Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-07-06
2003-06-24
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C564S026000, C564S052000, C564S055000, C544S140000, C546S256000, C546S275400, C549S069000, C549S371000
Reexamination Certificate
active
06583282
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to novel processes for preparing new aryl- and heteroaryl-substituted urea compounds of formula (I):
wherein Ar
1
, Ar
2
, X, L and Q are defined below, which are useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease.
BACKGROUND OF THE INVENTION
Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases.
A key step in the synthesis of these compounds is the formation of the urea bond. Various methods have been reported to accomplish this. For example, as reported in the above references, an aromatic or heteroaromatic amine, II, may be reacted with an aromatic or heteroaromatic isocyanate III to generate the urea IV (Scheme I)
If not commercially available, one may prepare the isocyanate III by reaction of an aryl or heteroaryl amine Ar
2
NH
2
with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chloroformate (diphosgene). K. Kurita, T. Matsumura and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate III, followed by reaction with Ar
1
NH
2
to provide the urea. Other approaches to forming the urea known in the chemical literature are to form a carbamate, as shown in Scheme II below, by reaction of an amine with a chloroformate derivative, such as phenyl chloroformate (B. Thavonekham, Synthesis, 1997, 1189), chloromethyl chloroformate (T. Patonay, E. Patonay-Peli, L Zolnai and F. Mogyorodi, Synthetic Communications, 1996, 26, 4253), p-nitrophenyl chloroformate (J. Gante, Chem. Ber. 1965, 98, 3334), or 2,4,5-trichlorophenyl chloroformate (A. W. Lipkowski, S. W. Tam and P. S. Portoghese, J. Med. Chem. 1986, 29, 1222) to form a carbamate V. This may then be reacted with an aryl or heteroaryl amine (II) to provide urea IV (Scheme II-reaction with phenyl chloroformate shown). The synthesis of ureas through (phenoxycarbonyl)tetrazole (R. W. Adamiak, J. Stawinski, Tetrahedron Lett. 1977, 1935) or 1,1′-carbonylbisbenzotriazole (A. R. Katritzky, D. P. M. Pleynet and B. Yang, J. Org. Chem. 1997, 62, 4155) has been reported. In addition, preparation of ureas by catalytic carbonation of amines with carbon monoxide or carbon dioxide has been documented in the literature (N. Sonoda, T. Yasuhara, K. Kondo, T. Ikeda and S. Tsutsumi, J. Am. Chem. Soc. 1971, 93, 691; Y. Morimoto, Y. Fujiwara, H. Taniguchi, Y. Hori and Y. Nagano, Tetrahedron Lett. 1986, 27, 1809). In each of these cases, Ar
1
and Ar
2
may be modified before and/or after the urea formation to produce desired compounds.
Each of the methods described above suffer from one or more disadvantages. For example, phosgene and phosgene equivalents are hazardous and dangerous to use, particularly in large-scale applications. In addition the isocyanate intermediate III is not stable and may undergo decomposition during preparation and storage. The urea formation may be done using a phenyl carbamate, as illustrated in Scheme II and U.S. application Ser. No. 09/484,638. However, the by-product phenol formed in the urea synthesis does not have sufficient water solubility to be easily removed by water washing especially at large scale. Thus it may require multiple washing and several crystallizations to obtain highly pure product. For these reasons these methods are not well-suited for industrial-scale production.
U.S. application Ser. No. 09/484,638 also discloses the synthesis of substituted naphthyl amino intermediates for use in making aryl- and heteroaryl-substituted urea compounds of the formula (I) as described therein. This synthesis begins with 4-aminonapthol which is protected with a Boc (tert-butoxycarbonyl) group on the amine prior to alkylation and deprotection. This procedure is also not amenable to industrial-scale production. The starting 4-aminonaphthol is very expensive and not available in large quantity. In addition the protection and deprotection steps are tedious and add to the expense.
Disclosed herein are novel processes for making the aryl- and heteroaryl-substituted urea compounds of the formula (I) including those disclosed in U.S. application Ser. No. 09/484,638 and novel intermediates useful in such processes.
BRIEF SUMMARY OF THE INVENTION
It is therefore an object of this invention to provide a general and cost-effective process for the preparation of the aryl- and heteroaryl-substituted urea compounds of the formula (I) shown below:
comprising the steps of:
reacting of intermediate of formula (II) with intermediate of formula (IV) to produce the product compound of formula (I):
wherein Ar
1
, Ar
2
, L, Q, X and Ra are as described below.
In addition, this invention provides efficient methods for preparing intermediates used in the preparation of preferred cytokine-inhibiting aryl- and heteroaryl-substituted ureas. These processes are especially well-suited for preparation of these compounds on an industrial scale.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the synthesis of compounds having formula (I):
wherein:
Ar
1
is a heterocyclic group selected from the group consisting of phenyl, pyridine, pyridone, pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ar
1
is optionally substituted by one or more R
1
, R
2
or R
3
;
Ar
2
is:
phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R
2
groups;
L, a linking group, is:
C
1-10
saturated or unsaturated branched or unbranched carbon chain;
wherein one or more methylene groups are optionally independently replaced by O, N or S; and
wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C
1-4
branched or unbranched alkyl optionally substituted by one or more halogen atoms;
or L is a cyclic group which is:
a) a C
5-8
cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo groups, 1-3 C
1-4
branched or unbranched alkyl, C
1-4
alkoxy or C
1-4
alkylamino chains;
b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 1-3 C
1-4
branched or unbranched alkyl, C
1-4
alkoxy, hydroxy, cyano, mono- or di-(C
1-3
alkyl)amino, C
1-6
alkyl-S(O)
q
, or halogen;
wherein said cyclic group is optionally attached to a C
1-4
saturated or unsaturated branched or unbranched carbon chain wherein said carbon chain is in turn covalently attached to Q, said carbon chain is optionally partially or fully halogenated and wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O)
2
or S, wherein said methylene groups are further optionally independently substituted with 1-2 oxo groups and one or more C
1-4
branched or unbranched alkyl optionally substituted by one or more halogen atoms;
Q is selected from the group consisting of:
a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen, C
1-6
alkyl, C
1-6
alkoxy, hydroxy, mono- or di-(C
1-3
alkyl)amino, C
1-6
alkyl-S(O)
m
and phenylamino wherein the phenyl ring is optionally substituted with one to two groups selected from the group consisting of halogen, C
1-6
alkyl and C
1-6
alkoxy;
b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, pi
Zhang Lin-Hua
Zhu Lei
Berch Mark L.
Boehringer Ingelheim Pharmaceuticals Inc.
Bottino Anthony P.
Habte Kahsay
Raymond Robert P.
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