Compounds of formulae I and Ia,

The present invention relates to chiral phosphinitemothyl-oxazolines; to a process for the preparation thereof; to intermediates used in the preparation thereof; to metal complexes with metals selected from sub-groups I and VII of the Periodic Table of the Elements (d-10 and d-8 metals, referred to as TM8 metals hereinbelow) and phosphinitomethyl-oxazolines as ligands; to a process for asymmetric synthesis by means of an addition reaction between hydrogen, borohydrides or silanes and a carbon-carbon or carbon-hetero atom multiple bond in prochiral organic compounds or by means of an addition reaction between C-nucleophiles or amines and allylic compounds, especially for asymmetric hydrogenation of carbon-carbon or carbon-hetero atom multiple bonds with hydrogen, in the presence of catalytic amounts of the metal complexes; and to the use of the metal complexes as catalysts for asymmetric synthesis by means of an addition reaction between hydrogen, borohydrides or silanes and a carbon-carbon or carbon-hetero atom multiple bond in prochiral organic compounds or by means of an addition reaction between C-nucleophiles or amines and allylic compounds, especially for asymmetric hydrogenation of carbon-carbon or carbon-hetero atom multiple bonds with hydrogen.
G. Helmchen and A. Pfaltz in Accounts of Chemical Research, Volume 33, Number 6, pages 336 to 345 (2000) describe chiral phosphinophenyl-oxazolines as P,N ligands for asymmetric catalysts that are used inter alia in the enantioselective addition of nucleophiles to carbon-carbon double bonds. The oxazoline ring is substituted with bulky groups in the xcex1-position to the nitrogen atom to form an asymmetric centre (carbon atom).
It has been found, surprisingly, that it is possible to prepare in simple manner P,N ligands that contain a phosphinitemethyl group in the xcex1-position to the nitrogen atom to form an asymmetric centre (carbon atom), which phosphinitemethyl group serves at the same time as a chelating group. Those substituted oxazolines form with TM8 metals chiral complexes that are excellent catalysts for the enantioselective addition of hydrogen, borohydrides or silanes to a carbon-carbon or carbon-hetero atom multiple bond in prochiral organic compounds or of C-nucleophiles or amines to allylic compounds or for the enantioselective coupling of aryl or alkenyl triflates to olefins (Heck reaction). Especially in the enantio-selective hydrogenation of prochiral olefins catalysed with Ir complexes, particularly high optical yields are observed. In addition, the phosphinite groups in the ligands exhibit a surprisingly high stability towards hydrolysis. The starting materials for the preparation of the ligands are simple, in some cases commercially available organic molecules that can be combined with one another in a variety of ways, so that the steric and electronic properties of the ligands in respect of catalytic activity and steric selectivity can be adapted to the substrates to be reacted in an outstanding manner.
The invention relates to compounds of formulae I and Ia,
wherein
X1 is secondary phosphino;
R3 is hydrogen, a hydrocarbon radical having from 1 to 20 carbon atoms, a heterohydro-carbon radical, bonded via a carbon atom, having from 2 to 20 atoms and at least one hetero atom selected from the group OS and NR, or ferrocenyl;
R is H or C1-C4alkyl;
each R4 individually or both R4 together are a hydrocarbon radical having from 1 to 20 carbon atoms; and
R01 and R02 are each independently of the other a hydrogen atom or a hydrocarbon radical having from 1 to 20 carbon atoms.
The phosphine group X1 may contain two identical or two different hydrocarbon radicals or the two hydrocarbon radicals may form with the P atom a 3- to 8-membered ring. Preferably the phosphine group contains two identical hydrocarbon radicals. The hydrocarbon radicals may be unsubstituted or substituted and they may contain from 1 to 22, preferably from 1 to 12, carbon atoms. Of the compounds of formulae I and la special preference is given to those wherein the phosphine group contains two identical or different radicals selected from the group: linear or branched C1-C12alkyl; C5-C12cycloalkyl or C5-C12cycloalkyl-CH2xe2x80x94 unsubstituted or substituted by C1-C6alkyl or by C1-C6alkoxy; phenyl or benzyl; and phenyl or benzyl substituted by halogen (for example F, Cl and Br), C1-C6alkyl, C1-C6haloalkyl (for example trifluoromethyl), C1-C6alkoxy, C1-C6haloalkoxy (for example trifluoromethoxy), (C6H5)3Si, (C1-C12alkyl)3Si, secondary amino or by xe2x80x94CO2xe2x80x94C1-C6alkyl (for example xe2x80x94CO2CH3).
The two radicals in the phosphine group may together also be dimethylene, trimethylene, tetramethylene or pentamethylene unsubstituted or substituted by halogen, C1-C6alkyl or by C1-C6alkoxy. The substituents are preferably bonded in the two ortho positions to the P atom.
The phosphine groups may also be those of formulae
wherein o and p are each independently of the other an integer from 2 to 10, and the sum of o+p is from 4 to 12, preferably from 5 to 8, and the phenyl rings are unsubstituted or substituted by C1-C4alkyl and C1-C4alkoxy. Examples are [3.3.1]- and [4.2.1]-phobyl of the formulae
Examples of secondary phosphine groups in which the two hydrocarbon radicals form with the P atom a 3- to 8-membered ring are especially those of the formula
which may be substituted in one or both ortho positions and optionally the meta positions to the P atom by C1-C4alkyl and/or by C1-C4alkoxy.
Examples of P substituents as alkyl, which preferably contains from 1 to 6 carbon atoms, are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the isomers of pentyl and hexyl. Examples of P substituents as unsubstituted or alkyl-substituted cycloalkyl are cyclopentyl, cyclohexyl, methyl- and ethyl-cyclohexyl and dimethylcyclohexyl. Examples of P substituents as phenyl and benzyl substituted by alkyl, alkoxy, haloalkyl and/or by haloalkoxy are methylphenyl, dimethylphenyl, trimethylphenyl, ethylphenyl, methylbenzyl, methoxyphenyl, dimethoxyphenyl, trifluoromethylphenyl, bis-trifluoromethylphenyl, tris-trifluoromethylphenyl, trifluoromethoxyphenyl and bis-trifluoromethoxyphenyl.
Preferred phosphine groups X1 are those which contain identical or different, preferably identical, radicals selected from the group C1-C6alkyl; cyclopentyl or cyclohexyl unsubstituted or substituted by from 1 to 3 C1-C4alkyl or C1-C4alkoxy substituents; benzyl and especially phenyl, which are unsubstituted or substituted by from 1 to 3 C1-C4alkyl, C1-C4alkoxy, F, Cl, C1-C4fluoroalkyl or C1-C4fluoroalkoxy substituents.
In the compounds of formula I, X1 is preferably the group xe2x80x94PR1R2 wherein R1 and R2 are each independently of the other a hydrocarbon radical having from 1 to 20 carbon atoms, which is unsubstituted or substituted by halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, (C6H5)3Si, (C1-C12alkyl)3Si or by xe2x80x94CO2xe2x80x94C1-C6alkyl; or wherein R1 and R2 together are dimethylene, trimethylene, tetramethylene or pentamethylene unsubstituted or substituted by C1-C4alkyl and/or by C1-C4alkoxy.
R1 and R2 are preferably identical or different, especially identical, radicals selected from the group: branched C3-C6alkyl; cyclopentyl or cyclohexyl unsubstituted or substituted by from one to three C1-C4alkyl or C1-C4alkoxy substituents; benzyl unsubstituted or substituted by from one to three C1-C4alkyl or C1-C4alkoxy substituents, and especially phenyl unsubstituted or substituted by from one to three C1-C4alkyl, C1-C4alkoxy, xe2x80x94NH2, OH, F, Cl, C1-C4fluoroalkyl or C1-C4fluoroalkoxy substituents.
R1 and R2 are more especially identical or different, especially identical, radicals selected from the group: phenyl unsubstituted or substituted by from one to three C1-C4alkyl, C1-C4alkoxy or C1-C4fluoroalkyl substituents.
The radicals R3 and R4 may be unsubstituted or substituted, for example by C1-C6alkyl, C1-C6alkoxy, cyclohexyl, C6-C10aryl, C7-C12aralkyl, C1-C4alkyl-C6-C10aryl, C1C4alkoxy-C6-C10aryl, C1-C4alkyl-C7-C12aralkyl, C1-C4alkoxy-C7-C12aralkyl, xe2x80x94COxe2x80x94OR5, xe2x80x94COxe2x80x94NR6R7 or by xe2x80x94NR6R7, wherein R5 is H, an alkali metal, C1-C6alkyl, cyclohexyl, phenyl or benzyl, and R6 and R7 are each independently of the other hydrogen, C1-C6alkyl, cyclohexyl, phenyl or benzyl, or R6 and R7 together are tetramethylene, pentamethylene or 3-oxapentylene.
The hydrocarbon radical R3 contains preferably from 1 to 16, more especially from 1 to 12, carbon atoms. The hydrocarbon radical R3 may be C1-C18alkyl, preferably C1-C12alkyl and more especially C1-C8alkyl; C3-C12cycloalkyl, preferably C4-C8cycloalkyl and more especially C5-C6cycloalkyl; or C6C16aryl and preferably C6-C12aryl.
When R3 is alkyl, it is preferably branched C3-C8alkyl. Examples of alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and eicosyl. Preferred alkyl is isopropyl, isobutyl, tert-butyl, isopentyl, isohexyl and 1,1,2,2-tetramethylethyl.
When R3 is cycloalkyl, it may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl or cyclododecyl.
When R3 is aryl, it may be, for example, phenyl, naphthyl, anthracenyl, phenanthryl, biphenyl or ferrocenyl.
The heterohydrocarbon radical R3 contains preferably a total of from 1 to 16, more especially a total of from 1 to 12, atoms and from 1 to 3 hetero atoms selected from the group O, S and NR. The heterohydrocarbon radical R3 may be C1-C18heteroalkyl, preferably C1-C2heteroalkyl and more especially C1-C8heteroalkyl; C3-C12heterocycloalkyl, preferably C4-C8heterocycloalkyl and more especially C4-C5heterocycloalkyl; or C4-C16heteroaryl and preferably C4-C11heteroaryl.
When R3 is ferrocenyl, the ferrocenyl is unsubstituted or substituted by at least one C1-C4alkyl, C1-C4alkoxy, trimethylsilyl or halogen substituent, for example methyl, ethyl, n- or iso-propyl, butyl, methoxy, ethoxy, F, Cl or Br.
