EP1461332A2 - Production of chirally pure alpha-amino acids and n-sulfonyl alpha-amino acids - Google Patents
Production of chirally pure alpha-amino acids and n-sulfonyl alpha-amino acidsInfo
- Publication number
- EP1461332A2 EP1461332A2 EP02786817A EP02786817A EP1461332A2 EP 1461332 A2 EP1461332 A2 EP 1461332A2 EP 02786817 A EP02786817 A EP 02786817A EP 02786817 A EP02786817 A EP 02786817A EP 1461332 A2 EP1461332 A2 EP 1461332A2
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- EP
- European Patent Office
- Prior art keywords
- substituted
- sulfonyl
- alkyl
- amino acid
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/64—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- This invention relates to a novel process of producing chirally pure ⁇ -amino acids and N-sulfonyl ⁇ -amino acids.
- Compounds of the present invention are useful for a variety of purposes, including for use in pharmaceutical compositions.
- the present invention comprises a process for preparing chirally pure S-enantiomers of ⁇ -amino acids.
- a process is provided for preparing chirally pure S- enantiomers of 2-aminoalcohols, aldehydes and oximes.
- a process for preparing chirally pure N-sulfonyl 2-aminoalcohols, aldehydes and oximes.
- the present invention is directed to a process for the preparation of chiral ⁇ -amino acids.
- the present invention provides a process for the resolution of chiral N-sulfonyl ⁇ -amino acids.
- Both processes of the invention produce chirally pure compounds which can be converted to suitable target compounds, including the corresponding 2- aminoalcohols or N-sulfonyl 2-aminoalcohols, aldehydes and oximes, among other desirable target compounds.
- chirally pure refers to compounds which are in greater than about 95% S-enantiomeric form, preferably greater than about 97%, as measured by chiral high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- Other methods of measuring chiral purity include conventional analytical methods, including specific rotation, and conventional chemical methods.
- the technique used to measure chiral purity is not a limitation on the present invention.
- the term "pharmaceutically useful” refers to compounds having a desired biological effect, whether as a therapeutic, immune stimulant or suppressant, adjuvant, or vaccinal agent.
- a variety of compounds which are suitable for use in non-pharmaceutical applications e.g., a diagnostic, a marker, among others may be produced by the method of the invention.
- other pharmaceutically useful compounds may be produced by this method.
- the compounds produced by the present invention and any target compounds into which they are converted can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases.
- salts include, but are not limited to, the following salts with organic and inorganic acids such as acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, mallic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids, and mixtures thereof.
- Other salts include salts with alkali metals or alkaline earth metals, such as sodium (e.g., sodium hydroxide), potassium (e.g., potassium hydroxide), calcium or magnesium.
- salts as well as other compounds produced by the method of the invention may be in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo.
- the prodrugs are esters. See, e.g., B. Testa and J. Caldwell, "Prodrugs Revisited: The “Ad Hoc” Approach as a Complement to Ligand Design", Medicinal Research Reviews, 16(3):233-241 3 ed., John Wiley & Sons (1996).
- ⁇ -amino acids are characterized by the formula (NH 2 )(CHR.)(COOH), in which R. is an aliphatic radical.
- R. is an aliphatic radical.
- the ⁇ -amino acids prepared according to the invention can be converted to N-sulfonyl ⁇ -amino acids and other desired compounds.
- Such other desired compounds include, without limitation, the corresponding 2-aminoalcohols, aldehydes, oximes, and pharmaceutically acceptable salts, hydrates, and prodrugs thereof.
- N-sulfonyl ⁇ -amino acids natural and unnatural N-sulfonyl 2-aminoalcohols, and intermediates thereof, may be prepared according to the present invention.
- the N-sulfonyl ⁇ -amino acids described herein can be readily reduced to 2- aminoalcohols, or converted to the corresponding aldehydes, oximes, and pharmaceutically acceptable salts, hydrates, and prodrugs thereof, using techniques known to those of skill in the art.
- chirally pure ⁇ -amino acids produced according to the method of the invention and having the formula (R) 2 CH(CH 2 ) n CH(CO 2 H)NH-R' can readily be converted to chirally pure 2-aminoalcohols.
