EP1246819A1 - Verfahren zur herstellung substituierter benzenderivate - Google Patents

Verfahren zur herstellung substituierter benzenderivate

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Publication number
EP1246819A1
EP1246819A1 EP00987203A EP00987203A EP1246819A1 EP 1246819 A1 EP1246819 A1 EP 1246819A1 EP 00987203 A EP00987203 A EP 00987203A EP 00987203 A EP00987203 A EP 00987203A EP 1246819 A1 EP1246819 A1 EP 1246819A1
Authority
EP
European Patent Office
Prior art keywords
purity
piperazine
alkyl
optionally
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP00987203A
Other languages
English (en)
French (fr)
Inventor
Thomas Ruhland
Mario Rottländer
Kim Andersen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
H Lundbeck AS
Original Assignee
H Lundbeck AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by H Lundbeck AS filed Critical H Lundbeck AS
Publication of EP1246819A1 publication Critical patent/EP1246819A1/de
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the present invention provides a method for the preparation of selectively substituted benzene derivatives by application of solid phase synthesis.
  • the invention provides a novel method for the preparation of substituted benzene derivatives containing two or three groups bound to the benzene ring via nitrogen-, oxygen-, sulphur-, selenium- or carbon-carbon bonds, by application of solid phase chemistry alone or in combination with post cleavage solution phase derivatisation.
  • Parallel synthesis and split and mix synthesis have become an important tool in the search for new compounds in e.g. the pharmaceutical industry. Using these concepts, a large number of compounds are synthesised.
  • Parallel synthesis is a particular form of chemical synthesis where a large number of chemical syntheses are performed separately to obtain a large number of new single discrete compounds, typically for research purposes, for example a large number, often hundreds, of analogues of a particular molecule in order to determine which analogue has the most desirable activities in a specific assay.
  • Split and mix synthesis is another form for organisation of organic synthesis where a large number of compounds are synthesised as mixtures of compounds.
  • Combinatorial chemistry is a form of parallel synthesis and split and mix synthesis where the order and the features of the individual steps are performed using a particular combinatorial approach.
  • Solid phase synthesis alone or in combination with post cleavage derivatisation is a technology to perform parallel and split and mix synthesis.
  • the substrate for the synthesis is linked to a suitable polymer, and when the solid phase synthesis sequence is completed, the final products are cleaved from the polymer.
  • solution phase synthesis steps are performed after cleavage from the polymer to obtain the desired final products.
  • solid phase synthesis is applicable for the synthesis of organic compounds in general within a variety of chemical classes.
  • the present invention provides a method for the preparation of benzene derivatives containing two or three groups selectively bound to the benzene ring via nitrogen-, oxygen-, sulphur-, selenium-, or carbon-carbon bonds in solid phase synthesis;
  • the present invention provides a method for applying the Pearson-type chemistry in 25 the solid phase.
  • This provides a synthesis method wherein the polymer-bound synthesis intermediate after the decomplexation reaction is easily isolated and highly selective nucleophilic mono-substitutions are obtained in the reaction with polymer bound nucleophiles due to the high dilution principle of solid phase synthesis.
  • the invention provides a method for the preparation of substituted benzene derivatives by solid phase synthesis by subjecting the polymer bound intermediate of formula IN, to the complex of formula V resulting in the complex of formula VII, which is subjected to the nucleophiles R 3' H and is subsequently and optionally subjected to R4'H to obtain compounds of formula VIII:
  • R 2' represents an optional substituent
  • X and Y represents hydrogen or halogen, with the proviso that they are not both hydrogen
  • Z is halogen
  • p) represents the solid support
  • MCp + represents
  • R 6" R 10 represent hydrogen or C ⁇ -alkyl
  • M is Fe or Ru
  • substituted benzene derivative VIII is obtained, which is decomplexed, optionally derivatised, cleaved from the support, and optionally further derivatised.
  • the positively charged complexes of formulas V, VII and VIII all contain a counterion such as PF 6 " , BPh 4 " , SO 3 CF 3 " , or another negatively charged ion.
