polystyrene-acrylonitrile (SAN).
They may also be incorporated into transparent cycloolefins, poly- or copolycondensates of terephthalic acid such as, for example, poly- or copolyethylene terephthalate (PET or CoPET) or glycol-modified PET (PETG).
The person skilled in the art will achieve excellent results with polycarbonates or copolycarbonates.
Thermoplastic aromatic polycarbonates for the purpose of the present invention are either homopolycarbonates or copolycarbonates; the polycarbonates may, in known manner, be linear or branched.
The oligocarbonates and polycarbonates or copolycarbonates are produced in known manner from diphenols, carbonic acid derivatives, optionally chain stoppers and optionally branching agents.
Details regarding the production of polycarbonates have been set down in many patent specifications for about 40 years. Here reference is made, by way of example, only to Schnell, xe2x80x9cChemistry and Physics of Polycarbonatesxe2x80x9d, Polymer Reviews, Vol. 9, Interscience Publishers, New York, London, Sydney, 1964, to D. Freitag, U. Grigo, P. R. Mxc3xcller, H. Nouvertne"", BAYER AG, xe2x80x9cPolycarbonatesxe2x80x9d in Encyclopedia of Polymer Science and Engineering, Vol. 11, Second Edition, 1988, pages 648-718 and finally, to Dres. U. Grigo, K. Kirchner and P. R. Mxc3xcller, xe2x80x9cPolycarbonatesxe2x80x9d in Becker/Braun, Kunststoff-Handbuch, Volume 3/1, Polycarbonate, Polyacetale, Polyester, Celluloseester, Carl Hanser Verlag, Munich, Vienna, 1992, pages 117-299.
Suitable diphenols for the production of polycarbonates are, for example, hydroquinone, resorcinol, dihydroxydiphenyls, bis(hydroxyphenyl)alkanes, bis(hydroxyphenyl)cycloalkanes, bis(hydroxyphenyl) sulfides, bis(hydroxyphenyl) ethers, bis(hydroxyphenyl) ketones, bis(hydroxyphenyl) sulfones, bis(hydroxyphenyl) sulfoxides, xcex1,xcex1xe2x80x2-bis(hydroxyphenyl)diisopropylbenzenes, as well as their ring-alkylated and ring-halogenated compounds.
Preferred diphenols are 4,4xe2x80x2-dihydroxydiphenyl, 2,2-bis(4-hydroxyphenyl)propane, 2,4-bis(4-hydroxyphenyl)-2-methylbutane, 1,1 -bis(4-hydroxyphenyl)-p-diisopropyl-benzene, 2,2-bis(3-methyl-4-hydroxyphenyl)propane, 2,2-bis(3-chloro-4-hydroxyphenyl)propane, bis(3,5-dimethyl-4-hydroxyphenyl)methane, 2,2-bis(3,5-dimethyl-4-hydroxyphenyl)propane, bis(3,5-dimethyl-4-hydroxyphenyl)sulfone, 2,4-bis(3,5-dimethyl-4-hydroxyphenyl)-2-methylbutane, 1,1 -bis(3,5-dimethyl-4-hydroxyphenyl)-p-diisopropylbenzene, 2,2-bis(3,5-dichloro-4-hydroxyphenyl)-propane, 2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane and 1,1-bis(4-hydroxyphenyl)-3,3,5-trimethylcyclohexane.
Particularly preferred diphenols are 2,2-bis(4-hydroxyphenyl)propane, 2,2-bis(3,5-dimethyl-4-hydroxyphenyl)propane, 2,2-bis(3,5-dichloro-4-hydroxyphenyl)propane, 2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane, 1,1 -bis(4-hydroxyphenyl)cyclohexane and 1,1 -bis(4-hydroxyphenyl)-3,3,5-trimethylcyclohexane.
These and other suitable diphenols are described for example in U.S. Pat. Nos. 3,028,635, 2,999,835, 3,148,172, 2,991,273, 3,271,367, 4,982,014 and 2,999,846, in Deutsche Offenlegungsschriften 1 570 703, 2 063 050, 2 036 052, 2 211 956 and 3 832 396, in the French Patent 1 561 518, in the monograph by H. Schnell, xe2x80x9cChemistry and Physics of Polycarbonatesxe2x80x9d, Interscience Publishers, New York, 1964 and in the Japanese published patent applications 62039/1986, 62040/1986 and 105550/1986.
