Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-12-15
2001-08-28
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C548S455000, C548S312100, C548S181000, C548S364700, C548S214000, C546S201000, C544S333000, C544S373000
Reexamination Certificate
active
06281356
ABSTRACT:
BRIEF SUMMARY OF THE INVENTION
The invention relates to substituted pyrroles. More particularly, the invention relates to substituted pyrroles of the formula
wherein
R
1
and R
1′
are independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl;
R
2
is hydrogen, nitro, cyano, halogen, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy; and
R
2′
is a heteroaryl, heterocycle, ethyl substituted with a heteroaryl, or ethoxy substituted with a heteroaryl or heterocycle; or
a pharmaceutically acceptable salt thereof.
The compounds of the invention are useful in the treatment or control of cell proliferative disorders, in particular cancer, particularly the treatment or control of solid tumors. In particular, the compounds of the invention have antiproliferative activity, specifically, they inhibit cell division in G2/M phase of the cell cycle.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to substituted pyrroles. More particularly, the invention relates to substituted pyrroles of the formula
wherein
R
1
and R
1′
are independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl;
R
2
is hydrogen, nitro, cyano, halogen, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy; and
R
2′
is a heteroaryl, heterocycle, ethyl substituted with a heteroaryl, or ethoxy substituted with a heteroaryl or heterocycle; or
a pharmaceutically acceptable salt thereof.
As used herein, the term “lower alkyl”, alone or in combination, means a straight or branched chain alkyl group containing a maximum of 3 carbon atoms, such as methyl, ethyl, propyl, and isopropyl, which is unsubstituted or substituted by one or more of hydroxy, lower alkoxy, amino, halogen, thio-lower alkyl or lower alkylsulphinyl. Examples of lower alkyl substituted by one or more halogen includes chloromethyl and triflouromethyl.
The term “lower alkoxy”, alone or in combination, means a group wherein the lower alkyl residue is defined as above, for example, methoxy, ethoxy, propoxy, isopropoxy and the like.
The term “heteroaryl”, alone or in combination, means a 5 or 6 membered aromatic ring containing 1 to 4 heteroatoms which may the same or different, and where the ring is unsubstituted or substituted by one or more of halogen, lower alkyl, hydroxy, carboxy, lower alkoxy, nitro, amino or cyano. The heteroatom(s) are selected from the group consisting of nitrogen, sulfur and oxygen. Examples of heteroaryl are furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
The term “heterocycle”, alone or in combination, means a 4 to 7 membered non-aromatic ring containing one or more heteroatoms which may be the same or different, and where the ring is partially or completely saturated and where the ring is unsubstituted or substituted by one or more of halogen, lower alkyl, hydroxy, carboxy, lower alkoxy, nitro, amino or cyano. The heteroatom(s) are selected from the group consisting of nitrogen, sulfur and oxygen. Examples of unsubstituted heterocycle are pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and trithiane.
The term “halogen” means flourine, chlorine, bromine or iodine.
The term “amino” means an unsubstituted amine group or an amine substituted by one or more substituents selected from alkyl, aryl, acyl, alkylsulfonyl or arylsulfonyl,
The term “alkenyl” means a straight or branched chain hydrocarbon group of 2 to 5 carbon atoms having at least one double bond.
The term “alkynyl” means a straight or branched chain hydrocarbon group of 2 to 5 carbon atoms having at least one triple bond.
In formula I above, preferably, R
1
and R
1′
are independently hydrogen, methyl or ethyl, which are unsubstituted or substituted by lower alkoxy, preferably methoxy or ethoxy. Most preferably, at least one of R
1
and R
1′
is lower alkyl, most preferably unsubstituted methyl.
Preferably, when R
2
is lower alkoxy, it is methoxy or ethoxy, most preferably methoxy. Preferably, when R
2
is lower alkyl, it is methyl or ethyl, which is unsubstituted or substituted by one or more of lower alkoxy or halogen. Most preferred when R
2
is lower alkyl it is methyl, which is w i substituted or substituted by methoxy. R
2
may also preferably be haloalkyl such as trifluoromethyl.