- chirally pure N- sulfonyl ⁇ -amino acids produced according to the invention and having the formula (R) 2 CH(CH 2 )nCH(CO 2 H)NH-S(0) 2 R' are readily converted to N-sulfonyl 2- aminoalcohols of the formula (R) 2 CH(CH 2 ) n CH(CH 2 OH)NHS(O) 2 R ⁇
- n is 0 to about 10;
- R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2 cyclo alkyl, CH 2 -3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4- methoxypheny
- an N-sulfonyl 2-aminoalcohol having the formula (R) 2 CH(CH 2 ) ceremoniCH(CH 2 OH)NH-S(0) 2 -2-C 4 H 2 S-5-Cl is prepared using the method of the invention.
- the chirally pure compounds produced by the methods of the present invention are not limited by the above formulae.
- alkyl is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms, preferably one to eight carbon atoms and, most preferably, one to six carbon atoms; "alkenyl” is intended to include both straight- and branched-chain alkyl groups with at least one carbon-carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms; "alkynyl” group is intended to cover both straight- and branched-chain alkyl groups with at least one carbon-carbon triple bond and two to eight carbon atoms, preferably two to six carbon atoms.
- substituted alkyl refers to any of the above-defined groups having one to six carbon atoms.
- substituted alkenyl refers to any of the above-defined groups having one to six carbon atoms.
- substituted lower alkyl refers to alkyl, alkenyl, alkynyl, lower alkyl, lower alkenyl, and lower alkynyl as just described having from one to three substituents selected from the group including halogen, CN, OH, NO 2 , a ino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, substituted alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylarnino, and arylthio. These substituents may be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
- aryl is used herein to refer to a carbocyclic aromatic system, which may be a single ring, or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system.
- the aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, and indane.
- substituted aryl refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylarnino, and arylthio.
- substituted benzyl refers to a benzyl (Bn) group, having substituted on the benzene ring, one to five substituents from the group including halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylarnino, and arylthio.
- heterocyclic is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms.
- the N and S atoms may be oxidized.
- the heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring.
- the heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable.
- heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, fiiryl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, isoquinolinyl, and tetrahydrothiopyran.
- substituted heterocyclic is used herein to describe the heterocyclic groups just defined having one to four substituents selected from the group which includes halogen, CN, OH, NO 2 , amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkyloxy, substituted alkyloxy, alkylcarbonyl, substituted alkylcarbonyl, alkylcarboxy, substituted alkylcarboxy, alkylarnino, substituted alkylarnino, arylthio, or substituted arylthio.
- substituted cycloalkyl is used herein to describe a carbon-based ring having more than 3 carbon-atoms which forms a stable ring and having from one to five substituents selected from the group consisting of halogen, CN, OH, NO 2 , amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylarnino, substituted alkylarnino, arylthio, heterocyclic, substituted heterocyclic, aminoalkyl, and substituted aminoalkyl.
- substituted alkylcycloalkyl substituted alkyl
- substituted alkylOBn substituted alkylpyridyl
- substituted alkylfuranyl substituted alkyl NHR 7
- substituted alkylOH substituted alkylSRs
- substitution may occur at the alkyl group or on the corresponding base compound.
- an N- substituted piperidinyl group may be defined as a substituted heterocyclic group.
- substituents are N-alkyl-, N-aryl-, N-acyl-, and N- sulfonyl piperidinyl groups.
- One particularly suitable N-acyl-piperidinyl group is N- t-butyloxycarbonyl (BOC)-piperidine.
- BOC t-butyloxycarbonyl
- substituents can be readily identified by one of skill in the art.
- alkoxy is used herein to refer to the O(alkyl) group, where the point of attachment is through the oxygen-atom and the alkyl can be optionally substituted.
- aryloxy is used herein to refer to the O(aryl) group, where the point of attachment is through the oxygen-atom and the aryl can be optionally substituted.
- alkylcarbonyl is used herein to refer to the CO(alkyl) group, where the alkyl can be optionally substituted and the point of attachment is through the carbon atom of the carbonyl group.
- alkylcarboxy is used herein to refer to the COO(alkyl) group, where the alkyl can be optionally substituted and the point of attachment is through the carbon atom of the carboxy group.
- aminoalkyl refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing one to eight carbon atoms, which may be either same or different, and the point of attachment is on the nitrogen atom
- halogen refers to Cl, Br, F, or I.
- ring structure, e.g., when R 3 and P ⁇ may form a ring structure in
- Formula I includes a monocyclic structure, a bridged cyclo structure, and fused cyclo structures, unless the type of ring structure is otherwise specified.