In the case of homopolycarbonates, only one diphenol is used. In the case of copolycarbonates, several diphenols are used.
Examples of suitable carbonic acid derivatives are phosgene or diphenyl carbonate.
Both monophenols and monocarboxylic acids are suitable chain stoppers. Suitable monophenols are phenol itself, alkylphenols, such as cresols, p-tert.-butylphenol, p-n-octylphenol, p-isooctylphenol, p-n-nonylphenol and p-isononylphenol, halophenols such as p-chlorophenol, 2,4-dichlorophenol, p-bromophenol and 2,4,6-tribromophenol, 2,4,6-triiodophenol, p-iodophenol, and mixtures thereof.
A preferred chain stopper is p-tert.-butylphenol.
Suitable monocarboxylic acids are benzoic acid, alkylbenzoic acids and halobenzoic acids.
Preferred chain stoppers are the phenols corresponding to formula (I)
wherein R is hydrogen, tert. butyl or a branched or unbranched C8- and/or C9-alkyl group.
The quantity of chain stopper to be used is 0.1 mol % to 5 mol %, based on moles of the respective diphenols used. The chain stoppers may be added prior to, during or after the phosgenation.
Suitable branching agents are the trifunctional or more than trifunctional compounds known in polycarbonate chemistry, in particular those having three or more than three phenolic OH groups.
Suitable branching agents are, for example, phloroglucinol, 4,6-dimethyl-2,4,6-tri(4-hydroxyphenyl)-2-heptene, 4,6-dimethyl-2,4,6-tri(4-hydroxyphenyl)heptane, 1,3,5-tri(4-hydroxyphenyl)benzene, 1,1,1 -tri(4-hydroxy-phenyl)ethane, tri(4-hydroxy-phenyl)phenylmethane, 2,2-bis[4,4-bis(4-hydroxyphenyl)cyclohexyl]propane, 2,4-bis(4-hydroxyphenylisopropyl)phenol, 2,6-bis(2-hydroxy-5xe2x80x2-methylbenzyl)-4-methylphenol, 2-(4-hydroxyphenyl)-2-(2,4-dihydroxyphenyl)propane, hexa(4-(4-hydroxyphenylisopropyl)-phenyl)orthoterephthalate, tetra(4-hydroxyphenyl)-methane, tetra(4-(4-hydroxyphenylisopropyl)phenoxy)methane and 1,4-bis(4xe2x80x2,4xe2x80x3-dihydroxytriphenyl)methyl)benzene, as well as 2,4-dihydroxybenzoic acid, trimesic acid, cyanuric chloride and 3,3-bis(3-methyl-4-hydroxyphenyl)-2-oxo-2,3-dihydro-indole.
The quantity of optionally used branching agent is 0.05 mol % to 2 mol %, again based on moles of the respective diphenols used.
The branching agents may either be introduced in the alkaline phase together with the diphenols and the chain stoppers, or added in solution in an organic solvent prior to the phosgenation. In the case of the transesterification process, the branching agents are introduced together with the diphenols.
All these steps in the production of thermoplastic polycarbonates are familiar to the person skilled in the art.
The plastic naturally constitutes the bulk of the compositions, so that as a rule it is present in quantities of between 85.0 and 99.9 wt. %, preferably 90 and 99 wt. %, particularly preferably between 93 and 98 wt. %, of the moulded article.
In an embodiment of the present invention, the moulded article contains, in addition to the oligocarbonates having iodine containing terminal groups, at least one transparent thermoplastic (e.g., a non-halogenated polycarbonate or non-halogenated copolycarbonate) in quantities of 80 to 99.9 wt. % based on the moulded article. The transparent thermoplastic(s) is preferably present in an amount of 85 to 98 wt. %, and particularly preferably in an amount of 90 to 97 wt. %, based on the moulded article.
In a preferred embodiment, the iodine content of the moulding is from 0.2 to 19.9 wt. %, preferably 0.3 to 15 wt. %, particularly preferably 0.4 to 10 wt. %.
