A sizing formulation adapted for use with carbon fiber yarn comprising an aqueous dispersion of a film-forming, heat-reactive resin having a Tg below about -50.degree. C. and a water-dispersible ethoxylated alkyl phenol provides yarn having improved resistance to abrasion, less breakage and low fuzz formation, permitting substantial handling of the fiber in fabrication and weaving operations with reduced losses. In addition, the sizing may be readily removed thermally without the production of noxious byproducts when deemed necessary for use in further processing and impregnation operations.

This invention relates to carbon fibers and more particularly to continuous carbon fiber yarn having improved handling characteristics including increased abrasion resistance, together with reduction in yarn breakage and low fuzz generation during processing, and to a method for improving the handling characteristics of carbon fiber yarn. While continuous carbon fiber yarn from a variety of sources may be improved when produced according to the invention, high modulus carbon fiber yams including those comprising pitch-based carbon fibers are particularly benefited.
Carbon fibers have long been known, and methods for their production from a variety of precursors are well-described in the art. Cellulosic precursors have been used for producing carbon fiber since the early 1960's, with rayon being the dominant carbon fiber precursor for nearly two decades. More recently, as the art has developed methods for producing carbon fiber derived from such materials as polyacrylonitrile (PAN) and pitch, the importance of rayon-based carbon fiber has declined. This shift has been due in part to the superior toughness, tensile strength and stiffness exhibited by both PAN-based and pitch-based carbon fiber.
Polyacrylonitrile fiber, when oxidized and carbonized under appropriate conditions, provides tough, high strength, high modulus carbon fiber. The overall conversion yield in producing fiber from PAN is good, and the finished fiber is capable of achieving the outstanding tensile strength needed for producing the high performance composite materials used in a variety of sports, automotive and aircraft applications. However, the tensile modulus of commercially available PAN-based fiber does not generally exceed about 50.times.10.sup.6 psi, which is somewhat deficient for use in applications that require a high degree of stiffness.
Pitch-based carbon fiber has generally been recognized as capable of providing greater stiffness than carbon fiber from other sources, and considerable effort has been directed toward the development of pitch-based ultra-high modulus carbon fibers.
Such carbon fibers find application in forming composites for use where good dissipation of electrical charges or heat is desired. In addition, the combination of high stiffness and good thermal conductivity with the negative coefficient of thermal expansion characteristically exhibited by pitch-based fibers provides composites that are extraordinarily dimensionally stable.
Carbon fibers are widely used in the manufacture of aircraft parts, space devices, precision machines, transport devices, sporting goods, and the like because of their excellent mechanical properties, such as specific strength, specific modulus, and chemical resistance. In such uses the carbon fiber is ordinarily used as reinforcement in composite materials comprising a matrix component such as a metal, graphitic carbon, a ceramic, a synthetic resin or the like. Carbon fiber-reinforced composites having synthetic resins as a matrix have found wide acceptance in view of the versatility, uniformity in performance and cost.
Fabricating composites is generally accomplished by processes such as filament winding, and by layup and impregnation using tape and fabric woven from carbon fiber yams. These processes generally require contacting the yam with rollers, guides, spreaders and the like. Continuous carbon fiber, particularly including those carbon fibers having high tensile modulus values designated in the art as "ultra-high modulus", characteristically exhibit poor abrasion resistance and can be regarded as brittle and difficult to handle. The conventional processing thus tends to damage the carbon filaments, which in turn may cause undesirable fuzz, flaws in the resulting composites and loss in production due to yam breakage. A variety of sizes and filer coatings have been devised for use with carbon fiber to improve abrasion resistance and reduce losses.
U.S. Pat. No. 3,837,904 discloses coating the carbon fiber with from 5 to 60 volume per cent of a resin formulation as a size to improve bonding between the matrix and the fiber surface. The coating is generally accomplished after fast surface treating the fiber to etch or pit the surface. The fiber is said to exhibit improved abrasion resistance and reduce fuzzing. Additional sizes are known in the art for this purpose, including, for example, those described in U.S. Pat. No. 4,219,457 and U.S. Pat. No. 4,496,671. Although improvement in handling characteristics is realized for these formulations, as the art has turned to use of higher modulus carbon fiber yam and to more complex and more demanding forming processes and equipment, the prior art sizes have been found inadequate. Further, the use of woven structures for composite fabrication has found greater acceptance in the art. The processes and equipment used in weaving complex structures place great stress on yam and tow surfaces and significantly increases the possibility of damage. In addition, bonding between the fiber and the matrix component that will subsequently be impregnated into the structure is greatly affected by the presence of the size, and it is often desirable to remove the size after weaving, ordinarily in a thermal operation. Prior art sizes, particularly those that are cross-linked, may be difficult to cleanly remove without causing fiber damage.
Methods and sizing formulations for carbon fiber that provide improved yam abrasion resistance and handling character, particularly for high modulus continuous carbon fiber yarn, and that are readily removed after the fabrication operations would thus be a useful advance in the composite manufacturing art.

Carbon fiber yarn having improved handling characteristics


Disclosed are novel pyrrole derivatives, a process for their manufacture, pharmaceutical compositions containing such compounds and the use of such compounds in the treatment of HIV mediated diseases.

The invention is concerned with novel pyrrole derivatives, a process for their manufacture, pharmaceutical compositions and the use of such compounds in the treatment of viral diseases. In particular, the compounds are inhibitors of the human immunodeficiency virus reverse transcriptase enzyme which is involved in viral replication. Consequently the compounds of this invention are useful in the treatment or therapy of diseases mediated by the human immunodeficiency virus (HIV).
The disease Acquired Immunodeficiency Syndrome (AIDS) is the end result of infection by the distinct retroviruses, human immunodeficiency virus type-1 (HIV-1) or type-2 (HIV-2). Several critical points in the virus""s life cycle have been identified as possible targets for therapeutic intervention. Inhibition of one of these, the transcription of viral RNA to viral DNA (reverse transcriptase, RT), has provided a number of the current therapies used in treating AIDS. Inhibition of reverse transcriptase provided the first form of treatment for HIV infection with 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT). Since then several inhibitors have been launched, broadly forming two classes: nucleoside analogues and non-nucleosides. As an example of the latter it has been found that certain benzoxazinones, e.g. efavirenz are useful in the inhibition of HIV RT. However, development of strains of the virus resistant to current RT inhibitors is a constant problem. Therefore, development of compounds effective against resistant strains is an important goal.
Certain pyrrole derivatives have been disclosed to have therapeutic utilities.
U.S. Pat. No. 3,644,631 describes pyrrole derivatives effective for the therapy of inflammatory syndromes.
U.S. Pat. No. 4,282,242 describes pyrrole derivatives effective for the therapy of lowering the blood glucose level in hyperglycemic mammals.
The object of the present invention is to provide novel compounds which are potent inhibitors of the human immunodeficiency virus reverse transcriptase enzyme, which is involved in viral replication, and which accordingly are useful as antiviral drugs. Specifically, this invention is directed to the compounds of formula I
wherein R1, R2, R3, R4, and R5 are as defined below.
This invention is also directed to pharmaceutical compositions containing compounds for formula I and the use of the compositions in the treatment or therapy of HIV.
This invention is directed, inter alia, to a compound of formula
wherein
R1 is alkyl, cycloalkyl, aryl or heterocyclyl;
R2 is alkyl cycloalkyl, aryl or heterocyclyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl;
R4 is hydrogen, alkyl, carboxyl, C(xe2x95x90O)R, CONRxe2x80x2Rxe2x80x3, cyano or alkenyl;
R is hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl-oxy-carbonyl;
Rxe2x80x2 and Rxe2x80x3, are each independently selected from hydrogen, alkyl or aryl;
R5 is alkyl, aryl or a group xe2x80x94Zxe2x80x94C(xe2x95x90O)Rxe2x80x2xe2x80x3;
Z is a single bond or xe2x80x94CHxe2x95x90CHxe2x80x94;
Rxe2x80x2xe2x80x3 is hydrogen or alkyl;
X represents S, S(O), S(O)2, O, N(alkyl), or Xxe2x80x94R2 together represent CH2-aryl or CH2-heterocyclyl;
provided that only one of R3 and R4 is hydrogen, and provided further that alkyl in R3 is not CF3;
or hydrolyzable esters or ethers of the foregoing compound, or a pharmaceutically acceptable salt thereof.
The term xe2x80x9calkylxe2x80x9d as used herein, and if not otherwise specified by the number of carbon atoms, denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, including their different isomers.
