Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
  • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
  • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• Inhibitors of 11 ⁇ -Hydroxysteroid Dehydrogenase Type 1 (1 l ⁇ -HSDl) are promising drugs for the treatment of a number of diseases and disorders as described in detail in U.S. Provisional Patent Application No. 60/962,058, filed July 26, 2007; U.S. Provisional Patent Application No. 61/001,253, filed October 31, 2007; U.S. Provisional Patent Application No. 61/049,650, filed May 1, 2008; and International Application No. PCT/US2008/ , (Attorney Docket No. 4108.1002- 007), filed July 25, 2008; all of which are herein incorporated by reference in their entirety.
• 1 1 ⁇ -HSDl inhibitors are promising for the treatment of diabetes, metabolic syndrome, obesity, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hypertension-related cardiovascular disorders, hyperlipidemia, deleterious gluco-corticoid effects on neuronal function (e.g. cognitive impairment, dementia, and/or depression), elevated intra-ocular pressure, various forms of bone disease (e.g., osteoporosis), tuberculosis, leprosy (Hansen's disease), psoriasis, and impaired wound healing (e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes).
• neuronal function e.g. cognitive impairment, dementia, and/or depression
• various forms of bone disease e.g., osteoporosis
• tuberculosis e.g., leprosy (Hansen's disease)
• psoriasis e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes.
• the present invention provides economical and efficient methods for the synthesis of 1 l ⁇ -HSDl inhibitors, for example, oxazinone compounds and tertiary alcohol oxazinone compounds as disclosed herein.
• One embodiment of the present invention is a method of preparing an oxazinone compound represented by structural formula (I):
• R 1 is (a) absent or (b) is selected from optionally substituted (Ci-C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (Ci-C 3 )alkoxy(Ci-C 3 )alkoxy, and optionally substituted (Q- C 3 )alkoxy(C i -C 3 )alkyl ;
• E is (a) a bond or (b) (Ci-C 3 )alkylene or (Ci-C 2 )alkoxy, wherein the O is attached to R 2 , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl and oxo;
• R 2 is selected from optionally substituted (Ci-C 6 )alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;
• R 3 is selected from optionally substituted (Ci-C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 3 - C 5 )cycloalkyl(Ci-C 4 )alkyl, optionally substituted (Ci-C 3 )alkoxy(Ci-C 3 )alkoxy and optionally substituted (Ci-C 3 )alkoxy(Ci-C 3 )alkyl;
• a 1 is (a) a bond, or (b) CH 2 CH 2 O, wherein the oxygen is attached to Cy 1 ;
• Cy 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted monocyclic cycloalkyl or optionally substituted monocyclic heterocyclyl;
• a 2 is (a) a bond, O, S or NR 4 , wherein R 4 is (Ci-C 3 )alkyl or (C 3 - C 6 )cycloalkyl; or (b) (Ci-C 3 )alkylene or (Ci-C 2 )alkoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, or trifluoromethyl.
• Cy 2 is (a) hydrogen or (b) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl.
• the method comprises the step of reacting a ⁇ -haolalcohol compound, for example a ⁇ -haloalcohol compound represented by structural formula (II)
• X is a leaving group
• Another embodiment of the present invention is a method of preparing an epoxide compound represented by structural formula (IV):
• the method comprises the step of oxidizing with an epoxidation reagent a 2-methyl- 3-propenyl intermediate represented by the following structural formula: - A -
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 and E in structural formulas (IV) and (V) are as defined in structural formula (I).
• Another embodiment of the present invention is a method of preparing tertiary alcohol oxazinone compound represented by structural formula (VI):
• the method comprises the step of reducing the epoxide group of the epoxide compound represented by structural formula (IV) with a reducing agent.
• a 1 , A , Cy 1 , Cy 2 , R 1 , R 2 and E in structural formula (VI) are as defined in structural formula (V).
• the tertiary alcohol oxazinone compound represented by structural formula (VI) can be prepared using the compound of structural formula VII:
• Example 22 provides details of the synthetic steps of FIG. 2 for the preparation of (S)-3 -((S)-I- (4-bromophenyl) ethyl)-6- (2- hydroxy-2-methylpropyl)- 6- phenyl- 1,3- oxazinan-2- one.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 and E in structural formula (VII) are as defined in structural formula (I).
• Another embodiment of the present invention is an epoxide compound represented by structural formula (IV) or a salt thereof.
• Yet another embodiment of the present invention is a 2-methyl-3-propenyl intermendiate represented by structural formula (V) or a salt thereof.
• Other embodiments of the present invention are the epoxide compounds and salts thereof, and 2-methyl-3-propenyl intermediates and salts thereof as prepared with the methods of the present invention, in particular, the epoxide compounds and 2-methyl-3-propenyl intermediates corresponding to the above described embodiments.
• FIG. 1 is a schematic, showing the synthesis of a specific tertiary alcohol oxazinone compound, a 1 l ⁇ -HSDl inhibitor, using the methods disclosed herein.