When R3 is alkyl, it is preferably C1-C8alkyl. Examples of heteroalkyl are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, isopropoxymethyl, isopropoxyethyl, isobutoxyethyl, tert-butoxyethyl, methylthioethyl and dimethylaminoethyl.
When R3 is heterocycloalkyl, it may be, for example, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, dioxanyl, pyrrolidinyl or N-methylazacyclohexyl.
When R3 is heteroaryl, it may be, for example, furanyl, thiophenyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl or quinoxalinyl.
In a preferred sub-group, R3 is a hydrocarbon radical selected from the group: branched C3-C12alkyl, C5-C6cycloalkyl, ferrocenyl and C6-C12aryl, the cyclic radicals being unsubstituted or substituted by halogen (F, Cl, Br), C1-C4alkyl or by C1-C4alkoxy.
R4 as a hydrocarbon radical contains preferably from 1 to 16, especially from 1 to 12, more especially from 1 to 8, carbon atoms. The hydrocarbon radical R4 may be C1-C18alkyl, preferably C1-C12alkyl and more especially C1-C8alkyl; C3-C12cycloalkyl, preferably C4-C8cycloalkyl and more especially C5-C6cycloalkyl; C6-C16aryl and preferably C6-C12aryl, or C7-C16aralkyl and preferably C7-C12aralkyl.
When the two R4 are a hydrocarbon radical, that radical is alkylene, which preferably contains from 3 to 7, more especially from 4 to 6, carbon atoms. Examples are 1,3-propylene, 1,3- or 1,4-butylene, 1,3-, 1,4- or 1,5-pentylene and 1,3-, 1,4-, 1,5-, 2,5-, 2,6- or 1,4-hexylene.
The embodiments and preferences given for R3 apply to R4 in respect of alkyl, cycloalkyl and aryl. When R4 is aralkyl, it is preferably benzyl or naphthylmethyl, which are unsubstituted or substituted by halogen (F, Cl, Br), C1-C4alkyl or by C1-C4alkoxy.
In a preferred sub-group, R4 is a hydrocarbon radical selected from the group: branched C3-C12alkyl, C5-C6cycloalkyl, C6-C12aryl and C7-C12aralkyl, the cyclic radicals being unsubstituted or substituted by halogen (F, Cl, Br), C1-C4alkyl, C1-C4haloalkyl (for example trifluoromethyl) or by C1-C4alkoxy.
The embodiments and preferences given for R4 apply independently to R01 and R02. When R01 and R02 are different radicals or one of R01 and R02 is a hydrogen atom, the compounds of formulae I and Ia contain a further chiral carbon atom. The invention relates also to racemates or diastereoisomers of those compounds. The relative configuration of the diastereoisomers may have a positive influence on the enantioselectivity in addition reactions catalysed according to the invention. R01 and R02 are preferably each hydrogen. In another preferred group, R01 is hydrogen and R02 is C1-C4alkyl.
A preferred sub-group of the compounds according to the invention comprises those of formulae Ib and Ic,
wherein
X1 is xe2x80x94PR1R2,
R1 and R2 are identical or different, especially identical, radicals selected from the group: xcex1-branched C3-C6alkyl; C5-C7cycloalkyl unsubstituted or substituted by from one to three C1-C4alkyl or C1-C4alkoxy substituents; phenyl unsubstituted or substituted by from one to three C1-C4alkyl, C1-C4alkoxy or C1-C4fluoroalkyl substituents; and dimethylene, trimethylene, tetramethylene or hexamethylene unsubstituted or substituted by C1-C4alkyl or by C1-C4alkoxy;
R3 is a hydrocarbon radical selected from the group: branched C3-C12alkyl, C5-C6cycloalkyl, C6-C12aryl and ferrocenyl, the cyclic radicals being unsubstituted or substituted by halogen, C1-C4alkyl, C1-C4haloalkyl or by C1-C4alkoxy; and
R4 is a hydrocarbon radical selected from the group: branched C3-C12alkyl, C5-C6cycloalkyl, C6-C12aryl and C7C12aralkyl, the cyclic radicals being unsubstituted or substituted by halogen, C1-C4alkyl or by C1-C4alkoxy.
The compounds of formulae I and Ia can be prepared in a small number of process steps in two different ways, xcex1-amino-xcex2-hydroxycarboxylic acid esters being a fundamental reagent. In a first variant, iminocarboxylic acid esters are cyclised with xcex1-amino-xcex2-hydroxycarboxylic acid esters to form oxazolinecarboxylic acid esters, the ester group is then converted into a tertiary alcohol group, and subsequently the phosphonite is formed. In a second variant, a carboxylic acid or a carboxylic acid derivative is reacted with an xcex1-amino-xcex2-hydroxycarboxylic acid ester, the ester group is then converted into a tertiary alcohol group, cyclisation to the oxazoline is carried out and subsequently the phosphonite is formed.
The invention relates also to a process for the preparation of compounds of formulae I and Ia,
wherein R01, R02, R3, R4 and X1 are as defined above, and xcx9c denotes the R- or S-form, in which process either
a1) a compound of formula II
or a salt thereof, wherein R3 is as defined above and R8 is C1-C4alkyl, is reacted with at least an equivalent amount of a compound of formula III,
wherein R9 is C1-C4alkyl, to form a compound of formula IV,
a2) the compound of formula IV is reacted with at least 2 equivalents of an organometal compound of formula V or Va
R4xe2x80x94X2xe2x80x83xe2x80x83(V),
R4xe2x80x94(X2)2xe2x80x83xe2x80x83(Va),
wherein R4 is as defined above, X2 is an alkali metal or xe2x80x94Me1X3, Me1 is Mg or Zn, and X3 is Cl, Br or I, to form a compound of formula VI
and
a3) the hydroxyl group in the compound of formula VI is metallated and then reacted with a halophosphine of formula VII,
X1xe2x80x94Y1xe2x80x83xe2x80x83(VII),
wherein X1 is as defined above and Y1 is Cl, Br or I, to form a compound of formula Ia or Ib; or
b1) a carboxylic acid of formula VIII
R3xe2x80x94COOHxe2x80x83xe2x80x83(VIII),
or a derivative of that carboxylic acid, is reacted with a compound of formula III to form a carboxylic acid amide of formula IX,
b2) the compound of formula IX is reacted with a compound of formula V or Va to form a compound of formula X,
b3) the compound of formula X is cyclised to form a compound of formula VI; and
b4) the hydroxyl group in the compound of formula VI is metallated and then reacted with a halophosphine of formula VII to form a compound of formula Ia or Ib.
The invention relates also to compounds of formula IV wherein R01 is a hydrogen atom and R02 is a hydrocarbon radical having from 1 to 20 carbon atoms, and R3, R4 and R9 are as defined above.
The invention relates also to compounds of formula VI wherein R01 and R02 are each independently of the other a hydrogen atom or a hydrocarbon radical having from 1 to 20 carbon atoms, and R3 and R4 are as defined above.
Process Step a1)
The preparation of iminocarboxylic acid esters of formula II is generally known and is described, for example, by L. Weintraub et al. in J. Org. Chem., Volume 33, No. 4, pages 1679 to 1681 (1968). The iminocarboxylic acid esters of formula II are advantageously used in the form of salts, for example tetrafluoroborates. In formula II, R8 may be, for example, methyl, ethyl, n- or iso-propyl or butyl. The reaction can be carried out at temperatures of from 20 to 150xc2x0 C. It is advantageous to use solvents such as, for example, halogenated hydrocarbons (methylene chloride, trichloromethane or tetrachloroethane). Equivalent amounts of the reactants are generally used. Serinecarboxylic acid esters of formula III are known. R9 may be, for example, methyl, ethyl, n- or iso-propyl or butyl.
Process Step a2)
The reaction of carboxylic acid esters with metal or metal halide hydrocarbons is known per se. When X2 is an alkali metal, it may be Na, K or especially Li. In the group Me1X3, Me1 may be, for example, Mg or Zn. The reaction is advantageously carried out by adding the compound of formula V at low temperatures, for example from xe2x88x9230 to xe2x88x9280xc2x0 C., to a solution of the compound of formula IV and then heating the mixture, for example to room temperature. The reaction can then be completed at that temperature or at higher temperatures (up to the boiling temperature of the solvents used). Suitable solvents are especially ethers, such as diethyl ether, dibutyl ether, tetrahydrofuran and dioxane.
Process Step a3)
The metallation of the compound of formula VI to form metal alcoholates can be carried out with alkali metal alkyls and especially lithium alkyl, for example lithium methyl, ethyl, propyl or butyl, or with Grignard reagents, such as methyl-, ethyl-, propyl-, butyl- or benzyl-magnesium halides. It is advantageous to use equivalent amounts or a slight excess of alkali metal alkyls or Grignard reagents. The addition is advantageously made at relatively low temperatures, for example from xe2x88x9220 to xe2x88x9280xc2x0 C. The presence of tertiary amines, for example trimethyl-, triethyl- or tributyl-amine or tetramethylethylenediamine may be advantageous. Then at room temperature the reaction can be completed, the halophosphine of formula VII added and the reaction ended at that temperature. The reaction is preferably carried out in the presence of inert solvents, for example ethers or hydrocarbons (pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene or xylene).
Process Step b1)
Suitable derivatives of carboxylic acids are esters, amides and especially halides. The reaction is advantageously carried out in the presence of solvents, for example halogenated hydrocarbons. When carboxylic acids of formula VII are used, the addition of equimolar amounts of tertiary amines is advantageous, for example diisopropylethylamine. The presence of at least equimolar amounts of carbodiimides is also advantageous. In order to suppress racemisation, the carboxylic acids can be converted into activated esters in the presence of metal salts, for example copper salts, with selected alcohols, for example hydroxybenzotriazole. The reaction can be carried out at temperatures of from xe2x88x9230 to 50xc2x0 C.
Process Step b2)
This reaction can be carried out analogously to Process step a2).
Process Step b3)
The reaction is advantageously carried out in the presence of a solvent, for example halogenated hydrocarbons, and at temperatures of preferably from 50 to 150xc2x0 C. A tertiary amine, for example triethylamine, and a sulfonic acid halide, such as p-toluenesulfonyl chloride, are added to a solution of the compound of formula X and the mixture is heated to reflux temperature. The reaction mixture is left to react for a period of time, water is added and then the reaction mixture is allowed to react to completion.
