WO2000063168A1 - Synthesis of azetidine derivatives - Google Patents
Synthesis of azetidine derivatives Download PDFInfo
- Publication number
- WO2000063168A1 WO2000063168A1 PCT/US1999/008361 US9908361W WO0063168A1 WO 2000063168 A1 WO2000063168 A1 WO 2000063168A1 US 9908361 W US9908361 W US 9908361W WO 0063168 A1 WO0063168 A1 WO 0063168A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lower alkyl
- process according
- reaction
- butyl
- mesylate
- Prior art date
Links
- 0 C*C(N(CC1)CCN1C(C1)CN1C(C(F)(F)F)=O)=O Chemical compound C*C(N(CC1)CCN1C(C1)CN1C(C(F)(F)F)=O)=O 0.000 description 2
- IHMHPLJFRNWFGU-UHFFFAOYSA-N C(c1ccccc1)N(C1)CC1N(CC1)CCN1c1ccccn1 Chemical compound C(c1ccccc1)N(C1)CC1N(CC1)CCN1c1ccccn1 IHMHPLJFRNWFGU-UHFFFAOYSA-N 0.000 description 1
- UEEXJOPJQJONFA-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)CCN1N1CCN(C)CC1)=O Chemical compound CC(C)(C)OC(N(CCC1)CCN1N1CCN(C)CC1)=O UEEXJOPJQJONFA-UHFFFAOYSA-N 0.000 description 1
- CJDYFMIDIQXELO-UHFFFAOYSA-N CC(C)(C)OC(N1CCN(C)CC1)=O Chemical compound CC(C)(C)OC(N1CCN(C)CC1)=O CJDYFMIDIQXELO-UHFFFAOYSA-N 0.000 description 1
- DVPJSGVYVFVSJJ-UHFFFAOYSA-N CN(CC1)CCN1c(cc1)ccc1OC(F)(F)F Chemical compound CN(CC1)CCN1c(cc1)ccc1OC(F)(F)F DVPJSGVYVFVSJJ-UHFFFAOYSA-N 0.000 description 1
- WQDDXVGJRSTLED-UHFFFAOYSA-N CN(CC1)CCN1c1ccccc1 Chemical compound CN(CC1)CCN1c1ccccc1 WQDDXVGJRSTLED-UHFFFAOYSA-N 0.000 description 1
- MYWNBGPUPDPECZ-UHFFFAOYSA-N CN(CC1)CCN1c1ncccn1 Chemical compound CN(CC1)CCN1c1ncccn1 MYWNBGPUPDPECZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to building blocks for the creation of a high degree of structural diversity among compounds within a combinatorial library. Provided herewith are compounds that serve as building blocks and methods for generating such compounds. The present invention further relates to a novel process for preparing 3-amino-azetidine derivatives, key intermediates of compounds with well-documented biological properties. The present invention also relates to azetidine compounds made by such a novel process.
- Combinatorial chemistry refers to techniques for creating a multiplicity of compounds, refe ⁇ ed to as a "library”, and then testing the library or each member of the library for biological activity. In recent years, combinatorial chemistry has become an important tool for the drug discovery efforts of many pharmaceutical
- a "building block” is a reagent or compound which can combine (i.e., react) with one or more reagents to yield the compounds which, together, form a combinatorial library.
- building block is a reagent or compound which can combine (i.e., react) with one or more reagents to yield the compounds which, together, form a combinatorial library.
- azetidine derived compounds are known in the art to have various biological properties.
- the Fluoroquinolone azetidines are widely known as antibacterial agents. See, for example, Friggola, Jordi et al, J. Med. Chem. (1995), 38(7), 1203-15; Friggola, Jordi et al, J. Med. Chem. (1993), 36(7), 801-10; Remuzon, P. et al, J. Med. Chem. (1991), 34(1), 29-37. A few of these compounds are currently undergoing preclinical studies and Phase I trials.
- Another class of compounds that contains the azetidine backbone is the carbapenem derivatives, which are used primarily for their antibacterial and antibiotic properties.
- Anti-viral, and specifically anti-AIDS, peptide mimetics are also prepared by using key azetidine intermediates. Greengrass, C.W. et al, WO 93/19059.
- 3-azetidinylalkypiperidines or - pyrrolidines as tachykinin antagonists are also synthesized via a 3-amino-azetidine derivative. Mackenzie, A.R. et al, WO 97/25322.
- R, Ri, R 2 are the same or different and represent hydrogen, -C 6 lower alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkyl, trifluoromethylcarbonyl; or R, Ri , R 2 are the same or different and represent (CH 2 ) n -phenyl or heteroaryl where n is 0 to 4 and where the phenyl or the heteroaryl is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, C ⁇ -C 6 lower alkyl, C ⁇ -C 6 alkoxy, C 2 -C 6 alkylcarbonyl, carboxy, Ci- C 6 carboxyalkyl or aryl or heteroaryl carbonyl where each ring portion is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, C ⁇ -C 6
- m is 1, 2, or 3; W is N, CH, or O, provided that when W is O, R 3 does not exist; and R 3 is hydrogen, C ⁇ -C 6 lower alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C -C 6 alkylcarbonyl, C 3 -C 6 cycloalkyl, carboxy, or C 2 -C 6 alkoxycarbonyl; or R 3 is aryl or heteroaryl optionally mono-, di-, or trisubstituted with up to three groups independently selected from C ⁇ -C 6 lower alkyl, halogen, trifluoromethyl, hydroxy, C 2 -C 6 alkenyl, C ⁇ -C 6 alkoxy, trifluoromethoxy, amino, mono or dialkylamino where each alkyl portion is C ⁇ -C 6 lower alkyl, -CO 2 R- ⁇ where R is C ⁇ -C 6 lower alkyl, or -(CH 2 ) q
- the present invention provides building blocks for
- the present invention provides a composition comprising a compound having structural Formula I as defined above in combination with an acceptable carrier.
- the present invention also provides a novel process for the preparation of compounds of Formula I, which in turn are intermediates for the synthesis of biologically active compounds.
- the present invention provides for a product of Formula I made by a novel process.
- the novel compounds encompassed by the instant invention can be described by the general Formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof.
- the present invention relates to building blocks for the synthesis of a collection of compounds as a combinatorial library.
- a "collection of compounds” comprises at least three different compounds, also referred to as the "disclosed building blocks" or the "member compounds".
- the collection comprises at least five different compounds, more preferably at least thirty different compounds.
- the collection comprises at least fifty different compounds.
