Pyrrole derivatives for treating aids

专利摘要:
The present invention relates to novel pyrrole derivatives, methods for their preparation, pharmaceutical compositions, and the use of such compounds in medicine. In particular, the compounds of formula (I) are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase enzymes involved in viral replication. Thus, the compounds of the present invention can be advantageously used as therapeutic agents in HIV mediated processes. The present invention describes novel compounds of formula (I), hydrolyzable esters or ethers thereof or pharmaceutically acceptable salts thereof: Formula I Where R 1 is alkyl, cycloalkyl, aryl or heterocyclyl, R 2 is alkyl, cycloalkyl, aryl or heterocyclyl, R 3 is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, R 4 is hydrogen, alkyl, carboxyl, C (= 0) R, CONR'R ", cyno or alkenyl, where R is hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl -Oxy-carbonyl, R 'and R "are each independently hydrogen, alkyl or aryl; R 5 is an alkyl, aryl or —ZC (═O) R ′ ″ group where Z is a single bond or —CH═CH— and R ″ ′ is hydrogen or alkyl, X represents S, S (O), S (O) 2 , O or N (alkyl), or XR 2 together represent CH 2 -aryl or CH 2 -heterocyclyl, However, the only one of R 3 and R 4 are hydrogen, alkyl in R 3 is not CF 3.
公开号:KR20030014321A
申请号:KR10-2003-7000138
申请日:2001-04-30
公开日:2003-02-15
发明作者:다이모크브라이언윌리엄；존스필립스티븐；메레트존허버트；파라트마틴존
申请人:에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

