Novel 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, intermediates and processes for the preparation thereof, and methods of reducing inflammation and cell proliferation, and relieving memory dysfunction, and inhibiting bacterial and fungal growth are disclosed.

The present invention relates to 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols. More particularly, the present invention relates to 1-alkyl-, 1-alkenyl-, and 1-alkylnylaryl-2-amino-1,3-propanediols of formula 1.
wherein R is
or
wherein R5 is CH3(CH2)mC"Xgr"C, CH3(CH2)mCHxe2x95x90CH, CH3(CH2)mCH2CH2,
CH3(CH2)mCH2O, or
wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen, hydroxy, alkyl, alkoxy, halogen, or trifluoromethyl, or
wherein R23 is loweralkyl; Z is S, O, or Cxe2x95x90O; and A is S or O; R1 is hydrogen, alkyl, Si(R23)2C(R23)3 wherein R23 is alkyl,
wherein R24 is alkyl or
wherein R6 is hydrogen, alkyl, alkoxy, N(R21)2 wherein R21 is hydrogen, alkyl, or
wherein W is as above, or
R2 is hydrogen or alkyl; R3 is hydrogen, alkyl or
wherein R6 is as above or NHR27 wherein R27 is alkyl; R35 is
wherein R36 is alkyl; R4 is
wherein R7 is hydrogen or alkyl, C(R25)2OR8 wherein R8 is hydrogen, alkyl, or
wherein R6 is as above and R25 is hydrogen or alkyl; R40 is alkyl or a group of the formula
wherein W is as above; R1 and R8 taken together with the oxygen to which they are attached form a group of the formula
wherein R9 and R10 are independently hydrogen or alkyl; R2, R3 and R4 taken together with the nitrogen and oxygen to which they are attached form a group of the formula
wherein W is as above; R3 and R4 taken together with the nitrogen and oxygen atoms to which they are attached form a group of the formula
wherein R2 is as above; R2 and R3 taken together with the nitrogen atom to which it is attached form a group of the formula
wherein W is as above; R3 and R4 taken together with the nitrogen and oxygen atoms to which they are attached form a group of the formula
wherein R2 is as above and R25 is alkyl; R1, R2 and R3 taken together with the nitrogen and oxygen atoms to which they are attached form a group of the formula
wherein R26 is alkyl; the optical isomers thereof, or the pharmaceutically acceptable salts thereof, which are useful for reducing inflammation by virtue of their ability to inhibit protein kinase C and thus indicated for the treatment of psoriasis and other skin disorders, for inhibiting tumor or neoplastic cell growth by virtue of their ability to reduce cell proliferation and thus indicated in cancer therapy, and relieving memory dysfunction and thus indicated in the treatment of Alzheimer""s disease, and as antibacterial and antifungal agents, alone or in combination with adjuvants.
Preferred 2-amino-1,3-propanediols of the present invention are those wherein R is
R1, R2, and R3 are hydrogen and R5 is CH3(CH2)mCH2CH2 or
Also preferred are compounds wherein R is
R1 and R2 are hydrogen; R4 is
and R5 is CH3(CH2)mC"Xgr"C.
The present invention also relates to compounds of the formulas
RCHOxe2x80x83xe2x80x831a
wherein R is
wherein R5 is CH3(CH2)mC"Xgr"C, CH3(CH2)mCHxe2x95x90CH, CH3(CH2)mCH2CH2, or
wherein m is 3 to 15, n is 0 to 12, W and X are independently hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl and Z is S or O; A is S or O; R40 is alkyl or a group of the formula
wherein W is as above;
wherein R is
wherein R5 is
CH3(CH2)mC"Xgr"C, CH3(CH2)mCH=CH, CH3(CH2)mCH2CH2, or