Suitable substituents for the alkyl chain can be selected from one or more of
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, heterocylyl 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.
In case more than one substituent is attached to the alkyl group, these substituents can be identical or different from each other.
The suitable substituents for the alkyl group aryl and heterocyclyl may be substituted with 1-3 substituents, preferably 1-2 substituents, more preferably 1 substituent selected from C1-4-alkyl (preferably methyl), C1-4-alkoxy (preferably methoxy), halogen (preferably chlorine) or trifluoromethyl. Examples for substituted alkyl are 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-pyridyl-ethyl, 3-pyridyl-propyl, 3-pyridyl-butyl, methyl-3-pyridyl-methyl, methyl-3-pyridyl-ethyl, dimethyl-3-pyridyl-methyl, ethyl-3-pyridyl-methyl, methoxy-3-pyridyl-methyl, methoxy-3-pyridyl-ethyl, dimethoxy-3-pyridyl-methyl, fluoro-3-pyridyl-methyl, difluoro-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-pyridyl-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, 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-pyridyl-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-dimethylphenylmethyl, 3,4-dimethylphenylmethyl, 3,5-dimethylphenylmethyl, 3,6-dimethylphenylmethyl, 2-ethyphenylmethyl, 3-ethylphenylmethyl, 4-ethylphenylmethyl, 2,3-diethylphenylmethyl, 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-trifluoromethyl-phenylethyl, 4-trifluoromethyl-phenylethyl, 2,3-di-trifluoromethyl-phenylmethyl, 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-methoxy3y-phenylethyl, 3-methoxy-phenylethyl, 4-methoxy-phenylethyl, 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-trimethoxy-phenylmethyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2,3-difluorophenylmethyl, 2,4-difluorophenylmethyl, 2,5-difluorophenylmethyl, 2,6-difluorophenylmethyl, 3,4-difluorophenylmethyl, 3,5-difluorophenylmethyl, 3,6-difluorophenylmethyl, 2-fluorophenylethyl, 3-fluorophenylethyl or 4-fluorophenylethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 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 or 4-bromophenylethyl. 2-phenyl-phenylmethyl, 3-phenyl-phenylmethyl, 4-phenyl-phenylmethyl, 2-phenoxy-phenylmethyl, 3-phenoxy-phenylmethyl, 4-phenoxy-phenylmethyl, 2-nitro-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-methanesulfonyl-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-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-(trifiuoromethyl)-quinolinyl-6-methyl, 4-chloro-2-(trifluoromethyl)-quinolinyl-6-methyl, 2-pyrimidyl, 4-pyrimidyl or 2[1,3,5-triazinyl].
Alkyl in R1 is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms as defined above or substituted C1-7-alkyl with 1-3 substituents, preferably 1-2 substituents, more preferably 1 substituent selected from heterocyclyl, aryl and cycloalkyl. Alkyl in R1 is more preferable methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, 2-pyridylmethyl, 2-pyridylethyl, 2-pyridylpropyl, 2-pyridylbutyl, 3-pyridylmethyl, 3-pyridylethyl, 3-pyridylpropyl, 3-pyridylbutyl, 4-pyridylmethyl, 4-pyridylethyl, 4-pyridylpropyl, 4-pyridylbutyl, 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-(trifluoromethyl)-3-pyridyl-1-methyl, 3-(trifluoromethyl)-2-pyridyl-1-methyl, 4-(trifluoromethyl)-2-pyridyl-1-methyl or N-benzylamidomethyl. Further preferred alkyl substituents for R1 are methyl, ethyl, isopropyl, cyclohexylmethyl, phenylmethyl or pyridylmethyl. Most preferred alkyl substituent for R1 is 4-pyridylmethyl.
Alkyl in R2 is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms as defined above, more preferable methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert.-butyl. Further preferred alkyl substituents for R2 are methyl or n-propyl. Most preferred alkyl in R2 is methyl.
Alkyl in R3 is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms as defined above or substituted C1-7-alkyl with 1-3 substituents, preferably 1-2 substituents, more preferably 1 substituent selected from heterocyclyl. More preferable alkyl in R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, 2-pyridylmethyl, 2-pyridylethyl, 3-pyridylmethyl, 3-pyridylethyl, 4-pyridylmethyl, 4-pyridylethyl. Further preferred alkyl substituents for R3 are isopropyl, n-propyl or pyridylmethyl. Most preferred alkyl in R3 is isopropyl. Alkyl in R3 is not CF3.
Alkyl in R4 is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms as defined above or substituted C1-7-alkyl (preferably C1-2-alkyl) with 1-3 substituents, preferably 1-2 substituents, more preferably 1 substituent selected from hydroxy, amino, C1-4-alkoxy (preferably, C1-2-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, (tert.-butyl)-carbonyl-amino-methyl-carbonyl-amino, methyl-sulfonyl-amino, phenyl-sulfonyl-amino, p-toluyl-sulfonyl-amino, (N1-acetyl-O-tert.-butyl-N2-yl)-L-serinamide, (N1-acetyl-N2-yl)-L-serinamide and [N1-(tert.-butoxycarbonyl)-O-tert.-butyl-N2-yl]-L-serinamide. More preferred substituents for C1-7-alkyl (preferably C1-2-alkyl) are selected from hydroxy, amino, C1-2-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, (tert.-butyl)-carbonyl-amino-methyl-carbonyl-amino, (N1-acetyl-O-tert.-butyl-N2-yl)-L-serinamide, (N1-acetyl-N2-yl)-L-serinamide and [N1-(tert.-butoxycarbonyl)-O-tert.-butyl-N2-yl]-L-serinamide. Most preferred substituents for C1-7-alkyl (preferably C1-2-alkyl) are selected from 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, (tert.-butyl)-carbonyl-amino-methyl-carbonyl-amino, (N1-acetyl-O-tert.-butyl-N2-yl)-L-serinamide, (N1-acetyl-N2-yl)-L-serinamide and [N1-(tert.-butoxycarbonyl)-O-tert.-butyl-N2-yl]-L-serinamide. In case more than one substituent is attached to the alkyl group, these substituents can be identical or different from each other. Alkyl in R4 is more preferable methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-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, (tert.-butyl)-carbonyl-amino-methyl-carbonyl-amino-methyl, (N1-acetyl-O-tert.-butyl-N2-ylmethyl)-L-serinamide, (N1-acetyl-N2-yl]methyl)-L-serinamide, [N1-(tert.-butoxycarbonyl)-O-tert.-butyl-N2-yl-methyl]-L-serinamide, methyl-sulfonyl-amino-methyl, phenyl-sulfonyl-amino-methyl or p-toluyl-sulfonyl-amino-methyl. Preferred alkyl for R4 is unsubstituted C1-7-alkyl (preferably C1-4-alkyl) or substituted C1-7-alkyl (preferably C1-4-alkyl, more preferred C1-2-alkyl) with hydroxy or amino or methoxy as substituents. More preferable alkyl in R4 is methyl or ethyl substituted with a hydroxy group or a methoxy group or (methyl)-carbonyl-amino-methyl. Further preferred alkyl groups for R4 are methyl or ethyl substituted with a hydroxy group or a methoxy. More preferred alkyl in R4 is methyl substituted with a hydroxy group or (methyl)-carbonyl-amino-methyl. Most preferred alkyl in R4 is methyl substituted with a hydroxy group.
Alkyl in R5 is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms (preferably, C1-4-alkyl), as defined above or substituted C1-7-alkyl (preferably C1-4-alkyl, more preferred C1-2-alkyl) with 1-3 substituents, preferably 1-2 substituents, more preferably 1 substituent selected from hydroxy, C1-4-alkoxy (preferably methoxy or ethoxy), methyl-carbonyl-oxy or amino-carbonyl-oxy. Alkyl in R5 is more preferable methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, 1,2-ethanediol, 1,2-propanediol, methoxy-methyl, ethoxy-methyl, (methyl-carbonyl-oxy)-methyl, (amino-carbonyl-oxy)-methyl. More preferable alkyl in R5 is methyl, ethyl, n-propyl, isopropyl or substituted C1-2-alkyl substituted with 1-3 substituents selected from hydroxy, methyl-carbonyl-oxy and amino-carbonyl-oxy. Further preferred alkyl in R5 is methyl, ethyl, (amino-carbonyl-oxy)-methyl or C1-2-alkyl substituted with a hydroxy group. Another preferred alkyl in R5 is methyl or (amino-carbonyl-oxy)-methyl, most preferred alkyl in R5 is methyl.