• FIG. 2 is a schematic, showing the synthesis of a specific tertiary alcohol oxazinone compound, a 1 l ⁇ -HSDl inhibitor, using the methods disclosed herein.
• the present invention provides methods for synthesizing 1 l ⁇ -HSDl inhibitors, for example, oxazinone compounds and tertiary alcohol oxazinone compounds as disclosed herein.
• the oxazinone compound represented by structural formula (I), for example, compounds 5 and 6 (see Figure), can be prepared by reacting a ⁇ -haloalcohol compound represented by structural formula (II) with an isocyanate compound represented by structural formula (III). Both, the ⁇ -haloalcohol compound and the isocyanate compound can be prepared from commercially available compounds using methods known in the art (see, Exemplification section).
• the tertiary alcohol oxazinone compound represented by structural formula (VI) such as, for example, compound 8 (see Figure 1) is prepared by first oxidizing 2-methyl-3-propenyl intermediate represented by structural formula (V) with an epoxidation reagent to obtain the epoxide compound represented by structural formula (IV).
• the 2-methyl-3-propenyl intermediate is an oxazinone compound that can be prepared using the method described in the previous paragraph, wherein R 3 is 2-methyl-3-propenyl.
• the epoxide group of the epoxide compound is reduced with a reducing agent to form the tertiary alcohol oxazinone compound.
• Oxazinone compounds and tertiary alcohol oxazinone compounds represented by structural formulas (I) and (VI), respectively, for which Cy 1 is phenyl substituted with a leaving group (e.g., -Br) and optionally substituted with one or more additional substituents, can be used to prepare biaryl group containing 1 l ⁇ - HSDl inhibitors, for example, by using a "Suzuki” coupling reaction as described in Example 111 of U.S. Provisional Patent Application No. 60/962,058, filed July 26, 2007.
• oxazinone compounds represented by structural formulas (I) and (VI), respectively, for which Cy 1 is phenyl substituted with a leaving group (e.g., -Br) and optionally substituted with one or more additional substituents can be used to prepare biaryl group containing 1 l ⁇ -HSDl inhibitors, by conversion of the leaving group (e.g. -Br) to a boronic acid or boronate ester, followed by using a "Suzuki” coupling reaction with Cy ⁇ Cl or Cy ⁇ Br (see EXAMPLE 23).
• biaryl group containing 1 l ⁇ -HSDl inhibitors can be obtained from isocyanate compounds that already contain the biaryl group using the methods of the present invention.
• the synthesis of a variety of biaryl compounds is provided in the Exemplification section. A detailed description of each reaction in the syntheses is provided below.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 and E have the meanings indicated above unless otherwise noted.
• synthetic intermediates and final products described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol, sulfonamide, amide and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate.
• Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W. Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis” John Wiley & Sons, Inc., New York 2007, herein incorporated by reference in its entirety).
• protected refers to the chemical group with its functional groups that may interfere with a desired reaction having been reacted with a protective group, e.g., the ring nitrogen atom in the case piperidine.
• the oxazinone compound represented by structural formula (I) is prepared by reacting a ⁇ -haloalcohol compound represented by structural formula (II) with an isocyanate compound represented by structural formula (III) as shown above.
• the reaction of the a ⁇ -haloalcohol with the isocyanate compound is carried out in the presence of a base. More typically, the reaction is carried out in the presence of a non-nucleophilic base. Most typically, the reaction is carried out in the presence of a non-nucleophilic amine base.
• Suitable non-nucleophilic amide bases include, but are not limited to as lithium amide (LiNH 2 ), sodium amide (NaNH 2 ), lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, lithium dicyclohexylamide, silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, lithium tetramethylpiperidide, and lithium tetramethylpiperidine.
• Other non-nucleophilic bases include but are not limited to sodium hydride, sodium tert-pentoxide and sodium tert-butoxide.
• non-nucleophilic amine bases include, but are not limited to, diisopropylethylamine, 2,2,6,6-tetramethylpiperidine, 4-dimethylaminopyridine, 2,6- di-tert-butyl-4-methylpyridine, l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,8,9-trimethyl-2,5,8,9-tetraaza-l-phosphabicyclo[3.3.3]undecane and the like.
• the base is l,8-diazabicyclo[5.4.0]undec-7-ene.
• the isocyanate compound is more commonly used in excess.
• from about one to about ten equivalents of base relative to ⁇ -haloalcohol are used, more typically from about one to about six equivalents, and, even more typically, from one to about 5 equivalents.
• the reaction is carried out in an anhydrous aprotic, non- nucleophilic solvent at ⁇ -haloalcohol compound concentrations between about 0.01 M and 5 M.
• ⁇ -Haloalcohol compound concentrations are more typically, however, between about 0.05 M and 2 M.