wherein m is 3 to 15, n is 0 to 12, R16 is hydrogen or a group of the formula
W and X are independently hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, and Z is 0; and
RCHxe2x95x90CHR4
wherein R is
wherein R5 is CH3(CH2)mC"Xgr"C, CH3(CH2)mCHxe2x95x90CH, CH3(CH2)mCH2CH2,
or
wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen, loweralkyl, loweralkoxy, halogen, or trifluoromethyl, Z is S, O, or Cxe2x95x90O; and A is S or O, and R4 is
wherein R7 is hydrogen or loweralkyl, C(R25)2OR8 wherein R8 is hydrogen, loweralkyl, or
is as above; and
wherein R5 is CH3(CH2)mC"Xgr"C, CH3(CH2)mCHxe2x95x90CH, CH3(CH2)mCH2CH2,
or
wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen, loweralkyl, loweralkoxy, halogen, or trifluoromethyl which are useful as intermediates for the preparation of the present 2-amino-1,3-propanediols.
Also included as intermediates for the preparation of the present 2-amino-1,3-propanediols are oxazolidinones of the formula
RCH(OR1)CHR18R19
wherein R is
and
wherein R5 is CH3(CH2)mC"Xgr"C, CH3(CH2)mCHxe2x95x90CH, CH3(CH2)mCH2CH2,
wherein m is 3 to 25, n is 0 to 12, and W and X are independently hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, Z is S, O, or Cxe2x95x90O; and A is S or O; R1 is hydrogen or
wherein R6 is hydrogen, alkyl, alkoxy, or
R18 is halogen or N3; and R19 is a group of the formula
wherein W is hydrogen, loweralkyl, loweralkoxy, halogen, or trifluoromethyl; or a group of the formula
wherein R20 is loweralkyl.
As used through the specification and appended claims, the term xe2x80x9calkylxe2x80x9d refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 10 carbon atoms. Examples of alkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 3-hexyl, 4-heptyl, 2-octyl, 3-nonyl, 4-decyl and the like. The term xe2x80x9calkanolxe2x80x9d refers to a compound formed by a combination of an alkyl group and hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and 2-propanol, 2,2-dimethylethanol, hexanol, octanol, decanol and the like. The term xe2x80x9calkanoic acidxe2x80x9d refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid, decanoic acid and the like. The term xe2x80x9chalogenxe2x80x9d refers to a member of the family fluorine, chlorine, bromine, or iodine. The term xe2x80x9calkanoylxe2x80x9d refers to the radical formed by removal of the hydroxyl function from an alkanoic acid. Examples of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl and the like. The term xe2x80x9clowerxe2x80x9d as applied to any of the aforementioned groups refers to a group having a carbon skeleton containing up to and including 8 carbon atoms.
The compounds of the present invention which lack an element of symmetry exist as optical antipodes and as the racemic forms thereof. The optical antipodes may be prepared from the corresponding racemic forms by standard optical resolution techniques, involving, for example, the separation of diastereomeric salts of those instant compounds characterized by the presence of a basic amino group and an optically active acid, those instant compounds characterized by the presence of a carboxylic acid group and an optically active base, or by synthesis from optically active precursors.
The present invention comprehends all optical isomers and racemic forms thereof and all geometric isomers of the compounds disclosed and claimed herein. The formulas of the compounds shown herein are intended to encompass all possible geometric and optical isomers of the compounds so depicted.
The compounds of the present invention that have adjacent chiral centers exist as diastereomers and are distinguished as the erythro- and threo-isomers. The erythro diastereomers are those that become meso, i.e., optically inactive, by virtue of having an element of symmetry in one of the possible conformations, when one of the dissimilar substituents is replaced by the other. The threo diastereomers are those that remain enantiomeric, i.e., optically active, by virtue of lacking an element of symmetry in one of the possible conformations, when one of the dissimilar substitutents is replaced by the other. For example, replacement of the amino group of an erythro-2-amino-1,3-propanediol 9a of the present invention by a hydroxyl group creates a meso-1,2,3-propanetriol 9b, having a plane of symmetry through the carbon backbone of the molecule, as shown below,
and replacement of the amino group of a threo-2-amino-1 ,3-propanediol 9c of the present invention by a hydroxy group creates an enantiomer 9d, lacking an element of symmetry in all conformations, one of which is 9d.
The chirality of the enantiomeric compounds of the present invention, prepared by asymmetric induction, is designated by the symbols xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d and is determined by application of the sequence-rule of Cahn-Ingold- and Prelog (see R. S. Cahn, C. Ingold, and v. Prelog, Angewandte Chemie, International Edition English, 5, 385 (1966) and 5, 511 (1966). Thus, for example, the handedness of the chiral centers at the 2- and 3-positions of the 2-amino-i1,3-propanediol 9e
prepared from (4S)-3-(bromoacetyl)-4-(phenylmethyl)-2-oxazolidinone, is designated 2R (right) and 3S (left). The centers of the enantiomeric 2-amino-1,3-propanediol 9f,
prepared from the enantiomeric (4R)-3-(bromoacetyl)-4-(phenylmethyl)-2-oxazolidinone, is designated 2S and 3R.
The novel 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention are prepared by the processes illustrated in Reaction Schemes A, B, and C for the pyridine series, D to L for the thiophene series, and M and N for the phenyl series, having an aralkyl side-chain. The transformations shown therein are applicable to the preparation of compounds of the invention wherein the aryl group is, among others, substituted and unsubstituted phenyl, furyl, thienyl, isoxazolyl, isothiazolyl, and pyrrolyl, thiazolyl, and oxazolyl, having a 1-alkyl, 1-alkenyl, or 1-alkyny1-side chain.
To prepare a 1-alkynylpyridiny1-2-amino-1,3-propanediol 7 wherein W and X are hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, a pyridinylcarboxaldehyde 2 wherein W and X are as above and Y is halogen is condensed with an amidomalonic acid ester 3 wherein R11 and R12 are alkyl to provide an alkyl pyridinylpropionate 4 wherein R11, R12, X, and Y are as above, which is alkynylated to alkynylpyridine 5 wherein R11, R12, W and X are as above and n is 3 to 15 and, in turn, reduced to pyridiny1-1,3-propanediol 6 wherein R12, W, and X are as above and hydrolyzed to 7.
The condensation of carboxaldehyde 2 and malonate 3 is conducted in an ethereal solvent in the presence of a tertiary amine. Among ethereal solvents there may be mentioned diethyl ether, methyl tert-butyl ether, 1,2-dimethyoxyethane, 2-methoxyethyl ether, dioxane, and tetrahydrofuran. Among tertiary amines there may be mentioned pyridines (pyridine, picoline, lutidine, and collidine) and trialkylamines (trimethylamine, triethylamine, and tripropylamine). Tetrahydrofuran and triethylamine are the preferred solvent and tertiary amine, respectively, While the condensation temperature is not critical, the reaction is preferably performed at about ambient temperature (25xc2x0 C.), although reduced temperatures (about 0xc2x0 C. to about 25xc2x0 C.) or elevated temperatures (about 25xc2x0 C. to the boiling point of the reaction mixture) may be employed.
The alkynylation is performed by treating a halopyridine 4 with an alkyne 13
wherein W and n are as above in an acid acceptor, e.g., a di- or trialkylamine, such as, diethylamine, dipropylamine, trimethylamine, triethylamine, or tripropylamine, in the presence of bis(triphenylphosphine)palladium dichloride/cuprous iodide at a temperature of about 0xc2x0 to about 75xc2x0 C. Triethylamine is the preferred acceptor. A temperature of about 50xc2x0 to 60xc2x0 C. is the preferred alkynylation temperature. An ethereal solvent may be employed. Ethereal solvents include diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 2-methoxyethy1-ether, dioxane, and tetrahydrofuran. Tetrahydrofuran is the preferred solvent.
The reduction of an alkyl pyridinylpropionate 5 to a propanediol 6 is accomplished by means of an alkali borohydride in an ethereal solvent at a reduction temperature within the range of about 0xc2x0 to about 50xc2x0 C. Included among alkali borohydrides are calcium borohydride, lithium borohydride, potassium borohydride, and sodium borohydride. Included among ethereal solvents are diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane, and tetrahydrofuran. A reducing system of lithium borohydride or calcium borohydride in tetrahydrofuran at a temperature of from about 0xc2x0 to 25xc2x0 C. is preferred.
The hydrolysis of a carboxamide 6 to an aminodiol 7 may be carried out by conventional hydrolysis techniques. For example, carboxamide 6 may be hydrolyzed by an alkali metal hydroxide, i.e., lithium hydroxide, sodium hydroxide, or potassium hydroxide, in an aqueous alkanol, i.e., methanol, ethanol, or 1- or 2-propanol, at a hydrolysis temperature of about 0xc2x0 C. to about 100xc2x0 C.
To prepare a 1-alkylpyridiny1-2-amino-1,3-propanediol 9 wherein W, X, and m are as hereinbeforedescribed, a 1-alkynylpyridinyl-2-amido-1,3-propanediol 6 is hydrogenated to a 1-alkylpyridinyl-2-amido-1,3-propanediol 8, which is converted to a 1-alkylpyridinyl-2-amino-1,3-propanediol 9.
The hydrogenation is effected by treating an alkyne 6 with hydrogen at about atmospheric pressure to about 60 psi, a pressure of about 40 psi being preferred, in the presence of a metal catalyst, e.g., platinum, palladium, rhodium, or ruthenium, unsupported or supported on carbon or calcium carbonate, palladium-on-carbon being preferred, in an alkanol, e.g., methanol, ethanol, or 1- or 2-propanol, ethanol being preferred, at a hydrogenation temperature of about 25xc2x0 to about 50xc2x0 C., a temperature of about 25xc2x0 C. being preferred.
The conversion of pyridinylamidodiol 8 to pyridinylaminodiol 9, i.e., the hydrazinolysis of 8, is conducted with hydrazine, free or in its hydrated form, in an alkanol such as, for example, methanol, ethanol, or 1- or 2-propanol, at a temperature of from about 25xc2x0 C. to the reflux temperature of the reaction mixture. Ethanol is the preferred solvent. A hydrazinolysis temperature of about the reflux temperature of the reaction mixture is also preferred.
Alternatively, entry into the 1-alkynyl- and 1-alkylpyridinyl-2-amino-1,3-propanediol systems, i.e., systems of formulas 7 and a, respectively, wherein W, X, and m are as hereinbeforedescibed may be achieved by alkynylation of pyridinylcarboxaldehyde 2 wherein W, X, and Y are as above to alkynylpyridinylcarboxaldehyde 10 wherein W, X, and m are as above followed by conversion of pyridinylcarboxaldehyde 10 to alkyl pyridinylpropionate 5 wherein R11, R12, W, X, and m are as above and hydrogenation of an alkynylpyridine 5 wherein R11, R12, W, X, and m are as above to 11 wherein R11, R 2, W, X, and m are as above. The alkynylation, conversion, and hydrogenation, i.e., the transformations of 2 to 5 and 11, via 10, are accomplished by processes substantially similar to the corresponding transformations of 4 to 5, 2 to 4, and 6 to 8.
Alkyl 1-alkylpyridinylpropionate 11 wherein R11, R12, W, X, and m are as above may be reduced to 1-alkyl pyridinylpropanediol 8 by the process essentially the same as that employed for the reduction of alkyl pyridinylpropionate 5 to propanediol 6.
Entry into the 1-alkynylpyridinyl-2-amino-1,3-propanediol series, i.e., the series encompassing compounds of formulas 5, 6 and 7, is also attained by reducing an alkyl pyridinylpropionate 4 wherein R11, R12, W, X and Y are as hereinbeforedescribed to a pyridinylpropanediol 12 and alkynylating a pyridinyldiol 12, so obtained, to alkynylpyridinyldiol 6. As described above, amidopropanediol 6 is converted to amino propanediol 7 by hydrolysis. Similarly, the reduction of 4 to 12 and the alkynylation of 12 to 6 are performed by processes substantially the same as those utilized for the conversion of 5 to 6 and 4 to 5.
Derivatives of an alkynylpyridinyl-2-amino-1,3-diol 7 are prepared from amidopropanediol 6 by acylation of 6 wherein R12, W, X, and m are as hereinbeforedescribed to an amidodiacyloxypropane 15 wherein R12, R13, R14, W, and m are as hereinbeforedescribed with, for example, an alkanoic acid anhydride such as acetic anhydride in the presence of triethylamine and 4-dimethylaminopyridine to 15, and dioxanylation of 6 to amidodioxane 14 wherein R12, R15, R16, W, X, and m are as hereinbeforedescribed with, for example, 2,2-dimethoxypropane in the presence of para-toluene sulfuric acid. Hydrolysis of 15 as described for the conversion of 6 to 7 provides aminopropanediol 7. An amidodiacyloxypropane 15 is selectively hydrolyzed to an amidodihydroxy propane 20 by, for example, an alkali metal carbonate such as lithium, sodium, or potassium carbonate in an alkanol such as methanol, ethanol, or 2-propanol. Potassium carbonate in methanol is the preferred hydrolysis medium. The hydrolysis proceeds readily at ambient temperature. Elevated temperatures to the reflux temperature of the hydrolysis medium may be employed.