In another preferred embodiment of the invention, alkyl in R5 is unsubstituted alkyl or substituted alkyl with hydroxy as substituent, more preferably wherein alkyl in R5 is methyl or ethyl optionally substituted with a hydroxy group, and most preferred wherein alkyl in R5 is methyl.
Alkyl in R, Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms as defined above and more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl.
Alkyl for N(alkyl) is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms and most preferred methyl.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein, and if not specified by the number of carbon atoms, denotes an optionally substituted cycloalkyl group containing 3 to 8 carbon atoms, e.g. cyclopropyl, cydobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The term xe2x80x9ccycloalkylxe2x80x9d preferably denotes a cycloalkyl group containing 3 to 6 carbon atoms.
Suitable substituents for cycloalkyl can be selected from those named for alkyl, in addition however an oxo group (xe2x95x90O) can be added to the selection.
Cycloalkyl in R1 and R2 are as defined above.
Cycloalkyl in R3 denotes an optionally substituted cycloalkyl group containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Most preferred cycloalkyl in R3 denotes a cyclopropyl group.
The term xe2x80x9calkoxyxe2x80x9d as used herein, and if not otherwise specified by the number of carbon atoms, denotes a straight or branched chain alkyl-oxy group wherein the xe2x80x9calkylxe2x80x9d portion is as defined above such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert.-butyloxy, pentyloxy, hexyloxy, heptyloxy including their different isomers. More preferred alkoxy groups within the invention are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert.-butyloxy.
Alkoxy in R is as defined above.
The term xe2x80x9calkenylxe2x80x9d as used herein, and if not specified by the number of carbon atoms, denotes an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, including their different isomers. Examples are vinyl or allyl.
Alkenyl in R4 is as defined above.
The term xe2x80x9cC(xe2x95x90O)R,xe2x80x9d as used herein for R4, denotes a hydrogen atom, an C1-7-alkyl group (preferably C1-4-alkyl as defined above for the alkyl substituent R), alkoxy (preferably C1-4-alkoxy), trifluoromethyl, methyl-oxy-carbonyl, ethyl-oxy-carbonyl, each of these substituents attached to a keto function xe2x80x94C(xe2x95x90O)xe2x80x94. Preferred examples are an aldehyde group (C(xe2x95x90O)H), methyl-carbonyl, ethyl-carbonyl, tert.-butoxy-carbonyl, trifluoromethyl-carbonyl, methyl-oxy-dicarbonyl or ethyl-oxy-carbonyl.
The term xe2x80x9cCONRxe2x80x2Rxe2x80x3 xe2x80x9d as used herein for R4, denotes, independently of each other, hydrogen, C1-7-alkyl (preferably C1-4-alkyl), substituted aryl (preferably phenyl), each of these substituents attached to a amino-carbonyl function. Preferred examples are amino-carbonyl (CONH2), (methyl-amino)-carbonyl, (dimethyl-amino)-carbonyl, (phenyl-amino)-carbonyl or (2, 4, 6-trimethoxy-methyl)-amino-carbonyl.
The term xe2x80x9cxe2x80x94Zxe2x80x94C(xe2x95x90O)Rxe2x80x2xe2x80x3 xe2x80x9d as used herein for R5, wherein Z is a single bond or xe2x80x94CHxe2x95x90CHxe2x80x94 and Rxe2x80x2xe2x80x3 is hydrogen or alkyl (preferably C1-4-alkyl) denotes an aldehyde group (C(xe2x95x90O)H), methyl-carbonyl or ethyl-carbonyl, aldehyde-ethylene (xe2x80x94CHxe2x95x90CH)C(xe2x95x90O)H), (methyl-carbonyl)-ethylene (xe2x80x94CHxe2x95x90CH)C(xe2x95x90O) CH3) or (ethyl-carbonyl)-ethylene (xe2x80x94CHxe2x95x90CH)C(xe2x95x90O)C2H5). The ethylene group of the invention can have the (E) or (Z) configuration. Both isomeric forms of these compounds are embraced by the present invention.
The term xe2x80x9carylxe2x80x9d as used herein denotes an optionally substituted phenyl and naphthyl, both optionally benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle e.g. to cyclohexyl or cyclopentyl.
Suitable substituents for aryl can be selected from those named for alkyl, in addition however C1-4-alkyl, trifluoromethyl, trifluoromethoxy, C2-4-alkenyl, 1,2-propanediol, cyano and hydroxy-methyl can be added to the selection.
In case more than one substituent is attached to the aryl group, these substituents can be identical or different from each other.
Aryl in R1 is preferably an unsubstituted or substituted phenyl with suitable substituents selected from 1 to 5 of halogen, nitro and unsubstituted straight or branched chain alkyl containing 1 to 4 carbon atoms.
Aryl in R2 is preferably an unsubstituted or substituted phenyl or naphthyl (preferably phenyl) with suitable substituents selected from 1 to 5 substituents, preferably 1-4 substituents, more preferably 1-3 substituent selected from C1-7-alkyl (preferable C1-4-alkyl), trifluoromethyl, C1-4-alkoxy (preferable C1-2-alkoxy), trifluoromethoxy, C2-4-alkenyl, 1,2-propanediol, fluorine, chlorine, bromine, iodine, nitro, cyano, phenyl, hydroxy-methyl, 4-pyridyl, 3-pyridyl and 2-pyridyl (preferably 1-3 substituent selected from C1-7-alkyl (preferable C1-4-alkyl), halogen and nitro; more preferably 1-3 substituent selected from halogen; most preferably 1-3 substituent selected from chlorine). In case more than one substituent is attached to the aryl group, these substituents can be identical or different from each other. Examples of substituted aryl groups are 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-fluorophenyl, 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-trichlorophenyl, 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-cyano-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-(trifluoromethoxy)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. Preferred example for aryl in R2 is 3,5-dichlorophenyl.
Aryl in R3 is preferably an unsubstituted or substituted phenyl with suitable substituents selected from 1 to 5 substituents, preferably 1-4 substituents, more preferably 1-3 substituent selected from C1-4-alkyl (preferable C1-2-alkyl), C1-4-alkoxy (preferable C1-2-alkoxy), fluorine, chlorine, bromine, iodine and phenyl (preferably 1-3 substituent selected from C1-4-alkyl (preferable C1-2-alkyl), C1-4-alkoxy (preferable C1-2-alkoxy) and halogen; more preferably 1-3 substituent selected from C1-4-alkyl (preferable C1-2-alkyl) and C1-4-alkoxy (preferable C1-2-alkoxy). Examples of substituted aryl groups are 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 R3 is phenyl.
Aryl in R5, Rxe2x80x2 and Rxe2x80x3 is as defined above, preferably phenyl.
The term xe2x80x9cheterocyclylxe2x80x9d as used herein denotes an optionally substituted saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocycle which contains 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur which can also be fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic carbocycle or heterocycle.
Examples of suitable heterocycles are oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-dioxolanyl, dihydropyranyl, thienyl, pyrazinyl, isothiazolyl, isoquinolinyl, indolyl, indazolyl, quinolinyl, dihydrooxazolyl, pyrimidinyl, benzofuranyl, tetrazolyl, pyrrolidinyl, pyrrolidinonyl, (N-oxide)-pyridinyl, pyrrolyl, triazolyl e.g. 1,2,4-triazolyl, pyrazolyl, benzotriazolyl, piperidinyl, morpholinyl, thiazolyl, pyridyl, dihydrothiazolyl, imidazolidinyl, pyrazolinyl, benzothienyl, piperazinyl, imidazolyl, thiadiazolyl e.g. 1,2,3-thiadiazolyl, and benzothiazolyl. Most preferred example is pyridyl.
Heterocyclyl in R1, R2 and R3 is preferably an unsubstituted or substituted pyridyl with suitable substituents selected from 1 to 5 of halogen, nitro and unsubstituted straight or branched chain alkyl containing 1 to 4 carbon atoms.
Suitable substituents for heterocyclyl can be selected from those named for alkyl, in addition however an oxo group (xe2x95x90O) as substituent can be added to the selection.
The term xe2x80x9cC(xe2x95x90O)R xe2x80x9d as used herein denotes an carbonyl group to which is attached a substituent selected from hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl and ethyl-oxy-carbonyl (preferably hydrogen or alkyl). Examples for suitable substituents for the carbonyl group are hydrogen, tert.-butoxy, trifluoromethyl, methyl, ethyl-oxy-carbonyl. In an other embodiment of the invention preferred acyl groups are those wherein R is hydrogen or an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms.