- Each of the disclosed building blocks is: 1) substantially pure; 2) is substantially free of contamination by the other building herein; and 3) contains at least one reactive group.
- a building block can contain one or more non- reactive functional groups.
- substantially pure means, for example, that the disclosed building block is at least about 80% pure, and preferably at least about 90% pure and more preferably at least about 95% pure.
- substantially free of contamination by other members of the collection means, for example, that the disclosed building block contains less than 5% of the other building blocks in the collection and more preferably less than 1.0% of the other building blocks in the collection, and even more preferably less than 0.1% of the other building blocks in the collection.
- a “reactive functional group” allows the compound in the collection to be reacted directly with other reagents or compounds to form a member of a combinatorial library or a precursor thereof. "Reacted directly” means, for example, that the reactive functional group can react and form covalent bonds with the other compounds without the need of intervening reactions such as a deprotection reaction.
- the reactive functional group determines the interconnection chemistries, i.e., the manner in which the disclosed building block can be reacted with other building blocks of the combinatorial library.
- reactive functional groups include a hydroxyl group, a primary amine group, a secondary amine group, a thiol, a carboxylic acid, an ester, an aldehyde, an azide, a nitrile, an isonitrile, an epoxide, an aziridine, an isocyanate, a thioisocyanate and a halide.
- non-reactive functional group is inert under the reaction conditions employed for interconnecting the disclosed building blocks with other building blocks used to prepare a member of a combinatorial library or a precursor thereof, unless the non-reactive functional group is, for example, first activated or undergoes a deprotection reaction.
- non-reactive functional groups include an ether, a thioether, a tertiary amine, an alkene, an alkyne, an alkoxycarbonyl, a ketal or an acetal.
- a member compound has at least one reactive functional group.
- More than one reactive functional group can be present in a member compound, provided that the reactivity of each reactive functional group is orthogonal to the reactivities of the other functional groups, i.e., each reactive functional group can selectively react in the presence of the others.
- a reactive functional group can be introduced into the building block or member compound by, for example, formation of a carbon-heteroatom bond between a precursor compound and a reagent. Specific examples are provided in the following paragraphs.
- the formation of a carbon-heteroatom bond between a precursor compound and a reagent can occur by reacting an electrophilic precursor compound and a nucleophilic reagent.
- a reactive functional group which can be introduced by this type of transformation is a secondary amine R 1 - ⁇ -, which is formed from the reaction of an electrophilic precursor compound and R L NH 2 , or the anion thereof (or by the reaction of a carbonyl group with a primary amine under reducing conditions).
- RI is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group.
- R 11 is an aliphatic or aromatic group substituted with at least one reactive functional group.
- nucleophilic reagent for this type of transformation is R ⁇ R IV NH, or the anion thereof, wherein R ⁇ and R IV , together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring or is substituted with a reactive functional group.
- the reaction of this nucleophilic reagent with an electrophilic precursor can introduce R m R IV N- into a member compound.
- Examples of other reactive functional groups which can be introduced into a member compound include H 2 N-, HO-, C1-, Br-, I-, CN-, N 3 -, NC-, which are formed by the reaction of a suitable electrophilic precursor compound with NH 3 (or NH 2 " ), H 2 O (or OH “ ), CI “ , Br “ , I “ , CN “ , N 3 “ , and trimethylsilycyanide, respectively.
- the nucleophile can also be a part of the elecrophilic precursor, i.e., the reaction is intramolecular, respectively.
- the nucleophile can also be part of the electrophilic precursor, i.e., the reaction is intramolecular.
- Epoxides and aziridines are examples of reactive functional groups formed in this manner.
- suitable electrophilic precursors which can be used to introduce reactive functional groups into a building block by reaction with a nucleophilic reagent include alkyl halies, aryl halides, alkyl sulfates, alkyl sulfonates, epoxides and aziridines.
- a reactive functional group can also be formed by converting a reactive functional group present in a member compound to a different reactive group.
- This type of reaction is the conversion of a primary amine to isocyanate by reaction with phosgene or Cl-COO-C(CL ) or the replacement of a halide with an amine.
- a reactive functional group can be formed by removing a protecting group present in a member compound. Examples include cleaving a tert- butoxycarbonyl group (hereinafter "BOC") to regenerate a free primary or secondary amine or hydrolyzing an acetal or ketal to liberate an aldehyde or ketone, respectively.
- BOC tert- butoxycarbonyl group
- the formation of a carbon-heteratom bond between a precursor compound and reagent can also occur by reacting a nucleophilic precursor compound, e.g., a compound containing one or more double and/or triple bonds, and an electrophilic reagent.
- a nucleophilic precursor compound e.g., a compound containing one or more double and/or triple bonds
- an electrophilic reagent e.g., -CI, -Br-, -I, -OH, -O-, -N 3 , and an aziridine
- an aziridine can be formed by reacting a compound containing one or more double and/or triple bonds with, for example, SC1 2 , RSC1, SBr 2 , SI 2 , N-bromosuccinimide, meta-chloroperbenzoic acid, NaN3 or tosyl chloramine.
- a non-reactive functional group can be introduced into a building block or member compound by formation of a carbon-heteroatom bond between a precursor compound and a reagent, for example, by reacting an electrophilic precursor compound and a neucleophilic reagent.
- electrophilic precursor compounds are as described above for introducing reactive functional groups into building blocks.
- suitable nucleophilic reagents for introducing non- reactive functional groups into a building block include R V R VI NH, R V SH, R v OH, or the anions thereof.
- R and R V1 are independently an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group.
- Substituted aliphatic and substituted aromatic groups represented by R v and R VI can contain non- reactive functional groups but no reactive functional groups.
- These nucleophilic reagents, together with a suitable electrophilic precursor compound, can be used to introduce R V R VI N-, R V S- and R v OH, respectively into a building block.
- Another example of a suitable necleophilic reagent for introducing a non-reactive functional group into the building block is R VII R VIII NH, or the anion thereof.
- R v ⁇ and R v ⁇ together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic group which does not contain -NH- in the non-aromatic heterocyclic ring and is not substituted with a reactive functional group.
- R VII R VIII NH or its anion and a suitable eletrophilic precursor compound R vll R vm N- can be introduced into a building block.
- R V1 NH 2 is R V1 NH 2 , or the anion thereof.
- the disclosed building blocks can be formed from virtually any combination of the eletrophilic precursor compounds and the nucleophilic reagents which are disclosed herein or from the nucleophilic precursor compounds (e.g., compounds containing one or more units of unsaturation) and the electrophilic reagents which are disclosed herein, provided that at least one reactive group is present in the building block.