  • libraries of compounds are prepared.
  • the library of compounds is optionally still attached to the solid support.
  • the groups R 1' , R 2' , R 3' and R 4' may be converted to the desired groups R 1 , R 2 , R 3 and R 4 , respectively, in the final product by decomplexation and optional derivatisation followed by cleavage from the support and optional derivatisation. Accordingly, each of the groups R 1' , R 2' , R 3' and R 4' are selected in such a way that they may be converted to the desired substituents R 1 , R 2 , R 3 and R 4 or they may be identical to the substituents R 1 , R 2 , R 3 and R 4 .
  • R 1' , R 3' and R 4' independently represent RSe, RS, RO, or R'RN, or R"R'"CH, wherein R represents a suitable chosen chemical moiety with restrictions not to contain structural elements which can interfere with the reaction sequence applied, R' is hydrogen, or alone or together with R form a suitable chosen chemical moiety with restrictions not to contain structural elements which can interfere with the reaction sequence applied; and R" and R'" represent groups which are suitable for stabilising the carbanion R"R"'CH ⁇ .
  • the nucleophiles must only contain one dominating reactive centre or they must be symmetrical.
  • R 2' represents the group R 2 in the final product prior to optional derivatisation on the solid support or optional post cleavage derivatisation.
  • R 2 in the final product represents optional substituents which can be arbitrarily chosen with restrictions not to contain structural elements which can interfere with the reaction sequence applied.
  • the substituents R 2 and R 4 are optional.
  • the substitution pattern of the final product is dependent on the structure of VI, as only one of X or Y being halogen will preclude the substituent R 4 in the final product.
  • R 2 is selected in the starting material for the complex VII.
  • R 2' represents an optional substituent which does not interfere with the reactions performed.
  • R 2' represents hydrogen or alkyl.
  • R 2' represents hydrogen or methyl.
  • R 3' H represents aryl-OH, alkyl-OH, aryl-SH, alkyl-SH, cycloalkyl-OH, cycloallcyl-SH, alkyl-SeH, aryl-SeH, or R 17 R 18 NH, wherein R 17 and R 18 independently represent alkyls, or R 17 and R ls together form a 4-8 membered ring, which optionally contains further heteroatoms and which is optionally substituted one or more times, and which is optionally partially saturated. All of the aryls and alkyls are optionally substituted.
  • R 3' H represents aryl-OH, aryl-SH, aryl-SeH.
  • the aryl is optionally substituted one or more times with substituents such as alkyl, aryl, alkoxy, alkylsulfanyl, dialkylamino, wherein the dialkyls are optionally forming a 4-8-membered ring, which optionally contains further nitrogen, oxygen or sulphur atoms.
  • R 3' H represents phenol, 5-hydroxy-l,3- benzodioxolane, 5-hydroxy-l,4-benzodioxane, 2-methoxyphenol, 3-dimethylaminophenol, 4-methylphenol, 4-methylsulfanylphenol, 2-methylphenol, 4-methoxyphenol, 2,6- dimethoxyphenol, 3-(4-morpholinyl)phenol, 3,4,5-trimethoxyphenol, 3-diethylaminophenol, selenophenol or thiophenol.
  • R 3' H represents R 17 R 18 NH, wherein R 17 and R 18 independently represent alkyls, or R 17 and R 18 together form a 4-8 membered ring, which optionally contains further heteroatoms and which is optionally substituted one or more times, and which is optionally partially saturated, and even more preferred R 17 R 18 NH represents 4-morpholine, piperazine, 2,6-dimethylmorpholine, 2-hydroxymethylpyrrolidine.
  • R 3' H represents alkyl-X N H, alkoxyalkyl-X N H or cycloalkyl-X N H wherein X N is O, S, Se, NH or NR' wherein R' is a substituent which does not interfere with the reaction sequence.
  • R 3' H represents alkoxyalkylalcohol or cyclohexylalcohol.
  • R 3' H represents ethoxyethanol, or cyclohexylmercaptane.
  • R 3' H are also the preferred embodiments of R 4' H.