Pyrrole derivative for treating AIDS {PYRROLE DERIVATIVES FOR TREATING AIDS}
[2] Acquired immunodeficiency disease (AIDS) is the end result of infection with the unique retrovirus human immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2). Several important points in the viral life cycle have been identified as possible targets for therapeutic intervention. One of these, namely, the inhibition of viral RNA transcription into viral DNA (reverse transcriptase, RT), has provided a number of current therapies used to treat AIDS. Inhibition of reverse transcriptase provided the first form in treating HIV infection with 3'-azido-3'-deoxythymidine (AZT). Since then, several inhibitors have been developed and broadly classified into two classes, nucleoside analogs and non-nucleosides. As the latter example, it has been found that certain benzoxazinones, such as efavirens, are useful for the inhibition of HIV RT. However, the development of viral strains resistant to current RT inhibitors is a permanent problem. Therefore, the development of compounds that are effective against resistant strains is an important goal.
[3] On the other hand, research has been conducted for the purpose of using a pyrrole derivative as a drug.
[4] US Patent No. 3,644,631 describes pyrrole derivatives effective for the treatment of inflammatory syndrome.
[5] US Pat. No. 4,282,242 describes pyrrole derivatives effective for the treatment of lowering blood glucose levels in hyperglycemic mammals.
[1] The present invention relates to novel pyrrole derivatives, methods for their preparation, pharmaceutical compositions and the use of such compounds in the treatment of medicaments, in particular viral diseases. Specifically, the compounds are inhibitors of human immunodeficiency virus reverse transcriptase enzymes involved in viral replication. Thus, the compounds of the present invention can be advantageously used as therapeutic agents for the treatment of diseases mediated by human immunodeficiency virus (HIV).
[6] It is an object of the present invention to provide novel compounds which are potent inhibitors of human immunodeficiency virus reverse transcriptase enzymes involved in viral replication and thus exhibit potent potential as antiviral agents.
[7] This object is achieved by a compound of formula (I), a hydrolyzable ester or ether thereof or a pharmaceutically acceptable salt thereof:
[8]
[9] Where
[10] R ¹ is alkyl, cycloalkyl, aryl or heterocyclyl,
[11] R ² is alkyl, cycloalkyl, aryl or heterocyclyl,
[12] R ³ is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl,
[13] R ⁴ is hydrogen, alkyl, carboxyl, C (= 0) R, CONR'R ", cyano or alkenyl, wherein R is hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl -Oxy-carbonyl, R 'and R "are each independently hydrogen, alkyl or aryl;
[14] R ⁵ is an alkyl, aryl or —ZC (═O) R ″ ′ group wherein Z is a single bond or —CH═CH— and R ″ ′ is hydrogen or alkyl,
[15] X represents S, S (O), S (O) ₂ , O or N (alkyl), or XR ² together represent CH ₂ -aryl or CH ₂ -heterocyclyl,
[16] However, the only one of R ³ and R ⁴ is hydrogen, aryl in R ³ is not CF _3.
[17] The term "alkyl" as used herein, unless specified by the number of carbon atoms, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, pentyl, hexyl, And optionally substituted straight or branched chain hydrocarbon residues containing 1 to 7 carbon atoms, such as heptyl and their different isomers.
[18] Suitable substituents on the alkyl chain include one or more aryl, heterocyclyl; Carboxyl; Alkoxy, cycloalkyl oxy, aryl oxy, heterocyclyl oxy, hydroxy; Amino carbonyl oxy, alkyl amino carbonyl oxy, dialkyl amino carbonyl oxy, aryl amino carbonyl oxy, heterocyclyl amino carbonyl oxy; Alkyl carbonyl, cycloalkyl carbonyl, aryl carbonyl, heterocyclyl carbonyl; Hydroxy carbonyl, alkoxy carbonyl, cycloalkyl oxy carbonyl, aryl oxy carbonyl, heterocyclyl oxy carbonyl; Amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, cycloalkyl amino carbonyl, aryl amino carbonyl, heterocyclyl amino carbonyl; Amino, alkyl amino, dialkyl amino, cycloalkyl amino, aryl amino, heterocyclyl amino; Alkyl carbonyl amino, cycloalkyl carbonyl amino, aryl carbonyl amino, heterocyclyl carbonyl amino; Alkoxy carbonyl amino, cycloalkyl oxy carbonyl amino, aryloxy carbonyl amino, heterocyclyl oxy carbonyl amino; Alkyl amino carbonyl amino, dialkyl amino carbonyl amino, cycloalkyl amino carbonyl amino, aryl amino carbonyl amino, heterocyclyl amino carbonyl amino; Alkyl sulfonyl amino, cycloalkyl sulfonyl amino, aryl sulfonyl amino, heterocyclyl sulfonyl amino; Nitro; Alkyl sulfinyl, cycloalkyl sulfinyl, aryl sulfinyl, heterocyclyl sulfinyl; Alkyl sulfonyl, cycloalkyl sulfonyl, aryl sulfonyl, heterocyclyl sulfonyl; Alkyl thio, cycloalkyl thio, aryl thio, heterocyclyl thio; Or halogen.
[19] When two or more substituents are bonded to an alkyl group, these substituents may be the same or different from each other.
[20] Suitable substituents for the aryl and heterocyclyl alkyl groups are C _1-4 -alkyl (preferably methyl), C _1-4 -alkoxy (preferably methoxy), halogen (preferably chlorine) and tri It may be substituted with one to three substituents, preferably one or two substituents, more preferably one substituent selected from fluoromethyl. Examples of substituted alkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-pyridylmethyl, 2-pyridylethyl, 2-pyridylpropyl, 2-pyridylbutyl, methyl-2- Pyridyl-methyl, methyl-2-pyridyl-ethyl, dimethyl-2-pyridyl-methyl, ethyl-2-pyridyl-methyl, methoxy-2-pyridyl-methyl, methoxy-2-pyridyl- Ethyl, dimethoxy-2-pyridyl-methyl, fluoro-2-pyridyl-methyl, difluoro-2-pyridyl-methyl, chloro-2-pyridyl-methyl, chloro-2-pyridyl-ethyl , Dichloro-2-pyridyl-methyl, dichloro-2-pyridyl-methyl, bromo-2-pyridyl-methyl, dibromo-2-pyridyl-methyl, 3-pyridyl-methyl, 3-pyri Dyl-ethyl, 3-pyridyl-propyl, 3-pyridyl-butyl, methyl-3-pyridyl-methyl, methyl-3-pyridyl-ethyl, dimethyl-3-pyridyl-methyl, ethyl-3-pyri Dil-methyl, methoxy-3-pyridyl-methyl, methoxy-3-pyridyl-ethyl, dimethoxy-3-pyridyl-methyl, fluoro-3-pyridyl-methyl, Fluoro-3-pyridyl-methyl, chloro-3-pyridyl-methyl, chloro-3-pyridyl-ethyl, dichloro-3-pyridyl-methyl, dichloro-3-pyridyl-methyl, bromo-3 -Pyridyl-methyl, dibromo-3-pyridyl-methyl, 4-pyridyl-methyl, 4-pyridyl-ethyl, 4-pyridyl-propyl, 4-pyridyl-butyl, methyl-4-pyri Dyl-methyl, methyl-4-pyridyl-ethyl, dimethyl-4-pyridyl-methyl, ethyl-4-pyridyl-methyl, 2- (trifluoromethyl) -4-pyridyl-1-methyl, 3 -(Trifluoromethyl) -4-pyridyl-1-methyl, 2- (trifluoromethyl) -3-pyridyl-1-methyl, 4- (trifluoromethyl) -3-pyridyl-1 -Methyl, 3- (trifluoromethyl) -2-pyridyl-1-methyl, 4- (trifluoromethyl) -2-pyridyl-1-methyl, methoxy-4-pyridyl-methyl, meth Methoxy-4-pyridyl-ethyl, dimethoxy-4-pyridyl-methyl, fluoro-4-pyridyl-methyl, difluoro-4-pyridyl-methyl, chloro-4-pyridyl-methyl, chloro 4-pyridyl-ethyl, dichloro-4-pyridyl-methyl, dichloro-4-pyri Di-methyl, bromo-4-pyridyl-methyl, dibromo-4-pyridyl-methyl, phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, 2-methylphenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 2-methylphenylethyl, 3-methylphenylethyl, 4-methylphenylethyl, 2,3-dimethylphenylmethyl, 2,4-dimethylphenylmethyl, 2,5-dimethylphenylmethyl, 2,6-dimethylphenyl Methyl, 3,4-dimethylphenylmethyl, 3,5-dimethylphenylmethyl, 3,6-dimethylphenylmethyl, 2-ethylphenylmethyl, 3-ethylphenylmethyl, 4-ethylphenylmethyl, 2,3-diethyl Phenylmethyl, 2,4-diethylphenylmethyl, 2,5-diethylphenylmethyl, 2,6-diethylphenylmethyl, 3,4-diethylphenylmethyl, 3,5-diethylphenylmethyl, 3, 6-diethylphenylmethyl, 2-trifluoromethyl-phenylmethyl, 3-trifluoromethyl-phenylmethyl, 4-trifluoromethyl-phenylmethyl, 2-trifluoromethyl-phenylethyl, 3-tri Fluoromethyl-phenylethyl, 4-trifluoromethyl-phenylethyl, 2,3-di-trifluoromethyl-pe Neylmethyl, 2,4-di-trifluoromethyl-phenylmethyl, 2,5-di-trifluoromethyl-phenylmethyl, 2,6-di-trifluoromethyl-phenylmethyl, 3,4-di -Trifluoromethyl-phenylmethyl, 3,5-di-trifluoromethyl-phenylmethyl, 3,6-di-trifluoromethyl-phenylmethyl, 2-methoxy-phenylmethyl, 3-methoxy- Phenylmethyl, 4-methoxy-phenylmethyl, 2-methoxy-phenylethyl, 3-methoxy-phenylethyl, 4-methoxyphenylethyl, dimethoxy-phenylmethyl, dimethoxy-phenylethyl, 2,4, 6-trimethoxy-phenylmethyl, 2-ethoxy-phenylmethyl, 3-ethoxy-phenylmethyl, 4-ethoxy-phenylmethyl, ethoxy-phenylethyl, diethoxy-phenylmethyl, diethoxy-phenylethyl , 2,4,6-triethoxy-phenylmethyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2,3-difluorophenylmethyl, 2,4-di Fluorophenylmethyl, 2,5-difluorophenylmethyl, 2,6-difluorophenylmethyl, 3,4-difluorophenylmethyl, 3,5-difluorofe Neylmethyl, 3,6-difluorophenylmethyl, 2-fluorophenylethyl, 3-fluorophenylethyl, 4-fluorophenylethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenyl Methyl, 2,3-dichlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,5-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 3,4-dichlorophenylmethyl, 3,5-dichlorophenylmethyl, 3,6-dichlorophenylmethyl, 2-chlorophenylethyl, 3-chlorophenylethyl, 4-chlorophenylethyl, 2-bromophenylmethyl, 3-bromophenylmethyl, 4-bromophenylmethyl, 2,3 -Dibromophenylmethyl, 2,4-dibromophenylmethyl, 2,5-dibromophenylmethyl, 2,6-dibromophenylmethyl, 3,4-dibromophenylmethyl, 3,5 -Dibromophenylmethyl, 3,6-dibromophenylmethyl, 2-bromophenylethyl, 3-bromophenylethyl, 4-bromophenylethyl, 2-phenyl-phenylmethyl, 3-phenyl-phenyl Methyl, 4-phenyl-phenylmethyl, 2-phenoxy-phenylmethyl, 3-phenoxy-phenylmethyl, 4-phenoxy-phenylmethyl, 2-ni Tro-phenylmethyl, 3-nitro-phenylmethyl, 4-nitro-phenylmethyl, 2-amino-phenylmethyl, 3-amino-phenylmethyl, 4-amino-phenylmethyl, 2-dimethylamino-phenylmethyl, 3- Dimethylamino-phenylmethyl, 4-dimethylamino-phenylmethyl, 2-cyano-phenylmethyl, 3-cyano-phenylmethyl, 4-cyano-phenylmethyl, 2-methanesulfonyl-phenylmethyl, 3-methane Sulfonyl-phenylmethyl, 4-methanesulfonyl-phenylmethyl, 2-acid methyl ester-phenylmethyl, 3-acid methyl ester-phenylmethyl, 4-acid methyl ester-phenylmethyl, 2-thiazolyl-methyl, 4 -Thiazolyl-methyl, 5-thiazolyl-methyl, benzothiophenyl-2-methyl, 4-chloro-benzothiophenyl-2-methyl, 5-chloro-benzothiophenyl-2-methyl, 6-chloro-benzo Thiophenyl-2-methyl, 7-chloro-benzothiophenyl-2-methyl, benzothiophenyl-3-methyl, 4-chloro-benzothiophenyl-3-methyl, 5-chloro-benzothiophenyl-3-methyl , 6-chloro-benzothiophenyl-3-methyl, 7-chloro-benzothiophenyl-3-meth Tyl, Quinolinyl-2-methyl, Quinolinyl-3-methyl, Quinolinyl-6-methyl, 4-chloro-quinolinyl-6-methyl, 2- (trifluoromethyl) -quinolinyl -6-methyl, 4-chloro-2- (trifluoromethyl) -quinolinyl-6-methyl, 2-pyrimidyl, 4-pyrimidyl or 2- [1,3,5-triazinyl] .
[21] Alkyl at R ¹ is an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms as defined above, or 1-3 substituents selected from heterocyclyl, aryl and cycloalkyl, preferably Is preferably C _1-7 -alkyl substituted with 1 or 2 substituents, more preferably with 1 substituent. Alkyl at R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2-pyridylmethyl, 2-pyridylethyl, 2-pyridylpropyl, 2 -Pyridylbutyl, 3-pyridylmethyl, 3-pyridylethyl, 3-pyridylpropyl, 3-pyridylbutyl, 4-pyridylmethyl, 4-pyridylethyl, 4-pyridylpropyl, 4-pyridyl Dibutyl, phenylmethyl (benzyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxy-phenylmethyl, 3-methoxy-phenylmethyl, 4-methoxy-phenylmethyl, 2 , 3-dimethoxy-phenylmethyl, 2,4-dimethoxy-phenylmethyl, 2,5-dimethoxy-phenylmethyl, 2,6-dimethoxy-phenylmethyl, 3,4-dimethoxy-phenylmethyl, 3 , 5-dimethoxy-phenylmethyl, 2,4,6-trimethoxy-phenylmethyl, 2-thiazolyl-methyl, 4-thiazolyl-methyl, 5-thiazolyl-methyl, benzothiophenyl-2-methyl , 4-chloro-benzothiophenyl-2-methyl, 5-chloro-benzothiophenyl-2-methyl, 6-chloro-benzothiophenyl-2-methyl, 7- Chloro-benzothiophenyl-2-methyl, benzothiophenyl-3-methyl, 4-chloro-benzothiophenyl-3-methyl, 5-chloro-benzothiophenyl-3-methyl, 6-chloro-benzothiophenyl- 3-methyl, 7-chloro-benzothiophenyl-3-methyl, quinolinyl-2-methyl, quinolinyl-3-methyl, quinolinyl-6-methyl, 4-chloro-quinolinyl-6- Methyl, 2- (trifluoromethyl) -quinolinyl-6-methyl or 4-chloro-2- (trifluoromethyl) -quinolinyl-6-methyl, 2- (trifluoromethyl) -4 -Pyridyl-1-methyl, 3- (trifluoromethyl) -4-pyridyl-1-methyl, 2- (trifluoromethyl) -3-pyridyl-1-methyl, 4- (trifluoro Methyl) -3-pyridyl-1-methyl, 3- (trifluoromethyl) -2-pyridyl-1-methyl, 4- (trifluoromethyl) -2-pyridyl-1-methyl or N- Benzyl amidomethyl is more preferred. More preferred alkyl substituents for R ¹ are methyl, ethyl, isopropyl, cyclohexylmethyl, phenylmethyl or pyridylmethyl. Most preferred alkyl substituents for R ¹ are 4-pyridylmethyl.
[22] Alkyl at R ² is an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms as defined above, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, s -Butyl, isobutyl or t-butyl are preferred. More preferred alkyl substituents for R ² are methyl or n-propyl. Most preferred alkyl in R ² is methyl.
[23] Alkyl at R ³ is 1 to 3 substituents, preferably 1 or 2 substituents selected from unsubstituted straight or branched chain hydrocarbon residues containing 1 to 7 carbon atoms as defined above, or heterocyclyl Preference is given to substituents, more preferably C _1-7 -alkyl, substituted by one substituent. More preferred alkyl at R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2-pyridylmethyl, 3-pyridylmethyl, 3-pyridylethyl , 4-pyridylmethyl or 4-pyridylethyl. More preferred alkyl substituents for R ³ are isopropyl, n-propyl or pyridylmethyl. Most preferred alkyl in R ³ is isopropyl. Alkyl at R ³ is not CF ₃ .
[24] Alkyl at R ⁴ is an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms as defined above, or hydroxy, amino, C _1-4 -alkoxy (preferably C _1-2 -Alkoxy), phenyl, methyl-oxy-carbonyl, ethyl-oxy-carbonyl, azido, 2-pyridyl-carbonyl-amino, 3-pyridyl-carbonyl-amino, 4-pyridyl-carbonyl -Amino, (phenoxy) -carbonyl-amino, (methoxy) -carbonyl-amino, (di-methyl-amino) -carbonyl-amino, (phenyl-amino) -carbonyl-amino, (amino) -Carbonyl-amino, (phenyl) -carbonyl-amino, (methyl) -carbonyl-amino, methyl-carbonyl-amino-methyl-carbonyl-amino, (t-butyl) -carbonyl-amino-methyl -Carbonyl-amino, methyl-sulfonyl-amino, phenyl-sulfonyl-amino, p-toluyl-sulfonyl-amino, (N1-acetyl-Ot-butyl-N2-yl) -L-serinamide, ( N1-acetyl-N2-yl) -L-serineamide and [N1- (t-butoxycarbonyl) -Ot-butyl-N 2-1] 1 to 3 substituents selected from -L- serine amide, preferably one or two substituents, more preferably substituted with 1 substituent C _1-7 alkyl (preferably, C _{1 -2} -alkyl) is preferred. More preferred substituents on C _1-7 -alkyl (preferably C _1-2 -alkyl) are hydroxy, amino, C _1-2 -alkoxy, 2-pyridyl-carbonyl-amino, 3-pyridyl- Carbonyl-amino, 4-pyridyl-carbonyl-amino, (phenoxy) -carbonyl-amino, (methoxy) -carbonyl-amino, (di-methyl-amino) -carbonyl-amino, (phenyl -Amino) -carbonyl-amino, (amino) -carbonyl-amino, (phenyl) -carbonyl-amino, (methyl) -carbonyl-amino, methyl-carbonyl-amino-methyl-carbonyl-amino, (t-butyl) -carbonyl-amino-methyl-carbonyl-amino, (N1-acetyl-Ot-butyl-N2-yl) -L-serineamide, (N1-acetyl-N2-yl) -L-serine Amide and [N1- (t-butoxycarbonyl) -Ot-butyl-N2-yl] -L-serineamide. More preferred substituents on C _1-7 -alkyl (preferably C _1-2 -alkyl) are hydroxy, 2-pyridyl-carbonyl-amino, 3-pyridyl-carbonyl-amino, 4-pyridyl -Carbonyl-amino, (phenoxy) -carbonyl-amino, (methoxy) -carbonyl-amino, (di-methyl-amino) -carbonyl-amino, (phenyl-amino) -carbonyl-amino , (Amino) -carbonyl-amino, (phenyl) -carbonyl-amino, (methyl) -carbonyl-amino, methyl-carbonyl-amino-methyl-carbonyl-amino, (t-butyl) -carbonyl -Amino-methyl-carbonyl-amino, (N1-acetyl-Ot-butyl-N2-yl) -L-serinamide, (N1-acetyl-N2-yl) -L-serinamide and [N1- (t- Butoxycarbonyl) -Ot-butyl-N2-yl] -L-serineamide. When two or more substituents are bonded to an alkyl group, these substituents may be the same or different from each other. Alkyl at R ⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, 1,2-ethanediol, 1,2-propanediol, amino-methyl, amino-ethyl, methoxy-methyl, methoxy-ethyl, phenyl-methanol, (methyl-oxy-carbonyl)-(hydroxy-methyl ), (Ethyl-oxy-carbonyl)-(hydroxy-methyl), azido-methyl, azido-ethyl, 2-pyridyl-carbonyl-amino-methyl, 3-pyridyl-carbonyl-amino- Methyl, 4-pyridyl-carbonyl-amino-methyl, (amino-methyl) -carbonyl-amino-methyl, (phenoxy) -carbonyl-amino-methyl, (methoxy) -carbonyl-amino-methyl , (Di-methyl-amino) -carbonyl-amino-methyl, (phenyl-amino) -carbonyl-amino-methyl, (amino) -carbonyl-amino-methyl, (phenyl) -carbonyl-amino-methyl , (Methyl) -carbonyl-amino-methyl, methyl-carbonyl-amino-methyl-carbonyl-amino-methyl, (t-butyl) -carbonyl- Mino-methyl-carbonyl-amino-methyl, (N1-acetyl-Ot-butyl-N2-ylmethyl) -L-serineamide, (N1-acetyl-N2-yl-methyl) -L-serineamide, [N1 -(t-butoxycarbonyl) -Ot-butyl-N2-yl-methyl] -L-serineamide, methyl-sulfonyl-amino-methyl, phenyl-sulfonyl-amino-methyl or p-toluyl-sul Phonyl-amino-methyl is more preferred. The preferred alkyl in R ⁴ is unsubstituted C _1-7-alkyl (preferably C _1-4 - alkyl), or as a substituent of hydroxy, C _1-7 substituted with amino or methoxy - are the alkyl (preferably C _1-4 -alkyl, more preferably C _1-2 -alkyl). More preferred alkyl in R ⁴ is methyl or ethyl substituted with a hydroxy or methoxy group, or (methyl) -carbonyl-amino-methyl. More preferred alkyl for R ⁴ is methyl or ethyl substituted with a hydroxy or methoxy group. More preferred alkyl in R ⁴ is methyl substituted with a hydroxy group, or (methyl) -carbonyl-amino-methyl. Most preferred alkyl in R ⁴ is methyl substituted with a hydroxy group.
[25] Alkyl at R ⁵ is an unsubstituted straight or branched chain hydrocarbon moiety containing 1 to 7 carbon atoms as defined above, or hydroxy, C _1-4 -alkoxy (preferably methoxy or ethoxy ), C _1-7 -alkyl substituted with 1 to 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, selected from methyl-carbonyl-oxy and amino-carbonyl-oxy Preference is given to C _1-4 -alkyl, more preferably C _1-2 -alkyl). Alkyl at R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, More preferred are 1,2-ethanediol, 1,2-propanediol, methoxy-methyl, ethoxy-methyl, (methyl-carbonyl-oxy) -methyl, (amino-carbonyl-oxy) -methyl. More preferred alkyl at R ⁵ is methyl, ethyl, n-propyl, isopropyl, or C _1-2 − substituted with _1-3 substituents selected from hydroxy, methyl-carbonyl-oxy and amino-carbonyl-oxy. Alkyl. More preferred alkyl at R ⁵ is methyl, ethyl, (amino-carbonyl-oxy) -methyl, or C _1-2 -alkyl substituted with a hydroxy group. Another preferred alkyl at R ⁵ is methyl or (amino-carbonyl-oxy) -methyl and the most preferred alkyl at R ⁵ is methyl.
[26] In another preferred embodiment of the invention, alkyl at R ⁵ is unsubstituted alkyl or substituted alkyl having a hydroxy group as a substituent, and in more preferred embodiments, alkyl at R ⁵ is methyl or optionally substituted with a hydroxy group In the most preferred embodiment, alkyl in R ⁵ is methyl.
[27] Alkyl in R, R ', R "and R"' is preferably an unsubstituted straight or branched chain hydrocarbon moiety containing 1 to 7 carbon atoms as defined above, methyl, ethyl, n-propyl, More preferred are isopropyl, n-butyl, s-butyl, isobutyl or t-butyl.
[28] Alkyl for N (alkyl) is preferably an unsubstituted straight or branched chain hydrocarbon moiety containing 1 to 7 carbon atoms, with methyl being most preferred.
[29] As used herein, the term "cycloalkyl", unless specified by the number of carbon atoms, is an optionally substituted cycloalkyl group containing 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cycloheptyl or cyclooctyl. The term "cycloalkyl" preferably denotes a cycloalkyl group containing 3 to 6 carbon atoms.
[30] Suitable substituents for cycloalkyl may be selected from the substituents mentioned for alkyl, but oxo groups (═O) may also be added to the substituents selected.
[31] Cycloalkyl at R ¹ and R ² is as defined above.
[32] Cycloalkyl at R ³ represents an optionally substituted cycloalkyl group containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Most preferred cycloalkyl in R ³ represents a cyclopropyl group.
[33] As used herein, the term "alkoxy" means that, unless specified by the number of carbon atoms, the "alkyl" moiety is methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t -Straight or branched chain alkyl-oxy groups as defined above, such as -butyloxy, pentyloxy, hexyloxy, heptyloxy and their different isomers. More preferred alkoxy groups within the scope of the present invention are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or t-butyloxy.
[34] Alkoxy at R is as defined above.
[35] The term "alkenyl" as used herein, unless specified by the number of carbon atoms, is unsubstituted having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms and having at least one olefinic double bond Or substituted hydrocarbon chain radicals and their different isomers. Examples are vinyl or allyl.
[36] Alkenyl at R ⁴ is as defined above.
[37] As used herein for R ⁴ , the term “C (═O) R” refers to a hydrogen atom bonded to a keto functional group —C (═O) —, a C _1-7 -alkyl group (preferably with respect to alkyl substituent R C _1-4 -alkyl), alkoxy (preferably C _1-4 -alkoxy), trifluoromethyl, methyl-oxy-carbonyl or ethyl-oxy-carbonyl as defined above. Preferred examples include aldehyde groups (C (═O) H), methyl-carbonyl, ethyl-carbonyl, t-butoxy-carbonyl, trifluoromethyl-carbonyl, methyl-oxy-carbonyl or ethyl-oxy There is carbonyl.
[38] As used herein for R ⁴ , the term “CONR'R” is each independently hydrogen, C _1-7 -alkyl (preferably C _1-4 -alkyl) or a substitution bonded to an amino-carbonyl functional group. Aryl (preferably phenyl) Preferred examples are amino-carbonyl (CONH ₂ ), (methyl-amino) -carbonyl, (dimethyl-amino) -carbonyl, (phenyl-amino) -carbonyl Or (2,4,6-trimethoxy-methyl) -amino-carbonyl.
[39] R ⁵ a "-ZC (= O) R" as used herein for "" (wherein, Z is a single bond or -CH = CH-, R "'is is hydrogen or alkyl (preferably, C _1-4 -Alkyl) is an aldehyde group (C (= 0) H), methyl-carbonyl, ethyl-carbonyl, aldehyde-ethylene ((-CH = CH) C (= 0) H), (methyl- Carbonyl) -ethylene ((-CH = CH) C (= 0) CH ₃ ) or (ethyl-carbonyl) -ethylene ((-CH = CH) C (= 0) C ₂ H ₅ ). The ethylene group of the present invention may have a (E) or (Z) configuration. All isomeric forms of these compounds are included in the present invention.
[40] As used herein, the term "aryl" refers to optionally substituted phenyl and naphthyl, both of which are optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycles or carbocycles (e.g. Optionally benz-conjugated to cyclohexyl or cyclopentyl).
[41] Suitable substituents for aryl may be selected from the substituents mentioned for alkyl, but the substituents selected may include C _1-4 -alkyl, trifluoromethyl, trifluoroethoxy, C _2-4 -alkenyl, 1,2 Propanediol, cyano and hydroxy-methyl may also be added.
[42] When two or more substituents are bonded to an aryl group, these substituents may be the same or different from each other.
[43] Aryl in R ¹ is preferably phenyl unsubstituted or substituted with a suitable substituent selected from unsubstituted straight or branched chain alkyl containing 1 to 5 halogens, nitro and 1 to 4 carbon atoms.
[44] Aryl at R ² is C _1-7 -alkyl (preferably C _1-4 -alkyl), trifluoromethyl, C _1-4 -alkoxy (preferably C _1-2 -alkoxy), trifluoro Methoxy, C _2-4 -alkenyl, 1,2-propanediol, fluorine, chlorine, bromine, iodine, nitro, cyano, phenyl, hydroxy-methyl, 4-pyridyl, 3-pyridyl and 2- 1 to 5 substituents selected from pyridyl, preferably 1 to 4 substituents, more preferably 1 to 3 substituents (preferably C _1-7 -alkyl (preferably C _1-4 -alkyl) , Phenyl unsubstituted or substituted with 1 to 3 substituents selected from halogen and nitro, more preferably 1 to 3 substituents selected from halogen, most preferably 1 to 3 substituents selected from chlorine), or Naphthyl, preferably phenyl, is preferred. When two or more substituents are bonded to an aryl group, these substituents may be the same or different from one another. Examples of substituted aryl groups include 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2-ethyl -Phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,6-dimethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl, 2,3,4-trimethylphenyl, 2,4,5-trimethylphenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2,3-dimethoxy-phenyl, 2,4-dimethoxy-phenyl, 2,5-dimethoxy-phenyl, 2, 6-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethoxy-phenyl, 3,6-dimethoxy-phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluoro Phenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5 -Difluorophenyl, 3,6-difluorophenyl, 2 -Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3 , 5-dichlorophenyl, 3,6-dichlorophenyl, 2,4,6-trichlorophenyl, 3,4,5-trichlorophenyl, 2,3,4-trichlorophenyl, 2,4,5-trichloro Rophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl, 2,5-dibromophenyl, 2, 6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 3,6-dibromophenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl- Phenyl, 4-trifluoromethyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 2,3-di-cyano-phenyl, 2,4-di-cya No-phenyl, 2,5-di-cyano-phenyl, 2,6-di-cyano-phenyl, 3,4-di-cyano-phenyl, 3,5-di-cyano-phenyl, 3, 6-di-cyano-phenyl, 2-nitro-phenyl, 3-nitro-phenyl, 4-nitro-phenyl, 2- (trifluoromethok ) Phenyl, 3- (trifluoromethoxy) phenyl, 4- (trifluoromethoxy) phenyl, 2- (phenyl) phenyl, 3- (phenyl) phenyl, 4- (phenyl) phenyl, 2- (hydroxymethyl ) Phenyl, 3- (hydroxymethyl) phenyl, 4- (hydroxymethyl) phenyl, 2- (2-pyridyl) phenyl, 3- (2-pyridyl) phenyl, 4- (2-pyridyl) phenyl , 2- (3-pyridyl) phenyl, 3- (3-pyridyl) phenyl, 4- (3-pyridyl) phenyl, 2- (4-pyridyl) phenyl, 3- (4-pyridyl) phenyl , 4- (4-pyridyl) phenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-methyl-phenyl, 3-chloro-5-bromo-phenyl, 3-chloro-5-propyl- Phenyl, 3-chloro-5-methyl-phenyl, 3-chloro-5-ethyl-phenyl, 3-chloro-5-vinyl-phenyl, 3-chloro-5-allyl-phenyl, 3-chloro-5-phenyl- Phenyl, 3-chloro-5- (hydroxymethyl) -phenyl, 3-chloro-5-cyano-phenyl, 3-chloro-5- (1,2-propanediol) -phenyl, 2-naphthyl or 3 Cyano-5-methyl. A preferred example for aryl in R ² is 3,5-dichlorophenyl.
[45] Aryl in R ³ is C _1-4 -alkyl (preferably C _1-2 -alkyl), C _1-4 -alkoxy (preferably C _1-2 -alkoxy), fluorine, chlorine, bromine, iodine And 1 to 5 substituents selected from phenyl, preferably 1 to 4 substituents, more preferably 1 to 3 substituents (preferably C _1-4 -alkyl (preferably C _1-2 -alkyl) , 1 to 3 substituents selected from C _1-4 -alkoxy (preferably C _1-2 -alkoxy) and halogen, more preferably C _1-4 -alkyl (preferably C _1-2 -alkyl ) And phenyl unsubstituted with a suitable substituent selected from C _1-4 -alkoxy (preferably _1-3 substituents selected from C _1-2 -alkoxy)). Examples of substituted aryl groups include 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-chlorophenyl , 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5- Dichlorophenyl or 3,6-dichlorophenyl. Most preferred aryl in R ³ is phenyl.