Process Step b4)
This reaction can be carried out analogously to Process step a3).
The compounds of formulae Ia and Ib are obtained in good total yields. By selection of the starting compounds it is possible for the compounds according to the invention to be synthesised in a modular manner, the simple starting compounds allowing a large number of substitutions in respect of R3 and R4.
The invention relates also to the intermediates of formulae IV, VI and X obtainable in the process according to the invention.
The compounds of formulae Ia and Ib according to the invention are ligands for metal complexes selected from the group of TM8 metals, especially from the group Ru, Rh and Ir, which are excellent catalysts or catalyst precursors for asymmetric syntheses, for example the asymmetric hydrogenation of prochiral, unsaturated, organic compounds. When prochiral unsaturated organic compounds are used, it is possible to induce a very large excess of optical isomers in the synthesis of organic compounds and to achieve a high chemical conversion in short reaction times. The enantioselectivities and catalyst activities that are achievable are excellent.
The invention relates also to metal complexes of metals selected from the group of TM8 metals with compounds of formulae I and Ia as ligands.
Examples of metals that come into consideration are Cu, Ag, Au, Ni, Co, Rh, Pd, Ir and Pt. Preferred metals are rhodium and iridium and also ruthenium, platinum and palladium.
Especially preferred metals are ruthenium, rhodium and iridium.
The metal complexes may, according to the oxidation state and coordination number of the metal atom, contain further ligands and/or anions. They may also be cationic metal complexes. Such analogous metal complexes and their preparation are frequently described in the literature.
The metal complexes may correspond, for example, to the general formulae XI and XII,
A1MeLnxe2x80x83xe2x80x83(XI),
(A1MeLn)(z+)(Exe2x88x92)zxe2x80x83xe2x80x83(XII),
wherein
A1 is a compound of formula I or Ia,
L denotes identical or different, monodentate, anionic or non-ionic ligands, or two L denote identical or different, bidentate, anionic or non-ionic ligands;
n is 2, 3 or 4 when L is a monodentate ligand, or n is 1 or 2 when L is a bidentate ligand;
z is 1, 2 or 3;
Me is a metal selected from the group Rh, Ir and Ru; the metal having the oxidation state 0, 1, 2, 3 or 4;
Exe2x88x92 is the anion of an oxyacid or complex acid; and the anionic ligands balance the charge of oxidation states 1, 2, 3 or 4 of the metal.
The preferences and embodiments described above apply to the compounds of formulae I and Ia.
Monodentate non-ionic ligands may be selected, for example, from the group of olefins (for example ethylene, propylene), allyls (allyl, 2-methallyl), solvating solvents (nitriles, linear or cyclic ethers, optionally N-alkylated amides and lactams, amines, phosphines, alcohols, carboxylic acid esters, sulfonic acid esters), nitrogen monoxide and carbon monoxide.
Monodentate anionic ligands may be selected, for example, from the group halide: (F, Cl, Br, I), pseudohalide (cyanide, cyanate, isocyanate) and anions of carboxylic acids, sulfonic acids and phosphonic acids (carbonate, formate, acetate, propionate, methylsulfonate, trifluoromethylsulfonate, phenylsulfonate, tosylate).
Bidentate non-ionic ligands may be selected, for example, from the group of linear or cyclic diolefins (for example hexadiene, cyclooctadiene, norbornadiene), dinitriles (malonic dinitrile), optionally N-alkylated carboxylic acid diamides, diamines, diphosphines, diols, acetonyl acetonates, dicarboxylic acid diesters and disulfonic acid diesters.
Bidentate anionic ligands may be selected, for example, from the group of anions of dicarboxylic acids, disulfonic acids and diphosphonic acids (for example of oxalic acid, malonic acid, succinic acid, maleic acid, methylenedisulfonic acid and methylenediphosphonic acid).
Preferred metal complexes are also those wherein E is xe2x80x94Clxe2x88x92, xe2x80x94Brxe2x88x92, xe2x80x94Ixe2x88x92, ClO4xe2x88x92, CF3SO3xe2x88x92, CH3SO3xe2x88x92, HSO4xe2x88x92, (CF3SO2)2Nxe2x88x92, (CF3SO2)3Cxe2x88x92, tetraaryl borates, for example B(phenyl)4xe2x88x92, B[bis(3,5-trifluoromethyl)phenyl]4xe2x88x92, B[bis(3,5-dimethyl)phenyl]4xe2x88x92, B(C6F5)4xe2x88x92 and B(4-methylphenyl)4xe2x88x92, BF4xe2x88x92, PF6xe2x88x92, SbCl6xe2x88x92, AsF6xe2x88x92 or SbF6xe2x88x92.
Especially preferred metal complexes, which are particularly suitable for hydrogenations, correspond to formulae XIII and XIV,
[A1Me2YZ]xe2x80x83xe2x80x83(XIII),
[A1Me2Y]+E1xe2x88x92xe2x80x83xe2x80x83(XIV),
wherein
A1 is a compound of formula I or Ia;
Me2 is rhodium or iridium;
Y denotes two olefins or a diene;
Z is Cl, Br or I; and
E1xe2x88x92 is the anion of an oxyacid or complex acid.
The embodiments and preferences described above apply to the compounds of formulae I and Ia.
Y as olefin may denote C2-C12-, preferably C2-C6- and more especially C2-C4-olefin. Examples are propene, but-1-ene and especially ethylene. The diene may contain from 5 to 12, preferably from 5 to 8, carbon atoms and it may be an open-chain, cyclic or polycyclic diene. The two olefin groups of the diene are preferably bonded by one or two CH2 groups. Examples are 1,3-pentadiene, cyclopentadiene, 1,5-hexadiene, 1,4-cyclohexadiene, 1,4- or 1,5-heptadiene, 1,4- or 1,5-cycloheptadiene, 1,4- or 1,5-octadiene, 1,4- or 1,5-cyclooctadiene and norbornadiene. Y preferably denotes two ethylene or 1,5-hexadiene, 1,5-cyclooctadiene or norbornadiene.
In formula XIII, Z is preferably Cl or Br. Examples of E1 are BF4xe2x88x92, ClO4xe2x88x92, CF3SO3xe2x88x92, CH3SO3xe2x88x92, HSO4xe2x88x92, B(phenyl)4xe2x88x92, B[bis(3,5-trifluoromethyl)phenyl]4xe2x88x92, PF6xe2x88x92, SbCl6xe2x88x92, AsF6xe2x88x92 and SbF6xe2x88x92.
The metal complexes according to the invention are prepared in accordance with methods known in the literature (see also U.S. Pat. Nos. 5,371,256, 5,446,844, 5,583,241, and E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I to III, Springer Verlag, Berlin, 1999, and literature referred to therein).
The metal complexes according to the invention are homogeneous catalysts, or catalyst precursors capable of being activated under the reaction conditions, which can be used for asymmetric addition reactions with prochiral, unsaturated, organic compounds.
The metal complexes can be used, for example, for the asymmetric hydrogenation (addition of hydrogen) of prochiral compounds having carbon-carbon or carbon-hetero atom multiple bonds, especially double bonds. Such hydrogenations with soluble homogeneous metal complexes are described, for example, in Pure and Appl. Chem., Vol. 68, No. 1, pp. 131-138 (1996). Preferred unsaturated compounds to be hydrogenated contain the groups Cxe2x95x90C, Cxe2x95x90N and/or Cxe2x95x90O. For the hydrogenation the use of metal complexes of rhodium and iridium is preferred according to the invention.
The metal complexes according to the invention can also be used as catalysts in the asymmetric hydroboration (addition of borohydrides) of prochiral organic compounds having carbon-carbon double bonds. Such hydroborations are described, for example, by Tamio Hayashi in E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I to III, Springer Verlag, Berlin, 1999, pages 351 to 364. Suitable borohydrides are, for example, catechol boranes. The chiral boron compounds can be used in syntheses and/or reacted in a manner known per se to form other chiral organic compounds that are valuable building blocks for the preparation of chiral intermediates or active ingredients. One example of such a reaction is the preparation of 3-hydroxy-tetrahydrofuran (according to DE 198 07 330).
The metal complexes according to the invention can also be used as catalysts in the asymmetric hydrosilylation (addition of silanes) of prochiral organic compounds having carbon-carbon or carbon-hetero atom double bonds. Such hydrosilylations are described, for example, by G. Pioda and A. Togni in Tetrahedron: Asymmetry, 1998, 9, 3093 or by S. Uemura, et al. in Chem. Commun. 1996, 847. Suitable silanes are, for example, trichlorosilane or diphenylsilane. For the hydrosilylation of, for example, Cxe2x95x90O and Cxe2x95x90N groups it is preferable to use metal complexes of rhodium and iridium. For the hydrosilylation of, for example, Cxe2x95x90C groups it is preferable to use metal complexes of palladium. The chiral silyl compounds can be used in syntheses and/or reacted in a manner known per se to form other chiral organic compounds that are valuable building blocks for the preparation of chiral intermediates or active ingredients. Examples of such reactions are hydrolysis to alcohols.
The metal complexes according to the invention can also be used as catalysts for asymmetric allylic substitution reactions (addition of C-nucleophiles to allyl compounds). Such allylations are described, for example, by A. Pfaltz and M. Lautens in E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I to III, Springer Verlag, Berlin, 1999, pages 833 to 884. Suitable precursors for allyl compounds are, for example, 1,3-diphenyl-3-acetoxy-1-propene and 3-acetoxy-1-cyclohexene. For that reaction it is preferable to use metal complexes of palladium. The chiral allyl compounds can be used in syntheses for the preparation of chiral intermediates or active ingredients.
The metal complexes according to the invention can also be used as catalysts in asymmetric amination (addition of amines to allyl compounds) or in asymmetric Heck reactions. Such aminations are described, for example, by A. Pfaltz and M. Lautens in E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I to III, Springer Verlag, Berlin, 1999, pages 833 to 884, and Heck reactions by O. Loiseleur et al. in Journal of Organometallic Chemistry 576 (1999), pages 16 to 22. Suitable amines, in addition to ammonia, are primary and secondary amines. For the amination of allyl compounds it is preferable to use metal complexes of palladium. The chiral amines can be used in syntheses for the preparation of chiral intermediates or active ingredients.