• Suitable solvents include, but are not limited to ethereal solvents such as diethyl ether, tetrahydrofuran (THF), tert-butyl-methyl ether and 1 ,4-dioxane, and non-ethereal solvents such as dimethyl formamide and dimethyl sulfoxide and the like.
• ethereal solvents such as diethyl ether, tetrahydrofuran (THF), tert-butyl-methyl ether and 1 ,4-dioxane
• non-ethereal solvents such as dimethyl formamide and dimethyl sulfoxide and the like.
• Suitable reaction temperatures generally range from about 0 0 C to about the boiling point of the solvent. More typically, temperatures are sufficiently high to allow refluxing, for example, about 68 0 C for tetrahydrofuran.
• the epoxide compound represented by structural formula (IV) is prepared by oxidizing the propenyl group of the 2-methyl-3-propenyl intermediate represented by structural formula (V) with an epoxidation reagent.
• the 2-methyl-3-propenyl intermediate is an oxazinone compound that can be prepared using the method described in the previous paragraphs (e.g., the reaction of a compound of Formula II with a compound of Formula III).
• Suitable epoxidation reagents include, but are not limited to peroxides (e.g., hydrogen peroxide, t-butyl hydroperoxide), peroxycarboxylic acids (e.g., 3-chloroperbenzoic acid (MCPBA), peracetic acid, pertrifluoroacetic acid), magnesium bis(monoperoxyphthalate) hexahydrate, potassium monoperoxysulfate optionally in the presence of l,2:4,5-di-O- isopropylidene- ⁇ -D-erythro-2,3-hexodiulo-2,6-pyranose, dimethyldioxirane and the like.
• peroxides e.g., hydrogen peroxide, t-butyl hydroperoxide
• peroxycarboxylic acids e.g., 3-chloroperbenzoic acid (MCPBA), peracetic acid, pertrifluoroacetic acid
• MCPBA 3-chloroperbenzoic acid
• the epoxidation reagent is a peroxycarboxylic acid, and, most typically, it is 3-chloroperbenzoic acid.
• the reaction is carried out in an aprotic, non-nucleophilic solvent at 2-methyl-3 -propenyl intermediate concentrations between about 0.01 M and 5 M.
• 2-Methyl-3 -propenyl intermediate concentrations are more typically, however, between about 0.05 M and 2 M.
• Suitable solvents include, but are not limited to, halogenated solvents (e.g., chloroform, dichloromethane and 1 ,2-dichloroethane, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), or hexamethylphosphorus triamide and ethereal solvents such as diethyl ether, tetrahydrofuran (THF) and 1 ,4- dioxane.
• the solvent is a halogenated solvent. More typically, the solvent is dichloromethane or 1 ,2-dichloroethane. Most typically, the solvent is dichloromethane.
• Suitable reaction temperatures generally range from about 0 0 C to about the boiling point of the solvent used. Most typically, the reaction is carried out at ambient temperature.
• the tertiary alcohol oxazinone compound represented by structural formula (VI) is prepared by reducing the epoxide group of the epoxide compound represented by structural formula (IV) with a reducing agent.
• Suitable reducing agents include, but are not limited to hydride reducing agents such as lithium triethylborohydride, LiAlH 4 , LiBH 4 , lithium tri-t-butoxyaluminum hydride in the presence of triethylborane, potassium tri-sec-butylborohydride or sodium bis(2- methoxyethoxy)aluminum hydride and the like.
• Suitable reducing agents include, but are not limited to BH 3 -Et 3 N-LiClO 4 , lithium di-tert-butylbiphenyl, or hydrogen or sodium formate in the presence of palladium on charcoal. Most typically, the reducing agent is lithium triethylborohydride (super hydride). Typically, from about one to about ten equivalents of reducing agent relative to the epoxide compound are used, more typically from about one to about six equivalents, and, most typically, from about one to about 2 equivalents. Typically the reaction is carried out in an anhydrous aprotic, non-nucleophilic solvent at epoxide compound concentrations between about 0.01 M and 5 M.
• Epoxide compound concentrations are more typically, however, between about 0.05 M and 2 M.
• Suitable solvents include, but are not limited to ethereal solvents such as diethyl ether, tetrahydrofuran (THF), tert-butyl -methyl ether and 1,4-dioxane, and non-ethereal solvents such as dimethyl formamide and dimethyl sulfoxide and the like.
• the solvent is an ethereal solvent.
• the solvent is anhydrous tetrahydrofuran.
• Suitable reaction temperatures generally range from about 0 0 C to about ambient temperature.
• a 1 is a bond, CH 2 , or CH 2 CH 2 , or CH when R 1 is present;
• a 2 is a bond, O,
• X is a Cl, Br, I or -OSO 2 R 5 wherein R is (d-C 4 )alkyl optionally substituted with one or more F, or phenyl optionally substituted with halogen, (Ci- C 4 )alkyl or NO 2 ; and E is a bond or (Ci-C 3 )alkylene.
• R 1 , R 2 , R 3 , X and E are as defined in the first preferred embodiment and A 1 is a bond or CH when R 1 is present; A 2 is a bond;
• Cy 2 is hydrogen; Cy 1 is phenyl substituted with Cl, Br, I or OSO 2 CF 3 , and optionally substituted with one or more additional substituents.
• a 2 , Cy 2 , R 1 , R 2 , R 3 , X and E are as defined in the second preferred embodiment and A 1 is -CH, R 1 is present and Cy 1 is represented by the following structural formula:
• Z is a Cl, Br, I, OSO 2 CF 3 , OSO 2 Me, or OSO 2 C 6 H 4 Me, r is O, 1, 2 or 3; and each G is independently selected from the group consisting of (Cj-C 4 )alkyl, halo(Cj-C 4 )alkyl, (Ci-C 4 )alkoxy, halogen, cyano and nitro.
• a 1 , A 2 , Cy 1 , Cy 2 , R 2 , R 3 , X, E, r, G 1 and Z are defined as in the third preferred embodiment and R 1 is methyl or ethyl.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , X, E, r, G 1 and Z are defined as in the fourth preferred embodiment and R 2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (CrC 6 )alkyl, protected hydroxy(C[-C 3 )alkyl, protected CONH 2 , protected carboxylic acid and SO 2 Me; and with regard to the preparation of an oxazinone compound, R 3 is methyl, ethyl, propyl, butyl, vinyl, allyl, 2-methyl-3-propenyl, or ethoxyethyl, each optionally substituted with up to two groups independently selected from (C 1 - C 4 )alkyl, (Ci-C 4 )alkoxy, (Ci-C 4 )alkoxycarbonyl, benzyloxycarbonyl, protected hydroxy
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X, E, r, G 1 and Z are defined as in the sixths preferred embodiment and R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, protected CONH 2 , (Ci-C 4 )alkyl, (d-C 4 )alkoxy and SO 2 Me.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X, E, r, G 1 and Z are defined as in the seventh preferred embodiment and, with regard to the preparation of an oxazinone compound, R is 2-methyl-3-propenyl or 2-cyano-2- methylpropyl.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X, E, r, G 1 and Z are defined as in the ninth preferred embodiment and R 2 is phenyl or fluorophenyl.
• a 1 , A 2 , R 1 , R 2 , R 3 , X and E are defined as in the first preferred embodiment and Cy 1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, azepanyl, pyridyl, thiazolyl, pyrimidinyl, each optionally substituted with 1 to 4 groups; and Cy 2 is phenyl, thienyl, pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S,S-dioxothiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benztriazolyl, oxodihydropyridyl
• a 1 , A 2 , Cy 1 , Cy 2 , R 2 , R 3 , X and E are defined as in the eleventh preferred embodiment and R 1 is methyl or ethyl.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , X and E are defined as in the twelfth preferred embodiment and R 2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (Ci-C 6 )alkyl, protected hydroxy(Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, protected CONH 2 , protected carboxylic acid and SO 2 Me; and, with regard to the preparation of an oxazinone compound, R 3 is methyl, ethyl, propyl, butyl, vinyl, allyl, 2-methyl-3-propenyl, or ethoxyethyl each optionally substituted with up to two groups independently selected from (Ci- C 4 )alkyl, (Ci-C 4 )alkoxy, (Ci-C 4 )alkoxycarbonyl, benzy
• a 1 , A 2 , Cy 1 , R 1 , R 2 , R 3 , X and E are defined as in the thirteenth preferred embodiment and Cy 2 is optionally substituted and selected from the group consisting of benzimidazolyl, benzotriazolyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl, oxodihydropyrazinyl, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl and thiadiazolyl.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X and E are defined as in the fifteenth preferred embodiment and R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, protected CONH 2 , (Ci-C 4 )alkyl, (d-C 4 )alkoxy and SO 2 Me.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are defined as in the seventeenth preferred embodiment and, with regard to the preparation of an oxazinone compound, R 3 is 3-propenyl-2-methyl, or 2-cyano-2- methylpropyl.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X and E are defined as in the eighteenth preferred embodiment and R 2 is phenyl or fluorophenyl.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , R 3 , X and E are defined as in the nineteenth preferred embodiment and suitable substituents for a substitutable ring nitrogen atom in the group represented by Cy 2 are selected from the group consisting of (Ci-C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci- C 2 )alkyl, (Ci-C 4 )alkoxycarbonyl and (Ci-C 4 )alkylcarbonyl; and suitable substituents for a substitutable ring carbon atom in the Cy 2 is selected from the group consisting fluorine, chlorine,
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and R 3 is 2-methyl-3-propenyl.
• a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and R 3 is 3-propenyl.
• a 1 , A 2 , Cy 1 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and Cy 2 is represented by one of the following structural formulas:
• G 2a is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl or (Ci-C 4 )haloalkyl
• G 2b is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (Ci-C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 - C 4 )cycloalkyl(Ci-C 2 )alkyl, halo(C]-C 4 )alkyl, (C r C 4 )alkoxy, (Ci-C 4 )haloalkoxy, CONH 2 , (Ci-C 4 )alkylaminocarbonyl, or (C 1 - C 4 )alkylcarbonylamino.
• inventions of the present invention are the epoxide compounds and salts thereof, and 2-methyl-3-propenyl intermediates and salts thereof as prepared with the methods of the present invention, in particular, the epoxide compounds and 2-methyl-3-propenyl intermediates corresponding to the above described preferred embodiments.
• ⁇ -haloalcohol compound refers to compound represented by structural formula (II)