[46] Aryl in R ⁵ , R 'and R "is as defined above, with phenyl being preferred.
[47] The term "heterocyclyl" as used herein contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be conjugated to an optionally substituted saturated, partially unsaturated or aromatic monocyclic carbocycle or heterocycle. To an optionally substituted saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocycle.
[48] Examples of suitable heterocycles include oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-dioxolanyl, dihydropyranyl, thienyl, pyrazinyl, isothiazolyl, isoquinolinyl, indolyl, Indazolyl, quinolinyl, dihydrooxazolyl, pyrimidinyl, benzofuranyl, tetrazolyl, pyrrolidinyl, pyrrolidinyl, (N-oxide) -pyridinyl, pyrrolyl, triazolyl (e.g. , 1,2,4-triazolyl), pyrazolyl, benzotriazolyl, piperidinyl, morpholinyl, thiazolyl, pyridyl, dihydrothiazolyl, imidazolidinyl, pyrazolinyl, benzothienyl, Piperazinyl, imidazolyl, thiadiazolyl (eg 1,2,3-thiadiazolyl) and benzothiazolyl. Most preferred is pyridyl.
[49] Heterocyclyl in R ¹ , R ² and R ³ is a pyridyl unsubstituted or substituted with a suitable substituent selected from unsubstituted straight or branched chain alkyl containing 1 to 5 halogens, nitro and 1 to 4 carbon atoms Dill is preferred.
[50] Suitable substituents for heterocyclyl may be selected from the substituents mentioned for alkyl, but oxo groups (═O) may also be added to the substituents selected.
[51] As used herein, the term "C (= 0) R" is selected from hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl and ethyl-oxy-carbonyl (preferably hydrogen or alkyl) The carbonyl group to which the substituent is bonded is shown. Examples of suitable substituents for the carbonyl group are hydrogen, t-butoxy, trifluoromethyl, methyl-oxy-carbonyl and ethyl-oxy-carbonyl. In other embodiments of the invention, preferred acyl groups are those wherein R is hydrogen or an unsubstituted straight or branched chain hydrocarbon moiety containing 1 to 7 carbon atoms.
[52] As used herein, the term "CONR'R""means that R 'and R" are independently of each other hydrogen, alkyl or aryl (preferably hydrogen or C _1-7 -alkyl (preferably C _1-4- ) Alkyl)). Examples of suitable substituents (R ′ and / or R ″) for the amide group are hydrogen, C _1-4 -alkyl (preferably methyl), phenyl and 2,4,6-trimethoxy-benzyl.
[53] Within the scope of the present invention, the term "X" denotes S, S (O), S (O) ₂ , O or N (alkyl), or XR ² together represent CH ₂ -aryl (preferably CH ₂ -phenyl) or CH ₂ -heterocyclyl (preferably CH _2- (4) -pyridyl, CH _2- (3) -pyridyl, CH _2- (2) -pyridyl) Preferably S, S (O), S (O) ₂ , O or N (alkyl), most preferably the term "X" stands for S.
[54] The term "halogen" refers to fluorine, chlorine, bromine and iodine. Most preferred halogen is chlorine.
[55] Any functional group (i.e., reactive group) present in the side chain can be protected, for example, "Protective Groups in Organic Synthesis", 2 ^nd Ed., TW Greene and PGM Wuts, John Wiley & Sons, New York, NY, 1991, is a group known as subtraction thereof. For example, the amino group may be protected by t-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z).
[56] The compounds of the present invention may contain one or more asymmetric carbon atoms and therefore may exist as racemic compounds, mixtures of racemic compounds, single enantiomers, diastereomeric mixtures and individual diastereomers. In addition, when the compound of the present invention contains an olefinic double bond, it may have an (E) or (Z) configuration. In addition, each chiral center may be in an R or S configuration. All such isomeric forms of these compounds are included in the present invention.
[57] Acidic compounds of formula (I) include bases and organic bases (eg, alkali metal hydroxides (eg, sodium and potassium hydroxides), alkaline earth metal hydroxides (eg, calcium hydroxide, barium hydroxide and magnesium hydroxide), and the like. N-ethyl piperidine, dibenzylamine, etc.) to form pharmaceutically acceptable salts. Compounds of formula (I) that are basic include inorganic acids (e.g., hydrobromic acids such as hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g. acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, Together with salicylic acid, citric acid, methanesulfonic acid, p-toluene sulfonic acid, etc.) to form pharmaceutically acceptable salts. Formation and separation of such salts can be carried out according to methods known in the art.
[58] A preferred embodiment of the present invention is a compound of Formula 1,
[59] And R ¹ is alkyl, preferably R ¹ is C _1-7 - alkyl or cycloalkyl, C _1-7 substituted with one to three substituents selected from aryl, and heterocyclyl-alkyl, more preferably R ¹ is methyl, ethyl, isopropyl, cyclohexylmethyl, phenylmethyl and pyridylmethyl, most preferably R ¹ is 4-pyridylmethyl,
[60] R is a ^divalent alkyl or aryl, preferably R ² is C _1-7 - alkyl, phenyl, or C _1-7 - phenyl substituted with 1 to 5 substituents selected from alkyl, halogen and nitro, more preferably Is R ² is methyl, n-propyl or phenyl substituted with 1 to 5 chlorine atoms, most preferably R ² is methyl or 3,5-dichlorophenyl,
[61] R ³ is alkyl, cycloalkyl or aryl, preferably R ³ is C _1-7 -alkyl, C _1-7 -alkyl, phenyl, or C _1-4 -alkyl, substituted with 1 to 3 heterocyclyls, Phenyl substituted with 1 to 5 substituents selected from C _1-4 -alkoxy and halogen, more preferably R ³ is isopropyl, n-propyl or pyridylmethyl, most preferably R ³ is isopropyl ,
[62] R ⁴ is hydrogen, alkyl, carboxyl, C (= 0) R, CONR'R ", cyano or alkenyl, where R is hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl -Oxy-carbonyl and R 'and R "are independently of each other hydrogen, alkyl or aryl), preferably R ⁴ is hydrogen, C _1-7 -alkyl, or hydroxy, amino, C _1-4 -Alkoxy, phenyl, methyl-oxy-carbonyl, ethyl-oxy-carbonyl, azido, 2-pyridyl-carbonyl-amino, 3-pyridyl-carbonyl-amino, 4-pyridyl-carbonyl- Amino, (phenoxy) -carbonyl-amino, (methoxy) -carbonyl-amino, (di-methyl-amino) -carbonyl-amino, (phenyl-amino) -carbonyl-amino, (amino)- Carbonyl-amino, (phenyl) -carbonyl-amino, (methyl) -carbonyl-amino, methyl-carbonyl-amino-methyl-carbonyl-amino, (t-butyl) -carbonyl-amino-methyl- Carbonyl-amino, methyl-sulfonyl-amino, phenyl-sulfonyl-amino, p-toluyl-sulfonyl-ami , (N1-acetyl-Ot-butyl-N2-yl) -L-serinamide, (N1-acetyl-N2-yl) -L-serinamide and [N1- (t-butoxycarbonyl) -Ot-butyl -N2-yl] -L-serineamide is C _1-7 -alkyl substituted with 1 to 3 substituents, more preferably R ⁴ is hydrogen or hydroxy, amino, C _1-2 -alkoxy, 2-pyridyl-carbonyl-amino, 3-pyridyl-carbonyl-amino, 4-pyridyl-carbonyl-amino, (phenoxy) -carbonyl-amino, (methoxy) -carbonyl-amino, (Di-methyl-amino) -carbonyl-amino, (phenyl-amino) -carbonyl-amino, (amino) -carbonyl-amino, (phenyl) -carbonyl-amino, (methyl) -carbonyl-amino , Methyl-carbonyl-amino-methyl-carbonyl-amino, (t-butyl) -carbonyl-amino-methyl-carbonyl-amino, (N1-acetyl-Ot-butyl-N2-yl) -L-serine 1 to 3 substituents selected from amide, (N1-acetyl-N2-yl) -L-serinamide and [N1- (t-butoxycarbonyl) -Ot-butyl-N2-yl] -L-serinamide Hwandoen C _1-2 - alkyl, most preferably R ⁴ is hydroxy, 2-pyridyl-carbonyl-amino, 3-pyridyl-carbonyl-amino, 4-pyridyl-carbonyl-amino, ( Phenoxy) -carbonyl-amino, (methoxy) -carbonyl-amino, (di-methyl-amino) -carbonyl-amino, (phenyl-amino) -carbonyl-amino, (amino) -carbonyl- Amino, (phenyl) -carbonyl-amino, (methyl) -carbonyl-amino, methyl-carbonyl-amino-methyl-carbonyl-amino, (t-butyl) -carbonyl-amino-methyl-carbonyl- Amino, (N1-acetyl-Ot-butyl-N2-yl) -L-serinamide, (N1-acetyl-N2-yl) -L-serinamide and [N1- (t-butoxycarbonyl) -Ot- C _1-2 -alkyl substituted with one or two substituents selected from butyl-N2-yl] -L-serinamide,
[63] R ⁵ is an alkyl, aryl or —ZC (═O) R ″ ′ group wherein Z is a single bond or —CH═CH— and R ″ ′ is hydrogen or alkyl, preferably R ⁵ is C _1-7 -alkyl, phenyl, or C _1-7 -alkyl substituted with 1 to 3 substituents selected from hydroxy, C _1-4 -alkoxy, methyl-carbonyl-oxy and amino-carbonyl-oxy, More preferably R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, or hydroxy, C _1-4 -alkoxy, methyl-carbonyl-oxy And C _1-2 -alkyl substituted with 1 to 3 substituents selected from amino-carbonyl-oxy, most preferably R ⁵ is methyl, ethyl, n-propyl, isopropyl, or hydroxy, methyl-carbo C _1-2 -alkyl substituted with 1 to 3 substituents selected from nil-oxy and amino-carbonyl-oxy,
[64] X is represented by S, O or N (alkyl) or, XR ² are together CH ₂ - aryl or CH ₂ - represents a heterocycle (provided that in R ³ the alkyl is not CF _3), is preferably X S To represent them.
[65] Another preferred embodiment of the present invention is a compound of Formula 1, a hydrolyzable ester or ether thereof or a pharmaceutically acceptable salt thereof,
[66] Formula I
[67]
[68] R ¹ is alkyl, cycloalkyl, aryl or heterocyclyl, preferably R ¹ is alkyl, more preferably R ¹ is alkyl substituted with heterocyclyl or aryl, unsubstituted C _1-7 -alkyl Or alkyl substituted with cycloalkyl, most preferably R ¹ is pyridylmethyl, phenylmethyl, methyl, ethyl, isopropyl or cyclohexylmethyl,
[69] R ² is alkyl, cycloalkyl, aryl or heterocyclyl, preferably R ² is alkyl or aryl, more preferably R ² is unsubstituted alkyl, unsubstituted phenyl, or 1 to 5 substituents Substituted phenyl with halogen, nitro or unsubstituted C _1-7 -alkyl, most preferably R ² is methyl, n-propyl or chlorinated phenyl,
[70] R ³ is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, preferably R ³ is alkyl or aryl, more preferably R ³ is unsubstituted alkyl, substituted alkyl with heterocyclyl as substituent , Unsubstituted phenyl, or substituted phenyl having 1 to 5 halogen, methoxy or unsubstituted C _1-7 -alkyl as substituents, most preferably R ³ is isopropyl, n-propyl or pyridyl Methyl,
[71] R ⁴ is hydrogen, alkyl, carboxyl, C (= 0) R or CONR ₂ , where R is hydrogen or alkyl, preferably R ⁴ is hydrogen, alkyl, carboxyl, C (= 0) R or CONR ₂ , more preferably R ⁴ is hydrogen, unsubstituted alkyl, substituted alkyl having hydroxy, amino or methoxy as substituent, carboxyl, C (═O) R or CONR ₂ , most preferably R Substituted methyl or ethyl, carboxyl, C (= 0) R or CONR ₂ with ^tetravalent substituents having hydroxy or methoxy,
[72] R ⁵ is hydrogen or alkyl, preferably R ⁵ is hydrogen, unsubstituted alkyl or substituted alkyl with hydroxy as substituent, more preferably R ⁵ is methyl or ethyl optionally substituted with hydroxy group ,
[73] X represents S, S (O), S (O) ₂ , O or N (alkyl), or XR ² together represent CH ₂ -aryl or CH ₂ -heterocyclyl, provided that R ³ , R ⁴ And only one of R ⁵ is hydrogen and alkyl in R ³ is not CF ₃ ), preferably X represents S, S (O), S (O) ₂ , O or N (alkyl), more preferably Where X represents S.
[74] Other preferred embodiments of the invention are methyl or C, wherein R ¹ is 4-pyridylmethyl, R ² is methyl or 3,5-dichlorophenyl, R ³ is isopropyl, and R ⁴ is substituted with a hydroxy group. = O) R, R ⁵ is methyl and X represents S.
[75] More preferred embodiments of the compounds of formula (I), hydrolyzable esters or ethers thereof or pharmaceutically acceptable salts thereof are listed in Table 1.
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104] Compounds of formula (I), hydrolyzable esters or ethers thereof, or pharmaceutically acceptable salts thereof, are inhibitors of human immunodeficiency virus reverse transcriptase in vivo and ex vivo, and are mediated by human immunodeficiency virus (HIV) It can be used for treatment or prevention.
[105] The pyrrole derivatives provided by the present invention are useful for the treatment of humans or animals.
[106] The pyrrole derivatives provided by the present invention are inhibitors of human immunodeficiency virus reverse transcriptase. Thus, the pyrrole derivatives of the present invention are therapeutically active substances in the treatment of diseases mediated by human immunodeficiency virus (HIV) and can be used as medicaments for the treatment of such diseases.
[107] They can in particular be used as medicaments for treating viral diseases, immune mediated diseases or diseases, bacterial diseases, parasitic diseases, inflammatory diseases, hyperproliferative vascular diseases, tumors and cancers.
[108] In particular, the compounds of the present invention and pharmaceutical compositions containing them are useful as chemotherapeutic agents, inhibitors of viral replication and modulators of the immune system, diseases mediated by human immunodeficiency virus (HIV), other viruses such as retroviral infections. In the treatment of sexual diseases (alone or in combination with other antiviral agents such as interferon or derivatives thereof such as conjugates with polyethylene glycol).
[109] They may be used alone or in combination with other therapeutically active agents such as immunosuppressants, chemotherapeutic agents, antiviral agents, antibiotics, antiparasitic agents, anti-inflammatory agents, antibacterial agents and / or anti-vascular hyperproliferative agents.
[110] All compounds prepared by the process of the invention are also an object of the invention.
[111] Compounds of the present invention can be prepared as shown in Scheme 1 below.
[112]
[113] Where
[114] R ¹ , R ² , R ³ , R ⁵ and R are as defined for the compound of formula I and Prot is an amino protecting group.
[115] According to the invention, a compound of formula VIII is prepared by reacting a compound of formula VII with an iodinating agent to obtain an iodo pyrrole derivative of formula VIII:
[116]
[117]
[118] Where
[119] R, R ³ and R ⁵ are as defined in formula (I).
[120] Iodide agents used in the reaction are known in the art and include, for example, N-iodosuccinimide, iodide in the presence of iodine, potassium iodide in the presence of sodium iodide, potassium iodide in the presence of hydrogen peroxide. Or sodium iodide.
[121] The reaction can be carried out by conventional methods known to those skilled in the art.
[122] In Scheme I, the N-protected glycine of formula II (commercially available from Fluka) is present in the presence of N-ethylmorpholine and N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride Under a nitrogen atmosphere under reaction with N, O-dimethylhydroxylamine hydrochloride. The term "amino protecting group" (Prot) as used herein refers to a group as used in peptide chemistry such as t-butoxycarbonyl group (t-BOC) or benzyloxycarbonyl group (Z). Preferred amino protecting group (Prot) for this reaction is t-butoxycarbonyl group. The reaction is typically a polar aprotic such as halogenated hydrocarbons such as anhydrous dichloromethane or N, N-dimethylformamide (DMF) or tetrahydrofuran (THF) at reaction temperatures from 0 ° C. to room temperature. In a solvent, preferably dichloromethane, to yield N-protected glycine N-methyl-N-methoxyamide of formula III.
[123] N-protected glycine-N-methyl-N-methoxyamides of Formula III may be prepared by Formula R ³ mgX [a commercially available or textbook on organic chemistry (eg, J. March, 1992, “Advanced Organic Chemistry Synthesized according to known methods from Reactions, Mechanisms, and Structure ", 4 ^th ed. John Wiley & Sons], wherein R ³ is as defined above except for hydrogen ( If R ³ is hydrogen, the reaction sequence begins with the compound of formula V; see below), X is halogen, for example chlorine, to convert to compound of formula IV. The reaction is conveniently carried out at a reaction temperature of 0 ° C. to room temperature in an inert solvent such as anhydrous tetrahydrofuran, diethyl ether, dioxane, or a mixture of these solvents. After the reaction, the Grignard product is worked up with methods known in the art, for example with a solution of dilute hydrochloric acid, to obtain an N-protected α-amino ketone of formula IV.
[124] In the next step of the reaction, the N-protected α-amino ketone of formula IV is reacted with trifluoroacetic acid or hydrogen chloride to give the deprotected α-amino ketone of formula V. In the formation of the compound of formula V, any conventional method for the deprotection reaction of a protected amino group can be used in carrying out this reaction. The deprotection reaction of the compound of formula IV is preferably carried out at a reaction temperature of 0 ° C. to room temperature, optionally using trifluoroacetic acid dissolved in dichloromethane or hydrogen chloride dissolved in ethyl acetate, dioxane or methanol. Most preferably, the deprotection reaction is carried out using hydrogen chloride dissolved in ethyl acetate.
[125] Α-amino ketones of formula (V) are converted to β-keto esters of formula (VI), wherein R ⁵ and R are as defined above [a commercially available or textbook on heterocyclic chemistry or organic chemistry (eg, And synthesized according to methods known from "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons) to form pyrrole derivatives of formula VII. Synthesis of pyrrole derivatives according to the Knorr synthesis of Formula VII is carried out by methods known in the art. The reaction of the compounds of formulas V and VI to obtain the compounds of formula VII is preferably carried out at a reaction temperature of 20 to 40 ° C. using a mixture of potassium hydroxide and K ₂ HPO ₄ in water. Most preferably, the reaction is carried out at a reaction temperature of 70-100 ° C. using a mixture of ethyl acetoacetate, sodium acetate and acetic acid.
[126] In the next step of the reaction, the iodo pyrrole derivative of formula VIII is formed by reaction of the pyrrole derivative of formula VII with an iodide agent. Iodide agents used in such reactions are known in the art and include, for example, N-iodosuccinimide, iodide in the presence of iodine, potassium iodide in the presence of potassium iodide or potassium iodide in the presence of hydrogen peroxide. Or sodium iodide. The reaction is for example an iodide, for example N-iodo, at an reaction temperature of 0 to 40 ° C., preferably at room temperature, in an inert solvent such as ether, hydrocarbon or halogenated hydrocarbon, preferably anhydrous dichloromethane. It is carried out in the presence of succinimide to give an iodo pyrrole derivative of formula VIII. After the reaction, the product is worked up by methods known in the art, for example the mixture is washed with an aqueous solution of sodium thiosulfate and an aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate and finally the organic solvent is evaporated. The reaction can be found in literature, for example in textbooks on organic chemistry (e.g., "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons) or Murata (Y. Murata) Bull. Chem. Soc. Jpn. 1996 (11), 3339). The use of such iodinating agents is described, for example, in Synthesis 1995 (12), 1480, Tetrahedron 1992 (48) 44, 9661 or Liebigs Ann. Chem. 1989 (9), 863.
[127] Reaction of an iodopyrrole derivative of formula (VIII) with a disulfide compound of formula (R ² SSR ² ) or of a compound of formula (R ² SX, wherein R ² is as defined above and X is halogen, preferably chlorine) Reaction to convert to the corresponding pyrrole thio compound of formula IX (compounds of formula R ² SSR ² and R ² SX are commercially available or may be synthesized according to methods known in the art as described in US Pat. No. 4,282,242). Can be). The reaction is conveniently carried out by treating the compound of formula VIII with a strong base such as sodium hydride or preferably lithium hydride at an reaction temperature of 0 ° C. to room temperature in an inert solvent (eg anhydrous dimethyl sulfoxide) under a nitrogen atmosphere, The mixture is then reacted with a compound of formula R ² SX or preferably with a disulfide compound of formula R ² SSR ² . The reaction is preferably carried out at a reaction temperature of 40 to 60 ° C. to obtain a compound of formula IX. After the reaction, the product is worked up by methods known in the art, for example extracted with diethyl ether, dried over anhydrous magnesium sulfate and finally the organic solvent is evaporated.
[128] Reference IX formula); In the next step of the reaction, the compound of formula R ¹ X to a compound of formula IX (wherein, R ¹ is hydrogen and is as defined above (R ¹ is hydrogen the compounds already described, except , X is halogen, for example bromo) [a commercially available or textbook on organic chemistry (eg, March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons) Synthesized according to the methods known in hereinafter, to obtain N-substituted compounds of formula XI. When forming a compound of formula (XI), any conventional substitution method may be used to carry out this reaction. The reaction of the compound of formula IX is preferably carried out under nitrogen in an inert solvent such as tetrahydrofuran (THF) or a polar aprotic solvent such as N, N-dimethylformamide (DMF), preferably in anhydrous THF. Presence of a base such as sodium hydroxide, potassium carbonate, sodium hydride or an amine of the formula R ₃ N, wherein R is methyl, ethyl or propyl, in the presence of tetra-n-butylammonium bromide at a reaction temperature of Is carried out under. The most preferred base is sodium hydroxide. Finally the mixture is reacted with a compound of formula R ¹ X to give a compound of formula XI.
[129] The conversion of a compound of Formula (XI) to a compound of Formula (Ia) wherein R, R ¹ , R ² , R ³ and R ⁵ are as defined above, R ⁴ is CH ₂ OH and X is S, is The compound of XI is carried out to be reduced to the compound of formula (Ia) by reaction with a reducing agent such as lithium aluminum hydride. The reaction is conveniently carried out by reducing the compound of formula XI with a reducing agent such as LiAlH ₄ , LiBH at a reaction temperature of 0 ° C. to room temperature in an inert solvent under a nitrogen atmosphere such as anhydrous diethyl ether, ether such as THF of dioxane. ₄ , BH ₃ ^* S (CH ₃ ) ₂ , iso-Bu ₂ AlH or Bitride® Vitride. Preferably the reaction is carried out using LiAlH ₄ and ether. Then a solution of ammonium chloride is added to give a compound of formula la. After the reaction, the product is worked up by methods known in the art, for example extracted with ethyl acetate, dried over anhydrous magnesium sulfate and finally the organic solvent is evaporated.
[130] A compound of Formula (Ib) wherein R, R ¹ , R ² , R ³ and R ⁵ are as defined above, R ⁴ is C (═O) H and X is S Oxidation of the compounds of formula (Ia) is performed in the presence of 2,2,6,6-tetramethylpiperidine N-oxide, in the presence of iodobenzene diacetate, dimethyl sulfoxide (DMSO) (COCl ₂ ), dichloromethane Pyridinium chlorochromate, or an oxidizing agent such as MnO ₂ in an aprotic polar solvent such as acetone or a halogenated hydrocarbon such as ether (e.g. diethyl ether), anhydrous dichloromethane or trichloromethane It is carried out to obtain the compound of Ib. The reaction is conveniently carried out using an oxidizing agent, preferably iodobenzene diacetate and 2,2,6,6- at a reaction temperature of 0 ° C. to room temperature in an inert solvent such as anhydrous dichloromethane under a nitrogen atmosphere. Treatment with tetramethylpiperidine N-oxide is carried out to give a compound of formula Ib. After the reaction, the product is worked up in a manner known in the art, for example washed with a solution of sodium thiosulfate and sodium bicarbonate, dried over anhydrous sodium sulfate and finally evaporated the organic solvent.
[131] Converting a compound of formula (Ib) to a compound of formula (Ic) wherein R, R ¹ , R ² , R ³ and R ⁵ are as defined above, R ⁴ is CH (R) OH, and X is S The compounds of formula (Ib) may be prepared by the Grignard reagent of formula (RmgX) or the reagent of formula (RLi), both of which are commercially available, or textbooks on organic chemistry such as March 1992. Reactions, Mechanisms, and Structure ", 4 ^th ed. Can be synthesized according to methods known from John Wiley & Sons, wherein R is as defined above, but not hydrogen (synthesis when R is hydrogen has already been described; see compounds of formula Ia), X is carried out by reaction with a halogen, for example bromo) to give a compound of formula Ic. The reaction is conveniently carried out at a reaction temperature from 0 ° C. to room temperature, for example, Grignard reagent of the formula RmgX in an inert solvent such as anhydrous tetrahydrofuran (THF), diethyl ether or dioxane, preferably THF, Preferably, methyl methyl bromide is used to treat the compound of formula (Ib) in a nitrogen atmosphere, followed by addition of a solution of ammonium chloride to obtain the compound of formula (Ib). After the reaction, the product is worked up by methods known in the art, for example extracted with ethyl acetate, dried over anhydrous magnesium sulphate and finally the organic solvent is evaporated.
[132] Compounds of formula la (where R, R ¹ , R ² , R ³ and R ⁵ are as defined above, R ⁴ is hydrogen and X is S) are synthesized according to methods known in the art do. For example, ester compounds of formula (XI) are described, for example, in textbooks on organic chemistry, such as in March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons] is hydrolyzed to the corresponding carboxylic acid according to methods known in the art. In the second step, the carboxylic acid functional groups of the pyrrole derivatives are known in the art and are described, for example, in SF Macdonald, J. Chem. Soc. 1952, 4176 or in K. Kleinspehn, J. Am. Chem. Soc. 1954, 76, 5641, followed by decarboxylation.
[133] Compounds of formula la (where R, R ¹ , R ² , R ³ and R ⁵ are as defined above, R ⁴ is alkyl and X is S) are synthesized according to methods known in the art do. For example, the compounds may be reacted in a two step reaction, i.e. in the presence of CH ₃ SO ₂ Cl and Et ₃ N in the first step, using a base such as potassium hydroxide or sodium hydroxide in the second step, The removal reaction can form a corresponding alkenyl compound, which can then be subsequently hydrogenated in the presence of hydrogen and palladium (Pd / C) on activated charcoal to yield the corresponding alkyl-substituted pyrrole derivatives. The reactions are all described in literature, for example in textbooks on organic chemistry such as March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons.