The term xe2x80x9cCONRxe2x80x2Rxe2x80x3 xe2x80x9d as used herein denotes amides wherein Rxe2x80x2 and Rxe2x80x3 are each independently selected from hydrogen, alkyl or aryl (preferably hydrogen or C1-7-alkyl (preferable C1-4-alkyl)). Examples for suitable substituents for the amide group (Rxe2x80x2 and/or Rxe2x80x3) are hydrogen, C1-4-alkyl (preferably methyl), phenyl, 2,4,6-trimethoxy-benzyl.
The term xe2x80x9cXxe2x80x9d represents S, S(O), S(O)2, O, N(alkyl) or Xxe2x80x94R2 together represent CH2-aryl (preferably CH2-phenyl) or CH2-heterocyclyl (preferably CH2-(4)-pyridyl, CH2-(3)-pyridyl, CH2-(2)-pyridyl), more preferable S, S(O), S(O)2, O, N(alkyl). Most preferably, xe2x80x9cXxe2x80x9d is S.
The term halogen stands for fluorine, chlorine, bromine and iodine, most preferably chlorine.
Any functional (i.e. reactive) group present in a side-chain may be protected, with the protecting group being a group which is known to one skilled in the art, for example, as described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Ed., T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, N.Y., 1991. For example, an amino group can be protected by tert.-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z).
The compounds of this invention may contain one or more asymmetric carbon atoms and may therefore occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Furthermore, where a compound of the invention contains an olefinic double bond, this can have the (E) or (Z) configuration. Also, each chiral center may be of the R or S configuration. All such isomeric forms of these compounds are embraced by the present invention.
Compounds of formula I which are acidic can form pharmaceutically acceptable salts with bases such as alkali metal hydroxides, e.g. sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides, e.g. calcium hydroxide, barium hydroxide and magnesium hydroxide, and the like; with organic bases e.g. N-ethyl piperidine, dibenzylamine, and the like. Those compounds of formula (I) which are basic can form pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid, and the like, and with organic acids, e.g. with acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulphonic acid and p-toluene sulphonic acid, and the like. The formation and isolation of such salts can be carried out according to methods known in the art.
A preferred embodiment of the invention are compounds of formula I wherein
R1 is alkyl,
preferably wherein
R1 is C1-7 alkyl or C1-7 alkyl substituted with 1-3 substituents selected from cycloalkyl, aryl and heterocyclyl,
more preferably wherein
R1 is methyl, ethyl, isopropyl, cyclohexylmethyl, phenylmethyl, pyridylmethyl,
most preferably wherein
R1 is 4-pyridylmethyl;
R2 is alkyl or aryl,
preferably wherein
R2 is C1-7 alkyl, phenyl or phenyl substituted with 1-5 substituents selected from C1-7 alkyl, halogen and nitro,
more preferably wherein
R2 is methyl, n-propyl or phenyl substituted with 1-5 chlorine atoms,
most preferably wherein
R2 is methyl or 3,5-dichlorophenyl;
R3 is alkyl, cycloalkyl or aryl,
preferably wherein
R3 is C1-7 alkyl, C1-7 alkyl substituted with 1-3 heterocyclyl, phenyl or phenyl substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy and halogen;
more preferably wherein
R3 is isopropyl, n-propyl or pyridylmethyl,
most preferably wherein
R3 is isopropyl;
R4 is hydrogen, alkyl, carboxyl, C(xe2x95x90O)R, CONRxe2x80x2Rxe2x80x3, cyano or alkenyl, wherein
R is hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl-oxy-carbonyl,
wherein
Rxe2x80x2 and Rxe2x80x3, are independently of each other, hydrogen, alkyl or aryl, preferably wherein
R4 is hydrogen, C1-7 alkyl or C1-7 alkyl substituted with 1-3 substituents selected from hydroxy, amino, C1-4-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, (tert.-butyl)-carbonyl-amino-methyl-carbonyl-amino, methyl-sulfonyl-amino, phenyl-sulfonyl-amino, p-toluyl-sulfonyl-amino, (N1-acetyl-O-tert.-butyl-N2-yl)-L-serinamide, (N1-acetyl-N2-yl)-L-serinamide and [N1-(tert.-butoxycarbonyl)-O-tert.-butyl-N2-yl]-L-serinamide,
more preferably wherein
R4 is hydrogen or C1-2 alkyl substituted with 1-3 substituents selected from hydroxy, amino, C1-2-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, (tert.-butyl)-carbonyl-amino-methyl-carbonyl-amino, (N1-acetyl-O-tert.-butyl-N2-yl)-L-serinamide, (N1-acetyl-N2-yl)-L-serinamide and [N1-(tert.-butoxycarbonyl)-O-tert.-butyl-N2-yl]-L-serinamide,
most preferably wherein
R4 is C1-2 alkyl substituted with 1-2 substituents selected from 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, (tert.-butyl)-carbonyl-amino-methyl-carbonyl-amino, (N1-acetyl-O-tert.-butyl-N2-yl)-L-serinamide, (N1-acetyl-N2-yl)-L-serinamide and [N1-(tert.-butoxycarbonyl)-O-tert.-butyl-N2-yl]-L-serinamide;
R5 is alkyl, aryl or a group xe2x80x94Zxe2x80x94C(xe2x95x90O)Rxe2x80x2xe2x80x3, wherein
Z is a single bond or xe2x80x94CHxe2x95x90CHxe2x80x94, and
Rxe2x80x2xe2x80x3 is hydrogen or alkyl, preferably wherein
R5 is C1-7 alkyl, phenyl, C1-7 alkyl substituted with 1-3 substituents selected from hydroxy, C1-4-alkoxy, methyl-carbonyl-oxy and amino-carbonyl-oxy,
more preferably wherein
R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl or C1-2-alkyl substituted with 1-3 substituents selected from hydroxy, C1-2-alkoxy, methyl-carbonyl-oxy and amino-carbonyl-oxy,
most preferably wherein
R5 is methyl, ethyl, n-propyl, isopropyl or C1-2-alkyl substituted with 1-3 substituents selected from hydroxy, methyl-carbonyl-oxy and amino-carbonyl-oxy;
X represents S, O, N(alkyl) or Xxe2x80x94R2 together represent CH2-aryl or CH2-heterocyclyl; and with the proviso that alkyl in R3 is not CF3,
preferably wherein
X represents S.
Other preferred embodiments of the invention are compounds of formula I
wherein
R1 is alkyl, cycloalkyl, aryl or heterocyclyl,
preferably wherein
R1 is alkyl,
more preferably wherein
R1 is alkyl substituted with heterocyclyl or aryl, unsubstituted C1-7 alkyl or alkyl substituted with cycloalkyl,
most preferably wherein
R1 is pyridylmethyl, phenylmethyl, methyl, ethyl, isopropyl, cyclohexylmethyl;
R2 is alkyl, cycloalkyl, aryl or heterocyclyl,
preferably wherein
R2 is alkyl or aryl,
more preferably wherein
R2 is unsubstituted alkyl, unsubstituted phenyl or substituted phenyl with 1 to 5 halogen or nitro or unsubstituted C1-7 alkyl as substituents,
most preferably wherein
R2 is methyl, n-propyl or chlorinated phenyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl,
preferably wherein
R3 is alkyl or aryl,
more preferably wherein
R3 is unsubstituted alkyl or substituted alkyl with heterocyclyl as substituent, unsubstituted phenyl or substituted phenyl with 1 to 5 halogen or methoxy or unsubstituted alkyl as substituents,
most preferably wherein
R3 is isopropyl, n-propyl or pyridylmethyl;
R4 is hydrogen, alkyl, carboxyl, C(xe2x95x90O)R or CONR2wherein
R is hydrogen or alkyl, preferably wherein
R4 is hydrogen, alkyl, carboxyl, C(xe2x95x90O)R or CONR2,
more preferably wherein
R4 is hydrogen, unsubstituted alkyl or substituted alkyl with hydroxy or amino or methoxy as substituents, carboxyl, C(xe2x95x90O)R, CONR2,
most preferably wherein
R4 is methyl or ethyl with hydroxy or methoxy as substituents, carboxyl, C(xe2x95x90O)R, CONR2;
R5 is hydrogen or alkyl,
preferably wherein
R5 is hydrogen, unsubstituted alkyl or substituted alkyl with hydroxy as substituent,
more preferably wherein
R5 is methyl or ethyl optionally substituted with a hydroxy group;
X represents S, S(O), S(O)2, O, N(alkyl) or Xxe2x80x94R2 together represent CH2-aryl or CH2-heterocyclyl; and with the proviso that only one of R3, R4 and R5 is hydrogen and alkyl in R3 is not CF3,
preferably wherein
X represents S, S(O), S(O)2, O, N(alkyl),
more preferably wherein
X represents S; and hydrolyzable esters or ethers thereof or a pharmaceutically acceptable salt thereof.