- the collection includes building block.
- the collection includes building blocks which are formed from an electrophilic precursor compound and a nucleophilic reagent disclosed herein or from a nucleophilic precursor compound containing one or more units of unsaturation and an electrophilic reagent disclosed herein.
- the collection consists of building blocks from an electrophilic precursor compound and a nucleophilic reagent disclosed herein or from a nucleophilic precursor compound containing one or more units of unsaturation and an electrophilic reagent disclosed herein.
- the collection includes the building blocks disclosed herein.
- the collection consists of the building blocks disclosed herein.
- the present invention provides a compound of Formula I wherein R, Ri, R 2 are independently selected from the group consisting of hydrogen, C ⁇ -C 6 lower alkyl, C 2 -C 6 alkylcarbonyl, trifluoromethylcarbonyl, or
- Ri and R 2 together with the nitrogen to which each is attached, may form azide or a structure shown below:
- the present invention provides a compound of Formula I wherein R is selected from CH 2 -phenyl, H, t-butyl,
- a compound of Formula I wherein R is CH 2 - ⁇ henyl and wherein Ri, R 2 and the N to which each is attached form azide or a structure selected from:
- R is hydrogen and wherein Ri, R2 and the N to which each is attached form a structure selected from:
- a compound of Formula I where R is t- butyl and where Ri, R 2 and the N to which each is attached form one of the following structures:
- R is
- O -C-CF 3 and Ri, R 2 and the N to which each is attached form one of the following structures:
- R is
- the most prefe ⁇ ed compounds include the following and their pharmaceutically acceptable salts: 2-methoxyphenylpiperazine; l-(2-pyridyl)- piperazine; 1-pyrimidylpiperazine; 1-phenylpiperazine; 1-methylpiperazine; morpholine; piperidine; py ⁇ olidine; dimethylamine; methylamine; isopropylamine; methally amine; sodium azide; azetidin-3-ol; 2-methoxyphenlpiperazine; 1(2- hydroxyethyl)-piperazine; piperazine; 1-tert-butoxycarbonyl perhydrodiazepine; 1- methylpiperazine; 1-phenylpiperazine; 1-pyrimidylpiperazine; 4- fluorophenylpiperazine; 4-methoxyphenylpiperazine; 4-methylphenylpiperazine; 4- trifluoromethoxyphenylpiperazine; 4-trifluoromethylphenylpiperazine; 1
- alkyl in the present invention is meant a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms (unless stated otherwise; preferably C ⁇ -C 6 ) and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and the like.
- halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
- alkenyl straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one double bond and includes ethenyl, 3-buten-l-yl, 2-ethenylbutyl, 3-hexen-l-yl, and the like.
- alkynyl means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one triple bond.
- Typical C 2 -C 10 alkynyl groups include propynyl, 2-butyn- 1-yl, 3-pentyn-l-yl, and the like.
- cycloalkyl in the present invention is meant a cyclic hydrocarbyl group such as cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl, and the like.
- alkoxy refers to the alkyl groups mentioned above bound through a single oxygen atom, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the
- Carboalkoxy refers to an organic acid esterified with a lower alcohol or amidated with an amine, respectively. Such groups include, for example,
- alkanoyl or alkylcarbonyl groups are alkyl as previously defined linked through a carbonyl, i.e., C ⁇ -C ⁇ o-C(O)- or C 2 -C 6 -C(O)-. Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
- acyl includes a
- Ci-Cio alkanoyl including substituted alkanoyl, wherein the alkyl portion can be substituted by NR'R" or a carboxylic or heterocyclic group.
- Typical acyl groups include acetyl, benzoyl, and the like.
- alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted by N, NR, phenyl, substituted phenyl, thio, C]-C ⁇ 0 alkyl (preferably C ⁇ -C 6 ), Ci-Cio alkoxy (preferably C ⁇ -C 6 ), hydroxy, carboxy, Ci-Cio alkoxycarbonyl (preferably C ⁇ -C 6 ), halo, nitrile, cycloalkyl, or a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur.
- "Substituted nitrogen” means nitrogen bearing Cj-do alkyl (preferably C ⁇ -C 6 ) or (CH ) n Ph where n is 1, 2, or 3.
- substituted alkyl groups examples include 2-aminoethyl,
- substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-( 1 -piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like.
- Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 3-diethylamino-2-hydroxy-propoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
- substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-l-yl, 5-ethylmethylamino-3-pentyn-l-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl-3- imidazolidin-1 -ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl,
- aliphatic groups comprise straight chained, branched or cyclic C ⁇ -C 8 hydrocarbons which are completely saturated or which contain one or more units of unsaturation.
- Suitable substituents for an aliphatic group or an aromatic group comprise reactive functional groups and non-reactive functional groups, as described above.
- Ar and aryl refer to unsubstituted and substituted aromatic groups.
- Heteroaryl groups are aryls having from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, andN.
- Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl.
- Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, benzofuranyl, indoyl, and the like.
- Aromatic groups may also comprise carbocyclic aromatic groups such as phenyl, 1 -naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl, and heterocyclic aromatic groups such as N-imidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole, 4-thiazole, 5-thiazole, 2- oxazolyl, 4-oxazolyl and 5-oxazolyl.
- carbocyclic aromatic groups such as phenyl, 1 -naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl
- aromatic groups may comprise fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
- Examples include 2-benzothienyl, 3-benzothienyl, 2- benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 1- isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridinyl.
- Preferred Ar groups are phenyl and substituted phenyl.
- the alkyl and alkoxy groups can be substituted as defined herein.
- typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.
- the starting azetidinols may be prepared utilizing a modified procedure of Gaertner (J. Org. Chem., 1967, 32. 2972) according to Scheme III, in which R is lower alkyl or arylalkyl.
- mesylation is carried out in a chlorinated solvent such as methylene chloride, 1,2-dichloroethane or chloroform at low temperature, typically between about -10°C to -70 °C, and prefe ⁇ ably about -40°C to
- the reaction is carried out in the presence of an organic tertiary base such as triethylamine or diisopropylethylamine.
- an organic tertiary base such as triethylamine or diisopropylethylamine.
- the mesylate is used immediately after its formation (within a period of no more than two hours after isolation of the product of the mesylation) to prevent decomposition (the decomposition of the mesylate is less than 20% at the time of displacement).
- the displacement reaction is carried out in water thereby providing easy removal of any by-products (a feature of ClickchemTM).