[134] Compounds of formula I, wherein R, R ¹ , R ² , R ³ and R ⁵ are as defined above and R ⁴ is C (= 0) R, wherein R is alkyl are known in the art Synthesized according to the established method. For example, hydroxy compounds of formula (Ic) are described, for example, in textbooks on organic chemistry, such as in March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons] oxidizes according to known methods to give the corresponding oxo derivatives.
[135] Compounds of formula I, wherein R, R ¹ , R ² , R ³ and R ⁵ are as defined above and R ⁴ is CONR ₂ , are synthesized according to methods known in the art. For example, an ester compound of formula (XI) is hydrolyzed as described above and then reacted with thionyl chloride to obtain an activated acid chloride, and finally with a compound of formula HNR ₂ , wherein R is hydrogen or alkyl Reaction to obtain the corresponding amide derivative. The reactions are all described in literature, for example in textbooks on organic chemistry such as March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons.
[136] Compounds of formula I, wherein R, R ¹ , R ² , R ³ and R ⁵ are as defined above and X is S (O) or S (O) ₂ are known in the art. Are synthesized according to. For example, the compound of formula (I), (la), (lb) or (Ic) is oxidized to yield the corresponding oxidized thio compound derivative. Such reactions are described in literature, for example in textbooks on organic chemistry such as in March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons.
[137] Compounds of formula I, wherein R, R ¹ , R ² , R ³ and R ⁵ are as defined above and X is O or N (alkyl) are synthesized according to methods known in the art. . For example, neutral oxygen nucleophilic compound in the presence of a compound of formula VII to give the 2-bromo substituted fur rolls with N- bromo-succinimide is reacted with the corresponding imide (NBS), and this, Et ₃ N (e.g. Further reaction with 3-methoxyphenol) to give the corresponding oxypyrrole derivatives. To obtain the corresponding N-substituted pyrrole derivatives, the 2-substituted bromopyrroles are reacted with secondary amines in polar aprotic solvents such as N, N-dimethylformamide (DMF). The reactions are all described in literature, for example in textbooks on organic chemistry such as March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons or G. Cirrincione et al., Synthesis, 1997, 1169.
[138] Compounds of formula I, wherein R, R ¹ , R ² , R ³ and R ⁵ are as defined above and XR ² together are CH ₂ -aryl or CH ₂ -heterocyclyl, are known in the art Synthesized according to the established method. For example, a compound of formula Va can be a β-keto ester of formula VI wherein R ⁵ and R are as defined above, which is commercially available, or a textbook on heterocyclic chemistry or organic chemistry, such as And synthesized according to March 1992's "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons, to form a pyrrole derivative of formula (VIIa) . Synthesis of pyrrole derivatives according to the Nord synthesis of formula (VIIa) is carried out by methods known in the art. Subsequently, the compound of formula VIIa is further reacted according to the reaction described above starting with compound (IX → XI → Ia → Ib → Ic).
[139]
[140]
[141] Where
[142] R, R ³ and R ⁵ are as defined above and XR ² together are CH ₂ -aryl or CH ₂ -heterocyclyl.
[143] Compounds of formula (VIII) are also novel intermediates and are therefore also subject of the invention.
[144]
[145] Where
[146] R ¹ , R ² , R ³ and R ⁵ are as defined for the compound of formula I,
[147] R ⁶ is C _1-4 -alkyl,
[148] R ⁷ is 2-pyridyl-carbonyl-amino-methyl, 3-pyridyl-carbonyl-amino-methyl, 4-pyridyl-carbonyl-amino-methyl, (amino-methyl)-with an amino-methyl group Carbonyl-amino-methyl, (phenoxy) -carbonyl-amino-methyl, (methoxy) -carbonyl-amino-methyl, (di-methyl-amino) -carbonyl-amino-methyl, (phenyl-amino ) -Carbonyl-amino-methyl, (amino) -carbonyl-amino-methyl, (phenyl) -carbonyl-amino-methyl, (methyl) -carbonyl-amino-methyl, methyl-carbonyl-amino-methyl -Carbonyl-amino-methyl, (t-butyl) -carbonyl-amino-methyl-carbonyl-amino-methyl, (N1-acetyl-Ot-butyl-N2-ylmethyl) -L-serinamide, (N1 -Acetyl-N2-ylmethyl) -L-serinamide, [N1- (t-butoxycarbonyl) -O-tert-butyl-N2-yl-methyl) -L-serinamide, methyl-sulfonyl- Amino-methyl, phenyl-sulfonyl-amino-methyl or p-toluyl-sulfonyl-amino-methyl.
[149] Primary alcohols Ia are described in a textbook on organic chemistry, such as in March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons] can be alkylated, acylated or reacted with isocyanates to obtain carbamates, according to methods known from. These are standard reactions in which multiple combinations of reagents are present, such as alkylation can be accomplished using alkyl iodide, bromide, chloride, triflate or any other suitable leaving group. Acylation can be accomplished via acid chlorides or other activated carbonyl compounds, such as activated carboxylic acids. Carbamates may be obtained by reacting compound Ia with isocyanates in standard procedures.
[150] Compound Ia is described in a textbook on organic chemistry, such as in March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons] can be further derivatized to azide Ie using a sodium azide or diphenylphosphoryl azide, according to a standard procedure known in the art. Compound Ie can be reduced to the primary amine If in a suitable solvent (e.g. ethyl acetate, methanol or ethanol) or using hydrogenation using a standard catalyst (e.g. 10% palladium on carbon) with trialkyl or aryl phosphine. Can be.
[151] Primary amines are described in textbooks on organic chemistry, such as in March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons] can be alkylated, acylated, sulfonylated or reacted with isocyanates (obtaining urea) to give carbamates. These are standard reactions in which multiple combinations of reagents are present, such as alkylation can be accomplished using alkyl iodide, bromide, chloride, triflate or any other suitable leaving group. Acylation can be accomplished via acid chlorides or other activated carbonyl compounds, such as activated carboxylic acids. Sulfonylation can be carried out via sulfonyl chloride using a base such as triethylamine, N-methyl morpholine or N-ethyl morpholine. All these reactions can be carried out in suitable solvents known to those skilled in the art such as dichloromethane, chloroform, dioxane, dimethylformamide, tetrahydrofuran and the like.
[152] Urea can be obtained by reacting compounds I-f with isocyanates in standard procedures.
[153] Derivatives of esters XI (Scheme 1), wherein the esters are substituted by other carbonyl groups (see Scheme 3), can be prepared according to Scheme 1 in which intermediate XII is changed to intermediate VI only.
[154] Scheme 3 (additional reagent of type Compound VI)
[155]
[156] Where
[157] R ¹ , R ² and R ³ are as defined above for the compound of Formula I,
[158] R ⁵ is alkyl,
[159] R ^5a is hydrogen, amino, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl-oxy-carbonyl.
[160] The chemistry and subsequent reactions for forming pyrrole are as for the reaction already described in Scheme 1.
[161] If R ^5a is methyl, another derivative of pyrrole can be prepared according to Scheme 4 below.
[162]
[163] Where
[164] R ¹ , R ² , R ³ and R ⁵ are as defined for the compound of formula (I).
[165] Compound Ih prepared according to Scheme 3 can be reduced to ethanol derivative Ii as described above. Removing the water to form the vinyl compound Ij can be achieved thermally by heating in a high boiling solvent such as DMSO, DMF, N-methyl pyrrolidinone or the like. The conversion of compound Ij to diol Ik is described in a textbook on organic chemistry such as March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. According to standard reactions according to methods known from John Wiley & Sons, osmium tetroxide can be achieved.
[166] Ketone reduction of compound Il, wherein R ^5a is COCOOEt, to compound Im is achieved using the same chemical reaction as in the preparation of compound Ii.
[167]
[168] Where
[169] R ¹ , R ² , R ³ and R ⁵ are as defined for the compound of formula (I).
[170] Pyrroles can also be prepared using cycloaddition reactions according to the method of Yavari, Synthetic Communications, 1996, 4495-4500 (Scheme 6).
[171]
[172] Where
[173] R ¹ , R ² and R ³ are as defined for the compound of formula (I).
[174] In Scheme 6, amino ketone V is reacted with diethylacetylene dicarboxylate of formula XIV in sodium acetate in reflux ethanol to give an intermediate, which is cyclized with acid to give compound XV. Other acetylenic esters such as methyl, benzyl or aryl can be used in alcoholic solvents such as propanol or butanol.
[175] Intermediate XV can be converted to compound XVI according to the method described above in Scheme 1.
[176] Reduction of all of the esters in compound XVI to compound I-n can be achieved according to the preparation of compound 1a from compound X1, preferably using lithium aluminum hydride in ether.
[177] Basic hydrolysis can be used to selectively remove the 2-position ester to yield the carboxylic acid XVII. Any strong inorganic base, preferably hydroxide ions (sodium or potassium hydroxide) in alcoholic solvents such as ethanol, propanol, butanol is suitable for this purpose.
[178] Compound XVII can then be derivatized with N, O-dimethyl hydroxylamine according to intermediate III to afford amide XVIII. Lithium aluminum hydride is used to reduce the amides and esters in compound XVIII (as described above with respect to the synthesis of compounds I-n) to afford aldehydes I-o. Using the same method as in the synthesis of compound I-c, Grignard is added to the aldehyde in compound I-o to give compound (I-p) (Scheme 1).
[179]
[180] Where
[181] R ¹ , R ² and R ³ are as previously defined for the compounds of formula (I).
[182] The preparation of intermediate XX can be prepared using cycloaddition reaction according to the method of Yabari's Synthetic Communications, 1996, 4495-4500, as in intermediate XV (Scheme 2a).
[183] Reduction of esters and ketones in compound XXI to compound I-q can be accomplished using lithium aluminum hydride in ether as in compounds I-p and I-a.
[184]
[185] Where
[186] R ¹ , R ² , R ³ and R ⁵ are as defined for the compound of formula (I).
[187] The t-butyl ester of formula XI-a (prepared according to Scheme 1) is hydrolyzed using methods known in the art such as trifluoroacetic acid in dichloromethane to give the carboxylic acid of formula XXII which is an unstable intermediate. The carboxylic acid may be thermally decarboxylated to form a compound of formula Ir or further derivatized to form an amide of formula Is. Amide bond formation of Formula (XXII) with various amines can be similarly performed to form amides of Formula (I-s '), wherein R' and R "are as defined above. Treatment with trifluoroacetic acid in order to obtain a primary amide of formula It: Nitrile according to Cava, Michael P .; Levinson, Matthew I., Tetrahedron (1985), 41 (22), 5061-87. A compound of formula (Iu) can be obtained by dehydrating the compound of formula (It) with a Lawessons reagent.
[188]
[189] Where
[190] R ¹ , R ² and R ³ are as defined for the compound of formula (I).
[191] In Scheme 9, the compound of formula Ir (R ⁵ is methyl and synthesized according to Scheme 8) can be oxidized with lead tetraacetate to give a mixture of the aldehyde of formula Iv and the acetate of formula Iw. Lead tetraacetate is an oxidizing agent well known in the art, but other oxidizing agents such as potassium permanganate may also be used to oxidize the aromatic methyl groups as in the compounds of formula Ir.
[192] The acetate (crude) of formula (I-w) can then be hydrolyzed using any method known in the art, such as alkali hydrolysis with sodium or potassium hydroxide, to obtain a primary alcohol of formula (I-x). By-products of formula I-y were isolated upon purification. Subsequently, trichloroacetyl isocyanate may be used to derivatize the alcohol of formula (I-x) to obtain a primary carbamate of formula (I-z). The starting alcohol can conveniently be dissolved in a suitable organic solvent such as dichloromethane or chloroform and the reactant trichloroacetyl isocyanate is added while maintaining the reaction temperature above -10 ° C and below 5 ° C. Post-treatment includes the use of a base such as sodium carbonate or potassium carbonate followed by purification using standard methods. Other methods known in the art such as chlorosulfonyl isocyanate or trimethylsilyl isocyanate are not effective for this conversion.
[193]
[194] Where
[195] R ¹ , R ³ and R ⁵ are as defined for the compound of Formula I;
[196] A is C _1-4 -alkoxy or amino;
[197] R is C _1-4 -alkyl.
[198] In Scheme 10, sp2-sp2 binding reactions known to those skilled in the art (e.g., March 1992, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 ^th ed. John Wiley & Sons) ) Can be used to convert intermediates of Formula XXIII (synthesized using 3-bromo-5-chlorophenyldisulfide according to Scheme 1) to compounds of Formula I-aa. This reaction is typically catalyzed by a suitable palladium species such as tetrakis (triphenylphosphine) palladium, palladium acetate or dibenzylideneacetone. Copper cyanide (I) may be used to form nitrile groups using the reactivity of the aryl bromide of formula (XXIII) to afford compounds of formula (I-ab). This reaction can also be carried out on aryl dibromide to yield aryl dinitrile.
[199]
[200] Where
[201] R ¹ , R ³ and R ⁵ are as defined for the compound of Formula I;
[202] n is 0 or 1;
[203] In Scheme 11, an intermediate of Formula (XXIV), which is a subset of Formula (XXIII), can be reduced to a saturated alkyl chain of Formula (I-ac) by palladium catalyzed hydrogenation. Oxidation of the compound of formula XXIV via osmium catalyzed dehydroxylation yields the compound of formula I-ae. Sodium periodate digestion of compounds of formula (I-ae) yields alcohols of formula (I-ad) according to standard methods well known in the art.
[204] The analytical method is described below.
[205] HIV-1 Reverse Transcriptase (RT) Assay: Inhibitor IC ₅₀Measure
[206] HIV-1 RT analysis was performed using a total volume of 50 μl of purified recombinant enzyme and a poly (rA) / oligo (dT) ₁₆ template-primer in a 96-well Millipore filtermat NOB50 plate. It was. This assay component was pre annealed in 50 mM Tris / HCl, 50 mM NaCl, 1 mM EDTA, 6 mM mgCl ₂ , 5 μM dTTP, 0.1 μCi [ ³ H] dTTP, 2.5 μg / ml oligo (dT) ₁₆ . A series of inhibitor concentrates in 5 μg / ml poly (rA), and final concentration 10% DMSO. 5 nM HIV-1 RT was added to initiate the reaction, followed by incubation at 37 ° C. for 30 minutes, and then 50 μl of ice-cold 20% TCA was added to stop the reaction, and then precipitated at 4 ° C. for 30 minutes. The plate was vacuumed to collect the precipitate and washed sequentially with 2 × 200 μl 10% TCA and 2 × 200 μl 70% ethanol. Finally the plate was dried and 15 μl of scintillation fluid added to each well and the radioactivity counted in Wallac Microbeta 1450. IC ₅₀ was calculated by plotting log ₁₀ inhibitor concentration versus percent inhibition.
[207] Antiviral Analysis Methods
[208] An anti-HIV antiviral activity was assessed by modifying the method of Powels et al. (See Paules et al., 1988, J. Virol. Methods 20: 309-321). This method is based on the activity of compounds that protect HIV-infected T lymphocytes (MT4 cells) from cell-death mediated by infection. The endpoint of this evaluation was calculated as the concentration of the compound ('50% inhibitory concentration ', IC ₅₀ ) in which the cell viability of the culture was preserved at 50%. The cell viability of the culture was uptake of soluble yellow 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT) and its purple insoluble formazan salt Measured by reduction. After solubilization, the amount of formazan product was determined using spectrophotometry.
[209] MT4 cells were prepared in the logarithmic growth stage and a total of 2 × 10 ⁶ cells were infected with HXB2- strain of HIV at a total volume of 200-500 μl at 0.0001 infection units per cell. The cells were incubated with the virus at 37 ° C. for 1 hour before the virus was removed. Cells were then washed with 0.01 M phosphate buffered saline, pH 7.2, and the test compounds were resuspended in serially diluted culture medium. The culture medium used was RPMI 1640 free of phenol red and supplemented with penicillin, streptomycin, L-glutamine and 10% fetal bovine serum (GM10).
[210] Test compounds were prepared as 2 mM solutions in dimethyl sulfoxide (DMSO). A 2-fold series of dilutions in 4-fold GM10 were then prepared and the amount of 50 μl was placed in a 96-well plate at a final concentration of 625-1.22 nM. 50 μl GM10 and 3.5 × 10 ⁴ infected cells were then added to each well. Also, a control culture containing no cells, a control culture containing uninfected cells (100% viability; fourfold) and a control culture containing cells infected without the compound (total virus-mediated) Cell death; 4-fold). The cultures were then incubated at 37 ° C. for 5 days in a humidified atmosphere of 5% CO ₂ in air.
[211] A fresh solution of 5 mg / ml MTT was prepared in 0.01 M phosphate buffered saline at pH 7.2 and added to 20 μl of each culture. Cultures were further incubated as above for 2 hours. This was then mixed with 170 [mu] l of Triton X-100 (10% v / v Triton X-100 in a mixture of concentrated hydrochloric acid vs. isopropanol 1: 250) in a pipette acidified isopropanol. The absorbance (OD) of the culture was measured at wavelengths of 540 nm and 690 nm when the formazan precipitate was fully solubilized by further mixing (690 nm recordings were used as blank for artefact between wells). . The percentage of protection for each treated culture was calculated by the following equation:
[212]
[213] In the assay, the compound of formula (I) has an activity range of IC ₅₀ about 0.5 to about 5000 nM, preferably about 0.5 to about 750 nM, more preferably about 0.5 to 300 nM, most preferably about 0.5 to about 50 nM Had a range.
[214]
[215]
[216]
[217]
[218]
[219] ND: No measurement.
[220] Reference to treatment herein should be understood to extend to prevention as well as treatment for existing symptoms. In addition, references to the treatment of animals should be understood to include the treatment of humans as well as other mammals.
[221] As used herein, "comprises" means "comprises or consists of" and "comprising" means "comprising or consists of."
[222] Features expressed in the specific form or means for carrying out the disclosed functions as described in the foregoing description, the following claims or the appended drawings, or methods or processes for achieving the disclosed results, if appropriate, individually Or any combination of such features, and can be used to implement the invention in its various forms.
[223] The pyrrole derivatives provided by the present invention can be used as medicaments in the form of pharmaceutical preparations with therapeutically inert carriers. The pharmaceutical preparations can be administered via the intestine, such as oral administration in the form of tablets, coated tablets, dragees, hard and soft capsules, solutions, emulsifiers or suspensions, or via the nasal cavity, for example in the form of nasal sprays. have. The pyrrole derivatives can also be administered rectally, for example in the form of suppositories, or parenterally (eg intramuscular, intravenous or subcutaneous), for example in the form of injection solutions.
[224] For the preparation of pharmaceutical preparations, the pyrrole derivatives may be formulated with a therapeutically inert inorganic or organic carrier.
[225] As carriers for tablets, coated tablets, dragees and hard and soft capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used.
[226] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.
[227] Suitable carriers for the preparation of injectable solutions are, for example, water, saline, alcohols, polyols, glycerin, vegetable oils and the like. Suitable carriers for the preparation of suppositories are natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like. In addition, the pharmaceutical formulations of the present invention may be provided in sustained release formulations or other suitable formulations.
[228] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for controlling osmotic pressure, buffers, blockers or antioxidants.
[229] In addition, the pharmaceutical preparations may contain other therapeutically active agents as described above.
[230] The pyrrole derivatives provided by the present invention can be used for the treatment of immune mediated diseases or diseases, viral diseases, parasitic diseases, inflammatory diseases, hyperproliferative vascular diseases, tumors or cancers.
[231] The dosage can vary widely and can, of course, be adjusted to the individual requirements in each particular application.
[232] Dosage levels of monotherapy and / or combination therapy of about 0.01 to about 100 mg / kg body weight are typically administered about 1 to 5 times per day. Typical formulations will contain about 5 to 95% w / w of active compound. The daily dose may be administered in a single dose or in divided doses.
[233] The pyrrole derivatives or medicaments thereof provided by the present invention can be used in monotherapy and / or in combination, i.e., the treatment can be carried out with the administration of one or more additional therapeutically active substances. If the treatment is a combination therapy, the administration can be carried out simultaneously or sequentially with the administration of the pyrrole derivatives of the invention. Therefore, simultaneous administration as used herein includes administering the agents together or in combination, or before and after each administration.
[234] Reference to treatment herein should be understood to extend to prevention as well as treatment for existing symptoms. Treatment of a disease or condition as used herein also includes the prevention, inhibition, attenuation, reversal, alleviation or alleviation of the condition or disease, or clinical syndrome thereof. As used herein, the term "subject" refers to an animal, including humans and other mammals.
[235] In the case of starting materials which are known compounds some of them can be purchased from commercial suppliers. Other starting materials and analogs thereof known in the art can be prepared by methods well known in the art. Examples of compounds available from commercial suppliers and citations for the synthesis of other compounds and analogs thereof are given below.
[236] The NMR spectra described were recorded on a Bruker DRX 400 MHz spectrophotometer with a probe temperature set to 300K.
[237] Mass spectra indicated as "(M +; EI)" were recorded under electron impact (EI) conditions on a THERMOQUEST MAT95 S at a source temperature of 200 ° C. Other mass spectra were recorded under electrospray ionization spectrum (ESI) conditions in one of the following instruments:
[238] a) ThermoQuest SSQ 7000 [solvent 90% acetonitrile / 0.085% TFA in water; Flow rate 100 μl / min; Capillary 250 ° C .; Spray voltage 5KV; Sheath gas 80 psi], or
[239] b) LC-MS System (Liquid Chromatography Linked to Mass Spectrum) Thermoquest TSQ 7000 Electrospray or MICROMASS PLATFORM Electrospray [0.1% TFA in solvent water, 0.085% TFA in 90% acetonitrile / water, Or 0.085% TFA in acetonitrile].
[240] The meanings of the abbreviations used in the examples below are as follows.
[241] EDAC: 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride
[242] HOBt: 1-hydroxybenzotriazole
[243] The following examples illustrate the invention.
[244] Example 1
[245] 5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol
[246] 0.1 g of ethyl 5- (3,5-dichlorophenylsulfanyl) -4-isopropyl-2-methyl-1-pyridin-4-yl-1H-pyrrole-3-carboxylate in 0.5 ml of anhydrous diethyl ether The solution was added dropwise to 0.54 ml of a 1 M solution of lithium aluminum hydride, which was stirred at 0-5 ° C. and cooled. The mixture was stirred at 5 ° C. for 1 hour and then at room temperature for 1 hour. The mixture was cooled again to 5 ° C., quenched with saturated ammonium chloride solution and then extracted three times with 10 ml of ethyl acetate. The combined extracts were washed with 10 ml brine, then dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol / dichloromethane (1:19) for elution to afford 5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1- [ 70 mg of (4-pyridyl) methyl] -1H-pyrrole-3-methanol was obtained as a pale orange rubber. Mass spectrum (ESI) m / z 421 [M + H] ⁺ . ¹ H NMR (CDCl ₃ ) 1.31 (d, 6H), 2.21 (s, 3H), 3.24 (m, 1H), 4.66 (s, 2H), 5.10 (s, 2H), 6.68 (d, 2H), 6.74 (m, 2 H), 6.98 (t, 1 H), 8.44 (m, 2 H).
[247] The starting material ethyl 5- (3,5-dichlorophenylsulfanyl) -4-isopropyl-2-methyl-1-pyridin-4-yl-1H-pyrrole-3-carboxylate was prepared as follows.
[248] (A) A solution containing 18.8 g of Nt-butoxycarbonylglycine in 180 mL of anhydrous dichloromethane was stirred under nitrogen, 11.5 g of N, O-dimethylhydroxylamine hydrochloride, 27.1 g of N-ethylmorpholine and N 22.5 g of -ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride were added and cooled at 0-5 ° C. The mixture was slowly warmed to rt and stirred for 16 h. The mixture was washed twice with 150 ml of 1 M hydrochloric acid and 150 ml of saturated sodium hydrogen carbonate, then dried over anhydrous sodium sulfate, filtered and evaporated to give 22.5 g of Nt-butoxycarbonylglycine N-methyl-N-methoxyamide. Obtained as a white solid, which was used without further purification.
[249] (B) A solution of 10.9 g of Nt-butoxycarbonylglycine N-methyl-N-methoxyamide in 300 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous diethyl ether, a 2M solution of isopropyl magnesium chloride in tetrahydrofuran 100 mL was slowly added and cooled at 0-5 ° C. The mixture was stirred at 0-5 [deg.] C. for 4 hours and then poured into 1.5 L of 1M hydrochloric acid. The product was extracted three times with 500 ml diethyl ether. The combined extracts were washed with 500 ml brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 8.38 g of 4-t-butoxycarbonylamino-2-methyl-3-butanone as colorless oil, It was used without further purification.
[250] (C) 7.03 g of 4-t-butoxycarbonylamino-2-methyl-3-butanone was added to 80 ml of an ice cold 4M solution of hydrogen chloride in ethyl acetate. The solution was stirred at 0-5 ° C. for 1 hour, during which time the precipitate separated. The mixture was evaporated under reduced pressure and the residue triturated with anhydrous ether. The white solid product was filtered off, washed with anhydrous diethyl ether and dried to give 4.14 g of 4-amino-2-methyl-3-butanone hydrochloride.