Other preferred embodiments of the invention are compounds of formula I wherein
R1 is 4-pyridyl methyl;
R2 is methyl or 3,5-dichlorophenyl;
R3 is isopropyl;
R4 is methyl substituted with a hydroxy group or C(xe2x95x90O)R;
R5 is methyl; and
X represents S.
Additional preferred embodiments of compounds of formula I, as well as hydrolyzable esters or ethers thereof or a pharmaceutically acceptable salt thereof, are listed in table 1 below.
The compounds of formula I and hydrolyzable esters or ethers thereof or a pharmaceutically acceptable salt thereof are inhibitors of the human immunodeficiency virus reverse transcriptase enzyme both in vitro and in vivo, and are useful in the control or prevention of diseases mediated by the human immunodeficiency virus (HIV).
These compounds are especially useful for treating viral diseases, immune mediated conditions or diseases, bacterial diseases, parasitic diseases, inflammatory diseases, hyperproliferative vascular diseases, tumors, and cancer.
In particular, compounds of the present invention and pharmaceutical compositions containing the same are useful as chemotherapeutic agents, inhibitors of viral replication and modulators of the immune system, and can be used (either alone or in combination with other antiviral agents such as interferon or derivatives thereof, such as conjugates with polyethylene glycol) for the treatment of diseases mediated by the human immunodeficiency virus (HIV) and other viral diseases such as retroviral infections.
Compounds of the invention can be used alone, or in combination with other therapeutically active agents, for example, an immunosuppressant, a chemotherapeutic agent, an anti-viral agent, an antibiotic, an anti-parasitic agent, an anti-inflammatory agent, an anti-fungal agent and/or an anti-vascular hyperproliferation agent.
The compounds of the present invention can be prepared as shown in the following scheme.
wherein R1, R2, R3xe2x80x2 R5 and R are as defined above for compounds of formula I and xe2x80x9cProtxe2x80x9d is an amino protecting group.
In accordance with the present invention, compounds of formula VIII are prepared by reacting the compound of formula VII
wherein R, R3 and R5 are as described above in formula I with a iodination agent to obtain the iodo pyrrole derivative of formula VIII
wherein R, R3 and R5 are as described in formula I.
Iodination agents useful for this reaction are known in the art and are for example N-iodosuccinimide, iodic acid in the presence of iodine, iodine in the presence of potassium iodide or sodium iodide, potassium iodide or sodium iodide in the presence of hydrogen peroxide.
The reactions can be carried out in a conventional manner known to the skilled in the art.
In reaction scheme I, N-protected glycine (commercially available from Fluka) of formula II is reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of N-ethylmorpholine and N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide hydrochloride under nitrogen atmosphere. The term xe2x80x9camino protecting groupxe2x80x9d (Prot) as used herein refers to groups such as those employed in peptide chemistry such as a tert.-butoxy-carbonyl group (t-BOC) or a benzyloxycarbonyl group (Z). Preferred amino protecting group (Prot) for this reaction is a tert.-butoxycarbonyl group. The reaction is conveniently carried out at a reaction temperature from 0xc2x0 C. to room temperature in an inert solvent, for example halogenated hydrocarbons such as anhydrous dichloromethane or polar aprotic solvents such as N,N-dimethylformamide (DMF) or tetrahydrofuran (THF), preferably dichloromethane, to yield the N-protected glycine N-methyl-N-methoxyamide of formula III.
The N-protected glycine N-methyl-N-methoxyamide of formula III is converted to the compound of formula IV by reaction with a Grignard reagent of the formula R3MgX (commercially available or synthesized according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) wherein R3 is as defined above but not hydrogen (for R3 being hydrogen, the reaction sequence starts with compound of the formula V; see below) and X represents a halogen for example chlorine. The reaction is conveniently carried out in an inert solvent, for example ethers such as anhydrous tetrahydrofuran, diethyl ether, dioxane or a mixture of the mentioned solvents at a reaction temperature from 0xc2x0 C. to room temperature. After the reaction, the Grignard product is worked-up in a manner known in the art for example with a solution of diluted hydrochloric acid, to yield the N-protected (xcex1-amino ketone of formula IV.
In the next step of the reaction, the N-protected xcex1-amino ketone of formula IV is reacted with trifluoroacetic acid or with hydrogen chloride thereby obtaining the deprotected xcex1-amino ketone of formula V. In forming the compound of formula V, any conventional method for deprotecting protected amino groups can be utilized in carrying out this reaction. The deprotection reaction of the compounds of formula IV is preferably carried out with trifluoroacetic acid optionally dissolved in dichloromethane or hydrogen chloride dissolved in ethyl acetate, dioxane or methanol at a reaction temperature from 0xc2x0 C. to room temperature. Most preferred, the deprotection reaction is carried out with hydrogen chloride dissolved in ethyl acetate.
The xcex1-amino ketone of formula V is coupled with a xcex2-keto ester of the formula VI wherein R5 and R are as defined above (commercially available or synthesized according to methods known from textbooks on heterocyclic chemistry or organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) to form a pyrrole derivative of the formula VII. The synthesis of the pyrrole derivatives according to the Knorr synthesis of the formula VII is carried out in a manner known in the art. The reaction of the compounds of formula V and VI to yield compounds of the formula VII is preferably carried out with a mixture of potassium hydroxide and K2HPO4 in water at a reaction temperature from 20 to 40xc2x0 C. Most preferred, the reaction is carried out with a mixture of ethyl acetoacetate, sodium acetate and acetic acid at a reaction temperature from 70 to 100xc2x0 C.
In the next step of the reaction, an iodo pyrrole derivative of formula VIII is formed by the reaction of pyrrole derivative of the formula VII with an iodination agent. The iodination agent used for this reaction is known in the art and are for example N-iodosuccinimide, iodic acid in the presence of iodine, iodine in the presence of potassium iodide or sodium iodide, potassium iodide or sodium iodide in the presence of hydrogen peroxide. The reaction is for example carried out in an inert solvent, such as ethers, hydrocarbons or halogenated hydrocarbons preferably anhydrous dichloromethane at a reaction temperature from 0 to 40xc2x0 C., preferably at room temperature in the presence of a iodination agent for example N-iodosuccinimide to yield the iodo pyrrole derivative of formula VIII. After the reaction, the product is worked-up in a manner known in the art, for example the mixture is washed with an aqueous solution of sodium thiosulphate and an aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulphate and finally the organic solvent was evaporated. The reaction is known in the literature for example from textbooks on organic chemistry e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons or as described in Y. Murata, Bull. Chem. Soc. Jpn. 1996 (11), 3339. The use of above-mentioned iodination agents is described for example in Synthesis 1995 (12), 1480, Tetrahedron 1992 (48) 44, 9661 or Liebigs Ann. Chem. 1989 (9), 863.
The iodo pyrrole derivatives of formula VIII are converted to the corresponding pyrrole thio compounds of formula IX by reaction with a disulphide compound of the formula R2SSR2 or by the reaction with a compound of the formula R2SX wherein R2 is as defined above and X is a halogen, preferably chlorine (the compounds of the formula R2SSR2 and R2SX are commercially available or can be synthesized according to methods known from the art for example as described in U.S. Pat. No. 4,282,242). The reaction is conveniently carried out by treating the compound of formula VIII under nitrogen atmosphere with a strong base for example sodium hydride or preferably lithium hydride, in an inert solvent for example anhydrous dimethyl sulphoxide at a reaction temperature from 0xc2x0 C. to room temperature and then reacting the mixture with the compounds of the formula R2SX or preferably with the disulphide compound of the formula R2SSR2. The reaction is preferably carried out at a reaction temperature from 40 to 60xc2x0 C., yielding the compound of formula IX. After the reaction, the product is worked-up in a manner known in the art for example extracted with diethyl ether, dried over anhydrous magnesium sulphate and finally the organic solvent is evaporated.