Acyl derivatives of amidopropanediol 12 wherein R12, X, and Y are as hereinbeforedescribed are prepared by treating 12 with an alkanoic acid anhydride under the conditions for the conversion of 6 to 15.
To prepare a 1-alkenyl-2-amino-1,3-propanediol 17 wherein W, X, and m are as hereinbeforedescribed a 1-alkynyl-2-amino-1,3-propanediol 6 wherein R12, W, X, and m are as above is hydrogenated to a 1-alkenyl-2-amino-1,3-propanediol 16 wherein R12, W, X, and m are as above and the configuation of the hydrogen atoms of the carbon-to-carbon double bond is cis, which is hydrolyzed to 17 wherein W, X, and m are also as above.
To fabricate an N,O,O-tribenzyloxycarbonyl-2-amino-1,3-propane 18 wherein R15 is
and 2-amino-1,3-propanediol 9 is treated with N-benzyloxycarbonyloxysuccinimide 20
in the presence of a tertiary amine, e.g., triethyl amine in an ethereal solvent, e.g., tetrahydrofuran at about ambient temperature.
To synthesize a 2-amino-1,3-propanediol 19, a 1,3-diacyloxy-2-propanylacetamide 13 is hydrolyzed by hydrazine hydrate in the presence of ethanol according to the procedure for the conversion of 8 or 9.
Generally, the ultimate 1-alkylaryl-2-amino-1,3-propanediols of the present invention are prepared from 1-alkynylarylcarboxaldehydes. See Reaction Scheme A for the conversion of 10 to 9 in the pyridine series. In the isoxazole series, the ultimate 1-alkylisoxazolyi-2-amino-1,3-propanediols may be prepared, for example, from a 5-(1-alkyl)-3-isoxazolecarboxaldehyde 21 wherein R5 is dodecyl.
A 3-isoxazolecarboxaldehyde 21 wherein R5 is dodecyl, in turn, is synthesized, for example, by condensing 1-nitrotridecane with O-trimethylsilylpropynol in the presence of phenylisocyanate and triethylamine followed tetrabutylamnonium fluoride to afford isoxazolemethanol 22
wherein R5 is dodecyl, which is oxidized by oxalyl chloride:dimethylsulfoxide to 21.
To prepare a 2-alkoxycarbonylamino-1,3-propanediol, for example, 1-alkynyl-2-t-butyloxycarbonylamino-1,3-propanediol 6 wherein R12 is OC(CH3)3, a 1-alkynyl-2-amino-1,3-propanediol 7 is acylated with di-t-butyldicarbonate in the presence of a base such as sodium bicarbonate in a halocarbon solvent such as chloroform at an elevated temperature of about 60xc2x0 C.
To prepare a 2-dialkylamino-1,3-propanediol, for example, a 1-alkenyl-2-dimethylamino-1,3-propanediol 23, a 1-alkeny1-2-amino-1,3-propanediol 17 is reductively alkylated with formaldehyde such as formalin in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as acetonitrile at ambient temperature.
Additional N-substituted 2-amino-1,3-propanediols of the present invention are prepared by acylation of an aminodiol, for example, a thienylaminodiol 30. Thus, treatment of amino 30 with an isocyanate 34
R27Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x8334
wherein R27 is as hereinbeforedescribed affords a urea 31 wherein R5, R27, and X are as hereinbeforedescribed, with an acyl halide 35
xe2x80x83R6COHalxe2x80x83xe2x80x8335
wherein R6 is as hereinbeforedescribed affords an amide 32 wherein R6 is as hereinbeforedescribed and Hal is chloro or bromo, and with haloformate 36
R28OCOHalxe2x80x83xe2x80x8336
wherein R28 and Hal are as hereinbeforedescribed affords a urethane 33. More specifically, treatment of amine 30 with an isocyanate 34 in a dipolar aprotic solvent (e.g., dimethylacetamide, dimethylformamide, hexamethylphosphoramide, or dimethylsulfoxide) in the presence of an acid acceptor (e.g., pyridine, 4-dimethylaminopyridine, triethylamine, or tripropylamine), or in a halocarbon (dichloromethane, trichloromethane, or 1,1- or 1,2-dichloroethane) affords urea 31. Similarly, treatment of amine 30 with a carboxylic acid halide 35 or a haloformate 36 in a dipolar aprotic solvent and acid acceptor such as those mentioned above provides amide 32 and urethane 33, respectively. While the reaction temperature at which the acylations are preformed are not narrowly critical, the transformations proceed at a reasonable rate at a temperature between about xe2x88x9210xc2x0 C. and about ambient temperature. A reaction temperature of about xe2x88x9210xc2x0 C. or about ambient temperature is preferred. The preferred dipolar aprotic solvent is dimethylformamide; the preferred halocarbon is dichloromethane.
The conversion of an N-acyl-2-amino-1,3-diol 6 to a 5-acylamino-2,2-dialkyl-1,3-dioxane 14 is depicted in Reaction Scheme B and described hereinbefore in the specification. A 5-amino-2,2-dialkyl-1,3-dioxane 37 is prepared form 2-amino-1,3-diol 30 by employing substantially the same conditions as hereinbeforementioned. A cosolvent such as a halocarbon, i.e., dichloromethane may be utilized. See Reaction Scheme E.
To prepare an oxazolinylmethane 38, a 2-amino-1,3-diol 30 is condensed with a benzonitrile 39
wherein W is an hereinbeforedescribed in the presence of a base, for example, an alkali metal carbonate such as lithium, sodium, or potassium carbonate, potassium carbonate being preferred, at an elevated temperature within the range of about 80xc2x0 C. to about 140xc2x0 C., a condensation temperature of about 110xc2x0 C. being preferred, in a high boiling solvent system consistent with the reaction temperature chosen to provide a reasonable rate of reaction. Included among such solvent systems are mixtures of trihydric alcohols, e.g., glycerol, and dihydric alcohols, e.g., ethylene glycol, suitable for maintaining a condensation temperature of about 110xc2x0 C.
To protect the arylic hydroxyl group, i.e., the hydroxyl group at the 1-position of the propane chain of an amidic propanoic ester for envisioned transformations, compound 40, for example, is treated with a silyl halide 43
wherein R29 is alkyl and Hal is chloro or bromo, preferably t-butyldimethylsilyl chloride, in the presence of a acid acceptor such as an imidazole, including imidazole itself, in a dipolar aprotic solvent comprising dimethylacetamide, dimethylformamide, hexamethylphosphoramide, or dimethylsulfoxide, dimethylformamide being preferred, to provide a silyloxy ester 41. The introduction of the protecting group proceeds readily at ambient temperature; however, reduced or elevated temperatures within the range of about 10xc2x0 C. to 40xc2x0 C. may be employed. Silyloxy ester 41 is then reduced to silyloxy carbinol 42 by processes such as those hereinbeforedescribed to the conversion of 5 to 6.
The transformations depicted in Reaction Schemes A to E refer to conversions in both the erythro- and threo- series. See pages 5 and 6 for a discussion of this nomenclature. threo-Compounds are prepared from the corresponding erythro-anologs by the conversions shown in Reaction Scheme F. Treatment of an erythro-hydroxyamide 43 with triphenylphosphine and diethyl azodicarboxylate in an ethereal solvent such as, e.g., tetrahydrofuran, provides, with inversion at the arylic position, a threo-carbalkoxyoxazoline 44, which is hydrolyzed under acidic conditions, i.e., aqueous acetic acid, at a hydrolysis temperature within the range of about ambient temperature to about 75xc2x0 C., a reaction temperature of about 50xc2x0 C. being preferred, to a threo-hydroxyester 45. Reduction of the ester group of an amidic ester 45 with, for example, lithium borohydride, as hereinbeforedescribed for the conversion of 5 to 6, affords a threo-amidic diol, which is hydrolyzed by, for example, aqueous sodium hydroxide to a threo-aminodiol 47.
To fabricate a dialkylaminoalkoxypropanol 49 wherein R15 is alkyl and R and X are as hereinbeforedescribed, an aminodiol 30 is N-dialkylated by the process for the conversion of 17 to 23 to provide a dialkylaminodiol 48, which is O-alkylated to provide a eedialkylaminoalkoxycarbinol 49. The O-alkylation is accomplished by treating 48 with an alkali metal hydride such as lithium, sodium, or potassium hydride, potassium hydride being preferred, in a dipolar aprotic solvent (e.g., dimethylacetamide, dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide) to form an alkoxy anion, which in turn is treated with a dialkyl sulfate 51
xe2x80x83(R15)2SO4xe2x80x83xe2x80x8351
wherein R15 is as hereinbeforementioned at ambient temperature to form an alkoxycarbinol 49.
An isoindoledione 50 is prepared by heating an aminodiol 30 with a phthalic anhydride 52
wherein W is as hereinbeforedesribed at an elevated temperature of about 100xc2x0 C.
Various other N-substituted derivatives of a 2-amino-1,3-propanediol 30 are prepared by the processes shown in Reaction Schemes H and I. Thus, alkylation of a oxazolinylmethanol 38 with an alkyl halide 57
R15Halxe2x80x83xe2x80x8357
wherein R15 is as hereinbeforedescribed and Hal is bromo, chloro, or iodo followed by hydrolysis affords an alkylaminopropanediol 56 wherein R15 is alkyl. The alkylation is performed in a dipolar aprotic solvent such as, for example, dimethylsulfoxide at about ambient temperature. The hydrolysis is effected without isolation of the alkylation product by means of an aqueous alkali metal hydroxide such as, for example, sodium hydroxide at a temperature within the range of about ambient temperature to about 100xc2x0 C., a hydrolysis temperature of about 60xc2x0 C. being preferred.
In contrast to the abovementioned process, alkylation of 38 with an alkyl halide 57 provides a methoxymethyloxazoline 53, which is hydrolyzed first to a methoxybenzamide 54 and then to a methoxyamine 55. The alkylation is carried out by forming the alkoxide ion of 38 of means of an alkali metal hydride such as sodium hydride in a dipolar aprotic solvent such as dimethylformamide at about ambient temperature to provide an O-alkoxymethyl oxazoline 53.
The first hydrolysis, i.e., the conversion of an oxazoline 53 to an amide 54 is accomplished under acidic conditions, for example, by an aqueous carboxylic acid such as aqueous acetic acid at a hydrolysis temperature of about 25xc2x0 to about 75xc2x0 C. The preferred hydrolysis temperature is about 50xc2x0 C. The second hydrolysis is effected by an aqueous alkali metal hydroxide such as aqueous sodium hydroxide in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol) at a hydrolysis temperature with in the range of about 50xc2x0 to about 90xc2x0 C. Ethanol is the preferred solvent. A hydrolysis temperature of about 70xc2x0 C. is the preferred.
Additional N-substituted derivatives of a 2-aminopropanediol 30 are prepared by the methods outlined in Reaction Scheme I. Thus, acylation of a 1,3-propanediol 33 by the procedure hereinbeforedescribed for the conversion of 6 to 15 gives a 1,3-dialkanoyloxycarbamate 58 which is alkylated and hydrolyzed to a 1,3-dihydroxy N-alkylcarbamate 59. The alkylation is achieved by the procedure described for the conversion of 48 to 49. The hydrolysis of 58 by aqueous potassium carbonate in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol). Methanol is preferred; a hydrolysis temperature of about ambient temperature is also preferred.
Similarly, reduction of a dihydroxyamide 60 with an alkali metal aluminum hydride, for example, lithium aluminum hydride in an ethereal solvent, for example, diethyl ether/tetrahydrofuran at about ambient temperature affords an N-ethyldihydroxyamine 61, which is acylated with a carboxylic acid anhydride 64
xe2x80x83(R31CO)2Oxe2x80x83xe2x80x8364
wherein R31 is alkyl in the presence of a base, for example, a mixture of triethylamine and 4-dimethylaminopyridine in an ethereal solvent, for example, tetrahydrofuran to provide an O,O-dialkanoyloxyamide 62. An amide 62 is then hydrolyzed under basic conditions, for example, potassium carbonate in methanol to give a dihydroxy-N-ethylamide 63.
The presence of chiral centers at positions 1 and 2 of the present 2-amino-1,3-propanediols, and derivatives thereof, provides an opportunity to prepare stereochemical isomers of the ultimate products and thereby adduce whether the enantiomers of this series of compounds exhibit different pharmacological properties, as has been generally deserved in the art. Significantly, desirable properties generally reside in an enantiomer, while adverse properties inhere in the other.
To gain access to the enantiomers of the present 2-amino-1,2-propanediols, and derivatives thereof, a thiophene 64 wherein R is as hereinbeforedescribed is condensed with a chiral 1,1-dialkylalkyl-4-fornyl-2,2-dialkyl-3-oxazolidinecarboxylate 70
wherein R32 is alkyl, the preparation of which is described in G. Garner and J. M. Park, Journal of Organic Chemistry, 52, 2761 to 2367 (1987), to afford a mixture of diastereomeric hydroxyoxazolidines 65a and 65b, i.e., erythro- and threo- isomers, wherein R32 is as above, which is acylated to a mixture acyloxyoxazolidines 66a and 66b, separated into a pure enantiomer 66b, and hydrolyzed to an enantiomeric hydroxyoxazolidine 67, then to an N-acyloxydiol 68, and finally to an enantiomeric 2-amino-1,3-propanediol 69.