  • a further embodiment of the invention is wherein R 3' H and R 4' H are identical and added simultaneously to the compound of formula VII, thereby affording a symmetrically substituted complex:
  • R 3 H and R 4 H together are forming a bi- functional nucleophile which can be attached to the phenyl ring and form a fused ring:
  • HR 3 -R H is represented by the following structures:
  • R s , R h , R j and R k represent hydrogen or optional substituents and s is 1 or 2 and t is 1 or 2; and wherein X N is as defined above; D represents a heteroatom such as O, S, Se, NR D wherein R D represents hydrogen, or a substituent which does not interfere with the applied reaction sequence, or D represents a bond.
  • D represents a heteroatom such as O, S, Se, NR D wherein R D represents hydrogen, or a substituent which does not interfere with the applied reaction sequence, or D represents a bond.
  • one of R ⁇ or R h together with one of R j or R k form a ring structure; or R g and R h or R J and R k together form a ring.
  • the ring is partially saturated and it can optionally be substituted if the substituents do not interfere with the reaction sequence.
  • HR 3 -R 4 H is represented by the structure:
  • X N is as defined above, wherein A represents an aromatic ring system and the groups HX N are attached to A at adjacent positions.
  • HR 3 -R 4 H is ethylenediamine, or 2,3-dihydroxy-naphthalene.
  • R 1 ' represents a diamine of the formula XI
  • R e and R independently represent hydrogen or alkyl or R e and R f together form a ring structure
  • R a , R b R c and R d represent hydrogen or optional substituents and p is 1 or 2 and q is 1 or 2
  • L represents a heteroatom such as O, S, Se, NH, NR L wherein R L represents an optional substituent, which does not interfere with the applied reaction sequence; or L represents a bond.
  • R a or R b together with one of R c or R d form a ring structure, or R a and R b or R c and R d form a ring.
  • R 1' is a cyclic diamine of the formula X
  • X wherein m represents 2, 3 or 4; and R 15 and R 16 represent hydrogen, alkyl or aryl; Especially preferred embodiments are wherein R 1' represents a piperazinyl, or a homopiperazinyl moiety.
  • reaction between the polymer bound nucleophile IV and the complex V and the reaction between the nucleophile R 3 H and the polymer bound complex of formula VII are performed in an aprotic solvent such as dry tetrahydrofuran either by the use of an appropriate base such as potassium carbonate or by deprotonation of the nucleophile, R 3' H, using a base such as sodium hydride prior to the reaction.
  • an aprotic solvent such as dry tetrahydrofuran
  • an appropriate base such as potassium carbonate
  • deprotonation of the nucleophile, R 3' H using a base such as sodium hydride prior to the reaction.
  • the reaction is performed by simultaneous addition of two nucleophiles of formula R 3' H and R 4' H or HR 3 - R 4 H using the reaction conditions described above.
  • R 2' , R 3' and R 4' are as defined above, whereby a compound of the formula A, B, C or D as below is formed:
  • R 1 , R 2 , R 3 and R 4 represent the substituents R 1' , R 2' , R 3' and R 4' , respectively, in the final product;
  • R 3 and R 4 together, or one of R 3 and R 4 together with R 1 or R 2 form a ring- containing chemical moiety fused to the benzene ring with the restrictions not to contain structural elements which can interfere with the reaction sequence applied;
  • the compound of formula VIII is decomplexed according to literature procedures (Pearson et al., J. Org. Chem. 1996, 61, 1297-1305). Decomplexation is carried out by using a suitable donor ligand such as acetonitrile or phenanthroline and visible light. In a preferred embodiment of the invention, 1 , 10-phenanthroline is used in a 3 : 1 mixture of pyridine/water and irradiated with visible light. The polymer support is then filtered and washed until the washing solution is colourless.
  • a suitable donor ligand such as acetonitrile or phenanthroline and visible light.
  • 1 , 10-phenanthroline is used in a 3 : 1 mixture of pyridine/water and irradiated with visible light.
  • the polymer support is then filtered and washed until the washing solution is colourless.