The invention relates also to the use of the metal complexes according to the invention as homogeneous catalysts in the preparation of chiral organic compounds by asymmetric addition of hydrogen, borohydrides or silanes to a carbon-carbon or carbon-hetero atom multiple bond in prochiral organic compounds or asymmetric addition of C-nucleophiles or amines to allyl compounds.
The invention relates further to a process for the preparation of chiral organic compounds by asymmetric addition of hydrogen, borohydrides or silanes to a carbon-carbon or carbon-hetero atom multiple bond in prochiral organic compounds or asymmetric addition of C-nucleophiles or amines to allyl compounds in the presence of a catalyst, wherein the addition is carried out in the presence of catalytic amounts of at least one metal complex according to the invention.
Preferred prochiral unsaturated compounds to be hydrogenated may contain one or more, identical or different groups Cxe2x95x90C, Cxe2x95x90N and/or Cxe2x95x90O in open-chain or cyclic organic compounds, the groups Cxe2x95x90C, Cxe2x95x90N and/or Cxe2x95x90O being part of a ring system or being exocyclic groups. The prochiral unsaturated compounds may be alkenes, cycloalkenes and heterocycloalkenes, and also open-chain or cyclic ketones, ketimines and ketohydrazones. They may correspond, for example, to formula X,
R07R08Cxe2x95x90Dxe2x80x83xe2x80x83(XVIII),
wherein
R07 and R08 are so selected that the compound is prochiral and are each independently of the other an open-chain or cyclic hydrocarbon radical or heterohydrocarbon radical having hetero atoms selected from the group O, S and N, that contains from 1 to 30, preferably from 1 to 20, carbon atoms;
D is O or a radical of formula Cxe2x95x90R09R10 or NR11;
R09 and R10 each independently of the other have the same meanings as R07 and R08,
R11 is hydrogen, C1-C12alkyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkyl-C1-C6alkyl, C3-C11heterocycloalkyl, C3-C11heterocycloalkyl-C1-C6alkyl, C6-C14aryl, C5-C13heteroaryl, C7-C16aralkyl or C6-C14heteroaralkyl,
R07 and R08 together with the carbon atom to which they are bonded form a hydrocarbon ring or heterohydrocarbon ring having from 3 to 12 ring members;
R07 and R08 each together with the Cxe2x95x90C group to which they are bonded form a hydrocarbon ring or heterohydrocarbon ring having from 3 to 12 ring members;
R07 and R11, each together with the Cxe2x95x90N group to which they are bonded form a hydrocarbon ring or heterohydrocarbon ring having from 3 to 12 ring members;
the hetero atoms in the heterocyclic rings being selected from the group O, S and N; and R07, R08, R09, R10 and R11 are unsubstituted or substituted by C1-C6alkyl, C1-C6alkoxy, cyclohexyl, C6-C10aryl, C7-C12aralkyl, C1-C4alkyl-C6-C10aryl, C1-C4alkoxy-C6-C10aryl, C1-C4alkyl-C7-C12aralkyl, C1-C4alkoxy-C7-C12aralkyl, xe2x80x94OH, xe2x95x90O, xe2x80x94COxe2x80x94OR12, xe2x80x94COxe2x80x94NR13R14 or by xe2x80x94NR13R14, wherein R12 is H, an alkali metal, C1-C6alkyl, cyclohexyl, phenyl or benzyl, and R13 and R14 are each independently of the other hydrogen, C1-C6alkyl, cyclohexyl, phenyl or benzyl, or R13 and R14 together are tetramethylene, pentamethylene or 3-oxapentylene.
Examples and preferences for substituents have been given above.
R07 and R08 may be, for example, C1-C20alkyl and preferably C1-C12alkyl, C1-C20heteroalkyl and preferably C1-C12heteroalkyl having hetero atoms selected from the group O, S and N, C3-C12cycloalkyl and preferably C4-C8cycloalkyl, C-bonded C3-C11heterocycloalkyl and preferably C4-C8heterocycloalkyl having hetero atoms selected from the group O, S and N, C3-C12cycloalkyl-C1-C6alkyl and preferably C4-C8cycloalkyl-C1-C6alkyl, C3-C11heterocycloalkyl-C1-C6alkyl and preferably C4-C8heterocycloalkyl-C1-C6alkyl having hetero atoms selected from the group O, S and N, C6-C14aryl and preferably C6-C10aryl, C5-C13heteroaryl and preferably C5-C9heteroaryl having hetero atoms selected from the group O, S and N, C7-C15aralkyl and preferably C7-C11aralkyl, C6-C12heteroaralkyl and preferably C6-C10heteroaralkyl having hetero atoms selected from the group O, S and N.
When R07 and R08, R07 and R09, or R07 and R11, in each case together with the group to which they are bonded, form a hydrocarbon ring or heterohydrocarbon ring, that ring preferably contains from 4 to 8 ring members. The heterohydrocarbon ring may contain, for example, from 1 to 3, preferably one or two, hetero atoms.
R11 is preferably hydrogen, C1-C6alkyl, C1-C6alkoxy, C4-C8cycloalkyl, C4-C8cycloalkyl-C1-C4alkyl, C4-C10heterocycloalkyl, C4-C10heterocycloalkyl-C1-C4alkyl, C6-C10aryl, C5-C9heteroaryl, C7-C12aralkyl or C5-C13heteroaralkyl.
Some examples of unsaturated organic compounds are acetophenone, 4-methoxyacetophenone, 4-trifluoromethylacetophenone, 4-nitroacetophenone, 2-chloroacetophenone, corresponding unsubstituted or N-substituted acetophenonebenzylimines, unsubstituted or substituted benzocyclohexanone or benzocyclopentanone and corresponding imines, imines from the group of unsubstituted or substituted tetrahydroquinoline, tetrahydropyridine and dihydropyrrole, and unsaturated carboxylic acids, esters, amides and salts, for example xcex1- and optionally xcex2-substituted acrylic acids or crotonic acids. Preferred carboxylic acids are those of the formula
R12xe2x80x94CHxe2x95x90C(R13)xe2x80x94C(O)OH
and their salts, esters and amides, wherein R12 is C1-C6alkyl; C3-C8cycloalkyl unsubstituted or substituted by from 1 to 4 C1-C6alkyl, C1-C6alkoxy or C1-C6alkoxy-C1-C4alkoxy substituents, or C6-C10aryl, preferably phenyl, unsubstituted or substituted by from 1 to 4 C1-C6alkyl, C1-C6alkoxy or C1-C6alkoxy-C1-C4alkoxy substituents; and R13 is linear or branched C1-C4C1-C6alkyl (for example isopropyl) or, unsubstituted or substituted as defined above, cyclopentyl, cyclohexyl, phenyl or protected amino (for example acetylamino).
The process according to the invention can be carried out at low or elevated temperatures, for example from xe2x88x9220 to 150xc2x0 C., preferably from xe2x88x9210 to 100xc2x0 C., more especially from 10 to 80xc2x0 C. The optical yields are generally better at lower temperature than at higher temperatures.
The process according to the invention can be carried out at normal pressure or excess pressure. The pressure may be, for example, from 105 to 2xc3x97107 Pa (Pascal). Hydrogenations can be carried out at normal pressure or at excess pressure. Better selectivities are often observed at normal pressure.
Catalysts are used preferably in amounts of from 0.0001 to 10 mol %, especially from 0.001 to 10 mol %, more especially from 0.01 to 5 mol %, based on the compound to be hydrogenated.
The preparation of the ligands and catalysts and also the addition reaction can be carried out without a solvent or in the presence of an inert solvent, it being possible to use one solvent or a mixture of solvents. Examples of suitable solvents are aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (methylene chloride, chloroform, di- and tetra-chloroethane), nitrites (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diethylene glycol monomethyl or monoethyl ether), ketones (acetone, methyl isobutyl ketone), carboxylic acid esters and lactones (ethyl or methyl acetate, valerolactone), N-substituted lactams (N-methylpyrrolidone), carboxylic acid amides (dimethylamide, dimethylformamide), acyclic ureas (dimethylimidazoline), and sulfoxides and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, tetramethylene sulfone) and alcohols (methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether) and water. The solvents can be used on their own or in a mixture of at least two solvents.
The reaction can be carried out in the presence of co-catalysts, for example quaternary ammonium halides (tetrabutylammonium iodide) and/or in the presence of protonic acids, for example mineral acids (see, for example, U.S. Pat. Nos. 5,371,256, 5,446,844 and 5,583,241 and EP-A-0 691 949). The co-catalysts are especially suitable for hydrogenations.
The metal complexes used as catalysts can be added in the form of separately prepared isolated compounds or alternatively they can be formed in situ prior to the reaction and then mixed with the substrate to be hydrogenated. It may be advantageous, when isolated metal complexes are being used in the reaction, additionally to add ligands or, in the case of in situ preparation, to use the ligands in excess. The excess may be, for example, from 1 to 10 mol, preferably from 1 to 5 mol, based on the metal compound used for preparation.
The process according to the invention is generally carried out by first introducing the catalyst into the reaction vessel and then adding the substrate, optionally reaction auxiliaries and the addition reaction compound and subsequently starting the reaction. Compounds to be added that are in gaseous form, for example hydrogen or ammonia, are preferably introduced under pressure. The process can be carried out continously or intermittently in various types of reactor.
The chiral organic compounds that can be prepared according to the invention are active ingredients or intermediates in the preparation of such ingredients, especially in the field of the manufacture of pharmaceuticals and agrochemicals. For example, o,o-dialkyl aryl-ketamine derivatives, especially those having alkyl and/or alkoxyalkyl groups, are effective as fungicides, especially as herbicides. The derivatives may be amine salts, acid amides, for example of choroacetic acid, tertiary amines and ammonium salts (see e.g. EP-A-0 077 755 and EP-A-0 115 470).
The following Examples illustrate the invention. Chromatographic separation and purification is carried out using C-Gel C-560 (Uetikon AG, Switzerland).