The condensation is effected by treating a thiophene 64 with a strong base, for example, an alkyl- or arylalkali metal such as n-butyllithium, sec-butyllithium or phenyllithium in an ethereal solvent such as 1,2-dimethoxyethane, 2-methoxyethylether, dioxane, or tetrahydrofuran, followed by adding, in this case, chiral oxazolidine 70, also in an ethereal solvent to the salt so formed to a afford a mixture of the erythro- and threo-hydroxyoxazolidines 65a and 65b. The condensation is generally carried out at a reduced temperature in the range of about xe2x88x92100xc2x0 to xe2x88x9250xc2x0 C., a reaction temperature of about xe2x88x9278xc2x0 C. being preferred.
The acylation is readily achieved by processes hereinbeforedescribed for the conversion of 6 to 15, namely, by treating a mixture of 65a and 65b with a carboxylic acid anhydride 71
(R32CO)2Oxe2x80x83xe2x80x8371
wherein R32 is alkyl in an ethereal solvent (e.g., tetrahydrofuran) in the presence of a base or combination of bases (e.g., triethylamine and/or 4-dimethylaminopyridine) at room temperature to yield a mixture of 0-acyloxyoxazolidines 66a and 66b.
The separation of the diastereomeric mixture is accomplished by selective crystallization techniques or chromatographic methods, for example, thin-layer, column, including high pressure and flash chromatography, using suitable absorbents and eluents. Among absorbents, there may be mentioned silica gel, cellulose, magnesium silicate, activated aluminum oxide and resins (e.g., Amberlite and Dowex ion exchange resins). Among suitable chromatography solvents, these may be mentioned acetone, dichloromethane, ethyl acetate, 2-ethoxyethyl ether, ethanol, hexanes, and heptane. Particularly suitable absorbent and solvent for the separation of the diastereomeric acylates are silica gel and ethyl acetate/heptane in a flash chromatographic apparatus.
The hydrolysis of an enantiomer 66b to a hydroxyoxazolidine 67 is achieved by means of an alkali metal carbonate (e.g. lithium, potassium, or sodium carbonate) in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol) at about ambient temperature; reduced temperatures in the range of about 0xc2x0 C. to about ambient temperature and elevated temperatures in the range of about ambient temperature to about 50xc2x0 C. may be employed to effect the hydrolysis.
The hydrolysis of a hydroxyoxazolidine 67 to an N-acyloxydiol 68 is preformed in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol) in the presence of an organic acid (e.g., sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, or 4-methylbenzenesulfonic acid, or a carboxylic acid, such as trifluoroacetic acid). Sulfonic acids are preferred; 4-methylbenzenesulfonic acid is most preferred. Methanol is also preferred. The hydrolysis of occurs readily at ambient temperature. Reduced temperatures in the range of about 0xc2x0 C. to ambient temperature and elevated temperatures in the range of about ambient temperature to about 50xc2x0 C. may be employed, however.
The hydrolysis of an N-acyloxydiol 68 to a 2-aminopropan-1,3-diol 69 is achieved by means of a mineral acid in an alkanol, or mixtures thereof. Included among mineral acids are hydrochloric, hydrobromic, and hydroiodic acids. Hydrochloric acid is preferred. Included among alkanols are methanol, ethanol, 1- and 2-propanol, and 1,1-dimethylethanol. Mixtures of methanol and ethanol are preferred. While the hydrolysis temperature is not narrowly critical, it is convenient to carry out the hydrolysis at ambient temperature.
The enantiomers of the 2-amino-1,2-propanediols of the present invention, and derivatives thereof, are also prepared by condensing a carboxaldehyde 72 with, for example, a chiral haloacetyl-4-phenylmethyloxazolidinone 77a
wherein Hal is chloro, bromo, or iodo, and W is as hereinbeforedescribed, having the S-configuration at the 4-position, the preparation of which is described in D. A. Evans and A. E. Weber, Journal of the American Chemical Society, 109, 7151 (1981), to provide an oxazolidinylhalohydrin 73 which is converted to an azidohydroxyoxazolidine 74, cleaved to an azidohydroxypropionate 75 and reduced to an aminodiol 76. The condensation is effected by treating an aldehyde 72 with a haloacetyloxazolidinone 73 in the presence of a condensing agent, for example, a dialkyl borontriflate 78
CF3SO3B(R34)2xe2x80x83xe2x80x8378
wherein R34 is alkyl, such as di-n-butyl borontriflate and an acid acceptor, for example, a trialkylamine such as triethylamine or 4-dimethylaminopyridine, triethylamine being preferred, in ethereal solvent. Among ethereal solvents, there may be mentioned diethyl ether, 1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane, and tetrahydrofuran. Diethyl is preferred. The condensation is generally carried out at a reduced temperature within the range of about xe2x88x9225xc2x0 to about 100xc2x0 C., a condensation temperature of about xe2x88x9278xc2x0 C. being preferred.
The conversion of a halohydrin 73 to an azidohydrin 74 is accomplished by treating a halo derivative 73 with an alkali metal azide, e.g., lithium, sodium or potassium azide, sodium azide being preferred, in a dipolar aprotic solvent, e.g., dimethylacetamide, dimethylformamide, hexamethylphosphoramide, N-methylpyrrolidione, or dimethylsulfoxide, dimethylsulfoxide being preferred, at about ambient temperature, although reduced temperatures (about 0xc2x0 C. to about ambient temperature) or elevated temperatures (about ambient temperature to about 50xc2x0 C.) may be employed.
The cleavage of a 4(S)-phenylmethyloxazolidinone 74 to an ester 75 is achieved by treating an oxazolidinone 74 with an alkoxymagnesium halide, for example, methoxymagnesium bromide, prepared in situ from an alkylmagnesium halide, for example, methylmagnesium bromine, and an alkanol, for example, methanol in an alkanol/halocarbon solvent, for example methanol/dichloromethane at about 0xc2x0 C. Elevated temperatures up to about 50xc2x0 C. may be employed to effect the cleavage.
The reduction of an azidoester 75 to an enantiomeric 2-amino-1,3-propanediol 76 having the S-absolute configuration is realized by treating an azidoester 75 with an alkali metal hydride, for example, lithium aluminum hydride (although sodium or potassium alumina hydride may be used), in diethyl ether (although other ethereal solvents such as 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran or dioxane may also be used). The reduction of both the azido and ester groups proceeds smoothly at about 0xc2x0 C. Elevated temperatures dependent upon the boiling point of the solvent system may also be employed.
A 2-aminopropane-1,3-diol 82, having the R-absolute configuration, is prepared by the aforementioned processes starting from carboxaldehyde 72 and haloacetyl-4-phenylmethyloxazolidinone 77b
wherein Hal is as hereinbeforementioned and W is as hereinbeforedescried, having the R-configuration at the 4-position.
Alternatively, an enantiomeric 2-aminopropane-1,3-diol of the present invention is prepared by reducing a trans-propenoate 83, prepared from an appropriate aldehyde and a (carbalkoxymethylene)triphenylphosphorane in a conventional Wittig reaction, is reduced to a carbinol 84 and epoxidized under asymmetric conditions to an epoxycarbinol 85, which in turn, is condensed with a benzoylisocyanate to provide a benzoylcarbamate, 86 cyclized to an oxazolidinone 87, and cleaved to an aminopropanediol 88.
The reduction is achieved by treating an alkyl propenoate 83 with an aluminum hydride such as, for example, diisobutylaluminium hydride in an ethereal solvent such as, for example, tetrahydrofuran, at a reduced temperature of about xe2x88x9278xc2x0 C. to provide a carbinol 84.
The asymmetrically induced expoxidation of a trans-alkyl propenate 84 to a 2S-trans-oxirane 85 is accomplished by means of a reaction system containing a base, an epoxidizing agent, and a chiral reagent in a suitable solvent. Among bases, there may be mentioned alkoxides such as alkali metal alkoxides, alkaline earth alkoxides, and transition metal alkoxides. Examples of alkali metal alkoxides include lithium, sodium, and potassium alkoxides. Examples of alkaline earth alkoxides include magnesium and calcium alkoxides. Examples of transition alkoxides include titanium, nickel, zinc alkoxides. Examples of alkoxy groups include methoxide, ethoxide, 1- and 2-propoxide, and 2,2-dimethylethoxide. Transition metal alkoxides are preferred; titanium (IV) 2-propoxide is most preferred.
A variety of epoxidizing agents may be used in this enantioselective synthesis. Among these are organic peracids, for example, perbenzoic acid, peracetic acid, performic acid, and monoperththalic acid, hydrogen peroxide and alkylhydroperoxides derivatives thereof such as tert-butylhydroxyperoxide, the preferred reagent.
The key reagent in this heterogeneous asymmetric epoxidation, the chiral reagent, may be selected from a wide group of optically active organic acids and ester or amide derivatives thereof. Included within this group are tartaric acid and dialkyltartrates, and camphoric acid and dialkyl camphorates. Optically active dialkyltartrates are preferred; di-2-propyltartrate is most preferred. When (+)-di-2-propyltartrate is used, a 2S-trans-oxirane 85 is formed selectively.
Suitable solvents for the expoxidation include halocarbons such as for example dichloromethane, 1,1- and 1,2-dichloroethane and ethylene dichloride. Dichloromethane is preferred.
The epoxidation is generally conducted at a reduced temperature of about xe2x88x9278xc2x0 to about 0xc2x0 C., a reaction temperature of about xe2x88x9220xc2x0 C. being preferred.
The condensation of an optically active hydroxyoxirane 85 with a benzoylisocyanote 89
wherein W is as hereinbeforedefined is conveniently carried out in a halocarbon solvent of the type mentioned immediately above, generally in dichloromethane at about ambient temperature, which temperature is not narrowly critical.
The cyclization of a carbamate 86 to a hydroxyoxazolidinone 87 is effected by an alkali metal hydride selected from the group comprising lithium, sodium, or potassium hydride in a ethereal solvent selected from the group comprising diethyl ether, 2-methoxyethyl ether, 1,2-dimethoxyether, tetrahydrofuran, or dioxane. Sodium hydride suspended in tetrahydrofuran is preferred, as is a cyclization temperature of about the reflux temperature of the reaction medium, although the reaction proceeds readily at reduced temperatures to about ambient temperature.
The hydrolysis of hydroxyoxazolidinone 87 to aminopropanediol 88 is achieved in an alkanol solvent, e.g., methanol, ethanol, 1-, 2-propanol or 2,2-dimethylethanol, by means of a base such as aqueous alkali metal hydroxide, e.g., sodium or potassium hydroxide, about ambient temperature. Ethanol and aqueous sodium hydroxide are the preferred solvent and base.
By applying the aforedescribed process depicted in Reaction Scheme M and employing the antipode of the chiral reagent, e.g., (xe2x88x92)-diethyltartrate in the preferred synthesis, 2-amino-1,3-propanediol 93 is obtained via hydroxy oxirane 90, benzoylcarbamate 91, hydroxyoxazolidinone 92.
A 1-alkenyl-2-amino-1,3-propanediol, e.g., a 1-alkenylpyridinyl-2-amino-1,3-propanediol 17, is prepared by reduction of a 1-alkynylpyridinyl-2-acylamino-1,3-propanediol 6 via a 1-alkenylpyridinyl-2-acylamino-1,3-propanediol 16. See Reaction Scheme C. Alternatively, a 1-alkenyl-2-amino-1,3-propanediol, e.g., a 1-alkenylthienyl-2-amino-1,3-propanediol 27, is prepared by condensation of a halothiophenecarboxyaldehyde 25 wherein X is bromo with a tri-n-butyl-1-alkenylstannane 24 in the presence of 2,6-di-t-butyl-4-methylphenol and tetrakis(triphenylphosphine)palladium(O) in an aromatic solvent such as toluene at room temperature to a 1-alkenylthiophenecarboxaldehyde 26 (see Reaction Scheme D), which, in turn, is converted to a 2-amino-1,3-diol 27 and derivatives thereof by the processes outlined in Reaction Schemes A, B, and C.
The requisite tri-n-butyl-1-alkenylstannane 24 is prepared by reductive condensation of an alkyne 28 with tri-t-butylhydride in the presence of azobisisobutyronitrile.
To synthesize a 2-amino-i -propanol 98 of the present invention, an aldehyde 94 is reduced to a methanol 95 wherein R38 is hydrogen by conventional methods, which is converted to an amidomalonate 96 wherein R5 and X are as hereinbeforedescribed and R37 is alkyl via a sulfonate 95 wherein R38 is SO2R39 wherein R39 is alkyl and, in turn, reduced to a hydroxyamide 97 and hydrolyzed to an aminocarbinol 98. The conversion is carried out by treating a methanol 95 (R38 is hydrogen) with an alkylsulfonyl halide 99a
R39SO2Halxe2x80x83xe2x80x8399a
