Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-10
2003-12-09
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S231500, C514S252160, C514S256000, C544S060000, C544S111000, C544S324000
Reexamination Certificate
active
06660733
ABSTRACT:
BACKGROUND
Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) composed of two subunits (p35 and p40), and plays key roles in immune responses by bridging innate resistance and antigen-specific adaptive immunity. Trinchieri (1993)
Immunol Today
14: 335. For example, it promotes type 1 T helper cell (Th1) responses and, hence, cell-mediated immunity. Chan et al. (1991)
J Exp Med
173: 869; Seder et al. (1993)
Proc Natl Acad Sci USA
90: 10188; Manetti et al. (1993)
J Exp Med
177: 1199; and Hsieh et al. (1993)
Science
260: 547. Overproduction of IL-12 causes excessive Th1 responses, and may result in inflammatory disorders, such as insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, or sepsis. See, for example, Gately et al. (1998)
Annu Rev Immunol.
16: 495; and Abbas et al. (1996)
Nature
383: 787. Thus, inhibiting IL-12 overproduction is an approach to treat the just-mentioned diseases. Trembleau et al. (1995)
Immmunol. Today
16: 383; and Adorini et al. (1997)
Chem. Immunol.
68: 175. For example, overproduction of IL-12 and the resultant excessive Th1 type responses can be suppressed by modulating IL-12 production. A compound that down-regulates IL-12 production can be used for treating inflammatory diseases. Ma et al. (1998)
Eur Cytokine Netw
9: 54.
SUMMARY
In one aspect, this invention features pyrimidine compounds of formula (I):
R
1
is
[referred to hereinafter as NC(R
a
R
b
)]; each of R
2
and R
4
is H; R
3
is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; R
5
is H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is NR
c
; Y is covalent bond, CH
2
, C(O), C═N—R
c
, C═N—OR
c
, C═N—SR
c
, O, S, S(O), S(O
2
), or NR
c
; Z is N or CH; one of U and V is N, and the other is CR
c
; and W is O, S, S(O), S(O
2
), NR
c
, or NC(O)R
c
; in which each of R
a
and R
b
, independently, is H, alkyl, aryl, heteroaryl; and R
c
is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl. Note that the left atom shown in any substituted group described above is closest to the pyrimidine ring. Also note that when there are more than one R
c
-containing substituted groups in a pyrimidine compound, the R
c
moieties can be the same or different.
In some embodiments, one of R
a
and R
b
is H or alkyl; and the other is
(e.g. 3-methylphenyl); in which R
d
is H, alkyl, or alkoxyl; R
e
is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and m is 0, 1, 2, 3, or 4.
In other embodiments, X is NH; Y is O; or n is 2.
In still other embodiments, U is N; V is CH; and R
3
is heteroaryl (e.g., 1-oxy-pyridin-2-yl). Preferably, X is NH; Y is O; n is 2; and one of R
a
and R
b
is H; and the other is 3-methylphenyl.
Alkyl, alkenyl, alkynyl, aryl, heteroaryl (e.g., 1-oxy-pyridinyl), cyclyl, heterocyclyl mentioned above include both substituted and unsubstituted moieties. The term “substituted” refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of substituents include, but are not limited to, halogen, hydroxyl, amino, alkylamino, arylamino, dialkylamino, diarylamino, cyano, nitro, mercapto, carbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfoamido, C
1
~C
6
alkyl, C
1
~C
6
alkenyl, C
1
~C
6
alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, wherein alkyl, alkenyl, alkoxy, aryl, heteroaryl cyclyl, and heterocyclyl are optionally substituted with C
1
~C
6
alkyl, aryl, heteroaryl, halogen, hydroxyl, amino, mercapto, cyano, or nitro. The term “aryl” refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term “heteroaryl” refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl. The terms “cyclyl” and “heterocyclyl” refer to partially and fully saturated mono- or bi-cyclic rings having from 4 to 14 ring atoms. A heterocyclyl ring contains one or more heteroatoms (e.g., O, N, or S). Exemplary cyclyl and heterocyclyl rings are cycylohexane, piperidine, piperazine, morpholine, thiomorpholine, and 1,4-oxazepane.
Below is an exemplary compound of this invention:
In another aspect, this invention features a pharmaceutical composition that contains a pharmaceutically acceptable carrier and an effective amount of at least one of the pyrimidine compounds of this invention.
In further another aspect, the present invention features a method for treating an IL-12 overproduction-related disorder (e.g., rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes mellitus). The method includes administering to a subject in need thereof an effective amount of one or more pyrimidine compounds of this invention.
The pyrimidine compounds of this invention include the compounds themselves, as well as their salts and their prodrugs, if applicable. Such salts, for example, can be formed between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing the pyrimidine compounds described above.
In addition, some of the pyrimidine compounds of this invention have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z-double isomeric forms.
Also within the scope of this invention are a composition containing one or more of the compounds described above for use in treating an IL-12 overproduction-related disorder, and the use of such a composition for the manufacture of a medicament for the just-described use.
Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
DETAILED DESCRIPTION
The compounds described above can be prepared by methods well known in the art, as well as by the synthetic routes disclosed herein. For example, a pyrimidine compound can be prepared by using 2,4,6-trichloro-pyrimidine as a starting material. The three chloro groups can be displaced by various substitutes. More specifically, first chloro group (e.g., at position 6) can react with, e.g., morpholine, to form a morpholinyl pyrimidine. 2-Aryl and 2-alkylpyrimidinde dichloro compounds can also be prepared by reacting an amidine with a malonic ester followed by treatment with phosphorous oxychloride. Second chloro group can be replaced by reacting with a nucleophile, such as an alcohol in the presence of base, e.g., sodium hydride. Isomeric forms may be produced. The desired isomeric product can be separated from others by, e.g., high performance liquid chromatography. Third chloro group undergoes a displacement reaction with, e.g., hydrazine, and the primary amine of the coupled hydrazine moiety further reacts with an aldehyde. Thus, a pyrimidine compound of this invention is obtained.
The chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or r
Kostic Elena
Ono Mitsunori
Przewloka Teresa
Sun Lijun
Wada Yumiko
Balasubramanian Venkataraman
Fish & Richardson P.C.
Shah Mukund J.
Synta Pharmaceuticals Corp.
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