In the next step of the reaction, the compound of formula IX is reacted with a compound of the formula R1X wherein R1 is as defined above with the exception hydrogen (the compound for R1 being hydrogen has already been described; see compound IX) and X represents a halogen for example bromo (commercially available or synthesized according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) to obtain the N-substituted compound of the formula XI. In forming the compound of formula XI, any conventional method of substitution can be utilized in carrying out this reaction. The reaction of the compounds of formulas IX is preferably carried out under nitrogen in an inert solvent for example polar aprotic solvents such as tetrahydrofuran (THF) or N,N-dimethylformamide (DMF), preferably anhydrous THF at a temperature from 0xc2x0 C. to room temperature in the presence of tetra-n-butylammonium bromide and in the presence of a base such as sodium hydroxide, potassium carbonate, sodium hydride or an amine of the formula R3N wherein R is methyl, ethyl or propyl. The most preferred base is sodium hydroxide. Finally the mixture is reacted with the compound of the formula R1X to obtain the compound of formula XI.
The conversion of a compound of the formula XI to a compound of the formula Ia wherein R, R1, R2, R3 and R5are as defined above and R4 is CH2OH and X represents S, is carried in that the compound of formula XI is reduced to the compound of formula Ia by reacting it with a reducing agent such as lithium aluminum hydride. The reaction is conveniently carried out by treating the compound of formula XI under nitrogen atmosphere with a reducing agent, for example LiAlH4, LiBH4, BH3*S(CH3)2, iso-Bu2AlH or Vitride(copyright), in an inert solvent such as ethers for example anhydrous diethyl ether, THF of dioxane at a reaction temperature from 0xc2x0 C. to room temperature. Preferably, the reaction is carried out with LiAlH4 and ethers. Then a solution of ammonium chloride is added to yield to a compound of the formula Ia. After the reaction, the product is worked-up in a manner known in the art for example extracted with ethyl acetate, dried over anhydrous magnesium sulphate and finally the organic solvent is evaporated.
Oxidation of a compound of the formula Ia to a compound of the formula Ib wherein R, R1, R2, R3 and R5are as defined above, R4 is C(xe2x95x90O)H and X represents S, is carried in that the compound of formula Ia is oxidized with an oxidizing reagent such iodobenzene diacetate in the presence of 2,2,6,6-tetramethylpiperidine N-oxide, (COCl)2 in the presence of dimethyl sulfoxide (DMSO), pyridinium chlorochromate in dichloromethane or MnO2 in ethers such as diethyl ether or in a halogenated hydrocarbons such as anhydrous dichloromethane or trichloromethane or in an aprotic polar solvent such as acetone and a compound of the formula Ib is obtained. The reaction is conveniently carried out by treating the compound of formula Ia under nitrogen atmosphere with an oxidizing agent, preferably iodobenzene diacetate and 2,2,6,6-tetramethylpiperidine N-oxide, in an inert solvent for example anhydrous dichloromethane at a reaction temperature from 0xc2x0 C. to room temperature to yield to a compound of the formula Ib. After the reaction, the product is worked-up in a manner known in the art for example washed with solutions of sodium thiosulphate and sodium hydrogen carbonate dried over anhydrous sodium sulphate and finally the organic solvent is evaporated.
Conversion of a compound of the formula Ib to a compound of the formula Ic wherein R, R1, R2, R3 and R5 are as defined above and R4 is CH(R)OH and X represents S, is carried in that the compound of formula Ib is reacted with a Grignard reagent of the formula RMgX or a reagent of the formula RLi (both compounds are commercially available or can be synthesized according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) wherein R is as defined above but not hydrogen (for R being hydrogen, the synthesis has already been described; see compound of the formula Ia) and X represents a halogen for example bromo to yield to a compound of the formula Ic. The reaction is conveniently carried out by treating the compound of formula Ib under nitrogen atmosphere, in an inert solvent for example ethers such as anhydrous tetrahydrofuran (THF), diethyl ether or dioxane, preferably THF with a Grignard reagent of the formula RMgX, preferably methyl magnesium bromide at a reaction temperature from 0xc2x0 C. to room temperature and then a solution of ammonium chloride is added to yield to a compound of the formula Ib. After the reaction, the product is worked-up in a manner known in the art for example extracted with ethyl acetate dried over anhydrous magnesium sulphate and finally the organic solvent is evaporated.
Compounds of the formula Ia wherein R, R1, R2, R3 and R5are as defined above, R4 is hydrogen and X represents S, are synthesized according to known methods from the art. For example the ester compounds of the formula XI are hydrolysed to the corresponding carboxylic acid according to methods known in the literature for example from textbooks on organic chemistry e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons. In a second step carboxylic acid function of the pyrrole derivative is then decarboxylated according to methods known in the art and for example described in S. F. Macdonald, J. Chem. Soc. 1952, 4176 or G. Kleinspehn, J. Am. Chem. Soc. 1954, 76, 5641.
Compounds of the formula Ia wherein R, R1, R2, R3 and R5 are as defined above, R4 is alkyl and X represents S, are synthesized according to known methods from the art. For example the compounds can be synthesised through elimination reaction of a compound of the formula Ic in a two step reaction, first in the presence of CH3SO2Cl and Et3N and secondly with a base such as potassium hydroxide or sodium hydroxide to form the corresponding alkenyl compound which is subsequently hydrogenated in the presence of hydrogen and palladium on activated coal (Pd/C) to the corresponding alkyl substituted pyrrole derivative. The reaction are all known in the literature for example from textbooks on organic chemistry e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons.
Compound of the formula I wherein R, R1, R2, R3 and R5 are as defined above and R4 is C(xe2x95x90O)R wherein R is alkyl are synthesized according to known methods from the art. For example, the hydroxy compounds of the formula Ic are oxidised according to methods known from the art for example from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) to obtain the corresponding oxo derivatives.
Compounds of the formula I wherein R, R1, R2, R3 and R5 are as defined above and R4 is CONR2 are synthesized according to known methods from the art. For example, the ester compounds of the formula XI is hydrolysed as described above, then reacted with thionyl chloride to obtain the activated acid chloride and finally reacted with a compound of the formula HNR2 wherein R is hydrogen or alkyl to obtain the corresponding amide derivative. The reaction are all known in the literature for example from textbooks on organic chemistry e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons.
Compounds of the formula I wherein R, R1, R2, R3 R4 and R5 are as defined above and X is S(O) or S(O)2 are synthesized according to known methods from the art. For example, the compounds of the formula I, Ia, Ib or Ic are oxidized, to obtain the corresponding oxidised thio compounds derivatives. The reaction is known in the literature for example from textbooks on organic chemistry e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons.
Compounds of the formula I wherein R, R1, R2, R3 R4 and R5 are as defined above and X is O or N(alkyl) are synthesized according to known methods from the art. For example, the compounds of the formula VII are reacted with N-bromosuccinimide (NBS) to obtain the corresponding 2-substituted bromopyrrole which is further reacted with a neutral oxygen nucleophile, such as 3-methoxyphenol in the presence of Et3N to obtain the corresponding oxy pyrrole derivative. To obtain the corresponding N-substituted pyrrole derivatives, the above-mentioned 2-substituted bromopyrrole is reacted with a secondary amine in a polar aprotic solvent such as N,N-dimethylformamide (DMF). The reactions are all known in the literature for example from textbooks on organic chemistry e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons or G. Cirrincione et al., Synthesis, 1997, 1169.
Compounds of the formula I wherein R, R1, R2, R3 R4 and R5 are as defined above and Xxe2x80x94R2 together represent CH2-aryl or CH2-heterocyclyl are synthesized according to known methods from the art. For example, compounds of the formula Va
wherein R3 is as defined above and Xxe2x80x94R2 together represent CH2-aryl or CH2-heterocyclyl are coupled with a xcex2-keto ester of the formula VI wherein R5 and R are as defined above (commercially available or synthesized according to methods known from textbooks on heterocyclic chemistry or organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) to form a pyrrole derivative of the formula VIIa
wherein R, R3, R5 and Xxe2x80x94R2 are as defined above. The synthesis of the pyrrole derivatives according to the Knorr synthesis of the formula VIIa is carried out in a manner known in the art. Subsequently the compound of the formula VIIa is further reacted according the above-described reactions starting with compound IXxe2x86x92XIxe2x86x92Iaxe2x86x92Ibxe2x86x92Ic.
The compounds of formula VIII are new intermediates and therefore are also an object of the present invention.
wherein R1, R2, R3 and R5 are as defined for compounds of formula I, R6 is C1-4-alkyl and R7 taken together with the amino-methyl group is 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, (tert.-butyl)-carbonyl-amino-methyl-carbonyl-amino-methyl, (N1-Acetyl-O-tert.-butyl-N2-ylmethyl)-L-serinamide, (N1-Acetyl-N2-yl]methyl)-L-serinamide, [N1-(tert.-butoxycarbonyl)-O-tert.-butyl-N2-yl-methyl]-L-serinamide, methyl-sulfonyl-amino-methyl, phenyl-sulfonyl-amino-methyl or p-toluyl-sulfonyl-amino-methyl.