wherein R39 is alkyl and Hal is chloro or bromo in a halocarbon solvent, e.g., dichloromethane, trichloromethane, 1,1- and 1,2-dichloroethane, dichloromethane being preferred, in the presence of an acid acceptor, e.g., a tertiary amine such as triethylamine, pyridine, and 4-dimethylpyridine, triethylamine being preferred, at about ambient temperature to provide a sulfonate 95 (R38 is SO2R39). Optionally, without isolation, the sulfonate 95 is then treated with an arnidomalonate 100
wherein R38 is alkyl in an alkanol in the presence of a corresponding alkali metal alkoxide. Included among alkanols and corresponding alkali metal alkoxides are methanol and lithium, sodium, and potassium methoxide, ethanol and lithium, sodium, and potassium ethoxide, 1- and 2- propanol and lithium, sodium, and potassium 1- and 2-propoxide, and 1,1-dimethyl ethanol and lithium, sodium, and potassium 1,1-dimethylethoxide. Sodium ethoxide in ethanol is preferred. This step of the conversion proceeds readily at about ambient temperature.
The reduction of a malonate 96 to an amido alcohol 97 is performed by treating the former with an alkali metal borohydride such as, for example, sodium or lithium borohydride, lithium borohydride being preferred, in an ethereal solvent such as, for example, diethylether, 2-methoxyethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, and dioxane, tetrahydrofuran being preferred, at a reduction temperature within a range compatible with the reaction medium. When tetrahydrofuran is used as the solvent, a reaction temperature within the range of about 40xc2x0 to about 80xc2x0 C. is preferred, a reaction temperature of about 60xc2x0 C. is most preferred.
The hydrolysis of an amide 97 to an amino alcohol 98 is achieved by treating an amide 97 with an alkali metal hydroxide, for example, lithium, sodium, or potassium hydroxide, sodium hydroxide being preferred in alkanol, for example, methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol, ethanol being preferred, at a hydrolysis temperature of about 65xc2x0 C., when ethanol is used as the solvent.
To gain entry into the indole series, i.e., to prepare a 2-amino-1,3-propanediol 104 characterized by the presence of an indole moiety, the nitrogen of an indole carboxaldehyde 101 is protected by, for example, a sulfonyl function to provide a protected indolecarboxaldehyde 102, which may be converted to an indolyaminopropanediol 104 by the processes described herein and conventional methods. To protect the indole function prior to subsequent transformations, an indole carboxaldehyde 101 wherein X is bromo is treated with a sulfonyl halide 99b
wherein W is a hereinbeforedescribed and Hal is bromo or chloro in an ethereal solvent, for example, tetrahydrofuran in the presence of an acid acceptor, for example, triethylamine at a reaction temperature about 65xc2x0 C. Other ethereal solvents and acid acceptors may be employed, however. Among them may be mentioned dioxane, 1,2-dimethoxyethane and 2-methoxyethyl ether, and pyridine and 2-dimethylaminopyridine, respectively. Other reaction temperatures, among them temperatures in the range of about 50 to 80xc2x0 C., may also be employed.
To fabricate a 2-amino-1,3-propanediol having an alkanoylaryl substituent at the 3-position of the aminodiole side-chain, i.e., to prepare, for example, an alkanoylphenylaminopropanediol 106 wherein R5 is alkyl, alkynylphenylaminopropanediol is hydrolyzed in an ethereal solvent, for example, tetrahydrofuran in the presence of mercuric oxide and a mineral acid, for example, sulfuric acid at a preferred reaction temperature of about room temperature.
To construct a 2-aminopropane-1,3-diol having an alkoxyaryl moiety at the 3-position of the aminodiol side-chain, i.e., to prepare, for example, alkoxy phenylaminopropanediol 111 wherein R5 is as hereinbeforedescribed, an alkanoyloxy benzaldehyde 107 wherein R41 ia alkyl is converted to an amidoester 108 wherein R11, R12, and R41 are as hereinbeforedescribed by processes also hereinbeforedescribed, which is reduced to hydroxyphenyldiol 109 wherein R12 is as hereinbeforedescribed and, in turn, alkylated to alkoxyphenyldiol 110 and hydrolyzed by processes hereinbeforedescribed to alkoxyphenylaminopropanediol 111. The reduction of an alkanoylphenylpropionate 108 is achieved by treating a propionate 108 with a alkali metal borohydride, e.g., lithium borohydride, in ethereal solvent, for example, tetrahydrofuran at a reduced temperature of about 0xc2x0 C. The alkylation is performed by treating a phenol 109 with an alkyl halide 112
R5Halxe2x80x83xe2x80x83112
wherein R5 is as hereinbeforedescribed and Hal is bromo, chloro, or iodo in a dipolar aprotic solvent, e.g., dimethylacetamide, dimethylformamide, hexamethylphosphoramide, or dimethylsulfoxide, dimethylformamide being preferred, in the presence of an alkali metal carbonate, including lithium, sodium, potassium, and cesium carbonate, and cesium carbonate being preferred. The alkylation is preferrably carried out at about room temperature. Reduced temperatures within the range of about 0xc2x0 C. to about room temperature and elevated temperatures form about room temperature to about 100xc2x0 C. may be employed to effect the alkylation.
By employing the appropriate starting materials and the processes described herein, additional 2-amino-1,3-propanediols of the present invention may be fabricated. For instance, starting from available substituted naphthalenes, naphthylaminopropanediols 112
wherein R5 and X are as hereinbeforedescribed may be constructed.
The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention are useful as agents for the relief of memory dysfunction, particularly dysfunctions associated with decreased cholinergic activity such as those found in Alzheimer""s disease. Relief of memory dysfunction activity of the instant compounds is demonstrated in the dark avoidance assay, an assay for the determination of the reversal of the effects of scopolamine induced memory deficits associated with decreased levels of acetylcholine in the brain. In this assay, three groups of 15 male CFW mice were usedxe2x80x94a vehicle/vehicle control group, a scopolamine/vehicle group, and a scopolamine/drug group. Thirty minutes prior to training, the vehicle/vehicle control group received normal saline subcutaneously, and the scopolamine/vehicle and scopolamine/drug groups received scopolamine subcutaneously (3.0 mg/kg, administered as scopolamine hydrobromide). Five minutes prior to training, the vehicle/vehicle control and scopolamine/vehicle groups received distilled water and the scopolamine/drug group received the test compound in distilled water.
The training/testing apparatus consisted of a plexiglass box approximately 48 cm long, 30 cm high and tapering from 26 cm wide at the top to 3 cm wide at the bottom. The interior of the box was divided equally by a vertical barrier into a light compartment (illuminated by a 25-watt reflector lamp suspended 30 cm from the floor) and a dark compartment (covered). There was a hole at the bottom of the barrier 2.5 cm wide and 6 cm tall and a trap door which could be dropped to prevent an animal from passing between the two compartments. A Coulbourn Instruments small animal shocker was attached to two metal plates which ran the entire length of the apparatus, and a photocell was placed in the dark compartment 7.5 cm from the vertical barrier and 2 cm off the floor. The behavioral session was controlled by PDP 11/34 minicomputer.
At the end of the pretreatment interval, an animal was placed in the light chamber directly under the light fixture, facing away from the door to the dark chamber. The apparatus was then covered and the system activated. If the mouse passed through the barrier to the dark compartment and broke the photocell beam within 180 seconds, the trap door dropped to block escape to the light compartment and an electric shock was administered at an intensity of 0.4 milliamps for three seconds. The animal was then immediately removed from the dark compartment and placed in its home cage. If the animal failed to break the photocell beam within 180 seconds, it was discarded. The latency is seconds for each mouse was recorded.
Twenty-four hours later, the animals were again tested in the same apparatus except that no injections were made and the mice did not receive a shock. The test day latency in seconds for each animal was recorded and the animals were then discarded.
The high degree of variability (due to season of the year, housing conditions, and handling) found in one trial passive avoidance paradigm is well known. To control for this fact, individual cutoff (CO) values were determined for each test, compensating for interest variability. Additionally, it was found that 5 to 7% of the mice in the scopolamine/vehicle control groups were insensitive to scopolamine at 3 mg/kg, sc. Thus, the CO value was defined as the second highest latency time in the control group to more accurately reflect the 1/15 expected control responders in each test group. Experiments with a variety of standards repeated under a number of environmental conditions led to the development of the following empirical criteria: for a valid test, the CO value had to be less than 120 sec and the vehicle/vehicle control group had to have at least 5/15 animals with latencies greater than CO. For a compound to be considered active the scopolamine/compound group had to have at least 3/15 mice with latencies greater than CO.
The results of the dark avoidance test are expressed as the number of animals per group (%) in which this scopolamine induced memory deficit is blocked as measured by an increase in the latency period. Relief of memory dysfunction activity for representative compounds of the present invention is presented in Table 1.
Scopolamine induced memory deficit reversal is achieved when the present 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediol, and related compounds are administered to a subject requiring such treatment as an effective oral, parenteral or intravenous dose of from 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.
The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention are also useful as antiiflammatory agents due to their ability to reduce inflammation in mammals. The antiinflammatory activity is demonstrated in the TPA-induced ear edema assay and the arachidonic acid-induced ear edema test (see J. M. Young, et al., Journal Investigative Dermatology, 80, 48 (1983)).
In the TPA-induced ear edema assay, TPA (12-O-tetradecanoylphorbol-13-acetate) was dissolved in 30/70 propylene glycol/ethanol and was applied to the right ear of groups of 6 female Swiss Webster mice, which were housed together in a cage under standard conditions for 1 week prior to use with food and water ad lib, at a volume of 20 xcexcl so that a total of 10 xcexcg of TPA is delivered to the inner and outer surfaces of the ear. The test compound was dissolved in the vehicle and was applied to the right ear (the inner and outer surface) at a volume of 20 xcexcl so that a total of 10 xcexcg of the compound was delivered to the ear. After about 5 hours, the animals were sacrificed, a 4 mm diameter plug was taken from each ear and weighed. The difference between the right and left ear plug weights for each animal was determined. The antiinflammatory activity of the test compound is expressed as the mean percent change in the ear plug weight of the treated animals compared to the mean percent change in the plug weight of the control animals. Antiinflammatory activity of representative compounds of the instant invention as determined in this assay are presented below in Table 2.
In the arachidonic acid-induced ear edema assay, the test compound was dissolved in 30/70 propylene glycol/ethanol and was applied to both ears of groups of 6 female Swiss Webster mice, which were housed together in a cage under standard conditions for 1 week prior to use with food and water ad lib, at a volume of 20 xcexcl so that a total of 1.0 mg of test compound was delivered to each ear over the inner and outer surfaces. The same volume (20 xcexcl) of vehicle was applied to each ear of a control group of mice. After 30 minutes, arachidonic acid was applied to the right ear of each mouse of each group in the amount of 4 mg/ear. Vehicle was applied to the left ear of each mouse of each group at a volume of 20 xcexcl/ear. After an additional hour, the mice were sacrificed and a 4 mm plug was taken from each ear and weighed. The difference between the right and left ear plugs was determined for each animal. The antiinflammatory activity of the test compound is expressed as the mean percent change in the ear plug weight of the treated animals relative to the mean percent change in weights of control animals"" ear. Antiinflammatory activity of representative compounds of the present invention as determined in this assay are presented below in Table 3.