[251] (D) A solution containing 0.32 g of 4-amino-2-methyl-3-butanone hydrochloride, 0.33 g of ethyl acetoacetate and 0.28 g of sodium acetate in 2 ml of 75% acetic acid was heated at 100 ° C. for 1.5 hours. The mixture was poured into 10 mL of water and extracted three times with 10 mL of diethyl ether. The combined extracts were washed three times with 10 ml saturated sodium hydrogen carbonate and 10 ml brine, then dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane for elution to yield 0.15 g of ethyl 4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate. Recrystallization from isohexane gave analytical pure material. Melting point 67-68.5 ° C. Mass spectrum (EI) m / z 195 [M] ⁺ .
[252] (E) A solution of 1.03 g of ethyl 4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate in 27 mL of anhydrous dichloromethane was treated with 2.06 g of N-iodosuccinimide and maintained at room temperature for 2 hours. Stirred. The mixture was diluted with 50 ml additional dichloromethane and washed with 50 ml saturated sodium thiosulfonate solution and 50 ml saturated sodium bicarbonate solution. The dichloromethane extracts were dried over anhydrous sodium sulfate, then filtered and evaporated. The residue was triturated with 50 mL of petroleum ether (boiling point 40-60 ° C.). The orange solid product was filtered off and dried to yield 1.32 g of ethyl 5-iodo-4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate. Mass spectrum (ESI) m / z 322 [M + H] ⁺ .
[253] (F) A solution of 1.3 g of ethyl 5-iodo-4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate in 8 ml of anhydrous dimethyl sulfoxide was stirred at room temperature under nitrogen to obtain 39 mg of lithium hydride. After 10 minutes, 0.86 g of bis- (3,5-dichlorophenyl) disulfide was added. The mixture was stirred under nitrogen, heated at 60 ° C. for 6 hours and then left at room temperature for 16 hours. The mixture was diluted with 150 mL of water and extracted three times with 75 mL of diethyl ether. The combined extracts were washed with 50 ml brine, then dried over anhydrous magnesium sulfate and evaporated to afford a brown rubber that crystallized. Recrystallization from methylcyclohexane gave 0.66 g of ethyl 5- (3,5-dichlorophenylsulfanyl) -4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate. Melting point 148 to 151 ° C. Mass spectrum (EI) m / z 371 [M] ⁺ .
[254] (G) A solution of 0.1 g of ethyl 5- (3,5-dichlorophenylsulfanyl) -4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate in 2 ml of anhydrous tetrahydrofuran at room temperature under nitrogen Stirred and treated with 65 mg 4-bromomethylpyridine hydrobromide, 5 mg tetra-n-butylammonium bromide and 24 mg powdered sodium hydroxide. The mixture was stirred at rt for 20 h, then diluted with 20 mL of water and extracted three times with 10 mL of ethyl acetate. The combined extracts were washed with 10 ml brine, then dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / isohexane (1: 1) for elution to yield ethyl 5- (3,5-dichlorophenylsulfanyl) -4-isopropyl-2-methyl-. 0.104 g of 1-pyridin-4-yl-1H-pyrrole-3-carboxylate was obtained as a colorless rubber. Mass spectrum (ESI) m / z 463 [M + H] ⁺ . ¹ H NMR (CDCl ₃ ) 1.32 (d, 6H), 1.40 (t, 3H), 2.45 (s, 3H), 3.61 (m, 1H), 4.34 (q, 2H), 5.16 (s, 2H), 6.69 (d, 2H), 6.76 (m, 2H), 8.47 (m, 2H).
[255] Example 2
[256] 5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrole-3-carboxaldehyde
[257] 0.2 g of 3,5-dichlorophenylsulfanyl-3-hydroxymethyl-4-isopropyl-2-methyl-1-pyridin-4-yl-pyrrole in 0.5 ml of anhydrous dichloromethane and 2,2,6,6- A solution of 7.5 mg of tetramethylpiperidine N-oxide was treated with 0.17 g of iodobenzene diacetate. The mixture was stirred at room temperature for 4 hours, then diluted with 10 mL of dichloromethane, washed with 10 mL of saturated sodium thiosulfate and 10 mL of saturated sodium bicarbonate, then dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol / dichloromethane (1:49) for elution to give 5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1- [ 50 mg of (4-pyridyl) methyl] -1H-pyrrole-3-carboxaldehyde was obtained as a rubber. Mass spectrum (ESI) m / z 419 [M + H] ⁺ . ¹ H NMR (CDCl ₃ ) 1.36 (d, 6H), 2.53 (s, 3H), 3.46 (m, 1H), 5.16 (s, 2H), 6.69 (d, 2H), 6.74 (m, 2H), 7.02 (t, 1 H), 8.47 (m, 2 H), 10.21 (s, 1 H).
[258] Example 3
[259] 5- (3,5-Dichlorophenylthio) -4-isopropyl-α (RS) -methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-ethanol
[260] A solution of 90 mg of 5- (3,5-dichlorophenylsulfanyl) -4-isopropyl-2-methyl-1-pyridin-4-yl-1H-pyrrole-3-carboxaldehyde in 1 ml of anhydrous tetrahydrofuran Was stirred under nitrogen and cooled at 0-5 ° C. with 0.21 ml of a 1.4 M solution of methyl magnesium bromide in toluene / tetrahydrofuran (75:25) dropwise. The mixture was stirred at 0-5 ° C. for 2 hours, then diluted with 10 ml saturated ammonium chloride solution and extracted twice with 10 ml ethyl acetate. The combined extracts were washed with 10 ml brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol / dichloromethane (1:19) for elution to afford 5- (3,5-dichlorophenylthio) -4-isopropyl-α (RS) -methyl-. 19 mg of 1-[(4-pyridyl) methyl] -1H-pyrrole-3-ethanol was obtained as a rubber. Mass spectrum (ESI) m / z 435 [M + H] ⁺ . ¹ H NMR (CDCl ₃ ) 1.26 (d, 3H), 1.29 (d, 3H), 1.55 (d, 3H), 1.77 (bs, 1H), 2.30 (s, 3H), 3.30 (m, 1H), 5.08 (s, 2H), 5.25 (q, 1H), 6.67 (d, 2H), 6.71 (m, 2H), 6.97 (t, 1H), 8.43 (m, 2H).
[261] Examples 4-9
[262] The compounds shown in Table 2 were also prepared in a similar manner to those described in Examples 1-3, starting with N-t-butoxycarbonylglycine (commercially available from Fluka or Aldrich).
[263]
[264]
[265] Examples 10-15
[266] The compounds shown in Table 3 were also prepared in a similar manner to the methods described in Examples 1-3, starting with N-t-butoxycarbonylglycine (prepared as described in Example 1A).
[267]
[268]
[269] Examples 16-20
[270] The compounds shown in Table 4 were also prepared in a similar manner to the methods described in Examples 1-3, starting with N-t-butoxycarbonylglycine (prepared as described in Example 1A).
[271]
[272]
[273] Examples 21-22
[274] In a similar manner to those described in Examples 1-3, starting with Nt-butoxycarbonylglycine (prepared as described in Example 1A), which is also converted to a compound of Formula XI, Prepared via intermediate XII (Scheme 3) when R was t-butyl (Example 21) via hydrolysis of compound XI and R ^5a was amino (Example 22).
[275]
[276] Example 23
[277] In a similar manner to those described in Examples 1-3, starting with Nt-butoxycarbonylglycine (prepared as described in Example 1A), wherein the compound shown in Table 6 is converted to a compound of Formula Ic, For example, it was prepared by mesylating with CH ₃ SO ₂ Cl and Et ₃ N, followed by reduction with Zn / acetic acid (for example, as described in J. Org. Chem. 1997, 62, 9223). equivalence).
[278]
[279] Examples 24 and 25
[280] Starting with Nt-butoxycarbonylglycine (prepared as described in Example 1A), the compounds shown in Table 7 were converted to chloride followed by chlorides in the same manner as described in Examples 1-3. Was substituted with azide and finally reduced with azide with hydrogen (Example 24), or by the nucleophilic substitution reaction of the chloride of the alcohol of formula (Ia) with the methoxide anion (Example 25).
[281]
[282]
[283] Examples 26-28
[284] The compounds shown in Table 8 were also prepared starting with Nt-butoxycarbonylglycine (prepared as described in Example 1A) to intermediate V in a similar manner as described in Examples 1 to 3, and then in Scheme 6 was performed. When R in ethyl VI is ethyl, Example 28 was prepared according to Scheme 1.
[285]
[286]
[287] Examples 29 and 30
[288] The compounds shown in Table 9 were also prepared in a similar manner to those described in Examples 1-3, starting with Nt-butoxycarbonylglycine (prepared as described in Example 1A). This example bromines the compound of Formula VII with the corresponding 2-substituted bromopyrrole, which is then further reacted with the corresponding neutral oxygen nucleophilic material in the presence of Et ₃ N to give the corresponding oxypyrrole derivative (Example 29) to obtain. In order to obtain the corresponding N-substituted pyrrole derivatives (Example 30), the aforementioned 2-substituted bromopyrroles are reacted with primary or tertiary amines.
[289]
[290] Examples 31 and 32
[291] The compounds shown in Table 10 were also prepared in a similar manner to those described in Examples 1-3, starting with N-t-butoxycarbonylglycine (prepared as described in Example 1A). This example was prepared by coupling the corresponding compound of formula 5a with the corresponding β-keto ester of formula VI to yield Examples 31 and 32.
[292]
[293] Examples 33 to 35
[294] Example 34 was prepared according to Scheme 9 starting with N-t-butoxycarbonylglycine (prepared as described in Example 1C) in a manner similar to the methods described in Examples 1-3.
[295]
[296] Example 93
[297]
[298] To a solution of 200 mg of 4-[[3- (chloromethyl) -5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-pyrrolyl] methyl] pyridine in 5 ml of DMF 137 mg sodium zide was added. The mixture was stirred at rt for 18 h. The yellow solution was quenched with saturated sodium bicarbonate solution and extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 2) followed by ethyl acetate for elution to yield 129 mg as a yellow oil. Mass spectrum (ESI) m / z 446 [M + H] ⁺ .
[299] Example 76
[300]
[301] Solution of 70 mg of 5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methylamine in 3 ml of dichloromethane To this was added 30 mg of isnicotinyl and 50 mg of triethylamine. The mixture was stirred at rt for 18 h, then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was preabsorbed on silica gel and then purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 9, then 1: 4) for elution to yield 50 mg as a cream solid. . Mass spectrum (ESI) m / z 525 [M + H] ⁺ .
[302] The starting material 5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methylamine was prepared as follows. .
[303] A solution of 2.33 g of 4-[[3- (azidomethyl) -5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-pyrrolyl] methyl] pyridine in 100 ml of ethyl acetate To 100 mg of 10% Pd catalyst on carbon was added. The mixture was hydrogenated for 1.5 hours. The mixture was filtered and evaporated to yield 2.2 g of yellow oil. Mass spectrum (ESI) m / z 446 [M + H] ⁺ .
[304] Example 95
[305]
[306] 90 mg of 5- (3,5-dichlorophenylthio) -4-isopropyl-α (RS) -methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-ethanol in 3 ml of DMSO The solution was heated at 160 ° C. for 30 minutes. The brown solution was cooled to room temperature and then quenched with saturated sodium bicarbonate solution and extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petroleum / ethyl acetate (1: 4 to 1: 1) for elution and then using ethyl acetate to give 28 mg as an oil. Mass spectrum (ESI) m / z 417 [M + H] ⁺ .
[307] Example 96
[308]
[309] Degassing 61 mg of 4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-5-methyl-4-vinyl-1-pyrrolyl] methyl] pyridine in 20 ml of dioxane and 3.5 ml of water To the solution was added 26 mg N-methyl morpholine N-oxide and 4 mg osmium tetroxide. The reaction was darkened by covering with aluminum foil and stirred at room temperature for 24 hours. The solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give a brown rubber which was solidified by adding ethyl acetate to give 29 mg of a brown solid. This solid was further purified by HPLC to yield 0.4 mg of product. Mass spectrum (ESI) m / z 451 [M + H] ⁺ .
[310] Example 75
[311]
[312] [5- (3,5-Dichloro-phenylsulfanyl) -4-isopropyl-2-methyl-1-pyridin-4-ylmethyl-1H-pyrrol-3-yl] -oxo-acetic acid in 5 ml of ethanol 54 mg of sodium borohydride was added to a solution of 140 mg of ethyl ester. The mixture was stirred for 2 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petroleum / ethyl acetate (1: 9 to 1: 4) for elution to give 22 mg as a white foam. Mass spectrum (ESI) m / z 493 [M + H] ⁺ .
[313] Example 107
[314]
[315] 1- [5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl in 3 ml of ether at 0 ° C. ] To a solution of 120 mg of ethanone was added a solution of 1 M lithium aluminum hydride in 1.25 mL of ether. The reaction was allowed to warm to room temperature for 30 minutes. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate for elution to yield 35 mg, which was further purified by HLPC to give the desired product and de-chlorinated derivative 5- (3-chlorophenylthio). 4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3- (2-ethanol) was obtained. Mass spectrum (ESI) m / z 451 [M + H] ⁺ .
[316] Starting material 1- [5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrol-3-yl] ethanone It was prepared as follows.
[317] (A) 2.45 g of pent-2-yn-4-one-oate ethyl ester, 3.19 g of 1-amino-3-methylbutan-2-one hydrobromide and 1.44 g of a mixture of sodium acetate were dissolved in 88 ml of ethanol and Heated to reflux for 30 minutes. Then, 8 ml of concentrated hydrochloric acid was added and the reflux was continued. After 1 h the solvent was evaporated and the residue was partitioned into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petroleum / ethyl acetate (1: 9 to 1: 4) for elution to afford 750 mg of 4-isopropyl-1H-pyrrole-3-ethanone-2-. Ethyl ester was obtained as a white foam. Mass spectrum (ESI) m / z 223 [M + H] ⁺ .
[318] (B) 5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] 1H-pyrrole-3-ethanone-2-ethyl ester was obtained.
[319] Example 108
[320]
[321] 5- (3,5-dichlorophenylthio) -4-isopropyl-3-ethyl ester-1-[(4-pyridyl) methyl] -1 H-2- [N-methyl- in 5 ml of THF at 0 ° C. To a solution of 88 mg N-methoxyamide] -pyrrole was added 0.33 mL of a lithium aluminum hydride 1M solution in ether. The reaction was warmed to room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petroleum / ethyl acetate (1: 2) for elution to give the desired product 29 mg of oil and 5- (3,5-dichlorophenylthio) -4-isopropyl. 6 mg of 1-[(4-pyridyl) methyl] -1 H-pyrrole-2,3-dicarboxaldehyde were obtained as an oil. Mass spectrum (ESI) m / z 438 [M + H] ⁺ .
[322] Starting material 5- (3,5-dichlorophenylthio) -4-isopropyl-3-ethyl ester-1-[(4-pyridyl) methyl] -2- [N-methyl-N-methoxyamide] -1H-pyrrole was prepared as follows:
[323] (A) A mixture of 0.5 g amino-3-methylbutan-2-one hydrochloride, 0.58 mL diethylacetylene dicarboxylate and 295 mg sodium acetate was refluxed in 18 mL ethanol for 10 minutes. A drop of concentrated hydrochloric acid was then added and the mixture was further boiled. The reaction was cooled to room temperature and then partitioned between dichloromethane and ice water. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petroleum / ethyl acetate (1: 9, 1: 6, then 1: 4) for elution and then ethyl acetate to 4-isopropyl-2,3-dicarboxylate. 323 mg of ethyl ester was obtained as a yellow oil. Mass spectrum (ESI) m / z 253 [M + H] ⁺ .
[324] (B) 5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl]-by iodide, sulfidation and alkylation according to the method described for example in Scheme 1 1H-pyrrole-2,3-bisethyl ester was obtained.
[325] (C) 462 mg of 5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2,3-bisethyl ester in 12 ml of ethanol 50 mg of potassium hydroxide was added to the solution. The mixture was refluxed for 18 hours, then additional 20 mg potassium hydroxide was added and reflux continued for 3 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and dilute hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was triturated with ether to give 417 mg of 5- (3,5-dichlorophenylthio) -4-isopropyl-3-ethyl ester-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-carboxylic acid Was obtained as an orange foam. Mass spectrum (ESI) m / z 493 [M + H] ⁺ .
[326] (D) 5- (3,5-dichlorophenylthio) -4-isopropyl-3-ethylester-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-carboxylic acid 417 in 10 ml of dichloromethane To the mg solution was added 243 mg of EDAC, 171 mg of HOBt, 124 mg of N, N-dimethyl hydroxylamine, and finally 0.33 ml of N-ethyl morpholine. The reaction mixture was then stirred at rt for 1 h. The orange solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petroleum / ethyl acetate (1: 4 to 1: 2) for elution and then ethyl acetate to give 5- (3,5-dichlorophenylthio) -4-isopropyl. 233 mg of 3-ethyl ester-1-[(4-pyridyl) methyl] -2- [N-methyl-N-methoxyamide] -1 H-pyrrole were obtained as a yellow oil. Mass spectrum (ESI) m / z 535 [M + H] ⁺ .
[327] Example 110
[328]
[329] 5- (3,5-dichlorophenylthio) -3- (hydroxymethyl) -4-isopropyl-1-[(4-pyridyl) methyl] -1H-pyrrole-2-carboxaldehyde in 1 mL of THF To 60 mg of solution was added 0.1 ml of a solution of methyl magnesium iodide 3M in diethyl ether. The mixture was stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate for elution to yield 22 mg of rubber. Mass spectrum (ESI) m / z 451 [M + H] ⁺ .
[330] The starting material 5- (3,5-dichlorophenylthio) -3- (hydroxymethyl) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-carboxaldehyde Prepared as follows:
[331] 5- (3,5-dichlorophenylthio) -4-isopropyl-3-ethylester-1-[(4-pyridyl) methyl] -2- [N-methyl-N- in 10 mL THF at 0 ° C To a solution of 371 mg of methoxyamide] -1H-pyrrole was added 1.4 ml of a lithium aluminum hydride 1M solution in ether. The mixture was stirred for 30 minutes and then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate for elution to give 5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1H as a rubber. 223 mg of -pyrrole-3-methanol-2-carboxaldehyde were obtained. Mass spectrum (ESI) m / z 434 [M + H] ⁺ .
[332] Example 111
[333]
[334] 5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1H as a solution in 3 ml of ether to 1M solution of lithium aluminum hydride in ether at 0 ° C. under nitrogen 70 mg of -pyrrole-2,3-bisethyl ester was added. The mixture was stirred for 1 h and then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 9 then 1: 4) for elution to yield 16 mg of rubber. Mass spectrum (ESI) m / z 437 [M + H] ⁺ .
[335] Example 117
[336]
[337] Of 243 mg of 5- (3,5-dichlorophenylthio) -4-phenyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrole-3-t-butyl ester in 6 ml of dichloromethane To the solution was added 6 ml of trifluoroacetic acid at room temperature. The mixture was evaporated for 1 h and the residue was purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 4 then 1: 1) for elution to give 155 mg of foam. Mass spectrum (ESI) m / z 469 [M + H] ⁺ .
[338] Example 115
[339]
[340] To a solution of 160 mg of 5- (3,5-dichlorophenylthio) -2-methyl-4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxylic acid in 10 ml of dichloromethane 60 mg EDAC, 40 mg HOBt, 68 mg 2,4,6-trimethoxybenzylamine hydrochloride and 0.11 ml N-ethyl morpholine were added. The reaction mixture was stirred at rt for 18 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 4 then 1: 2) for elution and then ethyl acetate to give 5- (3,5-dichlorophenylthio) -4- as oil. Isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrole 29 mg (mass spectrum (ESI) m / z 391 [M + H] ⁺ ) and 5- (3,5 as oil) -Dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrole-3-N-[(2,4,6-trimethoxy) benzyl] car 114 mg (mass spectrum (ESI) m / z 614 [M + H] ⁺ ) were obtained.
[341] Example 118
[342]
[343] 5- (3,5-dichlorophenylthio) -N- (2,4,6-trimethoxybenzyl) -2-methyl-4-phenyl-1-[(4-pyridyl) in 4 ml of dichloromethane To a solution of 110 mg of methyl] -1H-pyrrole-3-carboxamide 3 ml of trifluoroacetic acid was added at room temperature. The mixture was stirred for 1 h and then evaporated and the residue was purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 9, then 1: 4) for elution to give 26 mg of a white solid. . Mass spectrum (ESI) m / z 468 [M + H] ⁺ .
[344] Example 119
[345]
[346] Rabeson in a solution of 17 mg of 5- (3,5-dichlorophenylthio) -4-phenyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrole-3-carboxamide in toluene 22 mg of reagent was added. The mixture was refluxed for 1 hour and then cooled to room temperature. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. Petroleum / ethyl acetate (1: 4 then 1: 2) for elution and then purification by flash chromatography on silica gel using ethyl acetate gave 13 mg of rubber. Mass spectrum (ESI) m / z 450 [M + H] ⁺ .
[347] Example 113
[348]
[349] 200 mg of lead tetraacetate in a solution of 160 mg of 5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrole in 3 ml of acetic acid Was added over 30 minutes. After stirring for 2 hours at room temperature, further 100 mg of lead tetraacetate was added and the mixture was stirred for 18 hours. Then 100 mg of lead tetraacetate was further added and the mixture was stirred for 18 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 4 then 1: 2) for elution and then ethyl acetate to give 5- (3,5-dichlorophenylthio) -4- as a brown oil. Isopropyl-1-[(4-pyridyl) methyl] -1H-pyrrole-2-carbaldehyde 23 mg (mass spectrum ((ESI) m / z 405 [M + H] ⁺ )) and yellow effervescent with impurities 51 mg (mass spectrum (ESI) m / z, 5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1H-pyrrole-2-acylmethanol as an oil 447 [M + H] ⁺ ) was obtained.
[350] Examples 112 and 114
[351]
[352] Of 51 mg of 5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1H-pyrrole-2-acylmethanol with impurity in 4 ml of 50% aqueous acetone. 50 mg of powdered potassium hydride was added to the solution. The mixture was stirred for 2 hours at room temperature. The reaction was quenched with water and extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 4, then 1: 2) for elution and then ethyl acetate to give 5- (3,5-dichlorophenylthio) -4 as a yellow rubber. -Isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol 8 mg (mass spectrum (ESI) m / z 407 [M + H] ⁺ ) and as yellow rubber, 5- (3 , 5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2- [4'-but-3-en-2-one] 9 mg (mass spectrum (ESI) m / z 445 [M + H] ⁺ ) were obtained.
[353] Example 130
[354]
[355] Trichloroacetyl isocyanate in a solution of 103 mg of 5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1H-pyrrole-2-methanol in 3 ml of dichloromethane 57 mg was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours and then evaporated. To the residue was added 2 ml of methanol, 1 ml of water and 103 mg of potassium carbonate at 0 ° C. The mixture was allowed to warm to rt and stirred for 2 h. The solution then became homogeneous and orange in color. The reaction was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 4) for elution to give 27 mg of a white solid. It was. Mass spectrum (ESI) m / z 450 [M + H] ⁺ .
[356] Example 132
[357]
[358] Allyltributyl in a solution of 80 mg of 4-[[2- (3-bromo-5-chlorophenylthio) -3-isopropyl-5-methyl-1-pyrrolyl] methyl] pyridine in 5 ml of dimethoxyethane 156 μL of tin and 60 mg of tetrakis (triphenylphosphine) palladium were added. The mixture was heated to 70 ° C for 18 h. The mixture was purified by flash chromatography on silica gel using methanol / dichloromethane (1:19) for elution to yield 40 mg of a white solid. Mass spectrum (ESI) m / z 397 [M + H] ⁺ .
[359] Example 133
[360]
[361] To a solution of 10 mg of 4-[[2- (3-allyl-5-chlorophenylthio) -3-isopropyl-5-methyl-[(4-pyrrolyl) methyl] pyridine in 5 ml of warm ethanol 10 on carbon 1 mg% palladium was added. The mixture was hydrogenated for 10 minutes and then filtered through a pad of celite. The filtrate was evaporated to dryness to afford 10 mg of a white solid. Mass spectrum (ESI) m / z 399 [M + H] ⁺ .
[362] Example 135
[363]
[364] 5- [3-Chloro-5- (carboxaldehyde) phenylthio] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-ka in 5 ml of methanol To a solution of 25 mg of boxamide 3 mg of sodium borohydride was added. The mixture was stirred at rt for 2 h. Additional 3 mg sodium borohydride was added and the mixture was stirred for 1 h. 150 mg of silica gel was added to the reaction and the solvent was evaporated. The product absorbed onto silica was purified by flash chromatography on silica gel using methanol / dichloromethane (1: 9) for elution to yield 15 mg of a white solid. Mass spectrum (ESI) m / z 430 [M + H] ⁺ .
[365] Starting material 5- [3-chloro-5- (carboxaldehyde) phenylthio] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carbox Amides were prepared as follows:
[366] 5- [3-chloro-5-vinyl phenylthio] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H in 20 ml THF, 10 ml water and 6 ml t-butanol To the solution of pyrrole-3-carboxamide was added 290 mg of osmium tetroxide. The mixture was stirred at rt for 30 min and 330 mg sodium periodate was added. After 2 hours 60 mg of the product precipitated out as a white solid by the addition of ethyl acetate / water. Mass spectrum (ESI) m / z 425 [M + H] ⁺ .
[367] Example 127
[368]
[369] 4-[[2- (3-allyl-5-chlorophenylthio) -3-isopropyl-5-methyl [(4-pyrrolyl) methyl] pyridine in 7.5 ml THF, 4 ml water and 1 ml t-butanol To 30 mg of solution was added 18 mg of osmium tetroxide. The mixture was stirred at rt for 30 min and 20 mg of sodium periodate was added. After 2 hours, 15 mg of the product precipitated out as a white solid by the addition of diethyl ether. Mass spectrum (ESI) m / z 474 [M + H] ⁺ .
[370] Example 141
[371]
[372] 4-[[2- (3-bromo-5-chlorophenylthio) -3-isopropyl-5-methyl-1-pyrrolyl] methyl] pyridine 120 mg, copper cyanide (I) 96 mg, diphenylforce A mixture of 30 mg of pinot ferrocene, 40 mg of tetraethylammonium cyanide and 15 mg of bispalladium tris (dibenzylidene acetone) was dissolved in 15 ml of dioxane. The mixture was heated to 80 ° C. for 2 hours, followed by addition of another 96 mg of copper cyanide, 30 mg of diphenylphosphino ferrocene, 40 mg of tetraethylammonium cyanide and 15 mg of bispalladium tris (dibenzylidene acetone). And the mixture was heated for 72 hours. The reaction was then cooled and the mixture was stirred at rt for 18 h. The orange solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol / ethyl acetate (1: 4 then 1: 1) for elution and then ethyl acetate to give 57 mg as an oil, which was further purified by HPLC 17 mg was obtained. Mass spectrum (ESI) m / z 382 [M + H] ⁺ .
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权利要求:
Claims (24)
[1" claim-type="Currently amended] A compound of formula (I), a hydrolyzable ester or ether thereof or a pharmaceutically acceptable salt thereof:
Formula I