The primary alcohol I-a may be alkylated, acylated or reacted with isocyanates to give carbamates according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons. These are standard reactions of which there are many combinations of reagents, for example, alkylation may be achieved using alkyl iodides, bromides, chlorides, triflates or any other suitable leaving group. Acylation may be achieved via acid chlorides or other activated carbonyl compounds such as activated carboxylic acids. Carbamates are accessible by reacting I-a with isocyanates in a standard procedure.
I-a may be further derivatised to the azide I-e using sodium azide or diphenylphosphoryl azide in standard procedures according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons. I-e may be reduced to the primary amine I-f using hydrogenation with standard catalysts such as 10% palladium on carbon in suitable solvents, such as ethyl acetate, methanol or ethanol, or with a trialkyl or aryl phosphine.
The primary amine I-f may be alkylated, acylated, sulfonylated or reacted with isocyanates (to give ureas) to give I-g according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons. These are standard reactions of which there are many combinations of reagents, for example, alkylation may be achieved using alkyl iodides, bromides, chlorides, triflates or any other suitable leaving group. Acylation may be achieved via acid chlorides or other activated carbonyl compounds such as activated carboxylic acids. Sulfonylation may be via sulfonyl chlorides using a base such as triethylamine, N-methyl morpholine or N-ethyl morpholine. All these reactions may be conducted in suitable solvents known to those skilled in the art, for example, dichloromethane, chloroform, dioxane, dimethyformamide, tetrahydrofuran, etc.
Ureas are accessible by reacting I-f with isocyanates in a standard procedure.
Derivatives of ester XI (reaction scheme 1), where the ester is replaced by other carbonyl groups (see reaction scheme 3), may be prepared according to reaction scheme 1 where the only change is intermediate VI for intermediate XII:
wherein R1, R2 and R3, are as defined for compounds of formula I, where R5 is alkyl and R5a, is hydrogen, amino, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl-oxy-carbonyl.
The chemistry to form the pyrrole and the subsequent reactions are as for those reactions already described in reaction scheme 1.
When R5a=methyl, yet further derivatives of the pyrrole may be prepared according to reaction scheme 4:
wherein R1, R2, R3xe2x80x2 and R5 are as defined for compounds of formula I.
I-h, prepared according to reaction scheme 3, may be reduced to the ethanol derivative I-i as already described. Elimination of water to form the vinyl compound I-j is achieved thermally by heating in a high boiling solvent such as DMSO, DMF, N-methyl pyrrolidinone, etc. Conversion of I-j into diol I-k may be achieved with osmium tetroxide, a standard reaction according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons.
Ketone reduction of I-l (when R5axe2x95x90COCOOEt) to form I-m is achieved using the same chemistry as for preparation of I-i:
wherein R1, R2, R3 and R5 are as defined above for compounds of formula I.
The pyrrole may also be constructed using a cycloaddition reaction according to the method of Yavari, Synthetic Communications, 1996, 4495-4500 (reaction scheme 6).
wherein R1, R2 and R3 are as defined above for compounds of formula I.
In reaction scheme 6, the amino ketone V is reacted with diethylacetylene dicarboxylate of formula XIV in sodium acetate in refluxing ethanol to give an intermediate which is cyclised with acid giving XV. Other acetylenic esters may be used such as methyl, benzyl or aryl in a range of alcoholic solvents such as propanol or butanol.
Intermediate XV may be converted to XVI according to methods already described in reaction scheme 1.
Reduction of both esters in XVI to give I-n may be accomplished according to the preparation of 1a from X1 (see Reaction Scheme 1), preferably with lithium aluminum hydride in ether.
Using basic hydrolysis, the 2-position ester may be selectively cleaved to give carboxylic acid XVII. Any strong mineral base is suitable for this purpose, preferably hydroxide ions (sodium or potassium hydroxide), in an alcoholic solvent such as ethanol, propanol, butanol. XVII may then be derivatised with N,O-dimethyl hydroxylamine according to intermediate III (see Reaction Scheme 1) to give the amide XVIII. Reduction of this amide and the ester in XVIII with lithium aluminum hydride (as above for the synthesis of I-n) gives aldehyde I-o. Grignard addition to the aldehyde in I-o gives compounds I-p, using the same method as for the synthesis of I-c (reaction scheme 1).
wherein R1, R2 and R3xe2x80x2 are as defined for compounds of formula I.
Preparation of intermediate XX may be constructed using a cycloaddition reaction according to the method of Yavari, Synthetic Communications, 1996, 4495-4500 (Scheme 2a), as for intermediate XV.
Reduction of the ester and ketone in XXI to give I-q may be accomplished with lithium aluminum hydride in ether, as for I-p and I-a.
wherein R1, R2, R3xe2x80x2 and R5 are as defined for compounds of formula I.
Tert.-butyl ester XI-a (prepared according to reaction scheme 1) may be hydrolysed using methods known in the art, such as trifluoroacetic acid in dichloromethane, to give the carboxylic acid XXII, a versatile intermediate which may be either thermally decarboxylated to I-r or derivatised further to amide I-s. Similar amide bond formations of XXII may be carried out with a variety of amines to give amides I-s"" where, Rxe2x80x2 and Rxe2x80x3 are defined above. Treatment of I-s with trifluoroacetic acid in dichloromethane reveals the primary amide I-t. Dehydration of I-t to give I-u may be achieved with Lawessons reagent according to Cava, Michael P.; Levinson, Matthew I Tetrahedron (1985), 41(22), 5061-87, which gives the nitrile.
wherein R1, R2 and R3xe2x80x2 are as defined for compounds of formula I.
In reaction scheme 9, compound I-r (R5=methyl, synthesized according to reaction scheme 8), may be oxidised with lead tetraacetate to give a mixture of the aldehyde I-v and acetate I-w. Lead tetraacetate is a well known oxidant to those skilled in the art but other oxidants, such as potassium permanganate may also be used to oxidise aromatic methyl groups as in I-r.
Acetate I-w (crude) may then be hydrolysed to primary alcohol I-x using any method known in the art, such as alkaline hydrolysis with sodium or potassium hydroxide. On purification the by-product I-y was isolated. Alcohol I-x may then be derivatised to the primary carbamate I-z using trichloroacetyl isocyanate. The starting alcohol may be conveniently dissolved in a suitable organic solvent such as dichloromethane or chloroform and the reagent trichloroacetyl isocyanate added keeping the reaction temperature below 5 degrees but above xe2x88x9210 degrees. The work up involves use of bases such as sodium or potassium carbonate followed by purification using standard procedures. Other methods known in the art are not effective in this transformation, such as chlorosulfonyl isocyanate or trimethylsilyl isocyanate.
wherein R1, R3 and R5 are as defined for compounds of formula I, A is Cl-4-alkoxy or amino and R is C1-4-alkyl.
In reaction scheme 10, intermediate XXIII (synthesized according to reaction scheme 1 using 3-bromo-5-chlorophenyldisulfide) may be transformed to I-aa using sp2-sp2 coupling reactions known to persons skilled in the art (e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). Such reactions are typically catalysed by a suitable palladium species such as tetrakis(triphenyl-phosphine) palladium, palladium acetate or dibenylideneacetone palladium. Nitrile groups may be installed using the reactivity of the aryl bromide XXIII using copper (I) cyanide to give I-ab. This reaction may also be performed on the aryl dibromide to give the aryl dinitrile.
wherein R1, R3 and R5 are as defined for compounds of formula I and n is 0 or 1.
In reaction scheme 11, intermediate XXIV, a subset of XXIII, may be reduced to the saturated alkyl chain I-ac by palladium catalysed hydrogenation. Oxidation of XXIV via osmium catalysed dihydroxylation gives I-ae. Sodium periodate cleavage of I-ae gives alcohol I-ad, according to standard procedures well known in the art.
The following assay protocols were used to measure the enzyme inhibition and antiviral activity of the compounds of the invention.
HIV-1 Reverse Transcriptase Assay: Inhibitor IC50 Determination.