Inflammation reduction is achieved when the present 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols are administered topically, including ophthalmic administration, to a subject requiring such treatment as an effective topical dose of from 0.001 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.
The 1-alkyl-, 1-alkenyl-, and 1-alkynyl-2-amino-1,3-propanediols of the present invention are also useful as inhibitors of tumor or neoplastic cell growth by virtue of their ability to reduce cell proliferation as demonstrated in the protein kinase C assay. (see U. Kikkawa, et al., Biochemical and Biophysical Research Communications, 135, 636 (1986) and R. M. Bell, et al. xe2x80x9cMethods in Enzymology, Hormone Action,xe2x80x9d Part J, P.M. Conn, Ed., Academic Press, Inc., New York, N.Y. 1986, page 353).
Protein kinase C enzyme extract was prepared from the brain of male Wistar rats weighing 180 to 200 g and purified by the method of U. Kikkawa, et al., ibid. 636. The purified extract was stored at xe2x88x9280xc2x0 C., and aliquots were used in the protein kinase C assay performed by a modification of the method of R. M. Bell, et al., ibid. al 354.
To perform the assay, duplicate aliquots of duplicate samples are employed. Basal or unstimulated protein kinase C, phosphatidylserine/diacylglycerol stimulated protein kinase C, and test samples are run in each assay. Protein kinase C extract (1-5 xcexcg of protein; 10 xcexcl); an 8 xcexcl solution of N-2-hydroxyethylpiperazine-Nxe2x80x2-2-ethylsulfonic acid (500 mM), magnesium chloride (40 mM), and ethylenediaminoetetraacetic acid (10 mM); dithiothreitol (20 mM; 8 xcexcl), Type III histone (12 xcexcg; 8 xcexcl), and calcium chloride (11 mM; 8 xcexcl) was added to each unstimulated protein kinase C sample assay tube, chilled in ice. Phosphatidylserine/diacylglycerol (4 xcexcg; 8 xcexcl) was added to each stimulated protein kinase sample assay tube, chilled in ice. The test compound (10xe2x88x924 to 10xe2x88x9212M in 4 xcexcl dimethylsulfoxide) was added to the test sample tubes, chilled in ice. The volume for all sample tubes was brought to 72 xcexcl with distilled water (18 xcexcl for stimulated samples; 26 xcexcl for unstimulated samples without 8 4xcexcl of phosphatidylserine/diacylglycerol). The assay tubes were allowed to warm to 25xc2x0 C. and an 8 xcexcl mixture of adenosine 5xe2x80x2-triphosphate (100 xcexcM) and 32P-adenosine triphosphate (1 to 2xc3x97105 counts per minute) was added to each tube for a final volume of 80 xcexcl per tube. After 2 min, the reaction (the incorporation of phosphorous into Type III histone) was terminated by spotting the assay mixture on phosphocellulose paper. The spots are cut out of the paper and the radioactivity (counts per min) of each spot was determined in a scintillation counter. Percent protein kinase C inhibitory activity, i.e., the percent inhibition of the incorporation of 32phosphorous from 32P-adenosine triphosphate into Type III histone, is calculated as follows:             radioactively                    xe2x80x83                  of                    xe2x80x83                  test                    xe2x80x83                  sample                    xe2x80x83                          (        cpm        )                            radioactivity                          xe2x80x83                        of                          xe2x80x83                        stimulated                                      xe2x80x83                                          xe2x80x83                                  sample                          xe2x80x83                                  (          cpm          )                    -
                          radioactivity                          xe2x80x83                        of                          xe2x80x83                                  un                    stimulated                                              xe2x80x83                                          xe2x80x83                                  sample                          xe2x80x83                                  (          cpm          )                      xc3x97  100    %
Protein kinase C inhibitory activity of representative compounds of the present invention expressed as the calculated concentration of test compound effecting a 50% inhibition of phosphorous uptake (IC50) is presented below in Table 4.
Protein kinase C inhibition is achieved when the present 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, and related compounds are administered to a subject requiring such treatment as an effective oral, parenteral, intravenous, or topical dose of from 0.001 or 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.
The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention are also useful as antibacterial and antifungal agents due to their ability to inhibit bacterial and fungal growth in mammals. Antibacterial and antifungal activity are demonstrated in conventional antimicrobial assays assays (see D. J. Bibel, et al., The Journal of Investigative Dermatology, 92, 632 (1989).
In the aerobic antibacterial assay, the sensitivity of aerobic bacteria was tested by means of the agar dilution test in Mueller-Hinton agar. Plates were inoculated with a multipoint inoculator which delivered 5xc3x97104 CFU/spot of stationary, freshing diluted cultures of the strains concerned. The minimun inhibitory concentration (MIC) was taken as the lowest concentration at which no visible growth could be detected after 24 hours at 37xc2x0 C.
In the anerobic assay, the susceptibility of obligate gram-positive and gram-negative anaerobes was tested using the agar dilution test on Wilkins-Chalgren agar. Overnight cultures of the appropriate test strains diluted 1:10 in fresh thioglycollate medium were used as the inoculum. The MICs of the antibiotics were determined after the plates had been incubated in anaerobic jars for 48 hours at 37xc2x0 C.
Antibacterial activity of representative compounds of the instant invention as determined in this assay is presented below in Tables 5 and 6.
In the antifungal assay, utilizing a microtitration technique (U-shaped, 96 well-plate), the test compound (10 mg) is dissolved in a suitable solvent (10 ml dist. water, or 1 ml org. solvent+9 ml dist. water).
The microtiter plate is prepared as follows: The wells are each filled (2 rows/strain) with 50 xcexcl neopeptone-dextrose broth (12-channel pipette). In addition, one row/strain is coated with 50 xcexcl yeast-nitrogen base/well for yeasts and moulds. Subsequently, 50 xcexcl compound solution are added to each well in the first row, mixed and diluted further by transferral of 50 xcexcl respectively in the ratio 1:2. All wells are then inoculated with 150 xcexcl standardized organism suspension (yeasts: 1xc3x97103 organisms/ml suspension; cutaneous fungi and moulds: 1.6xc3x97105 organisms/ml suspension); the total volume is 200 xcexcl per well.
There is also a growth control (inoculated, not medicated), a solvent control (inoculated, not medicated, containing solvent as in medicated rows) and a negative control (not inoculated, not medicated).
Incubation for 5 days at 30xc2x0 C. is followed by photometric evaluation. The obtained measurements are checked visually (macroscopically and microscopically) and corrected where necessary.
Criteria for Evaluation of the Antimycotic Effect
a. Photometric measurements (matrix method)
b. Growth, macroscopic evaluation
c. Growth, microscopic evaluation (inversion light microscope, magn. 64xc3x97).
Antifungal activity of representative compounds of the instant invention as determined in the microtiter assay is presented below in Table 7.
Bacterial and fungal growth inhibition is achieved when the present 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, and related compounds are administered to a subject requiring such treatment as an effective oral, parenteral, intravenous, or topical, including ophthalimic administration, dose of from 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set for herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.
Compounds of the present invention include:
a. erythro-2-amino-1-(5-decyl-2-furyl)-1,3-dihydroxypropane;
b. erythro-2-amino-1-(5-decyl-3-isothiazolyl)-1,3-dihydroxypropane;
c. threo-2-amino-1-[5-decyl-3-(2-oxopyrrolyl)]-1,3-dihydroxypropane;
d. erythro-2-amino-1-[6-decyl-2-(4-methylpyridinyl)]-1,3-dihydroxypropane;
e. threo-2-amino- 1-[6-decyl-2-(4-methoxypyridinyl)]-1,3-dihydroxypropane;
f. erythro-2-amino-1-[6-decyl-2-(5-chloropyridinyl)]-1,3-dihydroxypropane;
g. threo-2-amino-1-[6-decyl-2-(4-trifluoromethyl-pyridinyl)]-1,3-dihydroxypropane;
h. erythro-2-amino-1-[6-(5-phenylpentyl-2-pyridinyl)-1,3-dihydroxypropane;
i. erythro-2-amino-1-(2-decyl-4-thiazolyl)-1,3-dihydroxypropane;
j. erythro-2-amino-1-(2-decyl-4-oxazolyl)-1,3-dihydroxypropane;
k. erythro-2-methylamino-1-(5-decyl-2-thienyl)-1,3-dihydroxypropane
l. erythro-2-dimethylamino-1-(3-decyl)phenyl-1,3-dihydroxypropane;
m. erythro-2-(1,1-dimethylethoxy)carbonylamino-1-(2-dodecynyl-6-pyridinyl)-1,3-dihydroxypropane;
n. erythro-2-amino-1-(3-(1-decenyl)phenyl)-1,3-dihydroxypropane;
o. ethyl erythro-2-methoxycarbonylamino-3-(2-dodecynyl-6-pyridinyl)-3-hydroxypropionate;
p. erythro-2-amino-1-(3-(1-decynyl)phenyl)-1,3-dihydroxypropane;
q. erythro-2-amino-1-(3-(1-undecynyl)phenyl)-1,3-dihydroxypropane;
r. erythro-2-amino-1-(4-(1-nonyl)-2-thienyl)-1,3-dihydroxypropane;
s. erythro-2-amino-1-(4-(1-dodecynyl)-2-thienyl)-1,3-dihydroxypropane;
t. erythro-2-amino-1-(4-(1-decyl)-2-thienyl)-1,3-dihydroxypropane;
u. erythro-2-amino- 1-(5-nonyl-2-thienyl)-1,3-dihydroxypropane;
v. erythro-2-amino-1-(3-dodecyl-5-isoxazolyl)-1,3-dihydroxypropane;
w. erythro-2-amino-1-(3-decyl-5-isoxazolyl)-1,3-dihydroxypropane;
x. erythro-2-amino-1-(6-(1-dodecenyl)-2-pyridinyl)-1,3-dihydroxypropane;
y. erythro-2-amino-1-(3-(6-phenyl-1-hexynyl)phenyl)-1,3-dihydroxypropane; and
z. erythro-2-amino-1-(5-(6-phenylhexyl)-2-thienyl)-1,3-dihydroxypropane.
Effective amounts of the compounds of the present invention may be administered topically to a subject in the form of sterile solutions, suspensions, ointments, creams, aerosols, or salves. The 1-alkyl-, 1-alkenyl, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid or base addition salts for purposes of stability, convenience or crystallization, increased solubility and the like.
Preferred pharmaceutically acceptable acid addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid and the like, salts of monobasic carboxylic acids such as, for example, acetic acid, propionic acid and the like, salts of dibasic carboxylic acids such as, for example, maleic acid, fumaric acid and the like, and salts of tribasic carboxylic acids such as, for example, carboxysuccinic acid, citric acid and the like. Preferred pharmaceutically acceptable base addition salts include salts of alkali metals, e.g. sodium or potassium, alkaline earth metals, e.g. calcium or magnesium; or complex salts such as ammonium or substituted ammonium salts such as a mono-, di- or trialkylammonium salts or a mono, di- or trihydroxyalkylammonium salts.
For the purpose of topical administration, the active compounds of the invention may be incorporated into a solution, suspension, ointment, cream, gel, aerosol, or salve. These preparations should contain at least 0.1% of active compound but may be varied to be between 0.05 and about 20% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred topically administered preparations should contain between 0.1 and 10% of active compound.
The topical compositions may also include the following components: water, fixed oils, polyethylene, glycols, glycerol, petroleum, stearic acid, beeswax, other synthetic solvents or mixtures thereof; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as a-tocopherol acetate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; emulsifying agents such as polyoxyethylene monooleate and coloring materials and adjuvants such as ferric oxide or talc. The topical preparation can be enclosed in tubes, bottles, or jars made of metal, glass or plastic.
The active compounds of the present invention may also be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 75% of the weight of the unit. The amount of present compound in such composition is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 mgs of active compound.
The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added. When the dosage unit is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purposes of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of the aforesaid compound, but may be varied between 0.5 and about 50% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 mgs of the active compound.
The oral solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino 1,3-propanediols and related compounds