Where
R ¹ is alkyl, cycloalkyl, aryl or heterocyclyl,
R ² is alkyl, cycloalkyl, aryl or heterocyclyl,
R ³ is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl,
R ⁴ is hydrogen, alkyl, carboxyl, C (= 0) R, CONR'R ", cyano or alkenyl, wherein R is hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl -Oxy-carbonyl, R 'and R "are each independently hydrogen, alkyl or aryl;
R ⁵ is an alkyl, aryl or —ZC (═O) R ″ ′ group wherein Z is a single bond or —CH═CH— and R ″ ′ is hydrogen or alkyl,
X represents S, S (O), S (O) ₂ , O or N (alkyl), or XR ² together represent CH ₂ -aryl or CH ₂ -heterocyclyl,
However, the only one of R ³ and R ⁴ are hydrogen, alkyl in R ³ is not CF _3.
[2" claim-type="Currently amended] The method of claim 1,
R ¹ is alkyl,
R ² is alkyl or aryl,
R ³ is alkyl, cycloalkyl or aryl,
R ⁴ is hydrogen, alkyl, carboxyl, C (= 0) R, CONR'R ", cyano or alkenyl, where R is hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl -Oxy-carbonyl, R 'and R "are each independently hydrogen, alkyl or aryl;
R ⁵ is an alkyl, aryl or —ZC (═O) R ″ ′ group where Z is a single bond or —CH═CH— and R ″ ′ is hydrogen or alkyl,
X represents S, O or N (alkyl), or XR ² together represent CH ₂ -aryl or CH ₂ -heterocyclyl,
Provided that the alkyl in R ³ is not CF ₃ .
[3" claim-type="Currently amended] The method according to claim 1 or 2,
Alkyl, - R ¹ is C _1-7 - alkyl, or cycloalkyl, aryl and heterocyclyl of C _1-7 substituted by one to three substituents selected from the reel
R ² is C _1-7 -alkyl, phenyl or phenyl substituted with 1 to 5 substituents selected from C _1-7 -alkyl, halogen and nitro,
1 to 5 R ³ is selected from C _1-7 -alkyl, phenyl, C _1-7 -alkyl substituted with 1 to 3 heterocyclyls, or C _1-4 -alkyl, C _1-4 -alkoxy and halogen Phenyl substituted with a substituent,
R ⁴ is hydrogen, C _1-7 -alkyl, or hydroxy, amino, C _1-4 -alkoxy, phenyl, methyl-oxy-carbonyl, ethyl-oxy-carbonyl, azido, 2-pyridyl-carbo Nyl-amino, 3-pyridyl-carbonyl-amino, 4-pyridyl-carbonyl-amino, (phenoxy) -carbonyl-amino, (methoxy) -carbonyl-amino, (di-methyl-amino ) -Carbonyl-amino, (phenyl-amino) -carbonyl-amino, (amino) -carbonyl-amino, (phenyl) -carbonyl-amino, (methyl) -carbonyl-amino, methyl-carbonyl- Amino-methyl-carbonyl-amino, (t-butyl) -carbonyl-amino-methyl-carbonyl-amino, methyl-sulfonyl-amino, phenyl-sulfonyl-amino, p-toluyl-sulfonyl-amino , (N1-acetyl-Ot-butyl-N2-yl) -L-serinamide, (N1-acetyl-N2-yl) -L-serinamide and [N1- (t-butoxycarbonyl) -Ot-butyl C _1-7 -alkyl substituted with 1 to 3 substituents selected from -N2-yl] -L-serinamide,
R ⁵ is C _1-7 - alkyl, phenyl, or hydroxy, C _1-4 - alkoxy, methyl-carbonyl-oxy and amino-carbonyl-a C _1-7 substituted with 1 to 3 substituents selected from oxy -Alkyl,
A compound wherein X represents S, O or N (alkyl), or XR ² together represents CH ₂ -aryl or CH ₂ -heterocyclyl.
[4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
R ¹ is methyl, ethyl, isopropyl, cyclohexylmethyl, phenylmethyl or pyridylmethyl,
R ² is methyl, n-propyl, or phenyl substituted with 1 to 5 chlorine atoms,
R ³ is isopropyl, n-propyl or pyridylmethyl,
R ⁴ is hydrogen or hydroxy, amino, C _1-2 -alkoxy, 2-pyridyl-carbonyl-amino, 3-pyridyl-carbonyl-amino, 4-pyridyl-carbonyl-amino, (phenoxy C) -carbonyl-amino, (methoxy) -carbonyl-amino, (di-methyl-amino) -carbonyl-amino, (phenyl-amino) -carbonyl-amino, (amino) -carbonyl-amino , (Phenyl) -carbonyl-amino, (methyl) -carbonyl-amino, methyl-carbonyl-amino-methyl-carbonyl-amino, (t-butyl) -carbonyl-amino-methyl-carbonyl-amino , (N1-acetyl-Ot-butyl-N2-yl) -L-serinamide, (N1-acetyl-N2-yl) -L-serinamide and [N1- (t-butoxycarbonyl) -Ot-butyl C _1-2 -alkyl substituted with 1 to 3 substituents selected from -N2-yl] -L-serinamide,
R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, or hydroxy, C _1-2 -alkoxy, methyl-carbonyl-oxy and amino-carbo C _1-2 -alkyl substituted with 1 to 3 substituents selected from nil-oxy,
A compound wherein X represents S, O or N (alkyl), or XR ² together represents CH ₂ -aryl or CH ₂ -heterocyclyl.
[5" claim-type="Currently amended] The method according to any one of claims 1 to 4,
R ¹ is 4-pyridylmethyl,
R ² is methyl or 3,5-dichlorophenyl,
R ³ is isopropyl,
R ⁴ is hydroxy, 2-pyridyl-carbonyl-amino, 3-pyridyl-carbonyl-amino, 4-pyridyl-carbonyl-amino, (phenoxy) -carbonyl-amino, (methoxy) -Carbonyl-amino, (di-methyl-amino) -carbonyl-amino, (phenyl-amino) -carbonyl-amino, (amino) -carbonyl-amino, (phenyl) -carbonyl-amino, (methyl ) -Carbonyl-amino, methyl-carbonyl-amino-methyl-carbonyl-amino, (t-butyl) -carbonyl-amino-methyl-carbonyl-amino, (N1-acetyl-Ot-butyl-N2- Yl) -L-serineamide, (N1-acetyl-N2-yl) -L-serineamide and [N1- (t-butoxycarbonyl) -Ot-butyl-N2-yl] -L-serineamide C _1-2 -alkyl substituted with one or two substituents,
R ⁵ is C _1-2 -alkyl substituted with one to three substituents selected from methyl, ethyl, n-propyl, isopropyl, or hydroxy, methyl-carbonyl-oxy and amino-carbonyl-oxy,
A compound wherein X represents S, O or N (alkyl), or XR ² together represents CH ₂ -aryl or CH ₂ -heterocyclyl.
[6" claim-type="Currently amended] The method according to any one of claims 1 to 5,
X represents S.
[7" claim-type="Currently amended] A compound of formula (I), a hydrolyzable ester or ether thereof or a pharmaceutically acceptable salt thereof:
Formula I