HIV-1 RT assay was carried out in 96-well Millipore filtermat NOB50 plates using purified recombinant enzyme and a poly(rA)/oligo(dT)16 template-primer in a total volume of 50 xcexcL. The assay constituents were 50 mM Tris/HCl, 50 mM NaCl, 1 mM EDTA, 6 mM MgCl2, 5 xcexcM dTTP, 0.1 xcexcCi [3H] dTTP, 5 xcexcg/ml poly (rA) pre annealed to 2.5 xcexcg/ml oligo (dT)16 and a range of inhibitor concentrations in a final concentration of 10% DMSO. Reactions were initiated by adding 5 nM HIV-1 RT and after incubation at 37xc2x0 C. for 30 min, they were stopped by the addition of 50 xcexcl ice cold 20% TCA and allowed to precipitate at 4xc2x0 C. for 30 min. The precipitates were collected by applying vacuum to the plate and sequentially washing with 2xc3x97200 xcexcl of 10% TCA and 2xc3x97200 xcexcl 70% ethanol. Finally the plates were dried and radioactivity counted in a Wallac Microbeta 1450 after the addition of 15 xcexcl scintillation fluid per well. IC50""s were calculated by plotting % inhibition versus log10 inhibitor concentrations.
Antiviral Assay Method
Anti-HIV antiviral activity was assessed using an adaptation of the method of Pauwels et al. {Pauwels et al., 1988, J Virol Methods 20:309-321}. The method is based on the ability of compounds to protect HIV-infected T lymphoblastoid cells (MT4 cells) from cell-death mediated by the infection. The endpoint of the assay was calculated as the concentration of compound at which the cell viability of the culture was preserved by 50% (xe2x80x9850% inhibitory concentrationxe2x80x99, IC50). The cell viability of a culture was determined by the uptake of soluble, yellow 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and its reduction to a purple insoluble formazan salt. After solubilization, spectrophotometric methods were employed to measure the amount of formazan product.
MT4 cells were prepared to be in logarithmic-phase growth and a total of 2xc3x97106 cells infected with the HXB2-strain of HIV at a multiplicity of 0.0001 infectious units of virus per cell in a total volume of between 200-500 microliters. The cells were incubated with virus for one h at 37xc2x0 C. before removal of virus. The cells are then washed in 0.01 M phosphate buffered saline, pH 7.2 before being resuspensed in culture medium for incubation in culture with serial dilutions of test compound. The culture medium used was RPMI 1640 without phenol red, supplemented with penicillin, streptomycin, L-glutamine and 10% fetal calf serum (GM10).
Test compounds were prepared as 2 mM solutions in dimethyl sulphoxide (DMSO). Four replicate, serial 2-fold dilutions in GM10 were then prepared and 50 microliters amounts placed in 96-well plates over a final nanomolar concentration range of 625-1.22. Fifty microliters GM10 and 3.5xc3x97104 infected cells were then added to each well. Control cultures containing no cells (blank), uninfected cells (100% viability; 4 replicates) and infected cells without compound (total virus-mediated cell death; 4 replicates) were also prepared. The cultures were then incubated at 37xc2x0 C. in a humidified atmosphere of 5% CO2 in air for 5 d.
A fresh solution of 5 mg/mL MTT was prepared in 0.01 M phosphate buffered saline, pH 7.2 and 20 microliters added to each culture. The cultures were further incubated as before for 2 h. They were then mixed by pipetting up and down and 170 microliters of Triton X-100 in acidified isopropanol (10% v/v Triton X-100 in 1:250 mixture of concentrated HCl in isopropanol). When the formazan deposit was fully solubilized by further mixing, the absorbance (OD) of the cultures was measured at 540 nm and 690 nm wavelength (690 nm readings were used as blanks for artifacts between wells). The percent protection for each treated culture was calculated using the equation:       %              xe2x80x83            Protection    =                                                                        (                                  OD                                                        xe2x80x83                                                      drug                                                        -                                                      treated                                                        xe2x80x83                                                      cultures                                )                            -                                                                          (                              OD                                                  xe2x80x83                                                untreated                                                  xe2x80x83                                                virus                                                  xe2x80x83                                                control                                                  xe2x80x83                                                cultures                            )                                                                                (                                  OD                                                        xe2x80x83                                                      uninfected                                                        xe2x80x83                                                      cultures                                )                            -                                                                          (                              OD                                                  xe2x80x83                                                untreated                                                  xe2x80x83                                                virus                                                  xe2x80x83                                                control                                                  xe2x80x83                                                cultures                            )                                            xc3x97    100        %
In the assay, compounds of the formulas I range in activity from an IC50 of about 0.5 to about 5000 nM, with preferred compounds having a range of activity from about 0.5 to about 750 nM, more preferably about 0.5 to 300 nM, and most preferably about 0.5 to 50 nM.
It will be understood that references herein to treatment extend to prophylaxis as well as to treatment of existing conditions. It will also be understood that references to the treatment of animals includes the treatment of humans as well as other mammals.
In the present specification xe2x80x9ccomprisexe2x80x9d means xe2x80x9cincludesxe2x80x9d and xe2x80x9ccomprisingxe2x80x9d means xe2x80x9cincludingxe2x80x9d.
The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilized for realizing the invention in diverse forms thereof.
The pyrrole derivatives provided by the present invention can be used together with a therapeutically inert carrier as medicaments in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered enterally, such as orally, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or nasally, e.g. in the form of nasal sprays. They can also be administered rectally, e.g. in the form of suppositories, or parenterally, (e.g. intramuscularly, intravenously, or subcutaneously), for example, in the form of injection solutions.
For the manufacture of pharmaceutical preparations the pyrrole derivatives can be formulated with therapeutically inert, inorganic or organic carriers.
Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.
Suitable carriers for the manufacture of injection solutions are, for example, water, saline, alcohols, polyols, glycerine, vegetable oils and the like. Natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable carriers for the manufacture of suppositories. The pharmaceutical preparations of the present invention may also be provided as sustained release formulations or other appropriate formulations.
The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourants, salts for adjustment of the osmotic pressure, buffers, masking agents or antioxidants.
The pharmaceutical preparations may also contain other therapeutically active agents such as those mentioned above.
The dosage can vary within wide limits and will, of course, be adjusted to the individual requirements in each particular case.
Dosage levels of between about 0.01 and about 100 mg/kg body weight per day in monotherapy and/or in combination therapy are commonly administered from about I to 5 times per day. A typical preparation will contain from about 5% to 95% active compound (w/w) . The daily dosage can be administered as a single dosage or in divided dosages.
The pyrrole derivatives provided by the present invention or the medicaments thereof may be for use in monotherapy and/or combination therapy, i.e. the treatment may be in conjunction with the administration of one or more additional therapeutically active substance(s). When the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the pyrrole derivatives of the present invention. Thus, concurrent administration, as used herein, includes administration of the agents in conjunction or combination, together, or before or after each other.
It will be understood that references herein to treatment extend to prophylaxis as well as to treatment of existing conditions. Treatment of a disease or condition, as used herein, also includes preventing, inhibiting, regressing, reversing, alleviating or relieving the disease or condition, or the clinical symptoms thereof. The term xe2x80x9csubjectxe2x80x9d as used herein refers to animals, including humans and other mammals.


A thin film transistor is provided. The thin film transistor includes an active layer, and the active layer includes a plurality of stacked structures, and each of the stacked structures includes: a N-layer indium oxidation layer; a gallium oxidation layer, the gallium oxidation layer is provided on the indium oxidation layer of the N-layer indium oxidation layer; and a zinc oxidation layer is provided on the gallium oxidation layer. These stacked structures improve the performance of the thin film transistor. A preparation method of the thin film transistor and a display panel containing the thin film transistor is also provided.

Recently, metal oxide thin film transistors (TFTs) have been widely used in active matrix liquid crystal display (AMLCD) devices and active-matrix organic light-emitting diode (AMOLED) display devices. AMLCD devices and AMOLED display devices that have adopted metal oxide TFTs have significant advantages such as high resolution, large size, high refresh frequency, and high transmittance across the spectrum of visible light, which have wide application prospects in the field of display.
Indium gallium zinc oxide (IGZO) TFTs are a representative oxide TFT, which has a variety of typical structures. Among them, top-gate IGZO TFTs have been widely used because of advantages such as a small parasitic capacitance, lower mask usage during a manufacturing process, and that a gate and a gate insulating layer can protect a channel region from being affecting by an atmospheric environment and subsequent plasma during the manufacturing processes. However, current top-gate IGZO TFTs cannot balance both high mobility and high uniformity, resulting in poor performance of the current top-gate IGZO TFTs and display panels that use them.

Method of manufacturing a thin film transistor

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