- strong non-nucleophilic base refers to a non-nucleophilic basic reagent, which does not act as a nucleophile or bind to the reagents utilized according to the reaction.
- a number of non-nucleophilic bases are known in the art and include sodium hydride, potassium hydride, lithium diisopropylamide and potassium hexamethyldisilazide.
- aqueous base refers to a solution composed of, at a minimum, a base and water.
- bases which readily dissolve in water are known in the art and include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, among others.
- the aqueous base solution may further contain other reagents which do not interfere with the reactions of the present invention, and include organic solvents such as tetrahydrofuran, methanol, ethanol, or hydrocarbon solvents, salts such as sodium chloride, and buffers, among others.
- aqueous acid refers to a solution composed of, at a minimum, an acid and water.
- the aqueous acid solution may further contain other reagents which do not interfere with the reactions of the present invention.
- strong acid or “strong base” refers to an acid or base that is completely ionized in solution.
- Common strong acids include HC1, HBr, HI, HNO 3 , H 2 SO 4 , and HClO 4 .
- Common strong bases include hydroxides of the alkali metals (Li, Na, K, Rb, Cs) and hydroxides of the heavy alkaline earths (Ca, Sr, Ba).
- inorganic acid or “inorganic” base includes acids and bases which do not contain carbon.
- organic solvent may include any carbon-containing solvent known in the art, which does not react with the reagents utilized in the reaction and includes saturated hydrocarbon solvents, unsaturated hydrocarbon solvents, including aromatic hydrocarbon solvents, alcohols, halocarbons, ethers, and acetates, among others.
- the chirally pure compounds can be prepared using the methods described below. Where reference to conventional techniques is made, one of skill in the art will be able to readily select appropriate synthetic methods and reagents, which are known in the synthetic organic arts or variations of these methods by one skilled in the art. See, generally, Comprehensive Organic Synthesis, "Selectivity, Strategy & Efficiency in Modern Organic Chemistry", ed., I. Fleming, Pergamon Press, New York (1991); Comprehensive Organic Chemistry, "The Synthesis and Reactions of Organic Compounds", ed. J.F. Stoddard, Pergamon Press, New York (1979).
- the invention provides a method for preparing chirally pure ⁇ - amino acids from chirally impure ⁇ -amino acids.
- a novel asymmetric variant of the Strecker ⁇ -amino acid synthesis is utilized (Scheme 14; J. Org. Chem. 54:1055-1062 (1989)).
- Scheme I an aldehyde XXXXVII is reacted with a cyanide salt and ⁇ - methylbenzylamine or a salt thereof in a 1 : 1 : 1 molar ratio in a suitable solvent to afford the compound XXXXVIII.
- cyanide salts include sodium cyanide and potassium cyanide.
- the solvent is 1:1 methanol to water.
- the reaction is performed for about 12 to about 24 hours, and most preferably, about 18 hours. However, longer or shorter reaction times may be readily utilized.
- a suspension containing- precipitate is formed, which is subjected to filtration and is washed (e.g., with water) to provide a powder.
- Compound XXXXVIII is dissolved with a strong inorganic acid which is desirably cold upon combination with the compound (e.g., about 0 ° C to about 10°C) to provide the compound XXXXIX.
- the strong inorganic acid is sulfuric acid.
- other strong inorganic acids may be readily selected.
- the reaction mixture is neutralized with an inorganic base and extracted with an organic solvent to compound XXXXIX.
- extraction may utilize ethyl acetate or another suitable compound, and further involves drying and concentrating to provide compound XXXXIX.
- the hydrogenolysis reaction takes place in the presence of a suitable catalyst under pressure, e.g., Pd or RaNi under 3 atm pressure, filtering to remove the catalyst followed by concentration to remove solvent provides compound XXXXX.
- a suitable catalyst under pressure, e.g., Pd or RaNi under 3 atm pressure, filtering to remove the catalyst followed by concentration to remove solvent provides compound XXXXX.
- Compound XXXXX is then dissolved with an aqueous acid to afford the derivatives of formula XXXXVI.
- XXXXX has been dried to powder form, it is dissolved in a strong inorganic acid at high temperature to afford a salt of a chirally pure ⁇ -amino acid.
- hydrochloric acid at 100°C may be utilized.
- other acids and other suitable temperatures may be readily selected by one of skill in the art.