  • Cleavage is carried out by methods known in the art and is dependent upon the choice of polymer support and the synthesis strategy chosen.
  • Derivatisations include reactions known to the skilled person to be performed on the solid phase or in solution phase if the derivatisation follows the cleavage reaction.
  • the cleavage could also finalise the reaction sequence and the compound is then not further derivatised.
  • the choice of strategy is dependent upon the desired structure of the final products.
  • cleavage and derivatisation is performed simultaneously:
  • n 1-12 and Q(OH) 2 is a polymer bound di l.
  • R 5 represents one or more optional substitutents with the proviso that one of the ortho-positions to the hydrazine substituent are unsubstituted; whereby an indole derivative of the formula:
  • XV is formed simultaneously with cleavage from the solid support.
  • the indole formation according to the method above is performed by the reaction of acetals of formula XVI with aryl hydrazines of formula XIV resulting in the corresponding hydrazones, which subsequently are converted into indoles by means of the Fischer indole synthesis.
  • the synthesis sequence is preferably performed as a one-pot procedure using a Lewis acid catalysts, preferably zinc chloride or boron fluoride, or protic acids, preferably sulfuric acid or phosphoric acid, in a suitable solvent such as acetic acid or ethanol at an elevated temperature.
  • R N is represented by the cyclic structure of formula X, and Q is as shown in detail below:
  • n is 1-12, more preferred 2-6 and most preferred 3-5.
  • the cleavage and simultaneous derivatisation are as demonstrated below:
  • R N , R 2 -R 4 are as defined above and R 11 is alkyl, which is optionally further substituted by further substituents, with the proviso that R 11 is not substituted with other nucleophilic centres capable of reacting at the reaction centre.
  • R N , R 2 -R 4 are as defined above.
  • the resulting secondary amines from the cleavage reaction from the polymer support are suitable for further derivatisations by methods obvious to the chemist skilled in the art.
  • the reactions following the cleavage are standard reactions such as alkylation reactions on the primary or secondary amine, optionally in the cyclic amine according to the invention, which is a free amine after cleavage from the solid support.
  • Alkylation reactions are performed by methods known in the art by halo-alkyl-derivatives.
  • the halogen can be replaced by other leaving groups known in the art such as mesylates, triflates, or tosylates.
  • the halo-alkyl- derivative is a halo-alkyl-aryl- derivatives.
  • a suitable solid support could be a Merrifield resin or a solid supported carbamate group such as the Wang resin based carbamate linkier (Zaragoza, Tetrahedron Lett., 1995, 36, 8677-8678).
  • halogen means fluoro, chloro, bromo or iodo.
  • alkyl refers to a branched or unbranched alkyl group having from one to eight carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl- 2- ⁇ ropyl, 2-methyl- 1-propyl etc.
  • alkoxy refers to O-alkyl, wherein alkyl is as defined above.
  • alkylsulfanyl refers to S-alkyl, wherein alkyl is as defined above.
  • aryl refers to a mono- or bicyclic carbocyclic or heterocyclic aromatic group, such as phenyl, indolyl, thienyl, pryimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl, naphtyl, furanyl, quinolinyl etc. Included are also non-aromatic carbocycles fused to the aryl-groups which optionally contain further heteroatoms such as benzodioxane, etc.
  • optional substituent refers to a substituent which does not interfere with the reaction sequence, ie. it does not contain other reactive nucleophile centres or other reactive sites, which will lead to side-reactions and consequently to the formation of side products.
  • the optional substituents are also resistent to the standard procedures applied to the products in the remaining synthesis steps.
  • ( ⁇ -P ⁇ ) represents a polymer containing functional groups suitable for the linking of the solid phase synthesis intermediates, which is stable to the synthesis sequence applied, and liberates the product when the solid phase synthesis is finalised.
  • Such polymers are known in the art and can be properly selected by the person skilled in the art.
  • the polymer support is derivatised to the compound IV:
  • R 1 ' is as defined above, by applying either a synthesis sequence known to the chemist skilled in the art using commercially available starting materials, or the compound IV is commercially available.