When R
2′
is heteroaryl, it is preferably thiophenyl, furanyl, imidazolyl which is unsubstituted or substituted with lower alkyl, thiazolyl, pyrazolyl which is unsubstituted or substituted with lower alkyl, pyrimdinyl, or isothiazolyl.
When R
2′
is is heterocycle, it is preferably unsubstituted morpholine, unsubstituted pyrrolidine, unsubstituted piperidine, or piperazine which is unsubstituted or substituted with lower alkyl, lower alkoxy or carboxy.
When R
2′
is ethyl substituted with heteroaryl, preferably the heteroaryl is imidazole. In addition, R
2′
may be methyl or propyl substituted with a heteroaryl.
In addition to ethoxy substituted with a heteroaryl or heterocycle, R
2′
may also be methoxy or propoxy substituted with a heteroaryl or heterocycle.
In a preferred embodiment, when R
2′
is thiophenyl, preferably R
1
and R
1′
are both methyl and R
2
is hydrogen or nitro.
In another preferred embodiment, when R
2′
is furanyl, preferably R
1
is hydrogen, methyl, R
1′
is methyl, and R
2
is hydrogen or nitro.
In another preferred embodiment, when R
2′
is imidazolyl which is unsubstituted or substituted with lower alkyl, preferably, methyl, preferably R
1
is methyl R
1′
is methyl and R
2
is hydrogen, nitro, cyano, halogen or methoxy.
In another preferred embodiment, when R
2′
is thiazolyl, preferably R
1
and R
1′
are both methyl and R
2
is hydrogen or nitro.
In another preferred embodiment, when R
2′
is pyrazolyl which is unsubstituted or substituted with lower alkyl, preferably methyl, preferably R
1
and R
1′
are both methyl and R
2
is hydrogen, nitro or halogen.
In another preferred embodiment, when R
2′
is pyrimdinyl, preferably R
1
and R
1′
is methyl and R
2
is hydrogen or nitro.
In another preferred embodiment, when R
2′
is isothiazole, preferably R
1
and R
1
is methyl and R
2
is hydrogen or nitro.
In another preferred embodiment, when R
2′
is pyrrolidinyl, preferably, R
1
is hydrogen or methyl, R
1
is hydrogen, methyl or methoxymethyl, and R
2
is hydrogen, nitro, cyano, halogen, trifluoromethyl, or methoxy.
In another preferred embodiment, when R
2′
is piperidinyl, preferably R
1
and R
1′
are both methyl and R
2
is hydrogen.
In another preferred embodiment, when R
2′
is morpholinyl, preferably R
1
is hydrogen, methyl, preferably R
1
is methyl, hydrogen or methoxymethyl, and R
2
is hydrogen, nitro, cyano, halogen, methyl, trifluoromethyl, or methoxy.
In another preferred embodiment, when R
2′
is ethoxy substituted by a heteroaryl or a heterocycle, preferably a heteroaryl and more preferably imidazolyl, preferably R
1
and R
1′
are both methyl and R
2
is nitro.
The compounds of formula I are prepared as follows.
The starting material, a compound of formula 4 can be prepared according to Scheme 1
When R
2′
is heterocycle or heteroaryl and R
1
is lower alkyl, compound 4 can be prepared according to Scheme 1.
A compound of formula 2, wherein X represents Br or I, is prepared by known methods (Moyer, M. P.; Shiurba, J. F.; Rapoport, H.
J. Org. Chem.
1986, 51, 5106.), and is alkylated by known methods (NaH and alkyl iodide in N,N-dimethylformamide (DMF) or tetrahydrofuran at 0° C. to about 25° C.) to give a corresponding compound of formula 3. Alternatively, alkylation can be carried out using dimethyl carbonate and a base (such as K
2
CO
3
) or a catalyst (such as TBAB) in DMF, by heating the reaction mixture to reflux (greater than 90° C.).
A compound of for
Fotouhi Nader
Kong Norman
Lovey Allen John
D'Souza Andrea M.
Hoffmann-La Roche Inc.
Johnston George W.
McKane Joseph K.
Rocha-Tramaloni Patricia S.
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