• X includes any suitable leaving group as described herein, not just halogen.
• Suitable leaving groups include, but are not limited to halides, alkylsulfonates, trifluoromethanesulfonate (triflate) and phenylsulfonates which are optionally substituted with a methyl, halogen, nitro and the like, for example, methanesulfonate (mesylate), p-toluenesulfonate (tosylate), p- bromobenzenesulfonate (brosylate), p-nitrobenzenesulfonate (nosylate) and the like.
• leaving groups are Cl, Br, I or -OSO 2 R, wherein R is (Ci-C 4 )alkyl optionally substituted with one or more F, or phenyl optionally substituted with halogen, (Ci-C-Oalkyl or NO 2 . Most typically, leaving groups are Cl, Br, I or - OSO 2 R.
• bias group refers to a group where an optionally substituted aryl or optionally substituted heteroaryl is bonded to another optionally substituted aryl or optionally substituted heteroaryl (e.g., biphenyl).
• alkyl refers to a straight chain or branched saturated hydrocarbyl group having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
• cycloalkyl means a monocyclic, bicyclic or tricyclic, saturated hydrocarbon ring having 3-10 carbon atoms and includes, for example, cyclopropyl (c-Pr), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, spiro [4.4]nonane, adamantyl and the like.
• cyclopropyl c-Pr
• cyclobutyl cyclopentyl
• cyclohexyl cycloheptyl
• cyclooctyl bicyclo[2.2.2]octyl
• bicyclo[2.2.1]heptyl bicyclo[2.2.1]heptyl
• spiro [4.4]nonane adamantyl and the like.
• aryl means an aromatic radical which is a phenyl group, a naphthyl group, an indanyl group or a tetrahydronaphthalene group.
• An aryl group is optionally substituted with 1-4 substituents.
• substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido.
• heteroaryl means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3- pyrrolyl, 2-,3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, lH-indol-6-yl, lH-indol-5- yl, lH-benzimidazol-6-yl, lH-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolinyl
• heteroaryl is optionally substituted.
• substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or by oxo to form an N-oxide.
• heterocyclyl means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
• heterocyclyls include pyrrolidine, pyrrolidin- 2-one, 1 -methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, l-(2,2,2-trifluoroethyl)piperazine, 1 ,2-dihydro-2- oxopyridine, 1 ,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4- oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3- dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1
• alkoxy group refers to an alkyl-O- group or a cycloalkyl-O- group, where the preferred alkyl and cycloalkyl groups and optional substituents thereon are those given above.
• An alkoxy group can be unsubstituted or substituted with one or more substituents.
• alkenyl group refers to a straight chain or branched hydrocarbyl group which includes one or more double bonds.
• an alkenyl group includes between 2 and 12 carbon atoms (i.e., (C 2 -Ci 2 )-alkenyl).
• Suitable alkenyl groups include but are not limited to rc-butenyl, cyclooctenyl and the like.
• An alkenyl group can be unsubstituted or substituted with one or more substituents.
• alkynyl group refers to a straight chain or branched hydrocarbyl group which includes one or more triple bonds.
• the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
• Suitable alkynyl groups include, but are not limited to, (C 2 -C 8 )-alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl,4-propyl-2-pentynyl- , and 4-butyl-2- hexynyl.
• An alkynyl group can be unsubstituted or substituted with one or more substituents.
• alkylene group refers to a group represented by -[CH 2 J 2 -, wherein z is a positive integer, preferably from one to eight, more preferably from one to four.
• cycloalkyl alkyl alkoxy alkyl
• alkoxy alkyl alkoxy alkyl
• a (C a -C b )alkoxy(C c -C d )alkyl is a group that includes an alkoxy group with between a and b carbon atoms that is covalently bonded to an alkyl group with between c and d carbon atoms.
• Suitable substituents are those which do not substantially interfere with the reactions described herein, that is, that do not substantially decrease the yield (e.g., a decrease of greater than 50%) or cause a substantial amount of by-product formation (e.g., where by-products represent at least 50% of the theoretical yield).
• "interfering" substituents can be used, provided that they are first converted to a protected form. Suitable protecting groups are known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007).
• solvates or hydrates of the compound or its physiologically acceptable salts are also included.
• Solvates refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization.
• Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc.
• Solvates, wherein water is the solvent molecule incorporated into the crystal lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. Certain of the disclosed compounds may exist in various stereoisomeric forms.
• Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol “*” in a structural formula represents the presence of a chiral carbon center. “R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. Thus, “R*” and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms.