  • the starting material of formula V prepared in analogy to literature procedures (Pearson and Gelormani, J. Org. Chem. 1994, 59, 4561-4570), is reacted with the starting polymer support IN at elevated temperature in an aprotic solvent such as dry tetrahydrofuran using an appropriate base such as potassium carbonate.
  • nucleophiles R 3' H and R 4' H are either commercially available, prepared by methods obvious to the chemist skilled in the art or according to literature procedures.
  • Polymer bound acetals of formula XVIII are prepared by reaction of aldehydes of formula Cl-(CH 2 ) n+1 -CHO with commercially available 2,2-dimethyl-l,3-dioxolan-4-yl- methoxymethyl polystyrene in a suitable solvent such as toluene, using p-toluenesulfonic acid as catalyst at elevated temperature.
  • 4-Chlorobutanal, 5-chloropentanal, and 6- chlorohexanal are prepared in analogy to the method described by Normant et al., Tetrahedron 1994, 50 (40), 11665.
  • Method 2 The gradient program was 90%o A to 40% in 4 min, 40%> A to 10% in 2 min, 10% A to 0% A in 1 min, 0% A for 5 min at 2 ml/min. If not otherwise mentioned, method 1 was applied. Purity was determined by integration of the UN trace (254 run). The retention times R ⁇ are expressed in minutes.
  • Preparative LC-MS-purification was performed on the same instrument.
  • the LC conditions 50 X 20 mm YMC ODS-A with 5 ⁇ m particle size
  • the LC conditions were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 22.7 mL/min.
  • Fraction collection was performed by split-flow MS detection. *H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument.
  • the resin was filtered off and washed with tetrahydrofuran (2 X 500 mL), water (2 X 250 mL), tetrahydrofuran (2 X 500 mL), water (2 X 250 mL), methanol (2 X 250 mL), dichloromethane (2 X 250 mL) and methanol (2 X 250 mL). Finally, the resin was washed with dichloromethane (3 X 500 mL) and dried in vacuo (25 °C, 36 h) to yield a dark orange resin (142 g).
  • the resin was filtered off and washed with tetrahydrofuran (2 X 50 mL), tetrahydrofuran water (1:1) (2 X 50 mL), N,N-dimethylformamide (2 X 50 mL), water (2 X 50 mL), methanol (3 X 50 mL), tetrahydrofuran (3 X 50 mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5 cycles). Finally, the resin was washed with dichloromethane (3 X 50 mL) and dried in vacuo (25 °C, 12 h) to yield a dark orange resin.
  • the resin was filtered off and washed with tetrahydrofuran (2 X 50 mL), tetrahydrofuran/water (1:1) (2 X 50 mL), N,N-dimethylformamide (2 X 50 mL), water (2 X 50 mL), methanol (3 X 50 mL), tetrahydrofuran (3 X 50 mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5 cycles). Finally, the resin was washed with dichloromethane (3 X 50 mL) and dried in vacuo (25 °C, 12 h) to yield an orange resin.
  • the resin was filtered off and washed with tetrahydrofuran (2 X 50 mL), tetrahydrofuran/water (1:1) (2 X 50 mL), water (4 X 50 mL), N,N-dimethylformamide (2 X 50 mL), water (2 X 50 mL), methanol (3 X 50 mL), tetrahydrofuran (3 X 50 mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5 cycles). Finally, the resin was washed with dichloromethane (3 X 50 mL) and dried in vacuo (25 °C, 12 h) to yield a dark orange resin. The subsequent procedure for decomplexation, cleavage and working-up followed the protocol described above.
  • the resin was filtered off and washed with tefrahydrofuran (2 X 50 mL), tetrahydrofuran/water (1:1) (2 X 50 mL), N,N-dimethylformamide (2 X 50 mL), water (1 X 50 mL), methanol (3 X 50 mL), tetrahydrofuran (3 X 50 mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5 cycles). Finally, the resin was washed with dichloromethane (3 X 50 mL) and dried in vacuo (25 °C, 12 h) to yield an intensively yellow resin. The subsequent procedure for decomplexation, cleavage and working-up followed the protocol described above.