But it can also be desirable for the iodine content of the moulding to be from 20.1 to 30 wt. %.
To achieve improved compositions, at least one other additive conventionally present in thermoplastic materials, preferably poly- and copolycarbonates, may in addition be incorporatedxe2x80x94such as, for example, stabilisers (as described, for example, in EP 0 839 623 A1 or EP 0 500 496 A1), particularly heat stabilisers, in particular organic phosphites or phosphines, for example, triphenylphosphine; mould release agents, for example, fatty acid esters of glycerol or of tetramethanolmethane, with unsaturated fatty acids also being wholly or partially epoxidisable, in particular glycerol monostearate or pentaerythritol stearate (PETS); flameproofing agents, antistatic agents, UV absorbers, for example, triazoles; fillers, foaming agents, dyes, pigments, optical brighteners, transesterification catalysts and nucleating agents or the likexe2x80x94preferably each in quantities of up to 5 wt. %, preferably 0.01 to 5 wt. %, based on the total mixture, particularly preferably 0.01 to 1 wt. %, based on the quantity of plastic.
Mixtures of these additives are also possible.
Particularly good properties are achieved by using UV stabilisers of the triazole series. Here the following in particular may be mentioned: 2-(3xe2x80x2,5xe2x80x2-bis(1,1-dimethylbenzyl)-2xe2x80x2-hydroxyphenyl)benzotriazole, 2-(2xe2x80x2-hydroxy-5xe2x80x2-(tert-octyl)-phenyl)benzotriazole, 2-(2xe2x80x2-hydroxy-3xe2x80x2-(2-butyl)-5xe2x80x2-(tert-butyl)phenyl)benzotriazole, bis(3-(2H-benzotriazolyl)-2-hydroxy-5-tert-octyl)methane, 2-(4-hexoxy-2-hydroxyphenyl)-4,6-diphenyl-1,3,5-triazine, and benzophenones such as, for example, 2,4-dihydroxybenzophenone.
The X-ray opaque polymer compositions thus obtained can be converted into moulded articles such as, for example, parts of toys, as well as fibres, films, tapes, sheets, multi-wall sheets, vessels, tubes and other profiles, by the conventional methods such as, for example, hot pressing, spinning, extrusion or injection moulding. The polymer compositions can also be processed to form cast sheets. Accordingly, the invention also relates to the use of the polymer compositions according to the invention for the production of a moulded article. The use of multilayered systems is also of interest. In this connection, the polymer composition according to the invention having a relatively high content of iodine-containing additives is applied in a thin layer to a moulded article made from a polymer which is X-ray transparent. The application may take place at the same time as or immediately after the shaping of the parent substance, for example, by coextrusion or multicomponent injection moulding. But the application may also be to the finally shaped parent substance, for example, by lamination with a film or by coating with a solution. The moulding compositions are particularly suitable for transparent parts of children""s toys or for medical applications. In this connection, such moulded articles are most particularly suitable for small parts of children""s toys.

Use of oligomeric iodinated polycarbonates


A compound of formula I

This invention relates to a method of decreasing platelet adhesiveness.
According to the present invention there is provided a method of decreasing platelet adhesiveness, in which a therapeutically effective amount of a compound of formula I
including enantiomers and pharmaceutically acceptable salts thereof, in which R1 and R2 are independently H or methyl, is administered in conjunction with a pharmaceutically acceptable diluent or carrier to a human in need thereof.
A preferred compound of formula I is N,N-dimethyl-1-[1-(4- chlorophenyl)cyclobutyl]-3-methylbutylamine or a salt. A preferred form of this hydrochloride is its monohydrate.
The preparation and use of compounds of formula I, such as N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine, N-{1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutyl}-N-methylamine, and 1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutylamine and salts thereof, in the treatment of depression is described in British Patent Specification 2098602 and U.S. Pat. No. 4,522,328. The use of compounds of formula I such as N,N-dimethyl-1-[1-(4- chlorophenyl) cyclobutyl]-3-methylbutylamine and salts thereof in the treatment of Parkinson""s disease is described in published PCT application WO88/06444. The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof in the treatment of cerebral function disorders is described in U.S. Pat. No. 4,939,175. The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutylamine hydrochlorid in the treatment of obesity is described in published PCT application WO90/061 10. A particularly preferred form of this compound is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate (sibutramine hydrochloride) which is described in European Patent Number 230742. The use of N,N-dimethyl-1-[1-(4- chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof for improving the glucose tolerance of humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus is described in published PCT application WO95/20949.