• the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
• Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
• the stereochemistry of a disclosed compound is named or depicted by structure
• the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers.
• the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
• the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
• the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
• Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
• Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.
• Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, s
• a protecting group may protect a hydroxyl group as ether.
• protecting groups include, but are not limited to methyl, methoxymethyl, methyl thiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p- methoxybenzyloxymethyl, [3,4-dimethoxybenzyl)oxy]methyl,;> nitrobenzyloxym ethyl, o-nitrobenzyloxymethyl, [(R)-I -(2- nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, [(p- phenylphenyl)oxy] methyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2-cyanoethoxymethyl, bis(2-chloroethoxy)methyl, 2,2,2-trichloro
• suitable protecting groups protect the hydroxyl group as esters, for example, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trichloroacetamidate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, phenylacetate, /»-P-phenylacetate, diphenylacetate, 3-phenylpropionate, bisfluorous chain type propanoyl (Bfp-OR), 4- pentenoate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate, 5-[3-Bis(4- methoxyphenyl)hydroxymethylphenoxy]levulinate, pivaloate, 1-adamantoate, crotonate, 4-methoxycrotonate, benzoate, /?-phenylbenzoate, 2,4,
• Protecting groups for a carbonyl group and reactions and conditions for protecting and deprotecting the carbonyl group are well known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007), Chapter 4 and references cited therein.
• a protecting group may protect a carbonyl group as acetal or ketal.
• acetals and ketals include acyclic acetals and ketals (e.g., dimethyl, diisopropyl, bis(2,2,2-trichloroethyl), cyclic acetals and ketals (e.g., 1,3-dioxanes, 1,3- dioxolanes, 1,3-dioxapane and the like), chiral acetals and ketals (e.g., (4R, 5R)- diphenyl-1 ,3-dioxolane, 4,5-dimethyl-l ,3-dioxolane, trans- ⁇ ,2-cyclohexanediol ketal and the like), dithio acetals and ketals (e.g., £,5" -dimethyl, 5,5" -diethyl, S,S'- dipropyl, 1,3-dithiane and the like), and monothio acetals and ketals.
• Protecting groups for a carboxyl group and reactions and conditions for protecting and deprotecting the carboxyl group are well known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007), Chapter 5 and references cited therein.
• a protecting group may protect a carboxyl group as ester.
• esters include, but are not limited to substituted methyl esters (e.g., 9-fiuorenylmethyl, methoxymethyl, methoxyethoxymethyl and the like), 2-substituted ethyl esters (e.g., 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)ethyl and the like), 2,6- dialkylphenyl esters (e.g., 2,6-dimethylphenyl, 2,6-di-J-butyl-4-methylphenyl, pentafluorophenyl and the like), substituted benzyl esters (e.g., triphenylmethyl, diphenylmethyl, 9-anthrylmethyl and the like), silyl esters (e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and the like.
• substituted methyl esters e.g., 9
• a protecting group may protect a carboxyl group as amide (e.g., N,N-dimethyl, pyrrolidinyl, piperidinyl and the like) or hydrazide (e.g., N-phenyl).
• amide e.g., N,N-dimethyl, pyrrolidinyl, piperidinyl and the like
• hydrazide e.g., N-phenyl
• a protecting group may protect an amino group as carbamate (e.g., 9- fluorenylmethyl, 2,2,2-trichloroethyl, 4-phenylacetoxybenzyl, 2-methylthioethyl, m- nitrophenyl, and the like) or amide (e.g., formamide, acetamide, 3- phenylpropanamide).
• carbamate e.g., 9- fluorenylmethyl, 2,2,2-trichloroethyl, 4-phenylacetoxybenzyl, 2-methylthioethyl, m- nitrophenyl, and the like
• amide e.g., formamide, acetamide, 3- phenylpropanamide
• a protecting group may protect an aromatic heterocycle as N-sulfonyl derivative (e.g., N ⁇ V-dimethylsulfonamide, methanesulfoneamide, mesitylenesulfonamide and the like), carbamate (e.g., benzyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl and the like), N-alkyl and N-aryl derivatives, N-trialkylsilyl, N-allyl, N-benzyl, amino acetal derivative, or amide.
• N-sulfonyl derivative e.g., N ⁇ V-dimethylsulfonamide, methanesulfoneamide, mesitylenesulfonamide and the like
• carbamate e.g., benzyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl and the like
• a protecting group may protect an amide group as N-methylamide, N- allylamide, N-t-butylamide and the like.
• Protecting groups for a sulfonamide group, and reactions and conditions for protecting and deprotecting the sulfonamide group are well known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007), Chapter 7 and references cited therein.
• a protecting group may protect a sulfonamide group as N-t- butylsulfonamide, N-diphenylmethylsulfonamide, N-benzylsulfonamide and the like.
• FIG. 1 shows a preferred synthesis of a specific tertiary alcohol oxazinone compound (compound 8) known to be a 1 l ⁇ -HSDl inhibitor.
• Compounds 3 to 8 of FIG. 1 were synthesized as described in Examples 1 to 4.