Embodiments of the present disclosure are applicable to the field of communications technologies, and provide an application recommending method and system, and a server. The method includes receiving data reported by at least one terminal, where the data includes static data and first application behavior data that are collected by the at least one terminal, and the static data is used to identify a type of a terminal; obtaining an activity index of each application on terminals of different types according to the first application behavior data; and receiving an application list request sent by a first terminal, querying, according to the application list request, an activity index of each application on terminals that are of the same type with the first terminal, and recommending an application with an activity index greater than a preset first activity index threshold to the first terminal.

Diversification of terminals is a tough problem that all application developers and distribution channels have to face. For different operating systems (OS) and different hardware, considerable workload needs to be taken in migration and adaptation.
For a same type of OS, for example, Android™, a large quantity of Android systems of different versions exist on an existing network, and a variety of read-only memories (ROMs) customized by different manufacturers and a large quantity of device models also exist. Therefore, it is unlikely that an overall coverage test can be conducted for an Android application. For a same application running on different devices, various compatibility problems usually occur, including an installation failure, a running failure, a failure in using some functions after the application runs, and so on.

Application recommending method and system, and server


A linear drive including a stator and a rotor configured for linear reciprocal movement along an axis, with the stator having a magnetic-field guide core having a plurality of legs extending each with one foot substantially toward the rotor, with the rotor having a plurality of magnets disposed in a linear array along the direction of the axis, wherein at least one of a respective one of respective lengths of the magnets along the axis and the respective widths of the legs along the axis and the respective spacings of the legs along the axis are different such that force components of the magnets along the axis will substantially compensate each other when the linear drive is in a de-energized state.

The invention relates to a linear drive having a stator and a rotor that can move therein back and forth along an axis, with the stator having a magnetizable magnetic-field guide core that has legs extending each with one foot substantially toward the rotor; to a linear compressor, a refrigerating device, in particular a refrigerator and/or freezer or an air-conditioning system, as well as to a method for refrigerating an item and/or compressing a fluid.
Linear drives having permanently energized rotors are selectively moved by appropriately driving the drive coils on the stator by applying a suitable current to them. The coil fields are guided through a magnetizable magnetic-field guide core having poles and are focused onto a region around the rotor.
DE 699 015 86 T2 discloses an electromagnetic linear actuator comprising a stator construction having two poles excited by at least one electric winding. A moving component has a magnet yoke and a magnetizable part, with the moving component having one or two magnets that are permanently magnetized in a direction perpendicular to the plane of the air gap and set into a recess in the moving magnet yoke. A stator part is therein formed from a piece of ferromagnetic material having legs that have feet embodied as polar protuberances.
The problem posed by known solutions is that the rotor is difficult to drive precisely and in particular that its back-and-forth motion cannot always be controlled as precisely as desired. The imprecision of said back-and-forth motion is disadvantageous particularly in association with linear compressors because the compressor piston needs then to be positioned as accurately as possible to minimize a dead volume in the compressor-piston housing: The compressor piston will when moving in an uncontrolled manner strike the piston housing or a valve plate if a safety clearance between the piston housing and compressor piston has been underdimensioned, as a result of which the valve plate, the compressor piston, and the piston rod between the rotor and compressor piston may be damaged. Albeit said problem can be obviated by suitably increasing the safety clearance between the piston housing and compressor piston, the dead volume in the piston housing ought nonetheless to be as small as possible lest the linear compressor's operating efficiency be too adversely affected.
It is known how through a regulating means the imprecision in the back-and-forth motion can be corrected by placing positioning sensors on the rotor and braking it in a timely fashion by driving the drive coils appropriately. Although such braking operations can effectively prevent striking by the compressor piston, they are nonetheless disadvantageous given the need for as great as possible operating efficiency since the braking energy will be lost to the system.

Linear drive with a reduced axial force component, as well as a linear compressor and refrigerator


An improved electrical cable design for high-speed, low loss signal transmission. The improved cable design may be a three-conductor cable having a center conductor, a middle conductor and an outer conductor, where each conductor is separated by a dielectric layer. The electrical cable provides an inverted cable design, in which signal transmission occurs within the middle conductor, the center conductor is used as a return or drain line to ground and the outer conductor is used as a shield. The middle conductor of the electrical cable provides a larger surface area for signal conductance than the center conductor, thereby transmitting signals with significantly less loss (e.g., at least 50% less loss).