- the hydrolysis step is performed over a period of about 12 to 18 hours, or longer. In one suitable embodiment, the step is performed over 16 hours.
- the resulting reaction mixture is concentrated to provide a product which consists of the amino acid salt and one equivalent of ammonium salt.
- the product is the amino acid hydrochloride salt and one equivalent of ammonium chloride. This product is dissolved in water to which the base, e.g., sodium hydroxide or ammonium hydroxide, is added to form a solution.
- the base e.g., sodium hydroxide or ammonium hydroxide
- chirally pure ⁇ -amino acids produced according to the method of the invention can be readily utilized in the form produced, or converted to a desired target compound.
- a chirally pure ⁇ -amino acid can be readily converted to a chirally pure 2-aminoalcohol by reducing the ⁇ -amino acid to the 2-aminoalcohol and recrystallizing the 2-aminoalcohol to afford the chirally pure 2-aminoalcohol.
- the invention provides a scheme for resolving a chirally impure N-sulfonyl ⁇ -amino acid having a ⁇ -branched alkyl substituent to provide a chirally pure N-sulfonyl ⁇ -amino acid.
- the N-sulfonyl ⁇ -amino acid is N- sulfonyl ⁇ -ethylnorvaline.
- the norvaline compound can be substituted with a compound selected from among N-sulfonyl ⁇ -ethylnorvaline, N- sulfonylvaline, and N-sulfonyl ⁇ -n-propylnorleucine.
- one of skill in the art may use the method of the invention with another selected N-sulfonyl ⁇ -amino acid having a ⁇ -branched alkyl substituent for preparing the corresponding chirally pure compound.
- N-sulfonyl ⁇ -ethylnorvaline (or another selected compound) is mixed with chirally pure ephedrine hemihydrate in ethanol at a molar ratio of 1 : 1.
- the mixture is then heated to dissolve the solids. In one embodiment, the mixture is heated to about 80°C. However, other suitable temperatures may be readily selected. Thereafter, the mixture is cooled in order to allow a precipitate to form This cooling step may be performed at room temperature or at reduced temperature (e.g., about 5°C) overnight (about 16 - 20 hours). The temperature and the period of the cooling step each may be adjusted upwardly or downwardly, as needed or desired.
- the suspension is filtered or washed following cooling.
- the salt is then recrystallized and then dissolved in a solvent and a strong aqueous acid.
- the recrystallizing step is performed in boiling ethyl acetate and the recrystallized salt is separated. This may be performed using filtration or other conventional methods.
- the salt is dissolved in an organic solvent and strong aqueous acid.
- the organic extract is washed, dried and concentrated to provide the chirally pure N- sulfonyl ⁇ -amino acid.
- the wash step is performed with a strong aqueous acid such as, for example, hydrochloric acid, and drying is performed with sodium sulfate or the like.
- these chirally pure ⁇ -amino acids and N-sulfonyl ⁇ -amino acids are useful for a variety of purposes.
- these chirally pure ⁇ -amino acids and N-sulfonyl ⁇ -amino acids can be converted to the corresponding N-sulfonyl 2- aminoalcohols by the methods described herein.
- the chirally pure ⁇ -amino acids produced according to the present invention are useful in the synthesis of chiral N-sulfonyl ⁇ -amino acids. Suitable methods for preparation of these chiral N-sulfonyl ⁇ -amino acids are provided herein. Conversion to 2-Aminoalcohols
- the processes of the invention provide efficient routes to the synthesis of chirally pure S enantiomers of ⁇ -amino acids and N-sulfonyl ⁇ -amino acids which are useful in preparing 2-aminoalcohols or N-sulfonyl 2-aminoalcohols, and intermediates thereof, which are useful for a variety of purposes.
- the exemplary compounds provided herein, the N-sulfonyl 2- amino alcohols and their corresponding aldehydes, oximes and salts are useful for modulating ⁇ -amyloid production, which is implicated in amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Alzheimer's Disease (AD), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, Down's syndrome, among others.
- the compounds of Formula (I) are useful in modulating beta amyloid production in subjects at risk for, or suffering from, AD or other diseases resulting from elevated levels of beta amyloid protein in the brain.