Where
R ¹ is alkyl, cycloalkyl, aryl or heterocyclyl,
R ² is alkyl, cycloalkyl, aryl or heterocyclyl,
R ³ is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl,
R ⁴ is hydrogen, alkyl, carboxyl, C (═O) R or CONR ₂ , where R is hydrogen or alkyl,
R ⁵ is hydrogen or alkyl,
X represents S, S (O), S (O) ₂ , O or N (alkyl), or XR ² together represent CH ₂ -aryl or CH ₂ -heterocyclyl,
However, R ^3, R ^4, and R is hydrogen and only one of the ^five, in R ³ is an alkyl compound, not CF _3.
[8" claim-type="Currently amended] The method of claim 7, wherein
A compound wherein X represents S, S (O), S (O) ₂ , O or N (alkyl).
[9" claim-type="Currently amended] In claim 7 or 8,
X represents S.
[10" claim-type="Currently amended] The method according to any one of claims 7 to 9,
R ¹ is alkyl,
R ² is alkyl or aryl,
R ³ is alkyl or aryl,
R ⁴ is hydrogen, alkyl, carboxyl, C (═O) R or CONR ₂ .
[11" claim-type="Currently amended] The method according to any one of claims 7 to 10,
R ¹ is alkyl substituted with heterocyclyl or aryl, unsubstituted C _1-7 -alkyl, or alkyl substituted with cycloalkyl,
R ² is unsubstituted alkyl, unsubstituted phenyl, or substituted phenyl having 1 to 5 halogen, nitro or unsubstituted C _1-7 -alkyl as substituents,
R ³ is unsubstituted alkyl, substituted alkyl with heterocyclyl as substituent, unsubstituted phenyl, or substituted phenyl with 1 to 5 halogen, methoxy or unsubstituted alkyl as substituent,
R ⁴ is hydrogen, unsubstituted alkyl, substituted alkyl with hydroxy, amino or methoxy as substituent, carboxyl, C (═O) R or CONR ₂ ,
R ⁵ is hydrogen, unsubstituted alkyl, or substituted alkyl having hydroxy as a substituent,
X represents S.
[12" claim-type="Currently amended] The method according to any one of claims 7 to 11,
R ¹ is pyridylmethyl, phenylmethyl, methyl, ethyl, isopropyl or cyclohexylmethyl,
R ² is methyl, n-propyl or chlorinated phenyl,
R ³ is isopropyl, n-propyl or pyridylmethyl,
R ⁴ is substituted methyl or ethyl, carboxyl, C (═O) R or CONR ₂ with hydroxy or methoxy as substituent,
R ⁵ is methyl or ethyl optionally substituted with a hydroxy group,
X represents S.
[13" claim-type="Currently amended] The method according to any one of claims 7 to 12,
R ¹ is 4-pyridyl methyl,
R ² is methyl or 3,5-dichlorophenyl,
R ³ is isopropyl,
R ⁴ is methyl substituted with a hydroxy group, or C (═O) R,
R ⁵ is methyl,
X represents S.
[14" claim-type="Currently amended] The method of claim 7, wherein
Compounds selected from the following compounds:
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxaldehyde,
5- (3,5-dichlorophenylthio) -4-isopropyl-α (RS) -methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-ethanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-1,2-dimethyl-1H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -1-ethyl-4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
1-benzyl-5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
1- (cyclohexylmethyl) -5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(2-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(3-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5-phenylthio-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3-chlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (3-nitrophenylthio) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dimethylphenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-5-isopropylthio-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5-methylthio-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -2-methyl-4-phenyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4- (4-chlorophenyl) -5- (3,5-dichlorophenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -2-methyl-4- (4-methylphenyl) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4- (4-methoxyphenyl) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4- (3,4-dichlorophenyl) -5- (3,5-dichlorophenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxylic acid,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-4,5-dimethyl-1H-pyrrol-1-yl] methyl] pyridine,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methylamine,
4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-4- (methoxymethyl) -5-methyl-1H-pyrrol-1-yl] methyl] pyridine,
5- (3,5-dichlorophenylthio) -3- (hydroxymethyl) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -2-ethyl-4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenoxy) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5-[(3,5-dichlorophenyl) methylamino] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5-benzyl-4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-1,5-bis [(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -1-isopropyl-3-methyl-4-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol, and
5- (3,5-dichlorophenylthio) -4-isopropyl-3-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol.
[15" claim-type="Currently amended] The method of claim 1,
Compounds selected from the following compounds:
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxaldehyde,
5- (3,5-dichlorophenylthio) -4-isopropyl-α (RS) -methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-ethanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-1,2-dimethyl-1H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -1-ethyl-4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
1-benzyl-5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
1- (cyclohexylmethyl) -5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(2-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(3-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5-phenylthio-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3-chlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (3-nitrophenylthio) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dimethylphenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-5-isopropylthio-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5-methylthio-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -2-methyl-4-phenyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4- (4-chlorophenyl) -5- (3,5-dichlorophenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -2-methyl-4- (4-methylphenyl) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4- (4-methoxyphenyl) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4- (3,4-dichlorophenyl) -5- (3,5-dichlorophenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxylic acid,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-4,5-dimethyl-1H-pyrrol-1-yl] methyl] pyridine,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methylamine,
4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-4- (methoxymethyl) -5-methyl-1H-pyrrol-1-yl] methyl] pyridine,
5- (3,5-dichlorophenylthio) -3- (hydroxymethyl) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -2-ethyl-4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenoxy) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5-[(3,5-dichlorophenyl) methylamino] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5-benzyl-4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-1,5-bis [(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -1-isopropyl-3-methyl-4-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-3-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol,
5- (3,5-dichlorophenylthio) -2,4-dimethyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-phenyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(3-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (2-chloro-4-fluorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-5- (4-methoxyphenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (2-chlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- [3- (trifluoromethyl) phenylthio] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- [4- (trifluoromethoxy) phenylthio] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (2,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3,5-dichlorophenylthio) -2,4-diisopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (2-naphthylthio) -1-[(4-pyridinyl) methyl] -1 H-pyrrole-3-methanol,
5- (2,4-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3-fluorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3-chlorophenylthio) -2,4-diisopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-5- (3,4-dimethoxyphenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (2,4,6-trimethylphenylthio) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (3,4-dimethylphenylthio) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-5- (2,5-dimethoxyphenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (2,5-dimethylphenylthio) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-5- (2-methoxyphenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (2-fluorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (4-methylphenylthio) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
1-benzyl-5- (3-chlorophenylthio) -4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
5- (3-chlorophenylthio) -4-isopropyl-1- (4-methoxybenzyl) -2-methyl-1H-pyrrole-3-methanol,
5- (3-chlorophenylthio) -4-isopropyl-1- (3-methoxybenzyl) -2-methyl-1H-pyrrole-3-methanol,
1-[(5-chloro-1-benzothiophen-3-yl) methyl] -5- (3-chlorophenylthio) -4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
α (RS)-[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] benzyl alcohol,
5- (3-chlorophenylthio) -4-isopropyl-2-methyl-1-[(4-thiazolyl) methyl] -1 H-pyrrole-3-methanol,
5- (3-chlorophenylthio) -4-isopropyl-2-methyl-1-[(3- (4-pyridyl) propyl] -1 H-pyrrole-3-methanol,
5- (3-chlorophenylthio) -4-isopropyl-2-methyl-1-[(2-quinolyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (2,4-dimethylphenylthio) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-5- (3-methylphenylthio) -1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (2-chloro-6-methylphenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3-chlorophenylthio) -1-[[4-chloro-2- (trifluoromethyl) -6-quinolyl] methyl] -4-isopropyl-2-methyl-1H-pyrrole-3- Methanol,
5- (4-ethylphenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-5- (3-methoxyphenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (2,4,6-trichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
N-benzyl-2- (3-chlorophenylthio) -4- (hydroxymethyl) -3-isopropyl-5-methyl-1-pyrroleacetamide,
5- (3-chlorophenylthio) -1-[[6- (trifluoromethyl) -3-pyridyl] methyl] -4-isopropyl-2-methyl-1H-pyrrole-3-methanol,
[5- (3,5-Dichloro-phenylsulfanyl) -4-isopropyl-2-methyl-1-pyridin-4-ylmethyl-1H-pyrrol-3-yl] -hydroxy-acetic acid ethyl ester,
N-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] methyl] -4- Pyridineacetamide,
2-acetamido-N-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl ] Methyl] acetamide,
N-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] methyl] -p- Toluenesulfonamide,
t-butyl [[[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] methyl] Carbamoyl] methyl] carbamate,
N2-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrol-3-yl] methyl] glycinamide,
N-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl-1H-pyrrol-3-yl] methyl] methanesulfonamide,
Phenyl [[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrol-3-yl] methyl] carbamate,
Methyl [[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrol-3-yl] methyl] carbamate,
N-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrol-3-yl] methyl] benzenesulfonamide ,
N1-acetyl-Ot-butyl-N2-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3 -Ylmethyl] -L-serineamide,
N1-acetyl-N2-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrole-3-yl] methyl ] -L-serineamide,
N1- (t-butoxycarbonyl) -Ot-butyl-N2-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl ] -1H-pyrrole-3-yl] methyl] -L-serineamide,
1-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] methyl] -3, 3-dimethylurea,
1-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrol-3-yl] methyl] -3- Methyl-3-phenylurea,
1-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] methyl] urea,
4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-4- (methoxymethyl) -5-methyl-1-pyrrolyl] methyl] pyridine,
4-[[2- (3-chlorophenylthio) -3-isopropyl-4- (methoxymethyl) -5-methyl-1-pyrrolyl] methyl] pyridine,
4-[[3- (azidomethyl) -5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-pyrrolyl] methyl] pyridine,
N-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] methyl] acetamide,
4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-5-methyl-4-vinyl-1-pyrrolyl] methyl] pyridine,
1 (RS)-[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] -1, 2-ethanediol,
N-[[5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] methyl] benzamide,
t-butyl 5- (3-bromo-5-chlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxylate,
t-butyl 5- (3,5-dibromophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxylate,
1- [5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-3-yl] -2,2,2 Trifluoroethanone,
1- [5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1H-pyrrol-3-yl] ethanone,
5- (3,5-dibromophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
4-isopropyl-5- (3,5-dimethoxyphenylthio) -2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (3-bromo-5-chlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
Ethyl 5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-glyoxalate,
5- (3-cyanophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (3-chlorophenylthio) -2- (hydroxymethyl) -4-isopropyl-α (RS) -methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-ethanol,
5- (3,5-dichlorophenylthio) -3- (hydroxymethyl) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-carboxaldehyde,
5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2,3-dicarboxaldehyde,
5- (3,5-Dichlorophenylthio) -3- (hydroxymethyl) -4-isopropyl-α (RS) -methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2- ethanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(3-pyridyl) methyl] -1 H-pyrrole-2,3-dimethanol,
5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-methanol,
[5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-2-yl] methyl acetate,
5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-2-carbaldehyde,
4- [5- (3,5-Dichloro-phenylsulfonyl) -4-isopropyl-1-pyridin-4-ylmethyl-1H-pyrrol-2-yl] -but-3-en-2-one,
4-[[2- (3,5-dichlorophenylthio) -5-methyl-3-phenyl-1-pyrrolyl] methyl] pyridine,
4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-5-methyl-1-pyrrolyl] methyl] pyridine,
5- (3,5-dichlorophenylthio) -N- (2,4,6-trimethoxybenzyl) -2-methyl-4-phenyl-1-[(4-pyridyl) methyl] -1H-pyrrole -3-carboxamide,
5- (3,5-dichlorophenylthio) -2-methyl-4-phenyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxylic acid trifluoroacetate (1: 1),
5- (3,5-dichlorophenylthio) -4-phenyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (3,5-dichlorophenylthio) -2-methyl-4-phenyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carbonitrile,
5- (3,5-dichlorophenylthio) -4-isopropyl-N, 2-dimethyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (3,5-dichlorophenylthio) -4-cyclopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (3,5-dichlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxanilide,
5- (3,5-dichlorophenylthio) -4-isopropyl-N, N, 2-trimethyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (3-allyl-5-chlorophenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (3-chloro-5-propylphenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (3-chloro-5-vinylphenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- [3-chloro-5- (2 (RS) -3-dihydroxypropyl) phenylthio] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole -3-carboxamide,
4-[[2- (3,5-dichlorophenylthio) -5- (ethoxymethyl) -3-isopropyl-1-pyrrolyl] methyl] pyridine,
4-[[2- (3,5-dichlorophenylthio) -3-isopropyl-5- (methoxymethyl) -1-pyrrolyl] methyl] pyridine,
[5- (3,5-dichlorophenylthio) -4-isopropyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-2-yl] methyl carbamate,
4-[[2- (3-bromo-5-chlorophenylthio) -3-isopropyl-5-methyl-1-pyrrolyl] methyl] pyridine,
4-[[2- (3-allyl-5-chlorophenylthio) -3-isopropyl-5-methyl-[(4-pyrrolyl] methyl] pyridine,
4-[[2- (3-chloro-5-propylphenylthio) -3-isopropyl-5-methyl-1-pyrrolyl] methyl] pyridine,
5- (3-chloro-5-ethylphenylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- [3-chloro-5- (hydroxymethyl) phenylthio] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
5- (2-biphenylylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (3-biphenylylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -5- [2- (3-pyridyl) phenylthio] -1 H-pyrrole-3-methanol,
5- [2- (hydroxymethyl) phenylthio] -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-methanol,
5- (5-chloro-3-biphenylylthio) -4-isopropyl-2-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrole-3-carboxamide,
3-chloro-5- [3-isopropyl-5-methyl-1-[(4-pyridinyl) methyl] -1H-pyrrol-2-ylthio] benzonitrile, and
5- [3-isopropyl-5-methyl-1-[(4-pyridyl) methyl] -1 H-pyrrol-2-ylthio] -1,3-dibenzonitrile.
[16" claim-type="Currently amended] A process for preparing a compound of formula VIII comprising reacting a compound of formula VII with an iodinating agent to yield an iodo pyrrole derivative of formula VIII:
Formula VII