- the product crashes out of solution in many instances (particularly in the case of aromatic nucleophiles where a slight excess of the mesylate is employed).
- the benzyl group is cleaved under high pressure in the presence of a catalyst at lightly elevated temperatures of about between 30°C to 80°C, and preferably at about 55°C to 65°C.
- the catalyst employed is a palladium catalyst such as palladium hydroxide.
- Acylative dealkylation is also contemplated by the instant invention. The procedure using acetic anhydride is developed by Dave (J. Org. Chem., 1996, 61, 5453), though its use is limited to three substrates due probably to difficulty in isolating the products. The present invention solves certain difficulties associated with the method of Dave.
- a co-solvent is used to increase the solubility of the substrate without the addition of an excess amount of a reactive carboxylic acid anhydride, such as, for example, acetic anhydride.
- a prefe ⁇ ed co-solvent is a Lewis acid as, for example, boron trifluoride etherate. This provides for a simplified work-up (i.e. the presence of excess acetic anhydride is very cumbersome) that makes product isolation easier.
- the work-up includes the filtering of the reaction product through a pad of silica.
- the hydrolysis of the amide bond is achieved by using a strong mineral acid in a suitable solvent, such as, for example, ethanol.
- a strong mineral acid is hydrogen chloride gas.
- the present invention also extends the scope of the acylative dealkylation method, and provides a method that allows the deprotection of acid sensitive compounds. For instance, several of the substrates in the cu ⁇ ent study contain acid- sensitive functional groups and cannot, therefore, be deprotected by either of the methods described above.
- the instant invention provides a new method for the cleavage of the tert-butyl group in these systems by employing a fluorinated carboxylic acid anhydride, as, for example, trifluoroacetic anhydride. Trifluoroacetic anhydride has previously been used to cleave 2,4-dimethoxybenzylamines (Nussbaumer, et al., Tetrahedron, 1991, 47, 4591).
- the instant invention provides a two step method first involving formation of the trifluoroacetamide followed by cleavage under basic conditions.
- the reaction takes place at lower temperatures of about -10°C to 25°C, and preferably at about 0°C.
- only slightly more than a stoichiometric amount of fluorinated carboxylic acid anhydride is required, preferably in an amount ranging from about 1 molar equivalent to 2 molar equivalents of the N-(t-butyl)-aminoazetidine.
- reaction is complete within one hour).
- amide hydrolysis is also rapid and takes place at room temperature.
- Other advantages to the reaction is that the work-up is simple and the reaction is very clean, thus simplifying product isolation.
- R1, R2 H, Imidazolyl, formimidoyl
- the compounds of Tables 1-4 are prepared using the 3-amino-azetidines synthesized by the improved process of the present invention.
- One improvement the process of the instant invention has over existing processes is that the yield and the scope of the azetidine preparation are greatly enhanced. Further, the process of the present invention provides access to a larger number of azetidines, which facilitates drug optimization and development.
- the 3-amino-azetidines produced by the instant invention can be used to prepare the fluoroquinolone azetidines of Table 1 by displacing a leaving group on the fluoroquinolone nucleus as shown in Scheme IV (See, for example, Friggola, Jordi et al, J. Med. Chem. (1995), 38(7), 1203-15; Friggola, Jordi et al, J. Med. Chem. (1993), 36(7), 801-10; Remuzon, P. et al, J. Med. Chem. (1991), 34(1), 29-37; Yazaki, A. et al, WO 97/38971; Yazaki, A.
- the 3-amino-azetidines produced by the instant invention can be used to prepare the tachykinin (neurokinin) antagonist compounds of Table 4 by nucleophilic substitution using the azetidine as the nucleophile, shown in Scheme VII (Mackenzie, A.R. et al, WO 97/25322). Base, MeCN, reflus
- N-t-butyl-O-trimethylsilylazetidine 400 g, 2 mol is added portionwise to 3 ⁇ Hydrochloric acid solution (733 mL) at room temperature, and the resulting mixture is sti ⁇ ed at ambient temperature. An exothermic reaction took place. After 1 hour, the pink mixture is extracted once with ether (ca. 500 mL) to remove the silyl ether. A solution of NaOH (100 g) in water (250 mL) is added to the aqueous layer and the resulting white suspension is saturated with K 2 CO 3 . The crude product is separated, and the aqueous layer is extracted with CH 2 C1 2 (500 mL x 2). The organics are combined, dried over Na 2 SO 4 , filtered, and evaporated in vacuo. The residue (colorless oil) solidified underhigh vacuum to afford the product as a white crystalline solid (165 g, 64%).
- reaction is heated to 55-60°C, and stirred for 12 hours. After being allowed to cool,
- methylene chloride 50ml is added in a dropwise fashion. Upon completion of the addition, the reaction is poured into saturated sodium bicarbonate solution (300ml). The organic layer is separated, and the aqueous layer is extracted with a further portion of methylene chloride (100ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude mesylate.
- aqueous ammonia 130ml, 2.29mol, 30%.
- reaction is heated to 55-60°C, and sti ⁇ ed for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) is added, and the mixture is extracted with diethyl ether (3 x 250ml). The combined organic extracts are dried over magnesium sulfate,
- reaction is heated to 55-60°C, and sti ⁇ ed for 12 hours. After being allowed to cool,
- methylene chloride 50ml is added in a dropwise fashion. Upon completion of the addition, the reaction is poured into saturated sodium bicarbonate solution (300ml). The organic layer is separated, and the aqueous layer is extracted with a further portion of methylene chloride (100ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude mesylate. To the mesylate is added triethylamine (45ml, 0.32mol), and isopropylamine
- the pressure is increased to 60psi, and shaking is continued for a further 48 hours (during this time the hydrogen pressure is recharged twice).
- the heater is then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure is released, the bottle is then opened, and the reaction is filtered through celite washing with hot methanol (8L) followed by water (3L).
- the hydrochloride salt 4-(l-benzylazetidin-3- yl)morpholine (162g, 0.53mol) is dissolved in methanol (IL) and palladium hydroxide (16.2g, 20% on carbon) is added.
- the bottle is evacuated and then pressurized under hydrogen (40psi) and shaken while being heated to 60°C. On reaching the desired temperature, the pressure is increased to ⁇ Opsi, and shaking is continued for a further 110 hours (during this time the hydrogen pressure is recharged four times after samples are removed for NMR analysis to monitor the progress of the reaction). The heater is then turned off and the reaction allowed to cool to room temperature under hydrogen.