- the compounds of Formula (I) include pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, wherein Formula (I) is:
- R 3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl
- R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl(substituted)alkyl, alkylOH, substituted alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH(OH)phenyl,
- R 7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, benzyl, substituted benzyl, alkylOH, substituted alkylOH, alkylSRs, or substituted alkylSRs;
- R 8 is alkyl, substituted alkyl, benzyl, or substituted benzyl; or R 3 and P may be joined to form a ring;
- R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH 2 cycloalkyl, substituted CH cycloalkyl, benzyl, substituted benzyl, and CH CH 2 QR 9 ;
- Q is O, NH or S
- R 9 is lower alkyl, substituted lower alkyl, phenyl, or substituted phenyl
- Rs is selected from the group consisting of hydrogen, halogen and CF 3 ;
- T is selected from the group consisting of
- Ri and R 2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyclo all y 1, substituted cycloalkyl, phenyl, substituted phenyl, and (CH 2 ) n (l,3)dioxane, where n is 2 to 5;
- W, Y and Z are independently selected from the group consisting of C, CR 10 and N, with the proviso that at least one of W, Y and Z must be C;
- Rio is selected from the group consisting of hydrogen and halogen
- X is selected from the group consisting of O, S, SO 2 , andNRn;
- R11 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, and substituted phenyl.
- the point of attachment of the W-X-Y-Z-C heterocyclic ring to the SO 2 group is not a limitation of the present invention.
- the ring is attached to the SO group through a carbon-atom.
- the ring may be attached through O, S, or N heteroatoms.
- the compounds of formula (I) contain one or more asymmetric carbon atoms and some of the compounds may contain one or more asymmetric (chiral) centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula (I), when the compounds of Formula (I) contain one or more chiral centers, at least the ⁇ -amino acid-derived chiral center must be of S- stereochemistry. Most preferably, the carbon atom to which N, T, R 3 and ⁇ are attached is of S -stereo chemistry. In one embodiment, the present invention is directed toward a process for preparing chiral S enantiomers of N-sulfonyl 2-aminoalcohols of the general formula la:
- R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, or CH(OH)-4-SCH 3 -phenyl and n is 0 to about 10.
- the compounds prepared according to the method of the invention contain at least one chiral carbon center, where R in the above-noted structures is the same.
- the R groups are methyl, ethyl, and n-propyl, and most preferably the R groups are ethyl.
- the invention further encompasses producing ⁇ -amino acids and 2-aminoalcohols of the general formulae provided herein where the R groups are different.
- one or more additional chiral centers may be present; however, the additional chiral centers must be optically pure and must not interfere with the production of the chirally pure ⁇ - amino acids, 2-aminoalcohols, and pure S enantiomers of N-sulfonyl 2-aminoalcohols of the present invention.
- the chiral carbon center is of S- stereochemistry which gives rise to enantiomerically pure products.
- the method of the invention is used to produce chirally pure ⁇ -amino acids which are readily converted to the N-sulfonyl ⁇ -amino acids.
- a chirally pure ⁇ -amino acid prepared according to the invention can be used to prepare a compound of Formula (I).
- Particularly desirable compounds of Formula (I) include thiophenesul&namides, and more desirably, 5-halo thiophenesulfonamides, and most desirably, 5-halo thiophene sulfonamides with ⁇ - branches in the side chain of a primary alcohol.
- the compound produced by the invention desirably has a structure in which X is S, W is C, Y is C (or CRio) and Z is C (or CRio), and the sulfonamide is attached to C2 of the thiophene ring. More desirably, X is S, W is C, Y is C (or CRio), Z is C (or CRio) and R ⁇ is a halogen.
- X is S
- W is C
- Y is C
- Z is C
- Re is a halogen
- T is C(OH)R ⁇ R
- Ri and R 2 are hydrogen
- R 3 is H
- R4 is a lower alkyl of S- stereo chemistry
- R5 is H.
- Other desirable compounds of Formula (I) are furansulfonamides, in which X is O, W is C, Y is C, and Z is C.
- the furansulfonamides of Formula (I) are further characterized by ⁇ -branches in the side chain of a primary alcohol.
- T is C(OH)R ⁇ R 2 , in which Ri and R 2 are hydrogen, R 3 is H, R is a lower alkyl of S-stereochemistry, R 5 is H and Re is halogen.
- Ri and R 2 are hydrogen
- R 3 is H
- R is a lower alkyl of S-stereochemistry
- R 5 is H
- Re is halogen.
- selected compounds of these structures have been found to have unexpectedly good beta-amyloid inhibitory activity, and in many cases, better activity than compounds of Formula (I) having other heterocycles (e.g., furans, where X is O).