Formula VIII

Where
R, R ³ and R ⁵ are as described for formula I in claim 1.
[17" claim-type="Currently amended] A compound of formula (VIII)
Formula VIII

Where
R, R ³ and R ⁵ are as described for formula I in claim 1.
[18" claim-type="Currently amended] A composition containing a compound of formula (I) or a hydrolysable ester, ether or pharmaceutically acceptable salt thereof, or a compound of formula (I) according to any one of claims 1 to 15 for use as a medicament.
[19" claim-type="Currently amended] A compound of formula I according to any one of claims 1 to 15 or a hydrolyzable ester, ether or pharmaceutically thereof for the manufacture of a medicament for the treatment of a disease mediated by human immunodeficiency virus (HIV). Use of a composition containing an acceptable salt or a compound of formula (I).
[20" claim-type="Currently amended] A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 15 or a hydrolyzable ester, ether or pharmaceutically acceptable salt thereof, and a pharmaceutically inert carrier, if necessary.
[21" claim-type="Currently amended] A method for the preparation of a medicament comprising the preparation of a compound according to any one of claims 1 to 15 or a hydrolyzable ester, ether or pharmaceutically acceptable salt thereof in a herbal dosage form with a pharmaceutically inert carrier.
[22" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 15 or a hydrolyzable ester, ether or pharmaceutically acceptable salt thereof in the treatment of a disease mediated by human immunodeficiency virus (HIV).
[23" claim-type="Currently amended] A human immunodeficiency virus (HIV) in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound according to any one of claims 1 to 15 or a hydrolyzable ester, ether or pharmaceutically acceptable salt thereof. Method of treatment of diseases mediated by).
[24" claim-type="Currently amended] The invention described above.

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同族专利:

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公开号 | 公开日

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US20020032221A1|2002-03-14|

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PA8516201A1|2002-07-30|

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BR0112241A|2003-06-24|

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AR028602A1|2003-05-14|

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GT200100111A|2002-03-18|

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WO2002002524A1|2002-01-10|

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AU2001263874B2|2006-10-19|

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ECSP014109A|2002-02-25|

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KR100549884B1|2006-02-06|

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EP1301481A1|2003-04-16|

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CN1440385A|2003-09-03|

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US6737429B2|2004-05-18|

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UY26720A1|2001-11-30|

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GB0016453D0|2000-08-23|

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MXPA02012409A|2003-04-25|

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PE20020269A1|2002-04-08|

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AU6387401A|2002-01-14|

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JP2004502674A|2004-01-29|

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CA2412270A1|2002-01-10|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-07-04|Priority to GBGB0016453.3A

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2000-07-04|Priority to GB0016453.3

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2001-04-30|Application filed by 에프. 호프만-라 로슈 아게

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2001-04-30|Priority to PCT/EP2001/004832

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2003-02-15|Publication of KR20030014321A

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2006-02-06|Application granted

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2006-02-06|Publication of KR100549884B1

优先权:

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申请号 | 申请日 | 专利标题

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GBGB0016453.3A|GB0016453D0|2000-07-04|2000-07-04|Pyrrole derivatives|

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GB0016453.3|2000-07-04|

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PCT/EP2001/004832|WO2002002524A1|2000-07-04|2001-04-30|Pyrrole derivatives for treating aids|