- the hydrochloride salt l-benzylazetidin-3- ylpiperadine (116g, 0.39mol) is dissolved in methanol (1.15L) and palladium hydroxide (12.2g, 20% on carbon) is added.
- the bottle is evacuated and then pressurized under hydrogen (40psi) and shaken while being heated to 60°C. On reaching the desired temperature, the pressure is increased to ⁇ Opsi and shaking is continued for another 72 hours (during this time the hydrogen pressure is recharged three times after samples are removed for NMR analysis to monitor the progress of the reaction).
- the hydrochloride salt of 3-[4-(l- benzylazetidin-3-yl)piperazinyl]propan-l-ol (116g, 0.39mol) is dissolved in methanol (1.15L) and palladium hydroxide (12.2g, 20% on carbon) is added.
- the bottle is evacuated and then pressurized under hydrogen (40psi) and shaken while being heated to 60°C. On reaching the desired temperature, the pressure is increased to ⁇ Opsi and shaking is continued for another 72 hours (during this time the hydrogen pressure is recharged three times after samples are removed for NMR analysis to monitor the progress of the reaction).
- a steady stream of hydrogen chloride gas is bubbled through a stirred suspension of the l-acetyl-3-[4-(2-pyridyl)piperizinyl]azetidine (40.4g, 0.15mol) in ethanol (IL) for 10 minutes at 0°C. Upon completion, the suspension is heated to reflux for 12 hours. After being allowed to cool, the precipitated solid is collected by filtration and washed with methyl tert-butyl ether to yield the pure product (45 g, 73%) as the hydrochloride salt.
- a steady stream of hydrogen chloride gas is bubbled through a stirred suspension of the l-acetyl-3-[4-(4-methoxyphenyl)piperizinyl]azetidine (93g, 0.32mol) in ethanol (500ml) for 10 minutes at 0°C. Upon completion, the suspension is heated to reflux for 12 hours. After being allowed to cool, the precipitated solid is collected by filtration and washed with methyl tert-butyl ether to yield the pure product (70.5 g, 62%) as the hydrochloride salt.
- a steady stream of hydrogen chloride gas is bubbled through a sti ⁇ ed suspension of the l-acetyl-3-[4-(4-methylphenyl)piperizinyl]azetidine (83.5g, 0.15mol) in ethanol (500ml) for 10 minutes at 0°C. Upon completion, the suspension is heated to reflux for 12 hours. After being allowed to cool, the precipitated solid is collected by filtration and washed with methyl tert-butyl ether to yield the pure product (93.5 g, 89.5%) as the hydrochloride salt.
- a steady stream of hydrogen chloride gas is bubbled through a sti ⁇ ed suspension of the l-acetyl-3-[4-(4-trifluoromethylphenyl)piperizinyl]azetidine (76g,
- the combined organic extracts are dried over magnesium sulfate.
- Purification of the product is carried out by passing it through a pad of silica gel eluting the product with 50 :50 ethyl acetate : hexanes.
- the product (42.9g, 78%) is obtained as a colorless solid.
- a steady stream of hydrogen chloride gas is bubbled through a sti ⁇ ed suspension of the 2,2,2-trifluoroacetyl-l-(3- ⁇ 3-[4-(4- trifluoromethoxy)phenyl]piperazinyl ⁇ azetidinyl)ethan-l-one (47. Ig, 0.12mol) in ethanol (500ml) for 10 minutes at 0°C.
- the suspension is heated to reflux for 12 hours.
- the precipitated solid is collected by filtration and washed with methyl tert-butyl ether to yield the pure product (32 g, 65%) as the hydrochloride salt.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1999/008361 WO2000063168A1 (en) | 1999-04-16 | 1999-04-16 | Synthesis of azetidine derivatives |
AU35659/99A AU3565999A (en) | 1999-04-16 | 1999-04-16 | Synthesis of azetidine derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1999/008361 WO2000063168A1 (en) | 1999-04-16 | 1999-04-16 | Synthesis of azetidine derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000063168A1 true WO2000063168A1 (en) | 2000-10-26 |
Family
ID=22272579
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/008361 WO2000063168A1 (en) | 1999-04-16 | 1999-04-16 | Synthesis of azetidine derivatives |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU3565999A (de) |
WO (1) | WO2000063168A1 (de) |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8158616B2 (en) | 2008-03-11 | 2012-04-17 | Incyte Corporation | Azetidine and cyclobutane derivatives as JAK inhibitors |
US8362000B2 (en) | 2009-04-22 | 2013-01-29 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8415341B2 (en) | 2009-04-22 | 2013-04-09 | Janssen Pharmaceutica, Nv | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors |
US8513423B2 (en) | 2010-10-22 | 2013-08-20 | Janssen Pharmaceutica, Nv | Piperidin-4-yl-azetidine diamides as monoacylglycerol lipase inhibitors |
US8575363B2 (en) | 2010-10-22 | 2013-11-05 | Janssen Pharmaceutica N.V. | Amino-pyrrolidine-azetidine diamides as monoacylglycerol lipase inhibitors |
US8637498B2 (en) | 2010-09-27 | 2014-01-28 | Janssen Pharmaceutica, Nv | Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors |
US8691807B2 (en) | 2011-06-20 | 2014-04-08 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US8722693B2 (en) | 2007-06-13 | 2014-05-13 | Incyte Corporation | Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8759333B2 (en) | 2010-09-03 | 2014-06-24 | Janssen Pharmaceutica Nv | Di-azetidinyl diamide as monoacylglycerol lipase inhibitors |
US8933086B2 (en) | 2005-12-13 | 2015-01-13 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-B]pyridines and pyrrolo[2,3-B]pyrimidines as Janus kinase inhibitors |
US8933085B2 (en) | 2010-11-19 | 2015-01-13 | Incyte Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
US8987443B2 (en) | 2013-03-06 | 2015-03-24 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US9034884B2 (en) | 2010-11-19 | 2015-05-19 | Incyte Corporation | Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors |
US9193733B2 (en) | 2012-05-18 | 2015-11-24 | Incyte Holdings Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
US9216984B2 (en) | 2009-05-22 | 2015-12-22 | Incyte Corporation | 3-[4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane—or heptane-nitrile as JAK inhibitors |
US9249145B2 (en) | 2009-09-01 | 2016-02-02 | Incyte Holdings Corporation | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