• EXAMPLE 2 triphosgene, DCM sat. aq. NaHCO 3 l-Bromo-4-((S)-l-isocyanato-ethyl)-benzene (4).
• To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87 mol, 2.30 equiv) and 5 L of deionized water. The resulting solution was agitated for 10-20 min, until the solids dissolved (homogeneous).
• To the clear solution was charged 250 g (1.25 mol, 1.00 equiv) of (S)-(-)-l-(4-bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane.
• the resulting solution was washed with 4.0 L of a 1.0 M aqueous solution of hydrogen chloride (note: the wash is slightly exothermic).
• the aqueous solution was cut and the remaining organic solution was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure.
• the resulting material was subjected to flash silica chromatography (5-30 % ethyl acetate/hexanes, 1.74 kg of silica) to produce 137.8 g of material (59 wt%, 3.1 :1 diastereomeric ratio favoring the desired diastereomer 6, 32.3 % yield).
• the material was used in the following epoxidation without further purification.
• the resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1x500 mL of 30 wt% solution of sodium thiosulfate and 1x500 mL of saturated aqueous solution of sodium bicarbonate.
• the wash sequence were repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of MCPBA is ⁇ 2.5 A% (220 nm), which in this example the wash sequence was repeated 3 times.
• the resulting solution was diluted with 1.00 L of methyl tert-butyl ether (MTBE) and washed with 1.00 L of water followed by 500 mL of a -30 wt% solution of sodium thiosulfate.
• the organic solution was dried with anhydrous sodium sulfate, filtered, and then concentrated via reduced pressure.
• the resulting material was subjected to flash silica chromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 g of material consisting of both diastereomers (1.98:1 dr) and 41 g of the desired diastereomer (>99:1 dr).
• the material consisting of the mixed fractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and 200 mL of heptane (anti-solvent) to produce upon filtration 31.3 g of product (95.7 A% at 220 nm, 74:1 dr). The two samples were combined to produce 72.3 g of product (83.6 % yield for the two step operation).
• IPAC isopropyl acetate
• heptane anti-solvent
• Step 1 l-Chloro-3-(4-fluorophenyl)hex-5-en-3-ol.
• Step 2 6-Allyl-6-(4-fluorophenyl)-3-((-S 1 )- 1 -phenylethyl)- 1 ,3-oxazinan-2-one.
• Step 2 (/?)-6-allyl-3 -((S)-I -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-l ,3-oxazinan- 2-one and (5)-6-allyl-3-((5)-l-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-l,3- oxazinan-2-one
• Step 5 Enantiomers of 6-methyl-6-phenyl-3-m-tolyl-l,3-oxazinan-2-one.
• EXAMPLE 8 6-allyl-3-((S)-l-cyclohexylethyl)-6-(4-fluorophenyl)-l,3-oxazinan-2-one
• the mixture was diluted with EtOAc (50 mL) and washed with 1% aq HCl (2 x 15 mL), satd aq NaHCO 3 (10 mL) and brine (10 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by chromatography on a 12-g silica cartridge eluted with a 10-45% EtOAc in hexanes gradient to afford two isomeric products.
• Step 4 To a solution of (/?)-l-bromo-4-(l-isocyanatoethyl)benzene (2.5 g, 11 mmol) in THF anhydrous (40 mL) was added l-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (1.69 g, 7 mmol) and DBU (5.68 g, 33 mmol) at ambient temperature and the reaction mixture was refluxed overnight. The reaction mixture was extracted with 1 N aq HCl and EtOAc. The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to afford the residue, which was purified by column chromatography to give two isomers.
• Step l 6-allyl-3-((-S)-l-(2',4 I -difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-l,3- oxazinan-2-one
• Step 1 A mixture of ( ⁇ )-6-allyl-3-((S)-l-(4-bromophenyl)ethyl)-6-phenyl-l,3- oxazinan-2-one (150 mg, 0.375 mmol) and 6-aminopyridin-3-ylboronic acid (56 mg, 0.45 mmol), Pd(Ph 3 P) 2 Cl 2 (15 mg), and aqueous Cs 2 CO 3 solution (0.5 mL, 2 M) in 1 ,4-dioxane (10 mL) was stirred and heated to reflux for 2 h.
• Step 3 To a solution of 2-((S)-3-((S)- 1 -(4'-fluorobiphenyl-4-yl)ethyl)-2-oxo-6- phenyl-l,3-oxazinan-6-yl) acetic acid (1 g, 2.3 mmol) in MeOH (15 mL) was added thionyl chloride (408 mg, 3.5 mmol) dropwise at 0 °C under N 2 atmosphere.
• Step 2 A mixture of (i?)-3-((S)-l -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-l,3-oxazinan-2-one (250 mg, 0.6 mmol), 5- (methoxycarbonyl)pyridin-3-ylboronic acid (163 mg, 0.9 mmol), PdCl 2 (PPh 3 ) 2 (50 mg, 20%) and aqueous Cs 2 CO 3 solution (2 M, 2 mL) in 1 ,4-dioxane (6 mL) was heated to reflux at 100 °C overnight under N 2 .
• Step 1 (S)- 1 -bromo-4-( 1 -isocyanatoethyl)benzene
• Step 3 (R)-6-allyl-3-((S)-l-(4-bromophenyl)ethyl)-6-phenyl-l,3-oxazinan-2-one
• Step 4 (iS)-3-((5)-l-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-l,3-oxazinan- 2-one and 3-((R)-3-((S)- ⁇ -(4-bromophenyl)ethyl)-2-oxo-6-phenyl-l ,3-oxazinan-6- yl)propanal
• Step 6 (S)-3-((S)-l- (4-bromophenyl) ethyl)-6- (2- hydroxy-2-methylpropyl)- 6- phenyl-1,3- oxazinan-2- one
• 1,3- oxazinan-3-yl)ethyl)phenyl)nicotinate 150 mg, 0.307 mmol
• NH 2 Me/MeOH 1O mL
• the mixture was stirred at rt overnight.
• the solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford 6-(4-((5)-l-((5)-6-(2- hydroxy-2-methylpropyl)-2- oxo-6- phenyl- l,3-oxazinan-3- yl) ethyl)phenyl)-N-methylnicotinamide (54 mg, 36%).