It will be appreciated by those skilled in the art that compounds of formula I contain a chiral centre. When a compound of formula I contains a single chiral centre it may exist in two enantiomeric forms. The present invention includes the use of the individual enantiomers and mixtures of the enantiomers. The enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
Preferred compounds of formula I are N,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutylamine, N-{1-[1-(4-chlorophenyl) cyclobutyl]-3-methylbutyl}-N- methylamine, and 1-[1-(4-chlorophenyl) cyclobutyl]-3-methylbutylamine including racemates, individual enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof.
The individual enantiomers can be prepared by enantioselective synthesis from optically active precursors, or by resolving the racemic compound which can be prepared as described above. Enantiomers of secondary amines of the formula I can also be prepared by preparing the racemate of the corresponding primary amine, resolving the latter into the individual enantiomers, and then converting the optically pure primary amine enantiomer into the required secondary amine by methods described in British Patent Specification 2098602.
Specific examples of compounds of formula I are:
(+)-N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine;
(xe2x88x92)-N-{(1-[1-(4-chlorophenyl)cyclobutyl-3-methylbutyl} N-methylamine;
(+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine;
(xe2x88x92)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine;
(+)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-dimethylamine;
(xe2x88x92)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-dimethylamine.
The hydrochloride salts are preferred in each case, but the free bases and other pharmaceutically acceptable salts are also suitable.
The compound of formula I may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 50 mg preferably 1 to 30 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmacist""s art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound. The tablets and capsules may conveniently each contain 1 to 50 mg of the active compound.
Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil. The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion. The granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
The therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol. Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
The therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity. Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
The therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
The invention further provides the use of compounds of formula I in the manufacture of a medicament for decreasing platelet adhesiveness.
In another aspect, the invention further provides a pharmaceutical composition for decreasing platelet adhesiveness, comprising a compound of formula I in conjunction with a pharmaceutically acceptable diluent or carrier.
Monoamine reuptake inhibitors have been used to treat certain of the disorders described in the present invention. However, these compounds are known to suffer from a number of disadvantages. Firstly such compounds are not effective in all patients. Secondly where the compounds are effective they may not provide a complete cure of the disorder. Thirdly, there are many undesirable side-effects known with this type of compound. Such side-effects include nausea, sexual dysfunction, light headedness, somnolence, sweating, tremor, dry mouth, asthenia, insomnia, diarrhoea, headache, vomiting, anxiety, drowsiness, dizziness, fever, rash or allergic reactions, arthralgia, myalgia, convulsions, hypomania and mania.
Sibutramine (Formula I, R1=CH3, R2 =CH3) has a pharmacological profile which is unique amongst monoamine reuptake inhibitors. Through its pharmacologically active metabolites, (metabolite 1, R1=H, R2=CH3 in Formula I and metabolite 2, R1=H, R2=H in Formula I) sibutramine inhibits the reuptake of all three monoamines differentiating it from serotonin (5-HT)-selective reuptake inhibitors, e.g. fluoxetine, noradenaline-selective reuptake inhibitors, e.g. desipramine, dopamine-selective reuptake inhibitors, e.g. bupropion, and serotonin-noradenaline reuptake inhibitors, e.g. venlafaxine (Table 1). It is this unique combination of pharmacological actions which renders sibutramine, and the other compounds of formula 1, efficacious in the decrease of platelet adhesiveness.
The assays below are performed in a similar manner to those described in WO98/41528.

Treatment to lower platelet adhesiveness

Abstract: A compound of formula I

Abstract: or a pharmaceutically acceptable salt thereof in which R1 and R2 are independently H or methyl (for example N,N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methylbutyl amine hydrochloride optionally in the form of its monohydrate) is used for decreasing platelet adhesiveness.