As the value and use of information continues to increase, individuals and businesses seek additional ways to process and store information. One option available to users is information handling systems. An information handling system generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes thereby allowing users to take advantage of the value of the information. Because technology and information handling needs and requirements vary between different users or applications, information handling systems may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in information handling systems allow for information handling systems to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. In addition, information handling systems may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
Electrical cables (or simply "cables") have become an integral part of many information handling systems such as, for example, desktop computers, laptop computers and servers. Cables may be used externally to connect multiple information handling systems together, or internally to connect printed circuit board (PCBs) within an information handling system together. When one or more servers are installed within a rack, for example, communication between racks can be easily accomplished through externally coupled cables. Internal cables are also commonly used within rack servers for connecting Serial Attached Small Computer System Interface (Serial Attached SCSI, or SAS), Serial Advanced Technology Attachment (SATA) and non-volatile memory (NVME) backplanes.
Cables are commonly used in high-speed signal transmission applications, since they provide a lower loss mode for signal propagation compared to printed circuit board (PCB). However, with signal speeds steadily increasing, lowering the loss through cables is becoming a major design challenge for future high-speed signal transmission applications. Even though cables provide a lower loss medium than PCB, the loss through the cables may not be adequate to meet the channel budget (e.g., 15 dB) specified in some high-speed data bus standards, such as the Peripheral Component Interconnect Express (PCIe) standard, at certain cable lengths (e.g., cable lengths greater than 700 mm). While ultra-low loss materials are currently being considered, there is an ever present need to provide a lower loss cable design.
A coaxial cable (or simply "coax") is one type of electrical cable commonly used for high-speed signal transmission. As known in the art, a coaxial cable typically includes a center conductor, an insulating dielectric layer surrounding the center conductor, and an outer conductor surrounding the insulating dielectric layer, all of which is surrounded by a protective outer jacket. In a coaxial cable, the center conductor is used for single-ended signal transmission, while the outer conductor (or shield) is connected to ground.
A dual-axial cable (or twin-axial cable) is another type of electrical cable commonly used for high-speed signal transmission. As the name implies, a dual-axial cable includes two axes or center conductors, which are arranged side-by-side, or parallel to one another, for transmitting differential signals. The dual-axial cable also includes an insulating dielectric layer surrounding each of the center conductors, one or more drain wires for connecting to ground, an outer conductor (or shield) and a protective outer jacket.
FIGS. 1 and 2 provide cross-sectional views of dual-axial cables commonly used for high-speed signal transmission. As shown in FIGS. 1 and 2, dual-axial cables 10, 20 my each include a pair of center conductors 12, an insulating dielectric layer 14 surrounding each of the center conductors 12, an outer conductor (or shield) 16 surrounding the insulated conductors, and a protective outer jacket 18 surrounding the outer conductor 16. In the dual-axial cable shown in FIG. 1, a single drain wire 19 is provided near the center of the cable 10 for connecting the cable to ground. In the dual-axial cable 20 shown in FIG. 2, two drain wires 22, 24 are provided and arranged on either side of the cable 20.
In the dual-axial cables 10, 20 shown in FIGS. 1 and 2, the center conductors 12 are used for signal transmission, while the drain wire(s) are used as a return or drain line to ground. When an alternating current (AC) signal is applied to the center conductors 12, the electric current is distributed within the conductors, such that the current density is largest near the surface (or "skin") of the conductors and decreases with increasing depth (or "skin depth") within the conductors. This effect, known as the "skin effect," causes the effective resistance of the center conductors 12 to increase at higher frequencies where the skin depth is smaller, thus reducing the effective cross-section of the conductors and increasing the loss through the conductors. In many cases, the center conductors 12 used within the dual-axial cables 10, 20 may be relatively small in diameter (e.g., 20 AWG to 26 AWG). When using such small center conductors 12, losses due to the skin effect and the dielectric material make it difficult to transmit high-speed, low loss signals.

Inverted cable design for high-speed, low loss signal transmission


The present invention provides a method and apparatus for scheduling a plurality of processing tools. The method comprises providing a first processing tool and a plurality of second processing tools, selecting one of the plurality of second processing tools, and determining a target output parameter of a combination of processing tools comprising said first processing tool and said selected one of the plurality of second processing tools. The method also includes determining at least one input parameter of a process model for controlling the first processing tool based upon the target output parameter of the combination of processing tools.

1. Field of the Invention
This invention relates generally to the field of semiconductor device manufacturing and, more particularly, to a method and apparatus for scheduling a plurality of processing tools.
2. Description of the Related Art
A variety of processing tools are used to fabricate a semiconductor device. The processing tools may include photolithography steppers, etch tools, deposition tools, polishing tools, rapid thermal processing tools, ion implantation tools, and the like. Wafers (or wafer lots) are processed in the tools in a predetermined order and each processing tool modifies the wafers according to a particular operating recipe. For example, a photolithography stepper may be used to form a patterned layer of photoresist (i.e. a mask) above a dielectric layer that has been deposited above the wafer. Features in the patterned layer of photoresist correspond to a plurality of features, e.g. gate electrode structures, which will ultimately be formed above the surface of the wafer. The wafer is then provided to an etch tool that etches away portions of the dielectric layer corresponding to features in the mask to form the plurality of features above the surface of the wafer.
The characteristics of the features formed above the surface of the wafer depend in part on the processing tools that participated in forming the feature. For example, the width of an etch line on a wafer is typically defined by both the etching and photolithography processes. For example, a layer of material may be deposited above a wafer. Then a patterned layer of photoresist (e.g. a mask layer) is formed above the layer of material by a photolithography tool. An etching process is then performed on the underlying layer of material through the patterned masking layer to define a plurality of features, e.g. lines, in the underlying layer of material. Thus, errors in either the photolithography process used to form the patterned masking layer or the etching process may lead to errors in the features formed in the underlying layer.
Feedback control may be provided to some of the processing tools to control the characteristics of the features formed above the surface of the wafer. For example, the exposure dose used by a photolithography stepper may be adjusted to control the width of printed resist lines formed in the mask layer. However, various practical considerations, including cost, complexity, and the like, usually limit the number of processing tools that can be placed under feedback control in conventional processing systems. Thus, conventional processing systems typically rely upon predetermined process models to account for the characteristics of features formed by the processing tools. For example, a process model may be used to relate a development inspection critical dimension (DICD) of a feature in a mask layer to a final inspection critical dimension (FICD) of the corresponding feature when formed above the wafer, i.e. after the etching process is complete. Thus, the exposure dose used in the photolithography step may be selected so that, on average, the final inspection critical dimension (FICD) of etched lines formed above the wafers in a wafer lot processed by the photolithography stepper and the etching tool will be near a target value for the final inspection critical dimension (FICD) of such a feature.
In some process flow arrangements, a single tool may be used to supply wafers to a selected one of a plurality of other processing tools. For example, a photolithography stepper can form a mask layer over a wafer in approximately one minute, whereas an etching tool may take three to four minutes to etch the wafer. Thus, at least in part to maintain a desired wafer throughput, conventional etch process flows may include, for example, two or three photolithography stepper tools that provide masked wafers to six or seven etching tools. Such conventional processing systems typically rely upon a single process model to account for the characteristics of features formed by the processing tools. For example, a single process model may be used to relate development inspection critical dimensions (DICD) of features in patterned masking layers formed by the aforementioned two or three photolithography stepper tools to final inspection critical dimensions (FICD) of corresponding features formed by the aforementioned six or seven etching tools.
However, a single process model may not be sufficient to characterize features that are formed in process flows that lack a one-to-one correspondence between the processing tools in the process flow. For example, each photolithography stepper may form a mask layer having a different development inspection critical dimension (DICD). Moreover, each etch tool in the process flow may have a different etch bias so that the relationship between the development inspection critical dimension (DICD) and the final inspection critical dimension (FICD) may vary depending on the etching tool used to form the feature. Thus, the actual final inspection critical dimension (FICD) of features formed on the wafer may differ from the value predicted by the process model and may also vary depending upon the particular combination of photolithography stepper and/or etching tool used to form the mask layer and/or feature. Consequently, attempting to control the final inspection critical dimension (FICD) of features etched by the different etch tools by controlling the exposure dose in the photolithography stepper based upon a single process model for all combinations of the various processing tools may result in different feature size populations for each of the etching tools.
The present invention is directed to addressing the effects of one or more of the problems set forth above.

Method and apparatus for scheduling a plurality of processing tools


Provided is a die cushion controller that controls an ascending/descending speed of a die cushion based on a predetermined pressure pattern 56. The pressure pattern 56 has a low pressure target value PL which is first followed by an increased cushion pressure, a high pressure target value PH corresponding to a requisite cushion pressure for retaining a workpiece, and a complementary target value PC which is followed by the cushion pressure at a substantially linear increase rate for a predetermined period of time T2 until the cushion pressure exceeds the low pressure target value PL and reaches the high pressure target value PH. The cushion pressure overshooting the low pressure target value PL continues to follow the complementary target value PC, so that an overshooting amount occurring at a time point at which the cushion pressure reaches the high pressure target value PH can be reduced. As a result, pressure variation in the cushion pressure can be suppressed.

For example, there has been known a die cushion controller disclosed in Patent Document 1, which controls an ascending/descending movement of a die cushion pad driven by an electric servomotor. In the die cushion controller of Patent Document 1, a load (a pressure) generated in a die cushion pad (hereinafter, this pressure will be referred to as a "cushion pressure") is obtained based on an electric current value of the electric servomotor, and the electric servomotor is controlled such that the obtained cushion pressure follows a pressure pattern of a preset cushion pressure.
In this regard, the pressure pattern as disclosed in Patent Document 1 is in a form of a free-form curve where the cushion pressure starts to gently increase at a time point at which an upper die contacts with a workpiece to reach a maximum target pressure and then gently decreases.
[Patent Document] JP-A-10-202327


A boot system and method are described for preventing water or debris from entering a hole in the ground in which a pole has been placed prior to filling the hole with dirt or concrete. A flexible sheet is attached to the pole above the ground, and the lower edge of the sheet is secured to the ground around the pole. The side edges of the sheet are connected together. This system sheds water and keeps all foreign material out of the hole.

Pole building construction initially involves drilling or digging holes in the ground in which long vertical poles are set. To prevent the poles from settling lower into the ground than desired, an oversized concrete pad or base is placed at the bottom of the hole for the pole to rest on. The diameter of the concrete pad is preferably larger than the diameter of the pole.
In some locations of the country, local building codes require inspection of the hole and concrete pad before the hole can be filled in with dirt and packed around the pole. Unfortunately, there is often a period of delay between when the holes are dug and when the inspector is able to make the necessary inspection. In the meantime, depending upon the weather, rain or snow could cause the hole to become filled (or partially filled) with water or snow. It is also possible for dirt or debris to fall into the hole before the necessary inspection is made. As a result, it may be necessary to remove the pole and dig out any foreign material which may have fallen into it before the inspection can be made.
There has not heretofore been provided a system for protecting holes in the ground having the features and advantages provided by the present invention.