US9334274B2 (en) | 2009-05-22 | 2016-05-10 | Incyte Holdings Corporation | N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
US9359358B2 (en) | 2011-08-18 | 2016-06-07 | Incyte Holdings Corporation | Cyclohexyl azetidine derivatives as JAK inhibitors |
US9464088B2 (en) | 2010-03-10 | 2016-10-11 | Incyte Holdings Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US9487521B2 (en) | 2011-09-07 | 2016-11-08 | Incyte Holdings Corporation | Processes and intermediates for making a JAK inhibitor |
US9498467B2 (en) | 2014-05-30 | 2016-11-22 | Incyte Corporation | Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1 |
US9655854B2 (en) | 2013-08-07 | 2017-05-23 | Incyte Corporation | Sustained release dosage forms for a JAK1 inhibitor |
WO2018174266A1 (ja) | 2017-03-24 | 2018-09-27 | 湧永製薬株式会社 | 新規ピリドンカルボン酸誘導体又はその塩 |
US10166191B2 (en) | 2012-11-15 | 2019-01-01 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US10596161B2 (en) | 2017-12-08 | 2020-03-24 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
US10758543B2 (en) | 2010-05-21 | 2020-09-01 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US10899736B2 (en) | 2018-01-30 | 2021-01-26 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US11304949B2 (en) | 2018-03-30 | 2022-04-19 | Incyte Corporation | Treatment of hidradenitis suppurativa using JAK inhibitors |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2241097A1 (de) * | 1971-08-21 | 1973-03-08 | Teikoku Hormone Mfg Co Ltd | Neue 3-substituierte-aminoazetidinderivate und verfahren zu ihrer herstellung |
JPS49109369A (de) * | 1973-03-02 | 1974-10-17 | ||
FR2560194A1 (fr) * | 1984-02-27 | 1985-08-30 | Midy Spa | 3-aminoazetidine, ses sels, procede pour leur preparation et intermediaires de synthese |
US4705853A (en) * | 1982-09-30 | 1987-11-10 | A. H. Robins Company, Inc. | Fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof |
EP0277725A2 (de) * | 1987-01-28 | 1988-08-10 | A.H. Robins Company, Incorporated | 4-Aryl-N-[2-(dialkylamino und heterocyclamino)alkyl]-1-piperazincarboxamide und ihre Verwendung als antiallergische Mittel |
EP0394120A1 (de) * | 1989-04-18 | 1990-10-24 | Laboratorios Del Dr. Esteve, S.A. | Substituierte Azetidinylisothiazolopyridonderivate, ihre Herstellung und ihre Anwendung als Arzneimittel |
EP0406112A1 (de) * | 1989-06-29 | 1991-01-02 | Laboratorios Del Dr. Esteve, S.A. | 1-Benzhydrylazetidine, deren Herstellung und Verwendung als Zwischenprodukte zur Herstellung von Verbindungen mit antimikrobieller Wirkung |
EP0438233A2 (de) * | 1990-01-18 | 1991-07-24 | Pfizer Inc. | Oral aktive Renin-Hemmer |
EP0536035A1 (de) * | 1991-10-01 | 1993-04-07 | Laboratoire Roger Bellon | 1,8-Benzonaphthyridinderivate und antimikrobielle Zusammensetzungen |
US5442044A (en) * | 1991-01-04 | 1995-08-15 | Pfizer Inc. | Orally active renin inhibitors |
WO1995031442A1 (en) * | 1994-05-18 | 1995-11-23 | Nisshin Flour Milling Co., Ltd. | Novel pyrimidine derivative |
WO1996005193A1 (en) * | 1994-08-09 | 1996-02-22 | Pfizer Limited | (azetidin-1-ylalkyl)lactams as tachykinin antagonists |
US5849780A (en) * | 1992-01-30 | 1998-12-15 | Sanofi | 1-benzenesulfonyl-1-1,3-dihydroindol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present |
WO1998057640A1 (en) * | 1997-06-18 | 1998-12-23 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
WO1999019297A1 (en) * | 1997-10-15 | 1999-04-22 | Coelacanth Chemical Corporation | Synthesis of azetidine derivatives |
-
1999
- 1999-04-16 WO PCT/US1999/008361 patent/WO2000063168A1/en active Application Filing
- 1999-04-16 AU AU35659/99A patent/AU3565999A/en not_active Abandoned
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2241097A1 (de) * | 1971-08-21 | 1973-03-08 | Teikoku Hormone Mfg Co Ltd | Neue 3-substituierte-aminoazetidinderivate und verfahren zu ihrer herstellung |
JPS49109369A (de) * | 1973-03-02 | 1974-10-17 | ||
US4705853A (en) * | 1982-09-30 | 1987-11-10 | A. H. Robins Company, Inc. | Fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof |
FR2560194A1 (fr) * | 1984-02-27 | 1985-08-30 | Midy Spa | 3-aminoazetidine, ses sels, procede pour leur preparation et intermediaires de synthese |
EP0277725A2 (de) * | 1987-01-28 | 1988-08-10 | A.H. Robins Company, Incorporated | 4-Aryl-N-[2-(dialkylamino und heterocyclamino)alkyl]-1-piperazincarboxamide und ihre Verwendung als antiallergische Mittel |
EP0394120A1 (de) * | 1989-04-18 | 1990-10-24 | Laboratorios Del Dr. Esteve, S.A. | Substituierte Azetidinylisothiazolopyridonderivate, ihre Herstellung und ihre Anwendung als Arzneimittel |
EP0406112A1 (de) * | 1989-06-29 | 1991-01-02 | Laboratorios Del Dr. Esteve, S.A. | 1-Benzhydrylazetidine, deren Herstellung und Verwendung als Zwischenprodukte zur Herstellung von Verbindungen mit antimikrobieller Wirkung |
EP0438233A2 (de) * | 1990-01-18 | 1991-07-24 | Pfizer Inc. | Oral aktive Renin-Hemmer |
US5442044A (en) * | 1991-01-04 | 1995-08-15 | Pfizer Inc. | Orally active renin inhibitors |
EP0536035A1 (de) * | 1991-10-01 | 1993-04-07 | Laboratoire Roger Bellon | 1,8-Benzonaphthyridinderivate und antimikrobielle Zusammensetzungen |
US5849780A (en) * | 1992-01-30 | 1998-12-15 | Sanofi | 1-benzenesulfonyl-1-1,3-dihydroindol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present |
WO1995031442A1 (en) * | 1994-05-18 | 1995-11-23 | Nisshin Flour Milling Co., Ltd. | Novel pyrimidine derivative |
WO1996005193A1 (en) * | 1994-08-09 | 1996-02-22 | Pfizer Limited | (azetidin-1-ylalkyl)lactams as tachykinin antagonists |
WO1998057640A1 (en) * | 1997-06-18 | 1998-12-23 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
WO1999019297A1 (en) * | 1997-10-15 | 1999-04-22 | Coelacanth Chemical Corporation | Synthesis of azetidine derivatives |
Non-Patent Citations (11)
Cited By (86)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8946245B2 (en) | 2005-12-13 | 2015-02-03 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors |
US9662335B2 (en) | 2005-12-13 | 2017-05-30 | Incyte Holdings Corporation | Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as janus kinase inhibitors |