Phosphinite-oxazolines and metal complexes thereof

Abstract: Compounds of formulae I and Ia,

Abstract: wherein

Abstract: X1 is secondary phosphino; R3 is hydrogen, a hydrocarbon radical having from 1 to 20 carbon atoms, a heterohydrocarbon radical, bonded via a carbon atom, having from 2 to 20 atoms and at least one hetero atom selected from the group O, S and NR, or ferrocenyl; R is H or C1-C4alkyl; each R4 individually or both R4 together are a hydrocarbon radical having from 1 to 20 carbon atoms; and R01 and R02 are each independently of the other a hydrogen atom or a hydrocarbon radical having from 1 to 20 carbon atoms, are chiral ligands for metal complexes with metals of sub-groups I and VII, which are catalysts for asymmetric addition reactions, for example of hydrogen, to prochiral unsaturated organic compounds.


A bottle dispenser is configured for storing and dispensing bottles having a neck rim. The dispenser includes a substantially rectangular housing with a central opening formed therein. A bottle carrier lid is secured within the central opening and includes a sloped guide track configured for slidably supporting the neck rims of a plurality of bottles for storing and dispensing the bottles. The guide track is sufficiently sloped to advance bottles along the guide track automatically as bottles are dispensed.

Bottles such as two-liter beverage containers are typically shipped in trays or shipping crates, and are loaded manually onto a display rack, shelving unit, or refrigeration display unit at grocery stores or convenience stores for sale. Because the display rack or shelving unit typically does not advance bottles automatically, the display shelves must be periodically rearranged for properly advancing the bottles in order to maintain a neat and effective sales display. Also, the bottles may require reshuffling in order to achieve an appropriate product rotation so that bottles are dispensed generally in the same order in which they are loaded.
Most bottles, particularly plastic bottles, include a neck rim or ring adjacent the bottle cap. So-called "neck-trackers" are used in some refrigeration units for supporting the neck rings and automatically advancing the bottles for display as a result of gravity as bottles are dispensed. However, such neck trackers require rear-loading which is sometimes inconvenient.
It is desirable to provide a bottle storage container which may be used for shipping as well as displaying and dispensing the bottles for sale. It is also desirable to provide a display unit which is front-loaded to allow convenient loading in floor display arrangements. It is further desirable to provide such a bottle storage and display dispenser which receives and dispenses the bottles in an upright position to properly align the bottle labels for convenience in bottle handling.


Various methods of assessing the regenerative potential of dermal tissue in a patient may be determined and methods to determine the potential development of stretch marks in a patient are provided. Through the analysis of a series of dermal tissue samples, a method of monitoring the aging process of the dermal tissue of a patient is possible. Damaged or stretched marked skin may also be used in the development of various diagnostic therapies relating to the inducement of the extracellular matrix components of the skin due to the loss of elastic fibers generally found in stretch marked skin.

Elastin is an amorphous protein present in the elastic fibers of tissues such as arteries, blood vessels, skin, tendons and elastic ligaments, the abdominal wall, and lungs. Unlike other fibrous tissues like collagen, elastin is unique in that it may be stretched to over 150 percent of its original length but it can rapidly return to its original size and shape. This property of elastin provides tissues that incorporate it, the required ability to resume their original form after stretching due to blood flow, breathing, or bending. Like collagen protein, elastin contains about 30% glycine amino acid residues and is rich in proline. Elastin differs from collagen in that it contains very little hydroxyproline and no hydroxylysine. Elastin has a very high content of alanine and also contains two unique amino acids isodesmosine and desmosine. These amino acids are believed to be responsible for elastin's ability to return to its original shape after stretching.
Tropoelastin is a soluble precursor of elastin; it is a peptide with a molecular weight in the range of 70-75 kDa, it is synthesized by dermal fibroblasts and secreted in association with the 67 kDa elastin binding protein (EBP). EBP acts as a molecular chaperone protecting the highly hydrophobic tropoelastin molecules from intracellular self-aggregation and premature degradation and facilitating their proper assembly on the microfibrillar scaffold in the extracellular space. In the arterial tissues tropoelastin is produced and secreted into the extacellular space by smooth muscle cells; in other tissues it is produced in cells, like fibroblast cells, and is also secreted into the extracellular space. In these cells tropoelastin is synthesized by ribosomes in the rough endoplasmatic reticulum and processed by the Golgi apparatus. The soluble tropoelastin molecules secreted (often referred to a proelastin before secretion) into the extracellular space synthesize to form Elastin filaments and sheets via cross linking of the tropoelastin molecules primarily by crosslinking of lysine amino acid residues to form desmosine and isodesmosine. Mature elastin is amorphous and contains many cross links which makes it nearly impossible to solublize.
The resiliency of skin is maintained by elastic fibers in the extracellular matrix (ECM). These ECM components are organized into a networks of rope-like structures and composed of two major components: an amorphous core, consisting of extensively crosslinked elastin which makes up the bulk (>90%) of the fiber; and the 10-12-nm microfibrils made up of several distinct glycoproteins.
In various tissue or biological functions, inelastic collagen fibers may be interwoven with the elastin to limit stretching of the elastin and prevent tearing of elastin comprising tissue. Elastic fibers may also contain glycoproteins as microfibrils, which may serve to organize tropoelastin molecules secreted into the extracellular space for later crosslinking. Examples of such glycoproteins include laminin, which is a large glycoprotein and a major component of basement membranes and is made by all epithelial cells, and fibronectin which is a cell-surface and blood glycoprotein involved in a variety of cell surface phenomena.
Combinations of components of the extracellular matrix have been incorporated into cosmetic compositions. Elastin is insoluble due to its high degree of cross linking at its lysine residues and also because of its high content (about 75%) of hydrophobic amino acids (Gly, Val, Ala, Pro). In some instances, normally cross-linked insoluble elastin (i.e., insoluble in water, organic solvents, and physiological fluids such as saline and blood) is rendered soluble using a variety of chemical and enzymatic methods to cleave insoluble elastin protein and form smaller peptide fragments.
The human skin consists of two layers; a superficial layer called the epidermis which is epithelial tissue and a deeper layer called the dermis that is primarily connective tissue. These two layers are bound together to form skin which varies in thickness from less than about 0.5 mm, to 3 or even 4 millimeters. The main types of proteins that make up the matrix include collagens, Elastin, fibronectin and laminin. Normal elastic fiber assembly is visualized as a spider web spanning the dermis. Exposure of the skin to ultraviolet and visible light from the sun, wind, and chemicals leads to loss of moisture in the epidermal layers and degradation of the elastin present in the skin. Loss of elasticity in skin primarily occurs because of an over-production of poorly assembled elastic fibers induced by exposure to sunlight. These poorly assembled elastic fibers can be visualized as "clumps" in the dermoepidermal junction and papillary dermis and is commonly referred to as solar elastosis. These effects, result in loss of skin elasticity, tone and texture, are collectively referred to as aging of the skin. Loss of elasticity in elastic tissues such as arteries is mainly due to calcification and glycation of elastic fibers.
Stretch marks, also known as striae gravidarum, or 'striae', are the lines that appear on the skin which are caused by a breaking of the elastic layer of the epidermis. Skin is composed of two layers, as described above. Stretch marks occur in the dermis, the resilient layer that helps skin retain its shape. As a result of this layer being constantly stretched over time it breaks down and becomes less and less elastic and the small connective fibers within it break. Striae may take many forms and colors, from almost invisible tiny lines to deep red lines. Both men and women suffer from this imperfection, although the majority of those who suffer from this skin condition are pregnant women. Stretch marks may occur on the breasts, the upper arms, the buttocks, thighs and across the entire abdomen. Stretch marks may appear in patients after a breast augmentation or other cosmetic surgery procedures.
Stretch marks are wide purplish red lines on the skin which appear on different areas of the body as the pregnancy develops with ever increasing stretching of the skin. Stretch marks are most noticeable in the beginning when they are raised, pink, reddish brown or dark brown lines that later turn to a brighter purplish or a brisk red. In the pregnancy context, hormonal changes help the skin and ligaments to relax and stretch. During the postpartum period, these red lines can turn to silver. They then gradually flatten and fade out to a less noticeable silvery color. Eventually they will become a few shades lighter than the natural skin tone.
One explanation for the formation of stretch marks is best explained through pregnancy related stretch marks. As the uterus becomes larger and the breasts develop, the skin in certain women is not able to keep up with this rapid growth. The fibrous and elastic tissue in the skin is damaged and stretch marks form. As the stretching process increases, more scar tissue is accumulated and the stretch marks increase in width.
Stretch marks are not a very well understood skin condition. There are some known factors that determine if one is susceptible to the condition of stretch marks. Stretch marks have been linked to genetics and some estimate that about 15 to 20 percent of the population is genetically "stretch mark free." Ethnicity also factors into whether one will develop stretch marks. Darker skinned people tend to get less stretch marks than fair-skinned people.
Some dermatologists have suggested that stretch marks are often mistakenly blamed on the rapid stretching of the skin associated with such life events as pregnancy and growth spurts. These dermatologists have stated that stretch marks are the result of an increased level of circulating glucocorticoids throughout the bloodstream. This hormone, secreted by the adrenal glands, becomes elevated during pregnancy, adolescence, with obesity, weight lifting and Cushing's disease.
These dermatologists speculate that the glucocorticoids responsible for the development of a stretch marks affect the dermis by preventing the fibroblasts from forming collagen and elastin fibers, necessary to keep rapidly growing skin taut. This creates a lack of supportive material, as the skin is stretched and leads to dermal tearing. The epidermal cells are also affected, so the epidermis becomes thin and flattened, allowing for more visibility of the defects below.
Striae are a disfiguring skin condition normally associated with obesity, pregnancy and adolescent growth and are a pathological symptom of Cushing's, Marfan's and Ehlers-Danlos syndrome syndromes, diabetes mellitus6 and long term use of topical and systemic steroids. The pathogenesis of stretch marks is as yet unknown but is thought to be a response to minimal or excessive stretching of skin1. Previous histopathological analysis of stretch marks demonstrated loss of dermal papillae and epidermal changes including atrophy, loss of rete ridges and conflicting observations regarding collagen and elastic fibers. More recent studies indicate that steady-state mRNA levels of collagens, elastin and fibronectin are decreased. Studies aimed at quantifying protein levels of elastin and fibrillin in stretch marks further confirmed decreased levels of both.
In 1982 Pieraggi and co-workers proposed that stretch marks are perhaps a consequence of fibroblast dysfunction, based upon their histological observations that fibroblasts were globular, quiescent, and appeared to lose all signs of fibrillar secretion in stretch marked skin. This implies that perhaps dermal fibroblasts in stretch marks have, temporarily or permanently, impaired proliferative and synthetic capabilities with regard to extracellular matrix. Elastic fibers are perhaps the most under-studied extracellular matrix components in skin and potentially a key player in stretch mark formation as there is no strong evidence that collagen levels are affected.
Stretch marks may be induced by excessive mechanical stretching of skin to the point of rupturing dermal elastic fibers and that local fibroblasts are unable to adequately repair or replace these ECM components that are solely responsible for the resilience of skin. Since many patients with stretch marks do not display any obvious signs of known genetic diseases permanently affecting connective tissue, these lesions may develop as a consequence of acquired metabolic disturbances that significantly diminish the reparatory abilities of dermal fibroblasts.
A better understanding of the development of stretch marks is necessary. It is generally understood that stretch marked skin contains lower collagen and elastin content than normal/healthy skin, but a biological analysis of stretch marked skin could lead to the development of enhanced therapeutic treatments.
Not all women will develop stretch marks associated with pregnancy. There are some factors that women may control to reduce the chance of stretch marks. Dry skin tends to be less elastic than well nourished or oily skin. Thus, dryer skin tends to be more susceptible to stretch marks. Part of keeping skin healthy and well-hydrated is dietary. Healthy skin will stretch better and will also repair itself quickly with little damage. Rapid or excessive weight gain will only compound the problem of stretch marks and likely cause more.
Some commonly known preventative measures to reduce the appearance of stretch marks include the follow therapies: massaging skin with a glove or a massage brush to increase circulation; and eating foods that contribute to the overall health of your skin, such as those high in vitamins C and E, zinc and silica. Zinc is especially important because it is linked to cellular growth. Exercising regularly and slow and steady weight gain during pregnancy also may prevent the formation of stretch marks. Several active ingredients have been identified as beneficial to the prevention of stretch marks including emu oil and vitamin E oil. Vitamin A is also a good overall moisturizer, but not as effective as tretinoin, or Retin-A, which helps exfoliate the skin and form healthy new cells.
Several treatments are also known to reduce the appearance of stretch marks. Stretch marks may never entirely be diminished. The sooner one begins treating stretch marks, while they are still reddish or purple, the better likelihood of diminishing their appearance. Once they flatten down and become more silvery they are more difficult to treat. There are several treatments on today's market that range from all-natural creams to invasive surgical measures.
Natural creams and oils include for example, Vitamins A and E and emu oil, are all natural, non-invasive treatments. Retin acid cream or glycolic acid are also known, which act to slough off the top skin layers and stimulate the skin. Another promising new treatment that can help the reduction and prevention of stretch marks include microdermabrasion. In this procedure, a dermatologist administers a stream of fine, chemically inert crystals onto the skin to exfoliate the outer most layers of the epidermis. Laser therapies have also been used to eliminate the appearance of stretch marks. A tiny pulse is emitted from the laser and is absorbed by the blood vessels in the affected area below the skin. Blood vessels rupture, bruise and recover in an accelerated healing process. Reducing contact with the sun and keeping the skin soft and moist have been general suggestions for patients with stretch marked skin.
Finally, cosmetic surgery, which is usually used as a last resort, may be used for the most severe scarring from stretch marks. A tiny incision is made along the length of the stretch mark and the affected area is removed and then stitched together.
There remains a need to identify patients who have a high incidence of stretch marks. There remains a need to identify the causes of stretch marks and how the skin's biological content changes from normal to stretch marked skin. There remains a need to objectively identify the likelihood of the development of stretch marks. There also remains a need to develop treatments and protocols, which may stimulate elastogenesis and the production of the extracellular matrix components in damaged or stretch marked skin. Additionally, stretch marked skin may provide a basis for therapies relating to the stimulation of cellular proliferation and elastogenesis. The use of stretch marked skin which contains a loss of elastin fibers may be used to determine the effectiveness of several potential therapies which may generate or stimulate cellular function in the skin.
Aspects of the present invention delineate possible functional differences between dermal fibroblasts derived from biopsies of unaffected skin regions of patients with stretch marks and fibroblasts derived from skin of normal age-matched individuals. Aspects further provide methods for determining functional differences between fibroblasts derived from these two groups, thereby allowing for the prediction of individuals that may be predisposed for development of striae distensae in skin, challenged by otherwise physiological stretch during the pregnancy. Aspects of the invention provide preventive treatment(s) for individuals diagnosed with predisposition to stretch mark development and eventual treatment of fully developed lesions.