- other such compounds of Formula (I) are also useful for the purposes described herein.
- N-sulfonyl 2- aminoalcohols which include the compounds of Formula (I).
- the compounds of Formula (I) are characterized by being sulfonamides of Formula (I), which have ⁇ - branches in the side chain of the primary alcohol group.
- T is C(OH)R ⁇ R 2
- Ri and R 2 are hydrogen
- R 3 is H
- R is a lower alkyl of S-stereochemistry
- R5 is H.
- a first method of preparation consists of reaction of a 2-aminoalcohol II with the appropriate sulfonyl halide in the presence of a base such as triethylamine (TEA) and in a suitable solvent to afford compounds of Formula III.
- a base such as triethylamine (TEA)
- a second method of preparation involves reaction of an ⁇ -amino acid or ester
- Rx H or alkyl
- the corresponding Weinreb amide (see Scheme 11) of the N-sulfonyl acid can be prepared and subsequently reacted with RiMgX and R 2 MgX.
- This route entails formation of the ⁇ , ⁇ -unsaturated amide XII of the Evans chiral auxiliary from an ⁇ , ⁇ -unsaturated acid XI, followed by conjugate addition of an organocuprate, trapping of the resulting enolate anion XIII with N-bromosuccinimide (NBS), displacement of the bromide XIV with azide anion (provided by tetramethylguanidinium azide (TMGA)) to afford XV, followed by reduction to the 2- aminoalcohol and subsequent sulfonylation to afford the target compound XVI.
- N-bromosuccinimide N-bromosuccinimide
- TMGA tetramethylguanidinium azide
- R 5 is H.
- the sulfonamide ester XVII can be N-alkylated by either treatment with a suitable base such as potassium carbonate followed by the alkylating agent R 5 X or by employing Mitsunobu conditions (R 5 OH/DEAD, TPP) L ⁇ BH 4 reduction of the N-alkylated sulfonamide ester affords the N-alkylated sulfonamide m the primary alcohol series VIII (Scheme 6)
- These primary alcohols VIII can be converted to the secondary alcohols V or aldehyde IV se ⁇ es by chemistry that has been outlined above
- the N-alkylated sulfonamide esters, or their corresponding Weinreb amides can be treated with Grignard reagents to afford the N-alkylated tertiary alcohols III
- the corresponding sulfone derivative XIX may be obtained by oxidation of the thiophene compound XVIII with MCPBA (Scheme 7).
- D-serine XXV is first sulfonylated to XXVI and subsequently converted to the ketone XXVII, which is reductively aminated to the target compounds of Formula XXVIII.
- This method which utilizes chemistry previously employed by Roux (Tetrahedron 50: 5345-5360 (1994)), consists of addition of Grignard reagents to the Weinreb amide XXX (derived from the requisite ⁇ -amino acid) followed by stereospecific reduction of the ketone XXXI to afford a single diastereomeric N-protected 2-arninoalcohol XXXII. Deprotection of this compound followed by reaction with sulfonyl chlorides affords the pure diastereomeric sulfonamide secondary alcohols of Formula XXXIII.
- the corresponding 5-iodo and 5 -fluoro -thiophene derivatives may be obtained by conversion of the 5-bromo-thiophene derivative XXXIV (obtained as in Scheme 2) to a 5-trialkyltin-thiophene intermediate XXXV which can be converted to either the 5-iodo-thiophene (XXXVII) by treatment with sodium iodide and chloramine T or the 5-fluoro-thiophene analog (XXXVI) by treatment with SELECTFLUORTM (Aldrich Chemical Co) (Scheme 12).
- Sulfonamides derived from cyclohexylglycinol substituted by alkoxy and amino groups at the 4 position of the cyclohexane ring can be prepared according to the methods described herein (Scheme 13). This route entails initial hydrogenation of 4-L-hydroxyphenylglycine XXXVIII, followed by sulfonylation, reduction of the carboxylic acid with diborane and formation of the N,O-acetonide XXXIX. The 4- hydroxy acetonide XXXIX is then O-alkylated using sodium hydride and an alkylating agent such as an alkyl or benzyl bromide.
- an alkylating agent such as an alkyl or benzyl bromide.
- oximes XXXXXTV can be derived from the corresponding aldehydes IV by standard methodology as depicted in Scheme 14.