US11331320B2 (en) | 2005-12-13 | 2022-05-17 | Incyte Holdings Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors |
US9974790B2 (en) | 2005-12-13 | 2018-05-22 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as janus kinase inhibitors |
US10639310B2 (en) | 2005-12-13 | 2020-05-05 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors |
US11744832B2 (en) | 2005-12-13 | 2023-09-05 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors |
US8933086B2 (en) | 2005-12-13 | 2015-01-13 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-B]pyridines and pyrrolo[2,3-B]pyrimidines as Janus kinase inhibitors |
US9814722B2 (en) | 2005-12-13 | 2017-11-14 | Incyte Holdings Corporation | Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as janus kinase inhibitors |
US9079912B2 (en) | 2005-12-13 | 2015-07-14 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as Janus kinase inhibitors |
US9206187B2 (en) | 2005-12-13 | 2015-12-08 | Incyte Holdings Corporation | Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as Janus kinase |
US10398699B2 (en) | 2005-12-13 | 2019-09-03 | Incyte Holdings Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors |
US10610530B2 (en) | 2007-06-13 | 2020-04-07 | Incyte Corporation | Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US9376439B2 (en) | 2007-06-13 | 2016-06-28 | Incyte Corporation | Salts of the janus kinase inhibitor (R)-3(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8829013B1 (en) | 2007-06-13 | 2014-09-09 | Incyte Corporation | Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8722693B2 (en) | 2007-06-13 | 2014-05-13 | Incyte Corporation | Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US11213528B2 (en) | 2007-06-13 | 2022-01-04 | Incyte Holdings Corporation | Salts of the janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8822481B1 (en) | 2007-06-13 | 2014-09-02 | Incyte Corporation | Salts of the janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US10016429B2 (en) | 2007-06-13 | 2018-07-10 | Incyte Corporation | Salts of the janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8158616B2 (en) | 2008-03-11 | 2012-04-17 | Incyte Corporation | Azetidine and cyclobutane derivatives as JAK inhibitors |
US8420629B2 (en) | 2008-03-11 | 2013-04-16 | Incyte Corporation | Azetidine and cyclobutane derivatives as JAK inhibitors |
US8722658B2 (en) | 2009-04-22 | 2014-05-13 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8399454B2 (en) | 2009-04-22 | 2013-03-19 | Janssen Pharmaceutica, Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8741887B2 (en) | 2009-04-22 | 2014-06-03 | Janssen Pharmaceutica, Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8450303B2 (en) | 2009-04-22 | 2013-05-28 | Janssen Pharmaceutica, Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8435977B2 (en) | 2009-04-22 | 2013-05-07 | Janssen Pharmaceutica, Nv | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors |
US8691805B2 (en) | 2009-04-22 | 2014-04-08 | Janssen Pharmaceutica, Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8362000B2 (en) | 2009-04-22 | 2013-01-29 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8455476B2 (en) | 2009-04-22 | 2013-06-04 | Janssen Pharmaceutica, Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8426401B2 (en) | 2009-04-22 | 2013-04-23 | Janssen Pharmaceutica, Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8623858B2 (en) | 2009-04-22 | 2014-01-07 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8962607B2 (en) | 2009-04-22 | 2015-02-24 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8415341B2 (en) | 2009-04-22 | 2013-04-09 | Janssen Pharmaceutica, Nv | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors |
US8362001B2 (en) | 2009-04-22 | 2013-01-29 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8445477B2 (en) | 2009-04-22 | 2013-05-21 | Janssen Pharmaceutica, Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8604017B2 (en) | 2009-04-22 | 2013-12-10 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8367653B2 (en) | 2009-04-22 | 2013-02-05 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US8697683B2 (en) | 2009-04-22 | 2014-04-15 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
US9334274B2 (en) | 2009-05-22 | 2016-05-10 | Incyte Holdings Corporation | N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
US9216984B2 (en) | 2009-05-22 | 2015-12-22 | Incyte Corporation | 3-[4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane—or heptane-nitrile as JAK inhibitors |
US9623029B2 (en) | 2009-05-22 | 2017-04-18 | Incyte Holdings Corporation | 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane- or heptane-nitrile as JAK inhibitors |
US9249145B2 (en) | 2009-09-01 | 2016-02-02 | Incyte Holdings Corporation | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
US11285140B2 (en) | 2010-03-10 | 2022-03-29 | Incyte Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US9999619B2 (en) | 2010-03-10 | 2018-06-19 | Incyte Holdings Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US9464088B2 (en) | 2010-03-10 | 2016-10-11 | Incyte Holdings Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US10695337B2 (en) | 2010-03-10 | 2020-06-30 | Incyte Holdings Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US10869870B2 (en) | 2010-05-21 | 2020-12-22 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US11571425B2 (en) | 2010-05-21 | 2023-02-07 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US10758543B2 (en) | 2010-05-21 | 2020-09-01 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US11590136B2 (en) | 2010-05-21 | 2023-02-28 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US11219624B2 (en) | 2010-05-21 | 2022-01-11 | Incyte Holdings Corporation | Topical formulation for a JAK inhibitor |
US8759533B2 (en) | 2010-09-03 | 2014-06-24 | Janssen Pharmaceutica Nv | Di-azetidinyl diamide as monoacylglcerol lipase inhibitors |
US8759333B2 (en) | 2010-09-03 | 2014-06-24 | Janssen Pharmaceutica Nv | Di-azetidinyl diamide as monoacylglycerol lipase inhibitors |
US8637498B2 (en) | 2010-09-27 | 2014-01-28 | Janssen Pharmaceutica, Nv | Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors |
US8575363B2 (en) | 2010-10-22 | 2013-11-05 | Janssen Pharmaceutica N.V. | Amino-pyrrolidine-azetidine diamides as monoacylglycerol lipase inhibitors |
US8513423B2 (en) | 2010-10-22 | 2013-08-20 | Janssen Pharmaceutica, Nv | Piperidin-4-yl-azetidine diamides as monoacylglycerol lipase inhibitors |
US10640506B2 (en) | 2010-11-19 | 2020-05-05 | Incyte Holdings Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidines derivatives as JAK inhibitors |
US8933085B2 (en) | 2010-11-19 | 2015-01-13 | Incyte Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
US9034884B2 (en) | 2010-11-19 | 2015-05-19 | Incyte Corporation | Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors |
US9023840B2 (en) | 2011-06-20 | 2015-05-05 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US10513522B2 (en) | 2011-06-20 | 2019-12-24 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US9611269B2 (en) | 2011-06-20 | 2017-04-04 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US11214573B2 (en) | 2011-06-20 | 2022-01-04 | Incyte Holdings Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US8691807B2 (en) | 2011-06-20 | 2014-04-08 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US9359358B2 (en) | 2011-08-18 | 2016-06-07 | Incyte Holdings Corporation | Cyclohexyl azetidine derivatives as JAK inhibitors |
US9718834B2 (en) | 2011-09-07 | 2017-08-01 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US9487521B2 (en) | 2011-09-07 | 2016-11-08 | Incyte Holdings Corporation | Processes and intermediates for making a JAK inhibitor |
US9193733B2 (en) | 2012-05-18 | 2015-11-24 | Incyte Holdings Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
US11337927B2 (en) | 2012-11-15 | 2022-05-24 | Incyte Holdings Corporation | Sustained-release dosage forms of ruxolitinib |
US11896717B2 (en) | 2012-11-15 | 2024-02-13 | Incyte Holdings Corporation | Sustained-release dosage forms of ruxolitinib |
US10874616B2 (en) | 2012-11-15 | 2020-12-29 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US11576864B2 (en) | 2012-11-15 | 2023-02-14 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US11576865B2 (en) | 2012-11-15 | 2023-02-14 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US10166191B2 (en) | 2012-11-15 | 2019-01-01 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US8987443B2 (en) | 2013-03-06 | 2015-03-24 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US9221845B2 (en) | 2013-03-06 | 2015-12-29 | Incyte Holdings Corporation | Processes and intermediates for making a JAK inhibitor |
US9714233B2 (en) | 2013-03-06 | 2017-07-25 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US11045421B2 (en) | 2013-08-07 | 2021-06-29 | Incyte Corporation | Sustained release dosage forms for a JAK1 inhibitor |
US10561616B2 (en) | 2013-08-07 | 2020-02-18 | Incyte Corporation | Sustained release dosage forms for a JAK1 inhibitor |
US9655854B2 (en) | 2013-08-07 | 2017-05-23 | Incyte Corporation | Sustained release dosage forms for a JAK1 inhibitor |
US9498467B2 (en) | 2014-05-30 | 2016-11-22 | Incyte Corporation | Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1 |
WO2018174266A1 (ja) | 2017-03-24 | 2018-09-27 | 湧永製薬株式会社 | 新規ピリドンカルボン酸誘導体又はその塩 |
US11278541B2 (en) | 2017-12-08 | 2022-03-22 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
US10596161B2 (en) | 2017-12-08 | 2020-03-24 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
US10899736B2 (en) | 2018-01-30 | 2021-01-26 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US11304949B2 (en) | 2018-03-30 | 2022-04-19 | Incyte Corporation | Treatment of hidradenitis suppurativa using JAK inhibitors |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
Also Published As
Publication number | Publication date |
---|---|
AU3565999A (en) | 2000-11-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2000063168A1 (en) | Synthesis of azetidine derivatives | |
US10336727B2 (en) | Histone demethylase inhibitors | |
EP1392316B1 (de) | Benzo[d]azepin-derivative als 5-ht6-rezeptor-antagonisten | |
JP4927733B2 (ja) | 置換ヒダントイン | |
US7439245B2 (en) | Compounds | |
US11655257B2 (en) | MK2 inhibitors, synthesis thereof, and intermediates thereto | |
HU227543B1 (en) | N-[4-(2-piperazin- and 2-piperidin-1-yl-ethyl)-cyclohexyl]-sulfon- and sulfamides, process for their preparation, their use and pharmaceutical compositions containing them | |
EP0900792B1 (de) | Piperidin- und Piperazin Derivate als 5-HT1-Rezeptor-Agonisten | |
JP2010508322A (ja) | システインプロテアーゼ阻害薬としての新規置換ピリジン誘導体 | |
US6867220B2 (en) | Phenoxypropanolamines, method for producing them and pharmaceutical compositions containing them | |
EP1497291B1 (de) | Chinolin- und aza-indolderivate und deren verwendung als 5-ht6 liganden | |
EP1730112B1 (de) | 3-((hetero)arylsulfonyl)-8-[(aminoalkyl)oxy]chinoline als antagonisten des 5-ht6-rezeptors zur behandlung von erkrankungen des zns | |
KR20050010861A (ko) | 중추 신경계 장애의 치료를 위한 5-ht6-수용체조절제로서 1-설폰일-4-아미노알콕시 인돌 유도체 | |
JP2003500488A (ja) | 薬理活性を有するスルホンアミド化合物 | |
WO1999019297A9 (en) | Synthesis of azetidine derivatives | |
JP2007504114A (ja) | 8−(1−ピペラジニル)キノリン誘導体およびcns疾患の治療におけるそれらの使用 | |
KR101386318B1 (ko) | 히스타민 h3 수용체의 길항제로서의 이소퀴놀린 및 벤조[h]이소퀴놀린 유도체, 그의 제조 및 치료 용도 | |
US20050197347A1 (en) | Polymorphic form B2 of ziprasidone base | |
HU225747B1 (en) | New benzenesulphonamide compounds, their preparation thereof and pharmaceutical compositions containing them | |
JP2005534668A (ja) | 新規なアリール−{4−ハロ−4−〔(ヘテロアリールメチルアミノ)メチル〕ピペリジン−1−イル}メタノン誘導体、その製造方法および医薬としてのその使用 | |
WO2006115245A1 (ja) | 4-エチニルイソキノリン誘導体及びこれを含有する医薬 | |
EP1556378B1 (de) | Acylderivate von 5-(2-(4-(1,2 benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2h-indol-2-on mit neuroleptischer wirkung | |
WO2022040111A2 (en) | Solid state forms of erdafitinib salts and processes for preparation of erdafitinib | |
EP4097093B1 (de) | Verfahren zur herstellung von glasdegib und salz davon sowie feste formen von glasdegib-maleat und verfahren zu seiner herstellung | |
WO2022197884A1 (en) | Solid state forms of zandelisib and salts thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
122 | Ep: pct application non-entry in european phase |