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Animal Behavior & Ethology (AREA)
• Diabetes (AREA)
• Immunology (AREA)
• Biomedical Technology (AREA)
• Physical Education & Sports Medicine (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Rheumatology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Ophthalmology & Optometry (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Dermatology (AREA)
• Urology & Nephrology (AREA)
• Psychiatry (AREA)
• Endocrinology (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Emergency Medicine (AREA)
• Virology (AREA)
• Vascular Medicine (AREA)
• Child & Adolescent Psychology (AREA)
• Pain & Pain Management (AREA)
• Gastroenterology & Hepatology (AREA)

Priority Applications (6)

Applications Claiming Priority (6)

Publications (1)

Family

ID=39942701

Family Applications (2)

Family Applications After (1)

Country Status (10)

Cited By (24)

Families Citing this family (36)

Citations (1)

Family Cites Families (210)

• 2008
  • 2008-07-25 JP JP2010518226A patent/JP5451611B2/ja not_active Expired - Fee Related
  • 2008-07-25 EP EP08794727.1A patent/EP2183228B1/en not_active Not-in-force
  • 2008-07-25 US US12/670,205 patent/US8575156B2/en not_active Expired - Fee Related
  • 2008-07-25 ES ES08794755T patent/ES2395081T3/es active Active
  • 2008-07-25 CA CA2697147A patent/CA2697147A1/en not_active Abandoned
  • 2008-07-25 WO PCT/US2008/009048 patent/WO2009017671A1/en not_active Ceased
  • 2008-07-25 US US12/670,209 patent/US8329897B2/en not_active Expired - Fee Related
  • 2008-07-25 EP EP08794755A patent/EP2183229B1/en not_active Not-in-force
  • 2008-07-25 WO PCT/US2008/009017 patent/WO2009017664A1/en not_active Ceased
  • 2008-07-25 AT AT08794755T patent/ATE554078T1/de active
  • 2008-07-25 CA CA2697168A patent/CA2697168A1/en not_active Abandoned
  • 2008-07-25 TW TW097128296A patent/TW200911796A/zh unknown
  • 2008-07-25 CL CL2008002199A patent/CL2008002199A1/es unknown
  • 2008-07-25 AR ARP080103215A patent/AR067673A1/es unknown
  • 2008-07-25 JP JP2010518233A patent/JP5470557B2/ja not_active Expired - Fee Related

Patent Citations (1)

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events