- the crude amino acid and ⁇ aOH mixture was dissolved in 300 mL of water. The mixture was cooled to 0 °C in an ice bath. 5-Chlorothiophene-2-sulfonyl chloride (17.3 g, 79.5 mmol) was dissolved in 100 mL of THF and added dropwise to the reaction mixture over 0.5 h. After 1 h the reaction mixture was allowed to warm gradually to 25°C and stirred for 16 h. THF was removed in vacuo and then the mixture was acidified to pH 1 with IN HC1. After about 15 min, a precipitate began to crash out of the milky white solution. After 1 h, the mixture was cooled in a refrigerator for 1 h and then filtered.
- the product peak was collected based on UV absorption and concentrated.
- Solvent A Water (0.02% TFA buffer)
- Solvent B Acetonitrile (0.02 % TFA buffer) Gradient: Time 0: 95% A; 0.3 min: 95% A; 4.7 min: 10% A; 4.9 min: 95% A. Flow rate 1.5 mL/min; Detection: 254 nm DAD; API-ES Scanning Mode Positive 150-700; Fragmentor 70 mV.
- Example 6 Represser Release Assay
- RRA Represser Release Assay
- the compounds generated as described in Examples 1 through 4 were tested in the RRA in accordance with published techniques [Shuey, D.J., Sheiffele, P., Jones, D., Cockett, M.I., and Quinet, E.M. (1999), "Repressor release: a useful tool for monitoring amyloid precursor protein (APP) proteolysis in mammalian cells", Society for Neuroscience Abstracts, Vol. 25, 29 th Annual Meeting of Society for Neuroscience, Miami Beach, Florida, October 23-28, 1999]. Briefly, this assay is performed as follows. A. Cell Culture
- CHO-K1 cells are cultured in whole DMEM media (DMEM - High Glucose with 10%> fetal bovine serum, 1%> Non-essential Amino Acids, and 1% Penicillin-Streptomycin) at 37°C with 5% C0 2 . Two million cells are plated into 10- cm dishes 24 hrs prior to transfection.
- DMEM - High Glucose with 10%> fetal bovine serum, 1%> Non-essential Amino Acids, and 1% Penicillin-Streptomycin
- Transient transfections are completed as recommended by Gibco BRL using their Lipofectamine Plus system.
- 6 ⁇ g of pRSVO-luc and 6 ⁇ g of APP- lacl construct DNA are added to 460 ⁇ L Opti-Mem transfection media and incubated with 30 ⁇ L Plus reagent for 15 minutes.
- a lipid mixture of 40 ⁇ L Lipofectamine reagent and 460 ⁇ L Opti-Mem transfection media is incubated with the DNA-Plus reagent mixture for 15 minutes.
- the CHO-K1 cells are washed once and covered in 5.0 mL DMEM media without Penicillin-Streptomycin.
- the DNA-lipid preparation is then layered onto these cells and incubated at 37°C overnight.
- One and one half million transfected cells per well (100 ⁇ L total volume) are plated into sterile, opaque Packard 96-well Cultur-Plates in clear DMEM whole media (DMEM - without phenol red) and incubated at 37° C with 5% C0 2 for 3-5 hours.
- Compound Dilution Compounds are diluted using two different protocols; one protocol is used for compounds supplied neat (weighed powder in vial) and the other protocol is used for compounds supplied in solution (20 mM in DMSO in 96-well plates). For both protocols, 25 mM Hepes and 25 mM Hepes/1% DMSO are prepared fresh to be used as diluent. The Hepes/DMSO is used as the diluent control on all experimental plates.
- Luciferase assays (LucLite reagent, Packard) are performed and are read on a Packard TopCount instrument. Media is removed from each 96-well plate and replaced with 100 ⁇ L PBS per well (with Mg 2+ and Ca 2+ ). An equal volume (100 ⁇ L) of the LucLite lysis/substrate buffer is added to each well and the plates are sealed and mixed in the dark on a rotary shaker for 15-30 minutes at room temperature. Luciferase readings are then taken on the TopCount instrument. Measurements are expressed as relative light units (RLU) and are calculated and analyzed in MS Excel as follows. D. Analysis of data
- a compound is considered active in RRA if it leads to at least a 1.5 fold increase in luciferase activity at 20 ⁇ g/mL and is non- toxic, as determined by loss of signal ( ⁇ 0.75 fold increase).
- Fold increase is the amount of luciferase activity (measured in relative light units) over diluent control. SEM represents the standard error of the mean for fold increase (not shown). All compounds tested were found to be non-toxic.