Prognostic tests for development of dermal stretch marks and implications for the preventive treatment thereof


Methods and compositions are disclosed utilizing the optically pure (+)-isomer of bupropion to assist in smoking cessation, for treating smoking and nicotine addiction, and for treating pain, including, but not limited to, chronic pain, neuropathetic pain and reflex sympathetic dystrophy, and other disorders such as narcolepsy, chronic fatigue syndrome, fibromyalgia, seasonal affective disorder and premenstrual syndrome, while avoiding adverse affects associated with racemic bupropion.

This invention relates to methods and pharmaceutical compositions for aiding smoking cessation, treating nicotine addiction, and pain, including chronic pain, neuropathetic pain and reflex sympathetic dystrophy, and other disorders.
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (xe2x88x92) or d and l are employed to designate the sign of rotation of plane-polarized light by the compound, with (xe2x88x92) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 16 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the xcex2-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer was a potent teratogen.
Bupropion is available only as a racemic mixture. That is, bupropion is available as an approximate 50/50 mixture of optical isomers, called enantiomers. The racemic mixture of bupropion which is commercially available is administered as a hydrochloride salt. In addition, European Patent Application No. 84101070.5 published Sep. 12, 1984 discloses the benefits of bupropion maleate over bupropion hydrochloride. The racemic mixture of bupropion is available as Wellbutrin(copyright) and Wellbutrin SR(copyright) for the treatment of depression and Zyban(copyright) to achieve smoking cessation, respectively.
Bupropion is used primarily in the treatment of depression, which along with mania, falls under the heading of affective disorders. Particularly, racemic bupropion is used in patients who do not respond to, or cannot tolerate other antidepressants, such as the tricyclic agents or monoamine oxidase inhibitors. Additionally, the racemic mixture of bupropion is useful in the management of patients with bipolar and schizo-affective disorder, attention-deficit disorder, psycho-sexual dysfunction, bulimia and other eating disorders, and Parkinson""s disease.
Affective disorders, including major depression, and the bipolar, manic-depressive illness, are characterized by changes in mood as the primary clinical manifestation. Major depression, the most common of the significant mental illnesses, is characterized by feelings of intense sadness, and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes can also occur, including insomnia, anorexia, and weight loss, decreased energy and libido, and disruption of hormonal circadian rhythms.
Through an as yet unknown mechanism of action, bupropion has been demonstrated to be an effective treatment in depression in short-term and longer duration clinical studies. The racemic mixture of bupropion has been reported to have antidepressant activity equal to amitriptyline, the tricyclic antidepressant, with fewer anticholinergic, sedative and cardiovascular side effects than with amitriptyline.
As mentioned above, racemic bupropion is used primarily in the treatment of depression and in smoking cessation and is available for these indications in the United States as Wellbutrin(copyright) and WellbutrinSR(copyright) (for depression) and Zyban(copyright) for smoking cessation), respectively (Physicians Desk Reference 1998 52nd edition, pp. 1120-1127 and 1139-1144). Studies regarding the mechanism of bupropion""s antidepressant activity have shown that bupropion is an atypical antidepressant that demonstrates a significant and unusual pattern of noradrenergic activity including some but not all of the effects seen after chronic administration of reuptake inhibitors. Bupropion produces a unique spectrum of biochemical effects that differ significantly from those produced by other antidepressants. However, the exact mechanism by which bupropion produces its antidepressant effects is still not completely understood. See Ascher, J. A., et al., 1995, J. Clin. Psychiatry 56:395-401.
The persistence of cigarette smoking despite widespread public awareness of the adverse health effects in large part results from an underlying addiction to nicotine. Nicotine is a highly addictive substance, which has been said to be as addictive as heroin. A number of nicotinic receptor subtypes have been discovered, which differ in both regional distribution in the nervous system and functional significance. Nicotine binds to these nicotine receptors to open a cation channel that causes depolarization and cell firing. Nicotine has been shown to increase neuronal firing rates in ventral tegmental area dopamine cells, and nicotine enhances dopamine release in striatal areas, including the nucleus accumbeus, which is implicated in drug reinforcement. Thus, it is known that nicotine activates the dopamine reward system. This reinforcement of activation of the dopamine reward system leads to nicotine addiction and difficulty in smoking cessation.
Bupropion inhibits dopamine reuptake, although this inhibition occurs at doses higher than needed for antidepressant activity. Racemic bupropion has been reported to increase success rates in smoking cessation treatment. Rose, J. E., 1996, xe2x80x9cNicotine Addiction and Treatment,xe2x80x9d Annu. Rev. Med. 47:493-507; Ferry, L. H. et al., 1994, xe2x80x9cEfficacy of Bupropion for Smoking Cessation in Non-Depressed Smokers,xe2x80x9d J. Addict. Dis. 13:A9. However, one researcher reported a case in which the cycle of smoking cessation, associated with weight gain, followed by depression and resumption of smoking was interrupted by the use of bupropion as a preventative measure. Lief, H. I., March 1996, xe2x80x9cBupropion Treatment of Depression to Assist Smoking Cessation,xe2x80x9d Am. J. Psychiatry 153:3, p. 442. In this case, it was thought that the administration of racemic bupropion had an indirect effect in preventing smoking resumption by treating the patient""s depression, which had been caused by weight gain associated with smoking cessation. Cf. Ferry, L. H. et al., 1992, xe2x80x9cEnhancement of Smoking Cessation Using the Anti-Depressant Bupropion Hydrochloridexe2x80x9d (abstract), Circulation 1992, 86:671; Ferry, L. H. et al., 1994, xe2x80x9cEvaluation of Bupropion Versus Placebo for Treatment of Nicotine Dependence,xe2x80x9d New Research Program and Abstracts, 147th Annual Meeting of the American Psychiatric Association, Wash., D.C., APA, pp. 199-200.
Patients who suffer from chronic pain may also experience depression. In studies on patients having chronic pain, the incidence of clinical depression ranges from 22 to 78%. Similarly, in studies on depression patients, the frequency of persistent pain complaints ranges from 30 to 100%. Bonica, J. J., The Management of Pain, Second Edition, Vol. I, Chapter 18, pp. 310-319 (1990). In comparison, the occurrence of major depression in the general population is about 4 or 5% with about 3% of men and 6% of women being depressed at any given time. Thus, it is generally believed that the occurrence of depression is greater in patients with chronic pain than in the normal population, but there is no consensus on the extent to which pain and depression may coexist.
In addition, pain and depression may coexist more often in certain clinical populations, such as women, perhaps because of the higher prevalence of depression in women in general. The most prevalent form of chronic pain syndromes associated with depression is chronic persistent headache.
There are presently several theories which attempt to explain why depression and pain frequently coexist; some theories hypothesize that depression comes first and others that pain comes first. See, e.g., Merskey, H., 1965, xe2x80x9cThe Effect of Chronic Pain Upon the Response to Noxious Stimuli by Psychiatric Patients,xe2x80x9d J. Psychosom. Res. 8:405. For example, one theory indicates that since anxiety is frequently associated with depression, and anxiety can potentially increase muscle tension, anxiety can therefore create pain.
Other theories link the connection between pain and depression to several biogenic amines including serotonin, norepinephrine, and dopamine. These compounds have been reported to play a role in the modulation of pain in animals. In addition, abnormalities in biogenic amine function, particularly nor-pinephrine and serotonin, have been hypothesized to play a role in the onset and maintenance of depression. According to these theories, a shared disturbance in noradrenergic and/or serotonergic function might link chronic pain and depression. See Charney D. S., and Heninger, G. R., 1983, xe2x80x9cMonoamine Receptor Sensitivity and Depression: Clinical Studies of Antidepressant Effects on Serotonin and Noradrenergic Function,xe2x80x9d Psychopharmacol. Bull., 19(3):490; Sulser, F., 1983, xe2x80x9cMolecular Mechanisms in Antidepressant Action,xe2x80x9d Psychopharmacol. Bull., 19(3):300.
Pain is generally considered by physicians to have either an organic or a functional psychologic basis. Pain having an organic basis is demonstrated by a specific lesion with well-defined characteristics of pain. However, it has also been found that there are biochemical (e.g. serotonergic) abnormalities that exist without specific lesions, which are manifested by dull, diffuse pains. The absence of a defined lesion does not mean that patients with chronic pain do not have something physically wrong with them. The abnormality might only be found at the molecular level.
Chronic fatigue syndrome (CFS) is a disorder characterized by fatigue of an incapacitating nature lasting for at least six months. Symptoms of chronic fatigue syndrome include, but are not limited to, mild fever or chills, sore throats, painful lymph nodes, unexplained general muscle weakness, myalgias, prolonged generalized fatigue after exercise previously tolerated, generalized headaches, migratory arthralgias, neuropsychologic complaints, sleep disturbance, and description of a main symptom complex developing over a few hours to a few days.
Physical signs of chronic fatigue syndrome include lowgrade fevers, nonexudative pharyngitis and palpable or tender anterior or posterior cervical or axillary lymph nodes. See Goodnick, P. J. and Sandoval, R., January 1993, xe2x80x9cPsychotropic Treatment of Chronic Fatigue Syndrome and Related Disorders,xe2x80x9d J. Clin. Psychiatry 54(1):13-20.
Fibromyalgia is a disorder related to chronic fatigue syndrome. However, in contrast to chronic fatigue syndrome, the major symptoms of fibromyalgia do not include fatigue. Instead, fibromyalgia is characterized by generalized aches or stiffness involving three or more anatomic sites for at least 3 months and at least six typical and reproducible tender points. Minor symptoms of fibromyalgia include fatigue, headache, sleep disturbance, neuropsychiatric symptoms, subjective joint swelling, numbness, irritable bowel syndrome, and modulation of symptoms by activity, weather and stress. Despite the differences in their definitions, patients with either fibromyalgia or chronic fatigue syndrome share many symptoms and epidemiologic factors. See Goodnick, P. J. and Sandoval, R.