  • the resin was filtered off and washed with tetrahydrofuran (2 X 500 mL), water (2 X 250 mL), tetrahydrofuran (2 X 500 mL), water (2 X 250 mL), methanol (2 X 250 mL), dichloromethane (2 X 500 mL), methanol (2 X 250 mL). Finally, the resin was washed with dichloromethane (3 X 500 mL) and dried in vacuo (25 °C, 36 h) to yield a dark orange resin (142 g).
  • the resin was filtered off and washed with tetrahydrofuran (2 X 50 mL), tetrahydrofuran/water (1:1) (2 X 50 mL), N,N-dimethylformamide (2 X 50 mL), water (2 X 50 mL), methanol (3 X 50 mL), tetraliydrofuran (3 X 50 mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5 cycles). Finally, the resin was washed with dichloromethane (3 X 50 mL) and dried in vacuo (25 °C, 12 h).
  • the resin (2.5 g, 1.84 mmol) was suspended in a 1:1 mixture of trifluoroacetic acid and dichloromethane (25 mL) and stirred at room temperature for 2 h. The resin was filtered off and washed with methanol (1 X 5 mL) and dichloromethane (1 X 5 mL). The combined liquid phases were collected and the volatile solvents were evaporated in vacuo to yield a dark brown oil (1.5 g)
  • the resin was filtered and washed with tetrahydrofuran (2 X 50 mL), tetrahydrofuran/water (1:1) (2 X 50 mL), N,N-dimethylformamide (2 X 50 mL), water (2 X 50 mL), methanol (3 X 50 mL), tetrahydrofuran (3 X 50 mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5 cycles). Finally, the resin was washed with dichloromethane (3 X 50 mL) and dried in vacuo (25 °C, 12 h).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
EP00987203A 1999-12-30 2000-12-28 Verfahren zur herstellung substituierter benzenderivate Ceased EP1246819A1 (de)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DKPA199901885 1999-12-30
DK188699 1999-12-30
DKPA199901886 1999-12-30
DK188599 1999-12-30
DK200000942 2000-06-16
DKPA200000942 2000-06-16
PCT/DK2000/000737 WO2001049681A1 (en) 1999-12-30 2000-12-28 A method for the preparation of substituted benzene derivatives

Publications (1)

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EP1246819A1 true EP1246819A1 (de) 2002-10-09

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JP (1) JP2003519227A (de)
AU (1) AU2351701A (de)
WO (1) WO2001049681A1 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE261959T1 (de) * 1999-12-30 2004-04-15 Lundbeck & Co As H Substituierte phenyl-piperazin-derivate, deren herstellung und verwendung
UA81749C2 (uk) 2001-10-04 2008-02-11 Х. Луннбек А/С Фенілпіперазинові похідні як інгібітори зворотного захоплення серотоніну
WO2004087156A1 (en) 2003-04-04 2004-10-14 H. Lundbeck A/S 4-(2-phenylsulfanyl-phenyl)-piperidine derivatives as serotonin reuptake inhibitors
JP2007106746A (ja) * 2005-09-13 2007-04-26 Tosoh Corp 新規アリールホモピペラジン類、またはその塩と製造方法
CA2636929A1 (en) * 2005-12-21 2007-07-12 Decode Genetics, Ehf Biaryl nitrogen heterocycle inhibitors of lta4h for treating inflammation
WO2015169180A1 (en) * 2014-05-04 2015-11-12 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods and use thereof

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AU7564296A (en) * 1995-11-17 1997-06-11 Ciba-Geigy Ag Solid phase synthesis of heterocyclic compounds and combinatorial compound library
CA2207088A1 (en) * 1996-06-14 1997-12-14 Eli Lilly And Company Scavenger assisted combinatorial process for preparing libraries of tertiary amine compounds
DE60034571T2 (de) * 1999-06-15 2007-12-27 Aventis Pharmaceuticals Inc. Festphasensynthese von n,n-disubstituierten diazacycloalkylcarboxy-derivaten

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Title
See references of WO0149681A1 *

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