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US10/014,304 US6610734B2 (en) | 2000-12-13 | 2001-12-11 | Heterocyclic sulfonamide inhibitors of beta amyloid production |
US14304 | 2001-12-11 | ||
US166896 | 2002-06-11 | ||
US10/166,896 US6657070B2 (en) | 2000-12-13 | 2002-06-11 | Production of chirally pure α-amino acids and N-sulfonyl α-amino acids |
PCT/US2002/038117 WO2003050062A2 (en) | 2001-12-11 | 2002-11-26 | PRODUCTION OF CHIRALLY PURE α-AMINO ACIDS ADN N-SULFONYL α-AMINO ACIDS |
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JP (1) | JP4615861B2 (en) |
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CA (1) | CA2470111A1 (en) |
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SI1341779T1 (en) | 2000-12-13 | 2006-12-31 | Wyeth Corp | Heterocyclic sulfonamide inhibitors of beta amyloid production |
CL2004000647A1 (en) | 2003-03-31 | 2005-02-04 | Wyeth Corp | COMPOUNDS DERIVED FROM SULFONAMIDE HETEROCICLES CONTAINING FLUORO AND TRIFLUORO RENT; PHARMACEUTICAL COMPOSITION; PHARMACEUTICAL KIT; PREPARATION PROCEDURE; AND ITS USE AS BETA AMILOID INHIBITORS TO TREAT ALZHEIMER, ANGIOPATIA AM |
JP2007517905A (en) | 2004-01-16 | 2007-07-05 | ワイス | Beta-amyloidogenic heterocyclic sulfonamide inhibitors containing azoles |
AU2007243490A1 (en) | 2006-04-21 | 2007-11-08 | Wyeth | Production of chirally pure amino alcohol intermediates, derivatives thereof, and uses thereof |
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EP0326934A1 (en) * | 1988-02-02 | 1989-08-09 | BASF Aktiengesellschaft | Process for the reduction of reducible compounds |
WO2001009084A1 (en) * | 1999-08-03 | 2001-02-08 | Eastman Chemical Company | Process for the preparation of cyclopropylglycine |
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US5264577A (en) * | 1992-04-22 | 1993-11-23 | Warner-Lambert Company | Cyclic amino acids and derivatives thereof |
US5968942A (en) * | 1992-08-25 | 1999-10-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
DK0656887T3 (en) * | 1992-08-25 | 1999-07-05 | Searle & Co | Hydroxyethylaminosulfonamides for use as inhibitors of retroviral proteases |
-
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- 2002-11-26 JP JP2003551090A patent/JP4615861B2/en not_active Expired - Fee Related
- 2002-11-26 EP EP02786817A patent/EP1461332A4/en not_active Withdrawn
- 2002-11-26 CA CA002470111A patent/CA2470111A1/en not_active Abandoned
- 2002-11-26 MX MXPA04005366A patent/MXPA04005366A/en active IP Right Grant
- 2002-11-26 WO PCT/US2002/038117 patent/WO2003050062A2/en active Application Filing
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EP0326934A1 (en) * | 1988-02-02 | 1989-08-09 | BASF Aktiengesellschaft | Process for the reduction of reducible compounds |
WO2001009084A1 (en) * | 1999-08-03 | 2001-02-08 | Eastman Chemical Company | Process for the preparation of cyclopropylglycine |
Non-Patent Citations (3)
Title |
---|
J.C. SPEELMAN ET AL: J. ORG. CHEM., vol. 54, no. 5, 1989, pages 1055-1062, XP002542789 * |
See also references of WO03050062A2 * |
T. INABA ET AL: J. ORG. CHEM., vol. 56, no. 3, 1991, pages 1274-1279, XP002542836 * |
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TWI260316B (en) | 2006-08-21 |
MXPA04005366A (en) | 2004-09-27 |
WO2003050062A3 (en) | 2003-11-20 |
AU2009251195A1 (en) | 2010-01-21 |
CA2470111A1 (en) | 2003-06-19 |
WO2003050062A2 (en) | 2003-06-19 |
EP1461332A4 (en) | 2009-10-21 |
TW200306292A (en) | 2003-11-16 |
AU2002351170B2 (en) | 2009-09-24 |
JP2005511727A (en) | 2005-04-28 |
JP4615861B2 (en) | 2011-01-19 |
AU2002351170A1 (en) | 2003-06-23 |
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