Seasonal affective disorders (SADs) are clinically significant disturbances of mood occurring in relationship to a change in season. Winter depression, the most widely recognized form of SAD, is characterized by the onset of depression in the fall or winter followed by spontaneous recovery in the spring. While phototherapy is the most widely studied and recognized treatment for SAD, one study has suggested that racemic bupropion is an effective treatment for winter depression. Dilsaver, S. C., et al., July 1992, xe2x80x9cThe Efficacy of Bupropion in Winter Depression: Results of an Open Trial,xe2x80x9d J. Clin. Psychiatry 53(7):252-255.
The racemic mixture of bupropion, in addition to its use in the treatment of depression, has been shown to have a wide spectrum of action which includes:
Treatment of the effects of ethanol (U.S. Pat. No. 4,393,078)
Treatment of Tardine Dyskinesia (U.S. Pat. No. 4,425,363)
Treatment of Minimal Brain Dysfunction (U.S. Pat. No. 4,435,449)
Treatment of amelioration of prostate hypertrophy and sexual dysfunction (U.S. Pat. No. 4,835,147)
Treatment of psychostimulant addiction (U.S. Pat. No. 4,935,429)
Treatment of Psychosexual dysfunction (U.S. Pat. No. 4,507,323)
Methods of reducing cholesterol (U.S. Pat. No. 4,438,138)
Methods of assisting weight loss (U.S. Pat. No. 4,895,845)
The racemic mixture of bupropion has been shown to have certain advantages over other antidepressant drugs. For example, bupropion does not inhibit monoamine oxidase, or block the reuptake of serotonin. At therapeutic concentrations, the compound presumably does not bind to adrenergic, dopamine, GABA, histamine, muscarinic, serotonin, or imipramine binding sites. While its specific neurochemical antidepressant action is unknown, it does have a relatively weak effect on blocking the reuptake of dopamine.
While the racemic mixture of bupropion has advantages, it also has disadvantages. Among these disadvantages are adverse effects in addition to those described above. The most serious adverse effect associated with the racemic mixture of bupropion is the incidence of seizures. In addition, other frequently reported adverse effects associated with the use of racemic bupropion include nausea, vomiting, excitement, blurred vision, agitation, restlessness, postural tremor, and some hallucinations/confusional states with the potential for abuse. Other adverse or side effects associated with the racemic mixture of bupropion include but are not limited to anxiety, insomnia, headaches and/or migraines, dry mouth, constipation, tremor, sleeping disturbances, dermatologic problems (e.g., rashes), neuropsychiatric signs and symptoms (e.g., delusions and paranoia), and weight loss or gain. See, The Physician""s Desk Reference(copyright) (1998). These effects are dose limiting in a number of patients. In Parkinsonian patients, the adverse effects can be the particular toxicity of the racemic mixture of bupropion or the result of a drug interaction (as most patients were receiving concomitant levodopa).
Thus, it is desirable to find a compound with the advantages of the racemic mixture of bupropion without the above-described disadvantages. In particular, there is a need for a compound which is effective for the treatment of pain and disorders such as, smoking and nicotine addiction, without the above-described disadvantages and adverse effects associated with the administration of racemic bupropion.
The active compound of compositions and methods disclosed herein is an optical isomer of the racemic compound bupropion which is described in U.S. Pat. Nos. 3,819,706 and 3,885,046. Chemically, this isomer is (+)-2-(tertbutylamino)-3xe2x80x2-chloropropiophenone or (+)-1-(3-chlorophenyl)-2[(1,1-dimethyl-ethyl)amino]-1-propanone. This isomer will hereinafter be referred to as xe2x80x9c(+)-bupropion,xe2x80x9d which also includes the substantially optically pure (+)-bupropion isomer.
It has been discovered that optically pure (+)-bupropion is effective in aiding or achieving smoking cessation while avoiding adverse effects associated with the administration of racemic bupropion. Another embodiment of the present invention relates to the treatment of smoking or nicotine addiction by administration of optically pure (+)-bupropion or a pharmaceutically acceptable salt thereof.
It has also been discovered that-the optically pure (+)-isomer of bupropion is effective for the treatment of pain, including chronic pain, neuropathic pain, pain associated with depression and reflex sympathetic dystrophy, while avoiding adverse effects, including, but not limited to, seizures, agitation, dry mouth, insomnia, headache/migraine, nausea, vomiting, dizziness, tachycardia, constipation, and tremor associated with the administration of the racemic mixture of bupropion. It has further been discovered that optically pure (+)-bupropion is useful in the treatment of chronic disorders, including narcolepsy, chronic fatigue syndrome, fibromyalgia, seasonal affective disorder and premenstrual syndrome, (or premenstrual dysphoric disorder) while avoiding adverse effects, such as those described above, associated with the administration of the racemic mixture of bupropion.
Thus, the present invention encompasses methods for treating the above-described conditions in a human while avoiding adverse effects that are associated with the racemic mixture of bupropion, by administering the optically pure (+)-isomer of bupropion or a pharmaceutically acceptable salt thereof, to said human. The present invention also relates to compositions comprising optically pure (+)-bupropion.
The present invention encompasses a method for aiding in smoking cessation in a human, which comprises administering to a human who smokes a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer. Thus, the invention encompasses the use of optically pure (+)-bupropion to achieve smoking cessation or a reduction in smoking.
The present invention further encompasses a method for aiding smoking cessation while avoiding the concomitant liability of adverse effects associated with the administration of racemic bupropion, which comprises administering to a human who smokes a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to achieve smoking cessation or a reduction in smoking, but insufficient to cause adverse effects associated with the administration of racemic bupropion.
The present invention further encompasses a method of treating nicotine addiction in a human, which comprises administering to said human suffering from nicotine addiction a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer. Nicotine addiction refers to nicotine addiction in all known forms, such as smoking cigarettes, cigars, or pipes and chewing tobacco.
The present invention further encompasses a method of treating nicotine addiction in a human while avoiding the concomitant liability of adverse effects associated with the administration of racemic bupropion, which comprises administering to said human suffering from nicotine addiction a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate said addiction, but insufficient to cause adverse effects associated with administration of racemic bupropion.
Addiction to nicotine or tobacco includes addiction to smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.
The present invention further encompasses a method for treating weight gain associated with smoking cessation in a human, which comprises administering to said human suffering from weight gain associated with smoking cessation, a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer.
The present invention further encompasses a method for treating weight gain associated with smoking cessation in a human while avoiding the concomitant liability of adverse effects associated with the administration of racemic bupropion, which comprises administering to said human suffering from weight gain associated with smoking cessation, a therapeutically effective amount of (+)-bupropion or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to achieve weight loss, but insufficient to cause adverse effects associated with administration of racemic bupropion.
The present invention is also directed to a method of treating pain in a human which-comprises administering to said human in need of treatment for pain a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate pain.
In addition, the present invention encompasses a method of treating pain in a human while avoiding the concomitant liability of adverse effects associated with the administration of racemic bupropion, which comprises administering to said human in need of treatment for pain, a therapeutically effective amount of (+)-bupropion or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate pain, but insufficient to cause adverse effects associated with racemic bupropion. The types of pain which may be treated according to the methods of the present invention include, but are not limited, chronic pain, pain associated with depression, neuropathic pain, persistent headache, and reflex sympathetic dystrophy.
The present invention also encompasses a composition for the treatment of pain in a human which comprises a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, and a pharmaceutically acceptable carrier. Preferred pharmaceutical compositions are those which have a means for controlled, and/or sustained release of the active ingredient, (+)-bupropion.
The present invention further encompasses a method of treating a chronic disorder in a human, which comprises administering to said human suffering from a chronic disorder a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer.
The present invention further encompasses a method of treating a chronic disorder in a human while avoiding the concomitant liability of adverse effects associated with the administration of racemic bupropion, which comprises administering to said human suffering from a chronic disorder a therapeutically effective amount of (+)-bupropion, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate said chronic disorder, but insufficient to cause adverse effects associated with administration of racemic bupropion.
The term xe2x80x9cchronic disorderxe2x80x9d as used herein shall mean disorders including, but not limited to, narcolepsy, chronic fatigue syndrome, seasonal affective disorder, fibromyalgia and premenstrual syndrome (or premenstrual dysphoric disorder).
The racemic mixture of bupropion (i.e., an approximately 50%xe2x80x9450% mixture of its two enantiomers) has been reported to be useful in reducing certain types of pain. Davidson, J. R. and France, R. D., August 1994, xe2x80x9cBupropion in Chronic Low Back Pain,xe2x80x9d J. Clin. Psychiatry 55(8):362. Although racemic bupropion may provide therapy and/or reduction of symptoms in a variety of conditions and disorders, this racemic mixture, while offering the expectation of efficacy, causes a broad range of adverse effects. According to the present invention, utilizing the optically pure (+)-isomer of bupropion results in clearer dose-related definitions of efficacy, diminished adverse effects, and accordingly an improved therapeutic index. It is therefore, more desirable to use the (+)-isomer of bupropion to treat the conditions described herein.
The term xe2x80x9cadverse effectsxe2x80x9d includes, but is not limited to, seizures, dry mouth, insomnia, dizziness, restlessness, anxiety, agitation, headache/migraine, nausea/vomiting, constipation, tremor, delusions, tachycardia, hallucinations, psychotic episodes, blurred vision, confusion, paranoia, rashes and sleep disturbances.
The term xe2x80x9csubstantially free of the (xe2x88x92)-stereoisomerxe2x80x9d as used herein means that the composition contains a greater proportion of the (+)-isomer of bupropion in relation to the (xe2x88x92)-isomer of bupropion. In a preferred embodiment the term xe2x80x9csubstantially free of its (xe2x88x92)-stereoisomerxe2x80x9d as used herein means that the composition contains at least 90% by weight of (+)-bupropion and 10% by weight or less of (xe2x88x92)-bupropion; in a more preferred embodiment at least 95% (+)-bupropion and 5% by weight or less of its (xe2x88x92)-isomer. These percentages are based on the total amount of bupropion present in the composition. In the most-preferred embodiment the term xe2x80x9csubstantially free of its (xe2x88x92)-stereoisomerxe2x80x9d means that the composition contains approximately 99% by weight of (+)-bupropion, and 1% or less of (xe2x88x92)-bupropion. In another preferred embodiment, the term xe2x80x9csubstantially free of its (xe2x88x92)-stereoisomerxe2x80x9d as used herein means that the composition contains greater than 99% by weight of the (+)-isomer of bupropion, again based on the total amount of bupropion present. The terms xe2x80x9csubstantially optically pure (+)-isomer of bupropion,xe2x80x9d xe2x80x9coptically pure (+)-isomer of bupropion,xe2x80x9d xe2x80x9coptically pure (+)-bupropionxe2x80x9d and xe2x80x9c(+)-isomer of bupropionxe2x80x9d are also encompassed by the above-described amounts.
The synthesis of the (+)-isomer of bupropion may start from readily available 3-chloropropiophenone (1). Reaction of (1) with a (2S,3S)-(xe2x88x92)-dialkyl tartrate such as (xe2x88x92)-dimethyl or diethyl tartrate in the presence of an acid catalyst such as methanesulfonic acid gives the chiral acetal (2) according to Castaldi (G. Castaldi, et al., J. Org. Chem. 1987, 52:3018). Steroselective bromination with bromine in carbon tetrachloride (or alternatively ethyl acetate) then produces the corresponding bromoacetal (3) as the major product according to the above-referenced procedure developed by Castaldi and co-workers. The bromoacetal (3) is purified by column chromatography to yield the optically pure bromoacetal (3) which is then hydrolyzed in the presence of an acid to afford the bromoketone (4). Treatment of the bromoketone (4) with tert-butylamine, followed by reaction with anhydrous hydrogen chloride, then produces optically pure (+)-bupropion hydrochloride (5) after recrystallization. See the scheme below.
Alternatively, the optically pure (+)-isomer of bupropion can be prepared according to the procedures reported by Musso et al., 1993, xe2x80x9cSynthesis and Evaluation of the Antidepressant Activity of the Enantiomers of Bupropion,xe2x80x9d Chirality 5:495-500, which is hereby incorporated by reference in its entirety.
In addition to the above-described methods, the stereoisomers of bupropion may be obtained by resolutions of a mixture of enantiomers of bupropion using conventional means such as an optically active resolving agent; see, for example, xe2x80x9cStereochemistry of Carbon Compoundsxe2x80x9d, by E. L. Eliel (McGraw-Hill, NY, 1962), and S. H. Wilen, p. 268 in xe2x80x9cTables of Resolving Agents and Optical Resolutionsxe2x80x9d (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).
The magnitude of a prophylactic or therapeutic dose of (+)-bupropion in the acute or chronic management of disease (or disorders) will vary with the severity of the condition to be treated and its route of administration. The dose and dose frequency will also vary according to the age, weight and response of the individual patient. In general, the recommended daily dose range for the conditions described herein lies within the range of from about 10 mg to about 750 mg per day, generally divided equally into doses given two to four times a day. Preferably, a daily dose range should be between 50 mg and 600 mg per day, usually divided equally into a two to four times a day dosing. Most preferably, a daily dose range should be between 60 mg and 450 mg per day, usually divided equally into a two to four times a day dosing. It may be necessary to use dosages outside these ranges in some cases. The physician will know how to increase, decrease or interrupt treatment based upon patient response. For use in aiding in smoking cessation or in treating nicotine addiction, the physician will generally prescribe the period of treatment and frequency of dose of (+)-bupropion on a patient-by-patient basis. In general, however, treatment with (+)-bupropion may be carried out for a period of 2 weeks to 6 months, and preferably from 7 weeks to 12 weeks. The various terms described above such as xe2x80x9csaid amount being sufficient to alleviate painxe2x80x9d, xe2x80x9csaid amount being sufficient to alleviate said addictionxe2x80x9d, xe2x80x9ctherapeutically effective amountxe2x80x9d, etc., are encompassed by the above-described dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing the patient with an effective dosage of (+)-bupropion. For example, oral, rectal, parenteral, transdermal, subcutaneous, intramuscular, intrathecal and the like may be employed as appropriate. Dosage forms include tablets, coated tablets, caplets, capsules, troches, dispersions, suspensions, solutions, patches and the like, including sustained release formulations well known in the art. See, e.g. Remington""s Pharmaceutical Sciences (1995) and the Physician""s Desk Reference(copyright) (1998).
The pharmaceutical compositions of the present invention comprise the (+)-isomer of bupropion as active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include maleic, acetic, benzene-sulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromaic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are hydrobromic, hydrochloric, maleic, phosphoric, and sulfuric acids.
The compositions include compositions suitable for oral, rectal, and parenteral administration (including subcutaneous, intramuscular, intrathecal and intravenous), although the most suitable route in any given case will depend on the nature and severity of the condition being treated. The most preferred route of the present invention is the oral route. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In the case where an oral composition is employed, a suitable dosage range for use is, e.g., from about 10 mg to about 750 mg per day, generally divided equally into a two to four times a day dosing, preferably from about 50 mg to about 600 mg per day, generally divided equally into a two to four times a day dosing and most preferably from about 60 mg to about 450 mg per day, generally divided equally into a two to four times a day dosing. Patients may be upward titrated from below to within this dose range to achieve satisfactory control of symptoms as appropriate.
In practical use, (+)-bupropion can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous injections or infusions). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, for example, suspensions, elixirs and solutions; or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, stabilizers, diluents, granulating agents, lubricants, binders, fillers, disintegrating agents and the like in the case of oral solid preparations such as, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. The preferred solid oral preparation is tablets. The most preferred solid oral preparation is coated tablets. Because of their ease of administration tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release or sustained release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200, 4,008,719, 4,687,660, and 4,769,027, the disclosures of which are hereby incorporated by reference. Preferred controlled release or sustained release tablets for use with (+)-bupropion are described in U.S. Pat. No. 5,427,798 which is incorporated herein by reference.
Pharmaceutical stabilizers may also be used to stabilize compositions containing (+)-bupropion or salts thereof; acceptable stabilizers include but are not limited to L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid and L-cysteine dihydrochloride. See, e.g. U.S. Pat. No. 5,358,970 which is incorporated herein by reference.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more of a binder, filler, stabilizer, lubricant, inert diluent, and/or surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 10 mg to about 250 mg of the active ingredient, and each cachet or capsule contains from about 10 mg to about 250 mg of the active ingredient. In a preferred embodiment, the tablet, cachet or capsule contains one of four dosages: about 50 mg, about 75 mg, about 100 mg and about 150 mg of active ingredient.
The invention is further defined by reference to the following examples describing in detail the preparation of the compound and compositions of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.
All temperatures are in degrees Celsius.

Methods and compositions for aiding in smoking cessation and for treating pain and other disorders using optically pure (+)-bupropion


A printing system is disclosed. The printing system includes a first printer to print a first type of data to a medium and to print a barcode on the medium including variable data to be printed on the medium and a second printer to print the variable data to the medium based on the barcode. The second printer includes a barcode reader, transfer location and a medium path having a fixed distance between the barcode reader and the transfer location.

In the printing industry, it is sometimes necessary to process media multiple times in order to create a final product. For example, media such as paper may be pre-printed in an offset press, then run through a digital press/printer in order to add unique (variable) information. In other instances, a digital printer may not have enough capability (e.g., an ink jet printer may not be able to print Magnetic Ink Character Recognition (MICR), or a monochrome printer may not be able to print color/highlight color).
In these cases, it may be necessary to process the media through multiple, independent digital printing devices in order to achieve the final product. To highlight their independence, the printing devices may be located in different buildings or countries and having no external network connection. Thus, the printed output may be processed immediately or hours or days apart.
Moreover, the second printing device that applies the MICR variable data is typically implemented with a third party post processor or is a third party post processor. However, such a solution requires the purchase of additional hardware from the third party vendor.
Accordingly, a single source integrated mechanism for processing media is desired.